Professional Documents
Culture Documents
2014 Book MetabolismOfHumanDiseases
2014 Book MetabolismOfHumanDiseases
Metabolism of
Human Diseases
Organ Physiology and Pathophysiology
Metabolism of Human Diseases
Eckhard Lammert • Martin Zeeb
Editors
Metabolism of Human
Diseases
Organ Physiology
and Pathophysiology
Editors
Eckhard Lammert Martin Zeeb
Department of Biology CardioMetabolic Diseases Research
Institute of Metabolic Physiology Boehringer Ingelheim Pharma
German Diabetes Center GmbH & Co KG
Heinrich Heine University Düsseldorf Biberach
Düsseldorf Germany
Germany
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Martin Zeeb and Eckhard Lammert
Part I Brain
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Lorraine V. Kalia
Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Donatella Marazziti, Grazia Rutigliano, Stefano Baroni,
and Liliana Dell’Osso
Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Peter F. Buckley and Adriana Foster
Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Wesley Plinke and Detlev Boison
Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Giulia Ambrosi, Silvia Cerri, and Fabio Blandini
Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Milos D. Ikonomovic and Steven T. DeKosky
Migraine and Cluster Headache. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Massimo Leone and Paola Di Fiore
Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Markus Kipp
Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Maria D. Torres and Jorge Busciglio
Part II Eye
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Anja Mataruga and Frank Müller
Age-Related Macular Degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . 67
Monika Fleckenstein and Frank G. Holz
v
vi Contents
Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Samuel D. Crish and Christine M. Dengler-Crish
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Kazuhiko Kawasaki and Kenneth M. Weiss
Dental Caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Colin Robinson
Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Emmanuel Biver and René Rizzoli
Part IV Joints
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Jessica Bertrand and Jan Hubert
Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Camille Roubille, Johanne Martel-Pelletier,
and Jean-Pierre Pelletier
Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Marianna Meroni, Elena Bernero, and Maurizio Cutolo
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Satish Keshav and Philip Allan
Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Peter C. Konturek and Stanislaw J. Konturek
Gastroenteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Christina Quigley and Xi Jiang
Lactose Intolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Anthony K. Campbell and Stephanie B. Matthews
Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Kishore Vipperla and Stephen J. O’Keefe
Part VI Pancreas
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Alexandra E. Folias and Matthias Hebrok
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Alena Welters and Eckhard Lammert
Contents vii
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Dieter Häussinger
Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Matteo Rosselli and Massimo Pinzani
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Gabriele Schoiswohl, Jules Aljammal, and Erin E. Kershaw
Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Kana Inoue, Norikazu Maeda, and Tohru Funahashi
Part IX Lung
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Martin Zeeb, Andreas Schnapp, and Michael-Paul Pieper
Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Kenji Izuhara, Shoichi Suzuki, Kazuhiko Arima, Shoichiro Ohta,
Masako Inamitsu, and Ken-ichi Yamamoto
Chronic Obstructive Pulmonary Disease (COPD) . . . . . . . . . . . . . . 221
Irena Konstantinova and Andrew C. Pearce
Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Salvador Sialer, Leonardo F. Difrancesco, Teresa Foix Fabregas,
and Antoni Torres
Part X Heart
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Axel Gödecke
Atherosclerotic Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Massimo Slavich and Juan Carlos Kaski
Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Roman Pfister and Erland Erdmann
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Victor W.M. van Hinsbergh, Rick Meijer, and Etto C. Eringa
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Dwi Setyowati Karolina and Kandiah Jeyaseelan
viii Contents
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Deena Iskander and Barbara J. Bain
Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Daniel A. Dworkis and Martin H. Steinberg
Hyperlipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Paul Durrington and Handrean Soran
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Christian Münz
Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Bruno Conti and Tamas Bartfai
Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Jean-Charles Preiser and Jean-Louis Vincent
Allergies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Norbert Meyer and James Yun
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Markus M. Rinschen, Linus A. Völker,
and Paul T. Brinkkötter
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
Colleen Flynn and George L. Bakris
Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Golaun Odabaei, George A. Kaysen, and Shubha Ananthakrishnan
Gout. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Sonia Nasi and Alexander So
Urinary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Matt S. Conover, Michael E. Hibbing, and Scott J. Hultgren
Kidney Stones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Andreas Neisius and Glenn M. Preminger
Contents ix
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Danny J. Schust and Donald R. Gullicks
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Tanja Fehm and Eugen Ruckhäberle
Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Rahul Aggarwal and Eric Small
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Zachary E. Stine and Chi V. Dang
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Introduction
The scientific community has increasingly recog- chapters of the section (Fig. 1). The overview
nized metabolic alterations as being critical com- introduces organ- or tissue-specific metabolism and
ponents or even drivers of human disease. signaling pathways as well as intra- and inter-organ
Metabolism of Human Diseases discusses the communication (i.e., “inside-in,” “inside-out,” and
metabolism and signaling pathways in tissues and “outside-in” signaling). The disease chapters dis-
organs known to be relevant for common human cuss pathomechanisms of the diseases with empha-
diseases. It thus bridges the existing gap between sis on metabolic alterations and affected signaling
biochemistry and physiology textbooks, on the one pathways. In addition, they briefly introduce major
hand, and pathology textbooks, on the other hand. treatments currently in use and in clinical trials as
Metabolism of Human Diseases is directed at well as their influence on the patient’s metabolism.
advanced students, doctors, and scientists from The diseases have been selected to cover a
all categories of life sciences and medicine (e.g., wide spectrum of human diseases in the industri-
biochemists, biologists, physiologists, pharma- alized world (as described in the tenth edition of
cologists, pharmacists, toxicologists, and physi- the International Classification of Diseases, ICD-
cians) with an interest in the metabolism and 10). They include many of the most common
molecular mechanisms of human diseases, irre- (based on diagnosis), most deadly (based on
spective of their specialization. numbers of deaths), and most expensive (based
The book is divided into different parts, each on treatment costs) illnesses.
related to a human organ or tissue. Each part begins Each chapter of Metabolism of Human
with an overview chapter presenting the anatomic Diseases contains up to three simplified figures
and physiological properties of the organ or tissue and tables that illustrate important elements of
in question relevant for the subsequent disease anatomy, physiology, metabolism, signaling path-
ways, or treatment. All figures are presented in a
M. Zeeb common layout to facilitate understanding of the
CardioMetabolic Diseases Research, contents of each chapter (Fig. 2). Since Yousun
Boehringer Ingelheim Pharma GmbH & Co KG,
Koh provided the layout and final presentation,
Birkendorfer Straße 65,
88400 Biberach (Riss), Germany we would like to express our gratitude to her.
e-mail: martin.zeeb@boehringer-ingelheim.com Finally, more than a hundred international
E. Lammert (*) experts contributed state-of-the-art chapters to
Department of Biology, the book, and we would like to thank all of them
Institute of Metabolic Physiology, for their work and dedication.
German Diabetes Center,
We wish the owner of the book a pleasant read!
Heinrich Heine University Düsseldorf,
Universitätsstraße 1, 40225 Düsseldorf, Germany Best regards,
e-mail: lammert@hhu.de Martin Zeeb and Eckhard Lammert
Brain
Overview
Major depressive disorder
Schizophrenia
Epilepsy Eye
Parkinson’s disease Overview
Alzheimer’s disease Macular degeneration
Migraine and cluster headache Glaucoma Blood
Lung
Multiple sclerosis
Overview
Teeth and bones Overview
Down syndrome
Asthma Sickle Cell Disease
Overview
Immune system COPD Hyperlipidemia
Dental caries
Overview Pneumonia
Osteoporosis Heart
Fever
Sepsis Reproductive system Overview
Cancer
Allergies Overview Atherosclerotic heart disease
Overview
Breast cancer Heart failure
Lorraine V. Kalia
Thalamus
Cerebellum
Pituitary
Hypothalamus
Midbrain
Brain stem Pons
Medulla
systems remove metabolic products and protect the nucleus and additional organelles required
the brain from sudden metabolic perturbations. for protein synthesis and metabolic maintenance.
Necessary nutrients are delivered via the circula- In most neurons, several dendrites and a single
tion and must cross the blood-brain barrier axon extend from the soma. Information is typi-
(BBB), which is formed by endothelial cells lin- cally transported from the dendrites to the soma
ing cerebral microvessels, their basal lamina, and to the axon within a neuron by means of elec-
the end-feet of specialized glial cells called astro- trical events, which are mediated by the opening
cytes. Astrocytes and the entire BBB protect neu- and closing of specific ion channels. Regulated
rons from toxic metabolites by preventing their transport of Na+ and K+ through the cell mem-
transport into the brain via exclusion or efflux brane is critical. Depolarization of the cell mem-
and by neutralizing harmful compounds via brane occurs if positive ions (Na+) enter the cell,
uptake or enzymatic inactivation [1]. Neuronal whereas hyperpolarization results from exiting of
dysfunction and associated neurological diseases positive ions (K+) from the cell. When the cell
can occur when the brain’s stable metabolic envi- reaches a threshold of depolarization, an electri-
ronment is disrupted. cal signal called an action potential is generated,
and this signal is propagated along the length of
the axon. At the axon terminal, the neuron com-
Brain-Specific Metabolic/Molecular municates with another neuron or an effector
Pathways and Processes tissue within a specialized structure called a syn-
apse. A typical synapse consists of a presynaptic
Neurons are uniquely designed to receive infor- axonal bouton, a postsynaptic dendritic spine,
mation from the environment or other neurons, and the intervening space called the synaptic
process this information, and send information cleft (Fig. 2). Arrival of the action potential at the
to other neurons or effector tissues (i.e., neuro- axonal bouton triggers the release of neurotrans-
transmission). The cell body, or soma, contains mitter from presynaptic vesicles into the synaptic
Overview 7
Synapse
Astrocyte Presynaptic axon
Vesicle
Neurotransmitter
Synaptic cleft
Postsynaptic dendrite
receptors transporters
Neuron
(Postsynaptic)
cleft, thereby transforming the electrical signal contain their own ion channel, but neurotrans-
into a chemical one. mitter binding can activate intracellular signal-
A variety of molecules can act as neurotransmit- ing cascades, which produce second messengers
ters: amino acids, such as glutamate (Glu) and that indirectly gate ion channels. Many neu-
γ-aminobutyric acid (GABA), biogenic amines rotransmitters utilize postsynaptic receptors
(including acetylcholine, serotonin, and the cate- from both classes. As an example, Glu receptors
cholamines dopamine, epinephrine, norepineph- include metabotropic Glu receptors, as well as
rine), nucleotides (e.g., adenosine), neuropeptides N-methyl-D-aspartate (NMDA) receptor, AMPA
(e.g., substance P), and even gases (e.g., nitric receptor, and kainate receptor, which are iono-
oxide). Neurotransmitters act either directly or indi- tropic receptors.
rectly in controlling the opening of ion channels in The actions of neurotransmitters are termi-
the postsynaptic neuron or effector tissue (see nated by their removal from the synaptic cleft
below). They can be classified based on their effects (Fig. 2). Three mechanisms are involved in neu-
on the postsynaptic cell; those neurotransmitters rotransmitter removal: diffusion, enzymatic deg-
that cause depolarization are classified as excitatory, radation, and reuptake into neurons or uptake
and those that cause hyperpolarization are classified into astrocytes. For example, dopamine is cleared
as inhibitory. The major inhibitory neurotransmitter from the synaptic cleft by dopamine transporters
in the brain is GABA, whereas Glu represents the on the presynaptic neuron or on astrocytes and
major excitatory neurotransmitter. then degraded by monoamine oxidase B and
To exert their effects on the postsynaptic tar- catechol-O-methyltransferase. The latter also
get, neurotransmitters first traverse the synaptic acts to degrade dopamine within the synaptic
cleft and then bind to specific postsynaptic cleft (see also chapters “Major depressive disor-
receptors. There are two major classes of recep- der” and “Parkinson’s disease”). Similarly, sero-
tors: ionotropic and metabotropic. Ionotropic tonin is removed from the synaptic cleft by a
receptors are transmembrane proteins with an reuptake mechanism as well as degrading
intrinsic ion channel, which opens upon binding enzymes such as monoamine oxidase A (see also
of the neurotransmitter to the receptor’s extracel- chapters “Major depressive disorder” and
lular domain. Metabotropic receptors do not “Migraine and cluster headache”).
8 L.V. Kalia
chapter “Overview” under part “Reproductive of the ketogenic diet (the second source of energy
system”), and somatotropin/growth hormone neurons are willing to accept) as treatment for
(which directly influences adipocytes and the epilepsy (see chapter “Epilepsy”).
liver, see also chapters “Overview” under part Metabolites of other tissues that enter the cir-
“Fat tissue” and “Overview” under part “Liver”). culation must be able to cross the BBB to influ-
Releasing or inhibiting hormones secreted by the ence brain function. Disorders in which
hypothalamus act on the anterior pituitary gland metabolites lead to brain malfunction resulting in
to regulate the release of these hormones into the altered mental status ranging from a mild confu-
circulation (see also chapter “Overview” under sion to coma are referred to as metabolic enceph-
part “Reproductive system”). alopathies. Hypoglycemia can cause such
One of many examples of how the action of encephalopathy (see above). Abnormalities due
neurotransmitters mediates neuronal circuits and to dysfunction in organs such as the kidney and
thereby regulates behaviors is the dopaminergic liver may also lead to metabolic encephalopa-
reward system, called the mesolimbic pathway. thies. More specifically, elevated ammonia in the
This circuit includes dopaminergic neurons brain due to liver failure is a major factor involved
within the medial substantia nigra and ventral in the pathogenesis of hepatic encephalopathy
tegmental area of the midbrain, which connect to (see chapter “Cirrhosis”).
the nucleus accumbens/ventral striatum, as well Certain hormones synthesized and secreted
as limbic structures such as the amygdala and from peripheral tissues can also cross the BBB.
hippocampus. The dopaminergic mesolimbic Most hormones exert their influence by acting on
pathway is involved in diverse motivational various nuclei within the hypothalamus. For
behaviors including those related to appetitive example, leptin is a hormone secreted by adipo-
and aversive motivational processes [6]. cytes, which acts on the arcuate nucleus and lat-
eral hypothalamic area to suppress appetite (see
chapter “Major depressive disorder”). Gonadal
Outside-In: Metabolites of Other hormones (e.g., estradiol, progesterone, testoster-
Tissues Affecting the Brain one) and adrenal hormones (e.g., cortisol) circu-
lating in the bloodstream act on the hypothalamus
The energy demand of the brain is immense and to suppress their own release (negative feedback
mainly satisfied by consumption of glucose. At control of the hypothalamo-pituitary-gonadal
rest, the brain accounts for 60 % of the body’s and hypothalamo-pituitary-adrenal axis, respec-
glucose utilization [7]. The majority of energy tively). Hormones are increasingly found to also
consumed by the brain is used by neurons for have effects on neuronal function in extra-
maintenance of the membrane gradient (driving hypothalamic brain areas. This is illustrated by
ion pumps necessary for electrical transmission), leptin and ghrelin, two peripherally secreted pep-
synthesis and recycling of neurotransmitters, as tide hormones implicated in depression (see
well as dendritic and axonal transport. Unlike chapter “Major depressive disorder”).
most other tissues, the brain has limited fuel
stores and is quite inflexible with regard to sub-
strates for energy metabolism, deriving most of Final Remarks
its energy from the oxidation of glucose. Thus,
neurons are particularly vulnerable to disruptions The brain is critical for the survival of the organ-
in glucose availability. For example, hypoglyce- ism, mediating functions and behaviors that range
mia is associated with aberrations of cerebral from basic and fundamental to incredibly com-
function, which can cause an altered mental state plex. Yet, the brain is vulnerable to perturbations
depending on severity and duration of glucose or defects in metabolism. Some important associa-
deprivation. Hence, nutrition critically influences tions between metabolism and brain disease will
brain function. This is also illustrated by the use be discussed in detail in the following chapters.
10 L.V. Kalia
Cellular damage
Depression MetS
Fig. 1 Pathophysiological overlap between depres- and nitrosidative stress (O&NS). An antidepressant
sion and metabolic syndrome. Depression and meta- efficacy has been demonstrated for leptin and ghrelin,
bolic syndrome (MetS) share common pathways in two peripheral hormones classically implicated in the
the stress system, involving an abnormal activation homeostatic control of food intake. NE norepineph-
of the hypothalamus-pituitary-adrenal (HPA) axis and rine, 5HT serotonin, DA dopamine, CRH corticotro-
an imbalance of the autonomic nervous system (ANS). pin-releasing hormone, ACTH adrenocorticotrophic
In both conditions, a low-grade systemic inflamma- hormone, ROS reactive oxygen species, NO nitric
tion manifests, which leads to enhanced oxidative oxide, LPL lipoprotein lipase
see also chapter “Diabetes mellitus”), and cell- on 5HT and DA neurons, allowing leptin to mod-
mediated macrophage activation, are increased. ulate the release of these monoamines. Leptin is
Interestingly, these cytokines induce degradation also known to decrease the release of corticoste-
of tryptophan, thus reducing the availability of roids during the stress response via the HPA axis.
tryptophan and 5-HT. They also inhibit the action Ghrelin is a gut-derived hormone, which
of lipoprotein lipase, inducing dyslipidemia (see induces a potent feeding response via its recep-
chapter “Hyperlipidemia”), and prevent vaso- tors in the hypothalamus, and probably mediates
dilatation of resistance vessels, predisposing to hyperphagia in response to stress [18]. Since
hypertension (see chapter “Hypertension”) [15]. ghrelin administration produces antidepressant
Furthermore, TNF-α impairs the function of the responses, it has been postulated that it helps
insulin receptor and insulin receptor substrate 1 the organism to cope with stress. In addition, it
via their phosphorylation, thus contributing to also activates the dopaminergic reward circuitry,
insulin resistance. while reinforcing the search for palatable sweet
food. Thus, depressed patients may be more sus-
ceptible to so-called “Stress eating” [19].
Oxidative Stress
The general mechanism of TCAs and the also activate peripheral α1 adrenergic recep-
reuptake inhibitors is to prevent presynaptic tors, contributing to hypertension (see chapter
reuptake of monoamines (5-HT, NE, DA), thus “Hypertension”) [27].
increasing their activity in the synaptic cleft. SSRIs show a more favorable tolerability pro-
In particular, they ameliorate depressed mood, file because of their selectivity. However,
psychomotor retardation, and suicidal ideation, increased availability of 5-HT may have negative
whereas sleep disturbances, concentration defi- effects as it regulates a multitude of functions,
cits, and lack of interest usually persist. However, such as sleep, sexual function, and appetite,
acutely enhanced levels of neurotransmitters may showing adverse effects on quality of life.
lead to adaptive desensitization of postsynaptic Although a weight loss has been observed during
neurotransmitter receptors. early treatment, long-term therapy is associated
Key to management and treatment of depres- with significant weight gain.
sion is the reduction or avoidance of depressive
episodes. Yet, metabolic derangements that
underlie both depression and MetS should also be Perspectives
screened and targeted, including eating patterns,
thyroid dysfunction, body mass index, and fasting It is predicted that by the year 2020, depression will
blood glucose. These risk factors should also be be the second leading cause of death after CVD.
considered a primary therapeutic target. In mild Thus, further targets, possibly within the inflamma-
cases, dietary [21] and exercise [22] intervention tory and nitrosidative pathways, should be consid-
improve anxiety, depression, and affective symp- ered for the treatment of depression in the future:
toms especially in obese patients, probably nor- proinflammatory cytokines and their receptors,
malizing derangements in the HPA axis, peripheral intracellular inflammatory mediators, glucocorti-
hormones, and inflammation. Furthermore, as coid receptors, and neurotrophic factors.
additive treatment options, cortisol synthesis
inhibitors could dampen the hyperactive HPA
axis; anti-inflammatory drugs could decrease References
inflammatory and nitrosidative pathway-induced
1. Wulsin LR, Vaillant GE, Wells VE (1999) A system-
damage [16]; and the antidiabetic drug metformin
atic review of the mortality of depression. Psychosom
could exert neuroprotective, neurotrophic, and Med 61:6–17
anti-inflammatory effects [23]. 2. McIntyre RS, Alsuwaidan M, Goldstein BI, Taylor
VH, Schaffer A, Beaulieu S, Kemp DE (2012) The
Canadian Network for Mood and Anxiety Treatments
(CANMAT) task force recommendations for the man-
agement of patients with mood disorders and comor-
Influence of Treatment on bid metabolic disorders. Ann Clin Psychiatry 24:
Metabolism 69–81
3. Osby U, Brandt L, Correia N, Ekbom A, Sparen P
(2001) Excess mortality in bipolar and unipolar disor-
Several psychotropic drugs are associated with der in Sweden. Arch Gen Psychiatry 58:844–850
adverse metabolic effects [24] that should be 4. Pan A, Keum N, Okereke OI, Sun Q, Kivimaki M,
taken into account, especially when dealing with Rubin RR, Hu FB (2012) Bidirectional association
between depression and metabolic syndrome: a sys-
patients with metabolic comorbidity [25].
tematic review and meta-analysis of epidemiological
The classic TCAs, albeit efficacious, exert studies. Diabetes Care 35:1171–1180
many undesired pharmacological actions. For 5. McIntyre RS, McElroy SL, Konarski JZ, Soczynska
example, they block histamine 1 receptors, JK, Bottas A, Castel S, Wilkins K, Kennedy SH (2007)
Substance use disorders and overweight/obesity in
potentially explaining associated weight gain
bipolar I disorder: preliminary evidence for competing
and dyslipidemia. TCAs may also interfere addictions. J Clin Psychiatry 68:1352–1357
with insulin secretion, blocking M3 muscarinic 6. McIntyre RS, Rasgon NL, Kemp DE, Nguyen HT,
acetylcholine receptors in β-cells [26]. TCAs Law CW, Taylor VH, Woldeyohannes HO, Alsuwaidan
16 D. Marazziti et al.
MT, Soczynska JK, Kim B, Lourenco MT, Kahn LS, 18. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky
Goldstein BI (2009) Metabolic syndrome and major SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa
depressive disorder: co-occurrence and pathophysio- M, Elmquist JK, Nestler EJ, Zigman JM (2008) The
logic overlap. Curr Diab Rep 9:51–59 orexigenic hormone ghrelin defends against depres-
7. Sadock BJ, Sadock VA (2009) Kaplan & Sadock’s sive symptoms of chronic stress. Nat Neurosci
comprehensive textbook of psychiatry, 9th edn. 11:752–753
Lippincott Williams & Wilkins, Philadelphia 19. Skibicka KP, Hansson C, Egecioglu E, Dickson SL
8. Gold PW, Chrousos GP (2002) Organization of the (2012) Role of ghrelin in food reward: impact of ghre-
stress system and its dysregulation in melancholic and lin on sucrose self-administration and mesolimbic
atypical depression: high vs low CRH/NE states. Mol dopamine and acetylcholine receptor gene expres-
Psychiatry 7:254–275 sion. Addict Biol 17:95–107
9. Bjorntorp P (2001) Do stress reactions cause abdomi- 20. van Reedt Dortland AK, Giltay EJ, van Veen T,
nal obesity and comorbidities? Obes Rev 2:73–86 Zitman FG, Penninx BW (2010) Metabolic syndrome
10. Golden RN, Markey SP, Risby ED, Rudorfer MV, abnormalities are associated with severity of anxiety
Cowdry RW, Potter WZ (1988) Antidepressants and depression and with tricyclic antidepressant use.
reduce whole-body norepinephrine turnover while Acta Psychiatr Scand 122:30–39
enhancing 6-hydroxymelatonin output. Arch Gen 21. Sanchez-Villegas A, Delgado-Rodriguez M, Alonso
Psychiatry 45:150–154 A, Schlatter J, Lahortiga F, Serra Majem L, Martinez-
11. Gans RO (2006) The metabolic syndrome, depres- Gonzalez MA (2009) Association of the
sion, and cardiovascular disease: interrelated condi- Mediterranean dietary pattern with the incidence of
tions that share pathophysiologic mechanisms. Med depression: the Seguimiento Universidad de Navarra/
Clin North Am 90:573–591 University of Navarra follow-up (SUN) cohort. Arch
12. Benthem L, Keizer K, Wiegman CH, de Boer SF, Gen Psychiatry 66:1090–1098
Strubbe JH, Steffens AB, Kuipers F, Scheurink AJ 22. Dunn AL, Trivedi MH, Kampert JB, Clark CG,
(2000) Excess portal venous long-chain fatty acids Chambliss HO (2005) Exercise treatment for depres-
induce syndrome X via HPA axis and sympathetic sion: efficacy and dose response. Am J Prev Med
activation. Am J Physiol Endocrinol Metab 279: 28:1–8
E1286–E1293 23. Ehret M, Goethe J, Lanosa M, Coleman CI (2010)
13. Kreier F, Yilmaz A, Kalsbeek A, Romijn JA, The effect of metformin on anthropometrics and insu-
Sauerwein HP, Fliers E, Buijs RM (2003) Hypothesis: lin resistance in patients receiving atypical antipsy-
shifting the equilibrium from activity to food leads to chotic agents: a meta-analysis. J Clin Psychiatry
autonomic unbalance and the metabolic syndrome. 71:1286–1292
Diabetes 52:2652–2656 24. Chokka P, Tancer M, Yeragani VK (2006) Metabolic
14. Catena-Dell’Osso M, Rotella F, Dell’Osso A, Fagiolini syndrome: relevance to antidepressant treatment.
A, Marazziti D (2013) Inflammation, serotonin and J Psychiatry Neurosci 31:414
major depression. Curr Drug Targets 14:571–577 25. Kozumplik O, Uzun S (2011) Metabolic syndrome in
15. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW patients with depressive disorder–features of comor-
(1999) C-reactive protein in healthy subjects: associa- bidity. Psychiatr Danub 23:84–88
tions with obesity, insulin resistance, and endothelial 26. McIntyre RS, Soczynska JK, Konarski JZ, Kennedy
dysfunction: a potential role for cytokines originating SH (2006) The effect of antidepressants on lipid
from adipose tissue? Arterioscler Thromb Vasc Biol homeostasis: a cardiac safety concern? Expert Opin
19:972–978 Drug Saf 5:523–537
16. Catena-Dell’Osso M, Bellantuono C, Consoli G, 27. Licht CM, de Geus EJ, Seldenrijk A, van Hout HP,
Baroni S, Rotella F, Marazziti D (2011) Inflammatory Zitman FG, van Dyck R, Penninx BW (2009)
and neurodegenerative pathways in depression: a new Depression is associated with decreased blood pres-
avenue for antidepressant development? Curr Med sure, but antidepressant use increases the risk for
Chem 18:245–255 hypertension. Hypertension 53:631–638
17. Lutter M, Elmquist J (2009) Depression and metabo-
lism: linking changes in leptin and ghrelin to mood.
F1000 Biol Rep 1:63
Schizophrenia
abnormalities. The overall brain volume is at least in a subgroup of patients, and occur with-
reduced (by around 5 %, in both white and gray out evidence of gliosis, commonly found in neu-
matter), and the temporal and frontal lobes are rodegenerative disorders. More recent drug
smaller. In addition, the hippocampus is smaller, development is focusing on the glutamate system
with predominance of finding more left-sided as novel and potentially (more) effective way to
reductions. In contrast, the ventricles (especially treat schizophrenia [9]. Schizophrenia has been
the lateral ones) are enlarged. On a cellular level, associated with metabolic abnormalities indepen-
changes more of attuned arrangement rather than dent of treatment with antipsychotic drugs; for
fundamental tissue loss or necrosis are observed, example, treatment-naïve patients with schizo-
likely resulting from convergence of genetic and phrenia have increased prevalence of abnormal
environmental factors, leading to abnormal neu- glucose tolerance and insulin resistance compared
ronal connectivity and synaptic signaling and to normal controls [10, 11].
altering dopaminergic and glutamatergic path-
ways of neurotransmission in the brain.
Altered dopaminergic function is considered Treatment of Schizophrenia
as the final common pathway in schizophrenia
[1]. This hypothesis has most influenced antipsy- Antipsychotic medications form the bedrock of
chotic drug development and the clinical treat- treatment for schizophrenia [12]. All these medi-
ment of schizophrenia, and it represents the best cations block dopamine (D2) receptors to some
(yet still inadequate) explanatory model for extent, although newer antipsychotic medications
schizophrenia and its treatment. According to tend to have broader effects that extend to other
this hypothesis, in schizophrenia, the mesolimbic (e.g., cholinergic, adrenergic, serotonergic) neu-
dopamine pathway, believed to have a role in rotransmitters. Antipsychotic medications should
thought and perception, is disrupted, especially be used in all florid psychosis, except drug-
through dopamine receptor D2 (DRD2)-mediated induced psychosis and brief psychosis [12, 13].
effects. An overactivation of this receptor is a Antipsychotic drugs are grouped into a first-
compelling pathobiological finding in schizo- and second-generation antipsychotics (FGAs and
phrenia. The hypothesis also explains other SGAs), based on their receptor and adverse effect
schizophrenia characteristics, as dopamine path- profiles. When starting schizophrenia treatment
ways in the brain affect cognition (through a (usually with a second-generation antipsychotic),
mesocortical pathway, which is important in the the lowest effective drug dose should be used.
flow of information in the frontal lobe), move- Antipsychotic drugs often appear to work in about
ment through the nigrostriatal pathway, which is 48 h, although it may take up to 4 weeks at ade-
instrumental as part of the basal ganglia motor quate dose to determine whether the drug is ulti-
loop, and endocrine function through the tuber- mately effective. Treatment response, tolerability,
oinfundibular pathway, which involves dopamine and side effects of any given drug are highly vari-
acting as an inhibitor of prolactin gene expres- able between patients [14], and side effects should
sion and secretion. thus be monitored closely. Switching antipsy-
Other emergent hypotheses include an oxida- chotic medications may be indicated, for either
tive stress and phospholipid dysregulation hypoth- lack of effect or presence of side effects on the
esis, a glutamate hypothesis [9], and a more present medications, although it is a complicated
“all-encompassing” neurodevelopmental hypoth- process and the switch to a new medication should
esis of schizophrenia [1, 8], which capitalize on be gradual and phased-in with a cross taper.
the fact that the pathological brain abnormalities Antipsychotic polypharmacy is common although
thought to be resulting from the gene-environ- probably not justified. At present, treatment
mental factors implicated in schizophrenia remains a clinical approach of “trial and error”
(smaller prefrontal cortex and hippocampus, with the selection of each antipsychotic medica-
enlarged ventricles) appear to be static in nature, tion. The mechanism of action of the FGAs
Schizophrenia 19
Hypothalamus
DA GnRH
FSH,
Prolactin LH
Gonads
Maturation
and function
Bone
Bone density
Fig. 1 Potential mechanism of side effects of antipsy- Increased prolactin can lead to gonadal dysfunction, via
chotics on gonadal system and bone structure. First- reduced amounts of gonadotropin-releasing hormone
generation antipsychotics (FGAs) act by inhibiting the (GnRH), follicle-stimulating hormone (FSH), and lutein-
binding of dopamine (DA), released from the hypothala- izing hormone (LH). Subsequently, gonadal failure can
mus, to D2 receptors in the pituitary gland. Without this cause bone loss and osteoporosis
activation, the DA block of prolactin secretion is released.
(e.g., haloperidol and perphenazine) is based pri- that medications may have neuroplastic effects
marily on the inhibition of dopamine D2 receptors. [15]. On the other hand, there is lingering con-
Clozapine, the initial SGA drug, only partially cern that antipsychotic medications might be
binds to dopamine D2 receptors. However, it also neurotoxic and thereby contribute to progressive
binds dopamine D4 receptors with high affinity. neurodegeneration in schizophrenia [16].
Other targets include dopamine D1, D3, and D5 The FGAs have a side effect profile largely
receptors as well as serotonin, adrenergic, and his- characterized by acute and long-term muscle
taminergic receptors. Other SGAs (like risperi- impairments through their effect on the dopami-
done, quetiapine, and olanzapine) maintain the nergic nigrostriatal pathway. In addition, FGAs,
combined inhibition of dopamine D2 receptors which antagonize the action of dopamine, which
and serotonin 5-HT2A receptors [14]. is also known as prolactin-inhibiting hormone
(see chapter “Overview” under part “Reproductive
system”), induce hyperprolactinemia by releas-
Influence of Treatment on ing the dopamine block of prolactin secretion in
Metabolism the pituitary gland. This can lead to gonadal fail-
ure and subsequently to bone loss and osteoporo-
As dopamine affects many neurological systems sis (see chapter “Osteoporosis”, Fig. 1) [17, 18].
in the brain (see above), antipsychotic and anti- SGAs show a more complex side effect profile
dopaminergic treatments have broad therapeutic that is increasingly characterized by metabolic
and adverse effects. Based on the all- disturbances [19]. While they yield less risk for
encompassing hypothesis, there is some evidence movement disorders and hyperprolactinemia,
20 P.F. Buckley and A. Foster
SGAs
e.g. Risperidone, Quetiapine,
Clozapine, Olanzapine
Pancreatic
Hypothalamus β-cell
Hyperglycemia
Weight Diabetes
Fig. 2 Side effect profile of second-generation antipsy- (right side). Blockade of 5-HT2C and H1 receptors releases
chotics. Second-generation antipsychotics (SGAs) show the inhibitory effect on appetite that these receptors share
side effects different from the first generation due to their with leptin. Increased appetite results in weight gain and
binding to 5-HT2C dopamine (5-HT) and H1 histamine associated effects. Blockade of M3 receptors may reduce
receptors in the hypothalamus (left side) and M3 musca- insulin secretion and subsequently cause hyperglycemia
rinic acetylcholine receptors on pancreatic β-cells and diabetes
due to lower blockade of dopamine D2 receptors drugs for schizophrenia, which can exercise ther-
and concomitant serotonin antagonism, SGAs apeutic effect without considerable metabolic
are known to induce dangerous metabolic effects and endocrine risk [24]. Pharmacogenetic analy-
[20], for example, weight gain, and alterations in ses have offered some insights into effectiveness,
glucose and lipid metabolism. SGAs increase tolerability, and side effects in individual patients.
appetite activating histamine H1 and serotonin However, the predictive potential to drive “per-
5-HT2C receptors [20]. Serotonin 5-HT2C recep- sonalized medicine” is still a long way off [25].
tors and leptin, a hormone implicated in the Although medications form the basis of treat-
pathophysiology of food and energy regulation ment, medications alone are insufficient for treat-
(see chapters “Diabetes mellitus” and “Metabolic ing schizophrenia. Other psychological and
syndrome”), have been associated with weight cognitive approaches (such as cognitive therapy
gain in replicated studies and may provide a basis adapted for schizophrenia and cognitive remedia-
for individualized adverse effect risk assessment tion training particularly when combined with
in the future (Fig. 2) [21]. Therefore, guidelines functional adaptation skills training [26]) are
on monitoring patients on antipsychotics for obe- important and impactful treatment modalities [27].
sity, diabetes, lipid abnormalities, and cardiovas- Research also focuses on earlier diagnosis and
cular risk have been issued [22, 23]. treatment of schizophrenia, thereby intuitively
leading to better results and less secondary con-
sequences of protracted psychosis. Indeed,
Perspectives research points to subtle signs of psychosis in
advance of more florid psychotic manifestations
In addition to the use of FGAs and SGAs in the [28]. Moreover, many of the neurobiological
treatment of schizophrenia, there are a variety of hallmarks of schizophrenia such as decreased
other novel approaches targeting specific aspects gray matter in the temporal, frontal, and cingu-
of the illness, e.g., treatment of negative symp- late cortex as well as subtle clinical symptoms
toms, and treatment of cognitive impairments. like attention difficulty, cognitive decline, social
The field is still awaiting a third generation of withdrawal, and affective flattening exist in early
Schizophrenia 21
states, albeit in much more attenuated forms [29]. treatment of schizophrenia and the management
of treatment resistance. World J Biol Psychiatry
Unfortunately, identification and clinical incor-
13:318–378
poration of disease biomarkers that could inform 13. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM,
and reliably predict treatment outcomes prove Boggs DL, Fischer BA, Himelhoch S, Fang B,
difficult [30]. Moreover, the lack of fundamental Peterson E, Aquino PR, Keller W, Schizophrenia
Patient Outcomes Research Team (PORT) (2010) The
understanding of the pathobiology of schizophre-
2009 schizophrenia PORT psychopharmacological
nia greatly hampers this quest. treatment recommendations and summary statements.
Schizophr Bull 36:71–93
14. Leucht S, Cipriani A, Spineli L et al (2013)
Comparative efficacy and tolerability of 15 antipsy-
References chotic drugs in schizophrenia: a multiple treatments
meta-analysis. Lancet 382:951–962
1. Van Os J, Kapur S (2009) Schizophrenia. Lancet 15. Ho BC, Andreasen NC, Ziebell S, Pierson R,
374:635–645 Vincent M (2011) Long term antipsychotic treat-
2. Tandon R (2013) Schizophrenia and other psychotic ment and brain volumes: longitudinal study of first
disorders in DSM-5: clinical implications of revisions episode schizophrenia. Arch Gen Psychiatry 68:
from DSM-IV. Clin Schizophr Relat Psychoses 128–137
7:16–19 16. Ronopaske GT, Dorph-Peterson KA, Sweet RA
3. Pescosolido BA, Medina TR, Martin JK, Long JS (2008) Effects of antipsychotic exposure on astrocyte
(2013) The “backbone” of stigma: identifying the and oligodendrocyte numbers in macaque monkeys.
global core of public prejudice associated with mental Biol Psychiatry 63:758–765
illness. Am J Public Health 103:853–860 17. Howard L, Kirkwood G, Leese M (2007) Risk of hip
4. Tandon R, Nassrallah HA, Keshavan MS (2012) fracture in patients with a history of schizophrenia. Br
Schizophrenia: just the facts 5. Treatment and preven- J Psychiatry 190:129–134
tion. Past, present, and future. Schizophr Res 122: 18. Inder WJ, Castle D (2011) Antipsychotic-induced
1–23 hyperprolactinemia. Aust N Z J Psychiatry 45:
5. McGrath J, Meyer-Lindenberg A (2013) Is it time 830–837
schizophrenia research left the museum? Clin 19. Buckley PF, Miller B, Singer B, Arena J, Stirewalt
Schizophr Relat Psychoses 6:170–171 EM (2005) Clinicians’ recognition of the metabolic
6. Owen MJ (2012) Implications of genetic findings for adverse effects of antipsychotic medications.
understanding schizophrenia. Schizophr Bull 38: Schizophr Res 79:281–288
904–907 20. Pramyothin P, Khaodhiar L (2010) Metabolic syn-
7. Cross-Disorder Group of the Psychiatric Genomics drome with the atypical antipsychotics. Curr Opin
Consortium (2013) Genetic Risk Outcome of Psychosis Endocrinol Diabetes Obes 17:460–466
(GROUP) Consortium. Identification of risk loci with 21. Arranz MJ, Rivera M, Munro C (2011)
shared effects on five major psychiatric disorders: a Pharmacogenetics of Response to Antipsychotics
genome-wide analysis. Lancet 381(9875):1371–1379 in Patients with Schizophrenia. CNS Drugs 25:
8. Piper M, Beneyto M, Burne T, Eyles D, Lewis D, 933–969
McGrath J (2012) The neurodevelopmental hypothe- 22. American Diabetes Association, American Psychiatric
sis of schizophrenia: convergent clues from epidemi- Association, American Association of Clinical
ology and neuropathology. Psychiatr Clin North Am Endocrinologists, North American Association for
35:571–584 the Study of Obesity (2004) Consensus Development
9. Jevitt D (2012) Twenty-five years of Glutamate and Conference on antipsychotic drugs and obesity and
schizophrenia: are we there yet? Schizophr Bull diabetes. Diabetes Care 27:596–601
38:911–913 23. De Hert M, Dekker JM, Wood D et al (2009)
10. Fernandez-Egea E, Bernardo M, Donner T et al Cardiovascular Disease and diabetes in people with
(2009) Metabolic profile of antipsychotic-naive indi- severe mental illness position statement from the
viduals with non-affective psychosis. Br J Psychiatry European Psychiatric Association (EPA), Supported
194:434–438 by the European Association for the study of Diabetes
11. Dasgupta A, Singh OP, Rout JK et al (2010) Insulin (EASD) and the European Society of Cardiology. Eur
resistance and metabolic profile in antipsychotic naïve Psychiatry 24:412–424
schizophrenia patients. Prog Neuropsychopharmacol 24. Dean OM, Data-Franco J, Giorlando F, Berk M
Biol Psychiatry 34:1202–1207 (2012) Minocycline: therapeutic potential in psychia-
12. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoi try. CNS Drugs 26:391–401
B, Gattaz WF, Thibaut F, Möller HJ (2012) World 25. Foster BA, Buckley PF. Pharmacogenetics of treat-
Federation of Societies of Biological Psychiatry ment refractory schizophrenia: in treatment refractory
(WFSBP). Guidelines for Biological Treatment of schizophrenia a clinical conundrum. In: Buckley PF,
Schizophrenia, part 1: update 2012 on the acute Graygran F (eds). Springer (in press)
22 P.F. Buckley and A. Foster
26. Keefe RS, Harvey PD (2012) Cognitive impair- The psychosis high-risk state: a comprehen-
ment in schizophrenia. Handb Exp Pharmacol 213: sive state-of-the-art review. JAMA Psychiatry 70:
11–37 107–120
27. Harvey PD, Bowie R (2012) Cognitive enhance- 29. Kerns J, Lauriello J (2012) Can structural neuroimag-
ment in schizophrenia: pharmacological and reme- ing be used to define phenotypes and course of schizo-
diation approaches. Psychiatr Clin North Am 35: phrenia? Psychiatr Clin North Am 35:633–644
683–698 30. Weickert CS, Weickert T, Pillai A, Buckley PF (2013)
28. Fusar-Poli P, Borgwardt S, Bechdolf A, Addington Biomarkers for schizophrenia: a brief conceptual con-
J, Riecher-Rossler A, Schultze-Lutter F et al (2013) sideration. Dis Markers 35:3–9
Epilepsy
Excitatory
presynaptic neuron
K+ [AdK]
(3) AMP
K + channel SA
Inhibitory (4)
Glu [GABA-T]
presynaptic Levetiracetam GAT-1
neuron GABA
SV2A Glu
(5)
GAT1
Na +
Na + GABA
(2) Glu
(Ca 2+) Ca 2+
SA
[GABA-T] AMPA-R NMDA-R
GABA
Postsynaptic
Neuron
Cl-
GABA
GABA A-R
Benzodiazepine
Tiagabine
Vigabatrin
Fig. 1 Disruption of multiple systems in epilepsy involv- transporters for K+ (not shown) and Glu (such as GAT-1)
ing neurons and astrocytes. (1) Hyperexcitable neurons on reactive astrocytes further enhance hyperexcitability.
are associated with overactivation of voltage-gated Na+ (5) Excessive Ca2+ intake in astrocytes even induces Glu
channels and reduced activity of K+ channels, which gen- release. Points of interference of a few antiepileptic drugs
erate an action potential that leads to (2) increased release are also shown. These drugs generally aim to decrease
of glutamate (Glu). This activates AMPA and N-methyl- hyperexcitability by reducing glutamate release or signal-
d-aspartate (NMDA) receptors on the postsynaptic mem- ing or by increasing glutamate removal or inhibitory sig-
brane, causing excitatory synaptic potentials. (3) naling. SV2A synaptic vesicle glycoprotein 2A, nt
Upregulated adenosine kinase (AdK) in reactive astro- nucleoside transporter, GABA γ-aminobutyric acid, GAT-
cytes increases the removal of extracellular adenosine, 1 GABA transporter-1, GABA-T GABA transaminase, SA
enhancing hyperexcitability. (4) Decreased membrane succinic semialdehyde
particularly those involving the temporal lobe, particular, overexpression of adenosine kinase,
are characterized by astrogliosis, a macroglial the key enzyme for the metabolic clearance of
response that leads to increased proliferation adenosine through astrocytes, has been identified
and hypertrophy of astrocytes. Astrogliosis in as a key pathological hallmark of epilepsy as it
turn is associated with changes in the membrane results in adenosine deficiency [2].
conductance for ions, which limits the buffering Adenosine is a key link between energy
capacity of astrocytes for K+, Ca2+, and H+, and homeostasis and metabolic activity and has been
disrupts the homeostasis of neurotransmitters termed a “retaliatory metabolite” due to its capa-
such as glutamate (Glu) and of neuromodulators bility to adjust energy consumption to energy
such as adenosine. As a consequence of those supplies [3]. In general, under any conditions of
alterations in astroglial physiology, the extracel- stress or distress, the levels of adenosine rise, and
lular concentrations of K+ and Glu are increased, it is this rise in adenosine that limits further neu-
whereas those of adenosine are decreased. In ronal energy consumption [4] by binding to
Epilepsy 25
inhibitory adenosine A1 receptors [5], which cou- and the global manipulation of ion channels leads
ple to inhibitory Gi and Go proteins and thereby to widespread side effects, particularly in the
(1) lead to a decrease in the intracellular messen- cognitive domain, at higher and more effective
ger cAMP, (2) induce neuronal hyperpolarization doses. Alternative treatments include surgical
by augmenting G protein-coupled inwardly recti- resection of a seizure focus. The goal of surgical
fying K+ channels, and (3) induce presynaptic resection is to remove the seizure origin or dis-
inhibition by limiting Ca2+ influx into the presyn- rupt the spread of the seizure throughout the
aptic neuron. More specifically, in epilepsy, sei- brain. If an epileptogenic focus is found and does
zures consume a large amount of energy, which not reside in cortical areas responsible for speech,
leads to a rise in adenosine that acts as an endog- it may be possible to remove without compromis-
enous anticonvulsant and seizure terminator [6]. ing neurological functions. Surgery has been suc-
cessful in reducing seizures and in some instances
may completely alleviate the need for other treat-
Treatment of Epilepsy ments [9]. While AEDs and surgery have been
the classical foundation of epilepsy treatment,
Treatment of epilepsy with antiepileptic drugs they do not provide a satisfactory solution for
(AEDs) generally attempts to correct the disrup- many patients (see below). In contrast, dietary
tion in normal electrical functionality via therapies may provide seizure control in drug-
decreases in excitatory processes or increases in resistant forms of epilepsy [10]. The therapeutic
inhibitory processes. AEDs aim to reduce sei- effect of fasting on the control of seizures has
zures by regulating the nervous system’s primary been known since Hippocrates. Fasting’s sup-
excitatory neurotransmitter, Glu, its primary pression of seizures can be mimicked by a high-
inhibitory neurotransmitter, GABA, or ion chan- fat, low-carbohydrate ketogenic diet (Fig. 2). The
nels that control the conduction of electrical anticonvulsant effects brought on by metabolic
impulses in neurons. It should be noted, however, changes during this diet therapy offer great prom-
that the treatment of epilepsy, based on the mod- ise for identifying new antiseizure targets as well
ulation of neuronal downstream targets, fails to as providing insight into the pathophysiology of
control seizures in more than 30 % of patients the epileptic brain (see below).
with epilepsy [7, 8]. The control of neuronal
excitability by blockade of ion channels such as
those for Na+, K+, and Ca2+ is a mechanism of Influence of Treatment
commonly used AEDs (e.g., phenytoin, carbam- on Metabolism
azepine, valproic acid). Newer AEDs act by
interfering with the synthesis, function, release, The sharp decrease in carbohydrate intake during
and metabolism of neurotransmitters and their ketogenic diet treatment reduces glucose utiliza-
receptors. Levetiracetam binds to the synaptic tion as an energy source. Instead, the liver utilizes
vesicle glycoprotein SV2A and inhibits presyn- fatty acids to produce ketone bodies, mainly
aptic Ca2+ channels. Presynaptic mechanisms are β-hydroxybutyrate and acetoacetate. Neurons in
thought to impede impulse conduction across turn will use these ketone bodies for cellular
synapses. Vigabatrin blocks GABA transami- metabolism in place of glucose (Fig. 2). Many
nase, the major GABA degrading enzyme, and hypotheses exist to explain the anticonvulsant
tiagabine blocks reuptake of GABA via GABA action of the ketogenic diet, but despite its name,
transporter 1 (GAT1), thereby increasing the the ketone bodies themselves may not necessar-
level of extracellular GABA in the brain. ily be the primary effector, and the underlying
Moreover, AEDs can enhance the effect of mechanisms leading to reduced seizure activity
GABA (e.g., benzodiazepine). However, conven- are largely unknown. Among beneficial meta-
tional pharmacological strategies frequently fail bolic changes induced by ketogenic diet therapy
due to the development of pharmacoresistance, are (1) increased levels of adenosine [11], (2)
26 W. Plinke and D. Boison
a
Ketone bodies GABA
Free fatty acids
Glu
β-oxidation Acetyl-CoA
Ion
channels
Acetyl-CoA
TCA cycle
Liver Brain
Adenosine
b Adenosine
[Nucleotidases]
cAMP A1R
Hyperpolarization
Pannexin
Presynaptic inhibition
ATP
Neuron
Fig. 2 Mechanism of action for the ketogenic diet. (a) reducing neuronal excitability. (b) Increased intracellular
Schematic diagram illustrating ketone body formation ATP moves ATP along its concentration gradient through
from fatty acids present in the ketogenic diet and their pannexin to the extracellular space. Here, it is degraded
subsequent use in the brain as fuel for ATP production. by nucleotidases to its core constituent, adenosine, which
Ketogenic diet is reported to increase adenosine and can act on inhibitory A1 receptors (A1R) to cause presyn-
γ-aminobutyric acid (GABA), to decrease glutamate (Glu), aptic inhibition and hyperpolarization to prevent seizures.
and to directly act on neurotransmitters subsequently cAMP cyclic adenosine monophosphate
increased GABA, (3) and decreased Glu, which anticonvulsant strategy with good efficacy and
all combine with a direct action of ketone bodies few side effects.
on ion channels to reduce neuronal excitability
[10]. Ketosis increases mitochondrial biogenesis
and thereby the production of ATP, which is a Perspectives
direct metabolic precursor of adenosine (as it
leaves the neuron via the transmembrane channel Inefficacy of current AED treatment in 30 % of
pannexin and is converted to adenosine extracel- patients signals the need for a deeper understand-
lularly (Fig. 2) [12]. It is this unique metabolic ing of homeostatic mechanisms that govern the
modulation that builds excitement not only for a pathophysiology of epilepsy. Future studies
deeper understanding of the ketogenic diet but should investigate the metabolic changes in epi-
for metabolic manipulations in general as a novel lepsy in order to establish novel treatment
Epilepsy 27
approaches. Current investigations consider a 5. Boison D (2005) Adenosine and epilepsy: from thera-
peutic rationale to new therapeutic strategies.
variety of alternative therapeutic interventions
Neuroscientist 11:25–36
such as focal cooling [13], cell therapy [14, 15], 6. Dragunow M (1991) Adenosine and seizure termina-
gene therapy [16–18], or focal adenosine aug- tion. Ann Neurol 29:575
mentation [15] to harness endogenous anticon- 7. Kwan P, Brodie MJ (2000) Early identification of
refractory epilepsy. N Engl J Med 342:314–319
vulsant mechanisms of the brain therapeutically.
8. Loscher W, Schmidt D (2011) Modern antiepileptic
Indeed, it is time to redefine epilepsy as a com- drug development has failed to deliver: ways out of
plex syndrome of disrupted network homeostasis, the current dilemma. Epilepsia 52:657–678
which includes seizures not only as the major 9. de Tisi J, Bell GS, Peacock JL, McEvoy AW, Harkness
WF, Sander JW, Duncan JS (2011) The long-term out-
pathological trait but also a wide range of so-
come of adult epilepsy surgery, patterns of seizure
called comorbidities including cognitive impair- remission, and relapse: a cohort study. Lancet 378:
ment, sleep dysfunction, depression (see chapter 1388–1395
“Major depressive disorder”), and psychiatric 10. Lutas A, Yellen G (2013) The ketogenic diet: meta-
bolic influences on brain excitability and epilepsy.
impairment. Conventional AEDs were solely
Trends Neurosci 36:32–40
designed to suppress seizures, which is only a 11. Masino SA, Li T, Theofilas P, Sandau US, Ruskin
symptom of epilepsy, albeit the most obvious. DN, Fredholm BB, Geiger JD, Aronica E, Boison D
Based on the neurocentric rationale of drug devel- (2011) A ketogenic diet suppresses seizures in mice
through adenosine A1 receptors. J Clin Invest 121:
opment, it becomes clear that conventional AEDs
2679–2683
are a poor choice to treat epilepsy as a syndrome 12. Masino SA, Geiger JD (2008) Are purines mediators
in a “holistic” sense. Novel therapeutic avenues of the anticonvulsant/neuroprotective effects of keto-
aimed at reconstructing the homeostasis of net- genic diets? Trends Neurosci 31:273–278
13. Rothman SM (2009) The therapeutic potential of focal
work regulation may ultimately provide better
cooling for neocortical epilepsy. Neurotherapeutics
treatment options and hopes for finding a cure for 6:251–257
epilepsy. In this regard, metabolic interventions 14. Thompson KW (2005) Genetically engineered cells
and focal adenosine augmentation appear to be with regulatable GABA production can affect after
discharges and behavioral seizures after transplanta-
promising homeostatic therapies, which might be
tion into the dentate gyrus. Neuroscience 133:
effective in pharmacoresistant epilepsy and poised 1029–1037
to reduce the disease burden of epilepsy. 15. Boison D (2009) Adenosine augmentation therapies
(AATs) for epilepsy: prospect of cell and gene thera-
pies. Epilepsy Res 85:131–141
16. Noe F, Nissinen J, Pitkanen A, Gobbi M, Sperk G,
References During M, Vezzani A (2007) Gene therapy in epi-
lepsy: the focus on NPY. Peptides 28:377–383
1. Steinhauser C, Boison D (2012) Epilepsy: crucial role 17. McCown TJ (2009) Adeno-associated virus vector-
for astrocytes. Glia 60:1191 mediated expression and constitutive secretion of galanin
2. Boison D (2012) Adenosine dysfunction in epilepsy. suppresses limbic seizure activity. Neurotherapeutics
Glia 60:1234–1243 6:307–311
3. Newby AC, Worku Y, Holmquist CA (1985) Adenosine 18. Raol YH, Lund IV, Bandyopadhyay S, Zhang G,
formation. Evidence for a direct biochemical link with Roberts DS, Wolfe JH, Russek SJ, Brooks-Kayal AR
energy metabolism. Adv Myocardiol 6:273–284 (2006) Enhancing GABA(A) receptor alpha 1 subunit
4. Fredholm BB (2007) Adenosine, an endogenous dis- levels in hippocampal dentate gyrus inhibits epilepsy
tress signal, modulates tissue damage and repair. Cell development in an animal model of temporal lobe epi-
Death Differ 14:1315–1323 lepsy. J Neurosci 26:11342–11346
Parkinson’s Disease
Peripheral Central
(SNc and associated brain areas)
SNc
RBC
Skeletal muscle
Oxidized dopamine
Cholesterol and Ions (Ca 2+)
fatty acid plasma levels Metals (Fe, Cu, Zn, Mg)
Citric acid cycle intermediates
Pyruvate
Parkinsonian patient
Fig. 1 Metabolic changes in Parkinson’s disease. neurotransmission. Mitochondrial viability and integrity
Metabolic changes in Parkinson’s disease include central are also strongly affected, both in the brain and in periph-
(right side) and peripheral (left side) alterations. Metabolic eral cells such as lymphocytes, platelets, red blood cells
changes in the brain affect the substantia nigra pars com- (RBCs) and skeletal muscle cells. Changes in lipid content
pacta (SNc) and (non)-dopaminergic associated areas. and metabolism, together with energetic imbalances, can
Increased levels of Ca2+, oxidized dopamine, and other also be found in the blood plasma
metals ions such as iron induce neuronal death and alter
occurring at central level and/or represent bio- lymphocytes, and skeletal muscle in PD
markers of ongoing pathology. patients [9]. Concerning metabolic intermedi-
Selective vulnerability of dopaminergic neu- ates, increased pyruvate concentrations, as well
rons likely involves DA oxidation and Ca2+ as decreased levels of citrate, acetate, succinate,
homeostasis, which are both elevated in the SNc and malate – intermediates of the citric acid cycle
of animal models of PD and patients [5]. In a (also called tricarboxylic acid cycle) – were
rodent model of PD, ions such as iron, manga- detected in the plasma of naïve PD patients [10].
nese, copper and zinc are increased in the brain All these conditions ultimately favor neurode-
regions associated with the dopaminergic path- generation, suggesting that changes in energy
way [6]. Changes in the striatal levels of excit- metabolism contribute to PD (Fig. 1).
atory (glutamate) and inhibitory (γ-aminobutyric
acid or GABA) neurotransmitters were found in
another rodent model of PD indicating imbal- Treatment of Parkinson’s Disease
anced neurotransmission in PD basal ganglia [7].
Epidemiologic data show that low levels of The pharmacological treatment currently avail-
circulating fatty acids and cholesterol increase able for PD is purely symptomatic and is based
the risk of developing PD, suggesting that also on the restoration of DA levels in the brain. The
lipid metabolism is affected [8]. The involvement typical treatment consists in the administration
of mitochondrial dysfunctions in the etiopatho- of l-3,4-hydroxyphenylalanine (l-dopa), which
genesis of PD suggests the existence of defects in crosses the blood-brain barrier (unlike DA itself)
energy metabolism. Reduced complex I activity and is directly converted into DA by the aro-
was observed in mitochondria from SNc, platelets, matic L-amino acid decarboxylase. In everyday
Parkinson’s Disease 31
Mesolimbic pathway
Electrode
SNc
Hypothalamus
Compulsive behavior
Binge eating
Appetite
Food intake
Weight gain
Fig. 2 Influence of Parkinson’s disease treatment on compulsive behavior and binge eating. Deep brain stimu-
metabolism. Metabolic changes after antiparkinsonian lation (right side) affects mostly the hypothalamus, a
therapy and surgical interventions are due to secondary brain nucleus dedicated to control of homeostatic behav-
effects on the intact mesolimbic pathway parallel to the iors such as eating and sleeping. In both cases, the effects
affected nigrostriatal system and on the hypothalamus. are increased appetite and food intake leading to weight
Dopamine-based medication (left side) hyperactivates the gain and therefore complications of the clinical spectrum.
mesolimbic pathway, associated with the brain nuclei SNc substantia nigra pars compacta, PD Parkinson’s
dedicated to the perception of reward, thereby causing disease
activation of the mesolimbic pathway, connect- underlie PD pathogenesis, since metabolites act
ing the dopaminergic ventral tegmental area with as indicators of cellular physiology and homeo-
limbic structures such as the nucleus accumbens stasis. Indeed, the identification of biomarkers to
and the amygdala. This pathway has been linked diagnose and monitor the progression of the dis-
to the biological perception of reward and the ease is currently one of the most intriguing and
activation of responses associated with it; there- challenging areas of PD research. The evaluation
fore, PD therapy causes compulsive behaviors of metabolomic profiles is a promising tool for
and binge eating through the hyperactivation of supporting the diagnosis of PD, possibly in the
this system [20]. Finally, weight gain in PD very early phases of the disease [10], and might
patients increases the risk for other metabolic also be useful to identify prognostic markers, as
disturbances, such as diabetes (see chapter well as to anticipate the response to pharmaco-
“Diabetes mellitus”) and cardiovascular diseases logical treatment. These studies will eventually
(see chapter “Atherosclerotic heart disease”), lead to a better description of PD molecular and
thereby adding further levels of complexity to the clinical phenotypes and therefore optimization
clinical phenotype (Fig. 2). of therapeutic intervention. New possible phar-
macological strategies to improve both neuro-
protection and motor dysfunction are in
Perspectives development. Thus far, encouraging results have
been obtained by adopting antagonists of ade-
Identification of metabolic changes in the brain nosine and glutamate receptors [11] and com-
or peripheral fluids is essential to develop bio- pounds that increase the endogenous levels of
markers and to unravel the mechanisms that antioxidants [21].
Parkinson’s Disease 33
Fig. 1 Clinical and neuropathological continuum of mild (ELISA). Aβ aggregation precedes p-tau aggregation.
cognitive impairment (MCI) and Alzheimer’s disease Impairment of neuronal metabolism and loss of synaptic
(AD). AD pathology is initiated over a decade prior to structure and function may begin in the preclinical stage
symptoms. The earliest detectable pathological changes and are detectable using fluorodeoxyglucose (FDG)-PET.
are amyloid-ß (Aß) plaque deposits in the brain paren- Finally, neuronal loss and resulting brain atrophy occur,
chyma, detectable using amyloid positron emission detectable with structural magnetic resonance imag-
tomography (PET) imaging, and decreased Aβ concentra- ing (MRI). Once initiated, these pathologies proceed to
tion in the cerebrospinal fluid (CSF), as Aβ is retained advance progressively and are believed to contribute to
in the brain rather than cleared to the CSF. The latter is clinical symptoms. MMSE mini-mental state examination
detectable using enzyme-linked immunosorbent assay
as hypertension (see chapter “Hypertension”), ages 35 and 50), yet they are responsible for less
hyperlipidemia (see chapter “Hyperlipidemia”), than 1 % of all AD cases. In contrast, nondominant
obesity, diabetes (see chapter “Diabetes mel- forms of AD are seen in over 99 % of cases and are
litus”), and metabolic syndrome (see chapter characterized by late onset (usually over age 65)
“Metabolic syndrome”); brain injury, such as trau- and slow clinical progression. There is a clear
matic brain injury, stroke (see chapter “Stroke”), genetic association with subjects’ inheritance of an
and microhemorrhages; substance abuse, e.g., apolipoprotein E4 allele (ApoE4, see below).
smoking and alcohol abuse; and depression (see
chapter “Major depressive disorder”).
Based on genetic risk factors, AD can be divided Pathophysiology of Alzheimer’s
into autosomal dominant familial AD (FAD) and Disease and Metabolic Alterations
nondominant forms, which are most commonly
those of late life onset [9]. FAD forms are caused Amyloid pathology is detectable in the preclinical
by mutations in several genes essential for metabo- phase of AD, prior to changes in any other bio-
lism of the amyloid precursor protein (APP, see markers and sometimes a decade or more before
below). Transgenic mice expressing these gene the earliest changes in an individual’s cognition
mutations are common animal models to study (Fig. 1) [10, 11]. This is in agreement with the
AD. FADs show earlier onset (usually between “amyloid cascade” hypothesis of AD, in which
Alzheimer’s Disease 37
(6)
(4) (5)
(3)
(2)
(1)
Reactive
microglia
Astrocyte
Intra
Extra γ Aβ
α
β
(7)
(8) Neuron
Neurofibrillary tangles
Fig. 2 Generation of Aβ and the pathological cascade in the oligomers form Aβ fibrils that comprise the dense
Alzheimer’s disease. The amyloid precursor protein APP β-pleated sheet of amyloid in plaques (5). Typical amy-
is metabolized (1) physiologically mainly by α-secretase loid plaques in the brain parenchyma consist of fibrillar
(left arrow), preventing excessive formation of the Aβ Aβ deposits (6) and apolipoproteins. In advanced stages,
peptide. β- and γ-secretase (right arrow) cleave APP to they are surrounded by dystrophic neuronal processes and
release soluble Aβ. Aβ monomers assemble into soluble are called neuritic plaques. Amyloid plaques probably ini-
Aβ oligomers (2). Aβ oligomers can be cleared via the tiate an inflammatory process that involves reactive
brain vasculature, but in advanced disease stages, Aβ microglia and astrocytes (7). Finally, Aβ is believed to
fibrils can deposit in cerebral blood vessels walls (3). contribute to the development of neurofibrillary tangles
Soluble Aβ oligomers are believed to interfere with syn- (8) and neuronal cell death
aptic function and cause memory impairment (4). Further,
altered metabolism of APP results in accumulation about APP metabolism, its primary function is
of Aβ peptides in extracellular fibrillar aggregates unclear [13]. Under physiological conditions, the
(amyloid plaques) or diffusible oligomeric forms, predominant APP metabolic pathway involves
driving AD pathogenesis [12]. Additionally, the enzyme α-secretase, which cuts the APP
neurofibrillary tangles consisting of intracellular within the Aβ peptide sequence, thus preventing
fibrillar bundles of the microtubule-associated its genesis (Fig. 2). An alternative metabolic
protein tau, which has been highly phosphory- pathway (the amyloidogenic pathway) produces
lated and cross-linked and thus rendered nonfunc- Aβ peptide via proteolytic actions of the enzymes
tional, are commonly observed in AD. β- and γ-secretase (Fig. 2).
APP is a putative transmembrane protein, with The Aβ sequence spans 40–43 amino acids
a short intracellular C-terminus and a long extra- from an N-terminal location (the β-secretase cut
cellular N-terminus. While much is now known site) to an intramembranous location (the
38 M.D. Ikonomovic and S.T. DeKosky
15. Braak H, Del Tredici K (2011) Alzheimer’s pathogen- Introduction to the recommendations from the
esis: is there neuron-to-neuron propagation? Acta National Institute on Aging-Alzheimer’s Association
Neuropathol 121:589–595 workgroups on diagnostic guidelines for Alzheimer’s
16. de Calignon A, Polydoro M, Suárez-Calvet M, disease. Alzheimers Dement 7:257–262
William C, Adamowicz DH, Kopeikina KJ, Pitstick 21. Sperling RA, Aisen PS, Beckett LA, Bennett DA,
R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J,
Hyman BT (2012) Propagation of tau pathology in a Montine TJ, Park DC, Reiman EM, Rowe CC,
model of early Alzheimer’s disease. Neuron Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B,
73:685–697 Morrison-Bogorad M, Wagster MV, Phelps CH
17. Liu L, Drouet V, Wu JW, Witter MP, Small SA, (2011) Toward defining the preclinical stages of
Clelland C, Duff K (2012) Trans-synaptic spread of Alzheimer’s disease: recommendations from the
tau pathology in vivo. PLoS One 7:e31302 National Institute on Aging-Alzheimer’s Association
18. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski workgroups on diagnostic guidelines for Alzheimer’s
JQ, Lee VM (2013) Synthetic tau fibrils mediate disease. Alzheimers Dement 7:280–292
transmission of neurofibrillary tangles in a transgenic 22. DeKosky ST, Williamson JD, Fitzpatrick AL,
mouse model of Alzheimer’s-like tauopathy. J Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke
Neurosci 33:1024–1037 G, Carlson MC, Fried LP, Kuller LH, Robbins JA,
19. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL,
R, Klunk WE, Mathis CA, Blennow K, Barakos J, Furberg CD (2008) Ginkgo biloba for prevention of
Okello AA, Martinez R, de Liano S, Liu E, Koller M, dementia: a randomized controlled trial. JAMA
Gregg KM, Schenk D, Black R, Grundman M (2010) 300:2253–2262
11C-PiB PET assessment of change in fibrillar 23. Jun G, Vardarajan BN, Buros J, Yu CE, Hawk MV,
amyloid-beta load in patients with Alzheimer’s dis- Dombroski BA, Crane PK, Larson EB, Alzheimer’s
ease treated with bapineuzumab: a phase 2, double- Disease Genetics Consortium, Mayeux R, Haines JL,
blind, placebo-controlled, ascending-dose study. Lunetta KL, Pericak-Vance MA, Schellenberg GD,
Lancet Neurol 9:363–372 Farrer LA (2012) Comprehensive search for
20. Jack CRJ, Albert MS, Knopman DS, McKhann GM, Alzheimer disease susceptibility loci in the APOE
Sperling RA, Carrillo MC, Thies B, Phelps CH (2011) region. Arch Neurol 69:1270–1279
Migraine and Cluster Headache
Table 2 Diagnostic criteria of cluster headache [1] Although CH attacks are clearly distinguish-
A. At least five attacks fulfilling criteria B–D able from migraine attacks, the two conditions
B. Severe or very severe unilateral orbital, supraorbital, share involvement of the trigeminovascular sys-
and/or temporal pain lasting 15–180 min (when tem at peripheral level and derangement of pain
untreated)
modulating structures within the brain. Today,
C. Either or both of the following:
both migraine and CH are regarded as neurovascu-
1. At least one of the following symptoms or signs,
ipsilateral to the headache: lar headaches, meaning that they are triggered by a
(a) Conjunctival injection and/or lacrimation complex series of neural but also vascular events.
(b) Nasal congestion and/or rhinorrhea
(c) Eyelid edema
(d) Forehead and facial sweating Pathophysiology of Head Pain
(e) Forehead and facial flushing and the Trigeminovascular System
(f) Sensation of fullness in the ear
(g) Miosis (pupil constriction) and/or ptosis The trigeminovascular system consists of trigem-
(droopiness of body parts, mostly face) inal neurons innervating cranial pain-sensitive
2. A sense of restlessness or agitation
structures such as dural, meningeal, and cerebral
D. Attacks have a frequency between one every other
day and eight per day or more than half of the time
arteries and veins, venous sinuses, and bones.
when the disorder is active Pain information is transmitted via peripheral tri-
E. Not better accounted for by another ICHD-3 geminal first-order sensitive neurons to the tri-
diagnosis geminal nucleus caudalis in the caudal brain stem
ICHD3 International Classification of Headache Disorders, and higher cervical spinal cord. The latter form
3rd edition the so-called trigeminocervical complex (Fig. 1).
Pain information from the craniofacial district is
lateral oculofacial autonomic symptoms, such as further transmitted via this complex to the ven-
lacrimation, rhinorrhea, conjunctival injection troposterior thalamus and then to the sensory cor-
(inflammation of the conjunctiva; see chapter tex, the frontal cortex, insulae, cingulate cortex,
“Overview” under part “Eye”), tearing, facial and other pain-related brain areas (the so-called
sweating, or ptosis; a sense of restlessness may be pain matrix), resulting in the experience of pain
present (Table 2). The prevalence of CH is esti- (Fig. 1).
mated to be at least 0.05–0.3 % [2] in the overall Pain-sensitive information from the trigeminal
population. CH is predominant in males, but nerve may also activate brain stem parasympa-
increasing in women; the ratio is now 2.5:1. The thetic autonomic neurons of the superior salivatory
most common age of onset is the third or fourth nucleus due to a direct connection between the two
decade of life. There are two forms of CH: episodic systems in the brain stem. Fibers from this nucleus
and chronic CH. About 80 % of CHs are episodic then run through the facial nerve to peripheral
and are characterized by periods with daily or parasympathetic ganglia (e.g., the sphenopalatine
almost daily attacks, up to 8 per day, followed by ganglion); from these ganglia, neurons project to
spontaneous remission. In chronic CH, remission cranial vessels including dura mater vascular sys-
periods are usually absent or last less than 1 month. tem and are responsible for vasodilation there
CH attacks often occur at fixed times of the day and (Fig. 1) [4]. Activation of parasympathetic fibers
of the night with a typical circadian periodicity. In accounts for autonomic phenomena (such as lacri-
episodic CH, most of cluster periods occur during mation, rhinorrhea, facial sweating) accompany-
spring or autumn. Alcohol; nitroglycerine, a vaso- ing CH attacks (see above, Table 2).
dilator used in chronic heart failure (see chapter In addition to activation of the central pain
“Heart failure”); and exercise are recognized pre- pathway, trigeminal sensory nerve endings anti-
cipitants of acute cluster attacks. It is of interest to dromically (“backward/upward”) release vasoac-
note that alcohol triggers attacks only during a tive and pro-inflammatory neuropeptides around
cluster period but not during remission. cranial vessels provoking dilation of cranial and
Migraine and Cluster Headache 43
Sensory cortex
Vasodilation ACC
(3)
Insula Thalamus
Pain sensitive
Brain structures PH
Facial sweating
PPT
Lacrimation SSN
Parasympathetic
pathways
Rhinorrhea
(1) (2)
Pain information
Facial region
TCC
Fig. 1 Structures and centers implicated in migraine and terminating and regulating attacks. It receives input from the
cluster headache. The trigeminovascular system consists of thalamus, but also from the pain matrix, directly. The PH is
the trigeminocervical complex (TCC), which includes the implicated in autonomic phenomena occurring during head-
trigeminal nucleus caudalis (TNC) located in the brain stem ache attacks. These (mostly) parasympathetic symptoms
and the upper cervical spinal cord (C1 and C2) and the affer- can be caused by a direct effect of the hypothalamus (not
ent trigeminal nerve(s), which receives and transfers pain shown) or by the TCC/ipsilateral trigeminal system via acti-
information from facial and cranial pain-sensitive structures vation of the superior salivatory nucleus (SSN). This nucleus
(e.g., blood vessels in the dura mater). The afferent first- activates parasympathetic efferents mainly via the spheno-
order neurons (1) are interconnected in the TCC to second- palatine (or pterygopalatine) ganglion (PPT). The PPT
order neurons (2) projecting to the thalamus. Subsequently, causes lacrimation, rhinorrhea, and facial sweating and is
cortical areas involved in pain transmission (third-order sen- also connected to the dura mater where it can cause vasodi-
sory neurons, (3) the pain matrix) are activated (including lation. A dysfunction or disturbance in interactions between
insula, sensory cortex, and anterior cingulate cortex (ACC)). these pain areas might enable headache attacks to take place
The posterior hypothalamus (PH) might have a role in (Adapted from Leone and Bussone [3])
meningeal vessels and inducing a so-called sterile in migraine (and CH), and some antimigraine
neurogenic inflammation. Involved neurotrans- drugs exert their effect by binding to 5-HT recep-
mitters are calcitonin gene-related peptide tors (most importantly 5-HT1B/1D, see below).
(CGRP), substance P, neurokinin A, enkephalins,
endothelin 1, somatostatin, and vasoactive intesti-
nal peptide. CGRP and substance P are thought to Treatment of Migraine
sensitize pain receptors by inducing the release of and Cluster Headache
inflammatory mediators such as histamine, brady-
kinin, tumor necrosis factor-α, nitric oxide, and An effective management plan must include acute
serotonin (5-hydroxytryptamine, 5-HT). 5-HT treatment to relieve the pain and may also include
has long been implicated as a key neurotransmitter prophylactic treatments with the aim of decreasing
44 M. Leone and P. Di Fiore
attack frequency, severity, and duration and of pro- Treatment of Acute Cluster Headache
moting an improved responsiveness to acute treat-
ments. Comorbidities will influence drug choice, In episodic and chronic CH, the drug of choice to
as will the side effect profile of the drug. treat acute attacks is subcutaneous sumatriptan.
Nasal spray formulation of sumatriptan or zolmi-
triptan can also be used. The triptans are the first-
Treatment of Acute Migraine line medication and have revolutionized the acute
treatment of both migraine and CH. Triptans exert
Acute antimigraine treatment includes ergot alka- an agonistic effect on both 5-HT1B and 5-HT1D
loid derivatives (ergotamine and dihydroergota- receptors. The primary sites of action are cranial
mine), triptans, analgesics, and nonsteroidal blood vessels, where they lead to vasoconstriction
anti-inflammatory drugs. Before intake of ergots, and block the release of pro-inflammatory neuro-
nonsteroidal anti-inflammatory drugs, analgesics, peptides. Activation of 5-HT1D receptors on nerve
and, to a lesser extent, triptans, oral metoclopramide, endings decreases the release of pro- inflamma-
or domperidone can be recommended to control tory peptides such as CGRP and substance P.
nausea and vomiting. Migraine prophylaxis should Second-line acute treatments include intrana-
be considered when attacks are frequent (more sal lidocaine (an anesthetic) and subcutaneous
than 4 headache days per month), disabling, and injection of octreotide (a somatostatin analog),
acute medication is failing. Prophylaxis also helps which likely acts via vasoconstrictive effects.
to prevent medication overuse headache. Inhalation of pure oxygen via a non-rebreathing
facial mask is also effective but to a lesser extent.
When these prophylactic drugs fail, cor- operating in migraine and CH, possibly offering
ticosteroids can be used for short periods of rationale for new therapeutic targets.
time and with caution. Corticosteroids such as In previous years, the increased CGRP levels
prednisolone, prednisone, and dexamethasone in jugular vein blood, during both migraine and
are the most effective preventive agents for CH, CH attacks, suggested a fundamental role for this
but prolonged use leads to potentially serious substance in the origin of neurovascular head-
adverse events, such as insulin resistance (see aches. New treatments based on anti-CGRP anti-
chapter “Diabetes mellitus”), osteoporosis (see bodies for both migraine and CH are currently
chapter “Osteoporosis”), and hypertension (see being developed.
chapter “Hypertension”). Intramuscular dexa-
methasone can be administered when CH attacks
are aggressive [6]. At the same time, other pre- References
ventive medication is to be started. Injection of
local corticosteroids plus local anesthetic in the 1. Headache Classification Committee of the International
Headache Society (IHS) (2013) International
area of the greater occipital nerve ipsilateral to
Classification of Headache Disorders, 3rd edition (beta
the pain may exert some benefit. In drug-resistant version). Cephalalgia 33:629–808
chronic CH, greater occipital nerve stimulation 2. Tonon C, Guttmann S, Volpini M, Naccarato S, Cortelli
and deep brain stimulation of the hypothalamus P, D’Alessandro R (2002) Prevalence and incidence of
cluster headache in the Republic of San Marino.
are recognized procedures to treat the condition.
Neurology 58:1407–1409
3. Leone M, Bussone G (2009) Pathophysiology of
trigeminal autonomic cephalalgias. Lancet Neurol 8:
Perspectives 755–764
4. May A, Goadsby PJ (1999) The trigeminovascular system
in humans: pathophysiologic implications for primary
In the last years, neuroimaging findings and the headache syndromes of the neural influences on the cere-
introduction of neurostimulation for the treat- bral circulation. J Cereb Blood Flow Metab 19:115–127
ment of primary headache such as migraine and 5. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A,
Sándor PS, European Federation of Neurological
CH have provided considerable contributions to
Societies (2009) EFNS guideline on the drug treatment
better understand the pathophysiology of these of migraine – revised report of an EFNS task force. Eur
headache syndromes. J Neurol 16:968–981
Functional imaging studies showed that several 6. May A, Leone M, Afra J, Linde M, Sándor PS, Evers S,
Goadsby PJ, EFNS Task Force (2006) EFNS guide-
brain regions are involved in head pain processing
lines on the treatment of cluster headache and other
and modulation. Hopefully, future studies will trigeminal-autonomic cephalalgias. Eur J Neurol 13:
improve our knowledge on neuronal networks 1066–1077
Multiple Sclerosis
Markus Kipp
Pathophysiology of Multiple 1
H-MRS brain imaging revealed profound
Sclerosis and Metabolic Alterations changes in the level of metabolites such as
N-acetylaspartate (NAA, a derivative of aspartic
On the histopathological level, MS lesions are acid acting as an important metabolic precursor
characterized by oligodendrocyte loss and subse- and osmolyte in the brain), choline, creatine,
quent demyelination of axons, neuroaxonal loss, myoinositol, glutamate (Glu), glutamine (Gln),
astroglia and microglia activation (i.e., gliosis), macromolecules, lipids, and lactate. Reduced
and, to a certain extent, regeneration of myelin NAA levels indicate neuronal/axonal loss.
around axons. Both white and gray matter areas of Increased choline and creatine levels suggest gli-
the brain are affected (Fig. 1). These pathological osis and cell-membrane turnover (de- and remy-
events are paralleled by the recruitment of periph- elination), respectively. Furthermore, lactate, the
eral inflammatory cells such as lymphocytes and end product of anaerobic glycolysis, is also
monocytes. Several advanced magnetic resonance increased in MS lesions [2, 3], along with Gln,
imaging (MRI) techniques have been developed fructose, and glucose (at early stages of MS)
that, compared with conventional MRI measures, highlighting severe metabolic changes (Fig. 2).
are better able to capture the complexity of the Interestingly, metabolic abnormalities were also
pathological processes occurring in the CNS of MS found in the “normal-appearing” white matter, hence
patients. Among those, proton MR spectroscopy in regions which are not yet affected by demyelin-
(1H-MRS) has the unique ability to provide chemi- ation. Furthermore, studies have demonstrated a
cal-pathological characterization of MR-visible reduction in cerebral blood flow of different white
lesions and normal-appearing brain tissues. [5] and gray matter regions [6] in MS patients
PLP
Abnormal perfusion
LFB
Metabolic changes
NAA Glutamate
Oxaloacetate Acetate
MHC-II Citrate Lactate
Alanine NO
β-hydroxybutyrate Creatine
Choline
Fig. 1 Pathological and metabolic changes in the brain cells into the perivascular space, and massive accumu-
of an MS patient. Classical active MS lesions [1] can be lation of major histocompatibility complex (MHC) II
found in the white and gray matter of the brain. expressing macrophages (bottom-left image). Likewise,
Hallmarks of such lesions are demyelination as indi- abnormal perfusion is present at multiple locations in
cated by loss of proteolipid protein (PLP) staining the CNS. The brain and cerebrospinal fluid demon-
(top-left image) and increased luxol fast blue (LFB) strate abnormal levels of several metabolites. NAA
staining (middle-left), recruitment of inflammatory N-acetyl aspartate, NO nitric oxide
Multiple Sclerosis 49
Blood vessel
Glc
Glc
Neuron GLUT
1/3 GLUT
Pyr Lac 1/3 ?
MCT
Lac
Ac-CoA
TCA Glc
Glc Glycogen
Cycle
MCT Pyr Pyr Ac-CoA
Res. TCA
Lac
chain MCT Lac Cycle
Lac
ATP Res. chain
Astrocyte
ATP
Oligodendrocyte
MCT
Axon
Ependymal
cells
Fig. 2 Movement of metabolites. The brain is mainly monocarboxylate transporters (MCTs). The extracellular
fueled by glucose (Glc), transported via the blood and lactate is taken up via distinct MCTs. Intracellularly, lac-
taken up by glucose transporters (GLUT) 1 and 3 tate is recycled to pyruvate and transformed into acetyl-
(expressed in endothelial and brain cells, respectively). CoA (Ac-CoA), which is metabolized in the tricarboxylic
Alternatively, astrocytes are the main reservoir of glyco- acid cycle (TCA, also called citric acid cycle) to finally
gen in the brain. Therefore, they might serve as supporters produce ATP via oxidative phosphorylation in the respira-
for neurons and oligodendrocytes during energy depriva- tory chain of the mitochondria. This interdependence is
tion periods. According to the lactate (Lac) shuttle hypothesized to occur mainly between astrocytes (center)
hypothesis for energy transfer between cells, a heavily and neurons (left). Recently, oligodendrocytes have been
glycolytic (i.e., non-oxidative) cell (e.g., an astrocyte) included in the hypothesis as critical intermediaries for
produces large amounts of pyruvate (Pyr) and subse- lactate transport to neurons [4]. Oligodendrocytes are also
quently lactate, which is then transported out of the cell able to take up glucose directly from the endothelial cells
along its concentration gradient through specific of the vessels, probably via GLUT 1 and 3 as well
(Fig. 1). The globally decreased blood perfusion in Metabolic alterations in MS patients can also
MS is thought to result from diffuse perivascular be detected by 1H-MRS in biofluids, most impor-
inflammation leading to microvascular damage, tantly cerebrospinal fluid (CSF), instead of imag-
thrombosis, and fibrin deposition. Furthermore, ing the brain. This enables quantification of a
hypoperfusion might result from widespread astro- much larger range of biochemical compounds. In
cyte dysfunction, which contributes to the regulation this context, it is important to note that many MS
of vascular tone in the CNS [7]. lesions are located in the periventricular white
50 M. Kipp
matter of the brain as well as in superficial areas of to compensate for reduced oxidative phosphory-
the spinal cord, which are close to the CSF space. lation caused by perturbed microcirculation and
Since MS lesions are not routinely biopsied, CSF hypoxia-like injury during MS plaque formation.
analysis remains an important tool to discern MS Continued perturbation of mitochondrial func-
pathology. CSF is a clear, colorless fluid surround- tion results in cellular energy deficit and loss of
ing the brain and the spinal cord to protect them mitochondrial transmembrane potential ulti-
from injury and is predominantly produced by the mately leading to apoptotic cell death. Thus, the
choroid plexus, a dense network of blood vessels increase in lactate in active plaques and CSF can
located in each of the four ventricles. CSF contains be interpreted as a result of inflammation, local
trace proteins, electrolytes, and nutrients that are ischemia, and mitochondrial dysfunction.
needed for the metabolism and normal function of Similarly, the concentration of β-hydroxybut-
the brain. Remarkably, it also serves to remove yrate (a ketone body and substrate for gluconeo-
waste products from the CNS parenchyma and is genesis) is increased in the CSF of CIS patients
thus a vital source of information on physiological corresponding to the presence of inflammatory
and pathological processes occurring within the lesions [9]. Recent evidence suggests that astro-
brain parenchyma. cytes are in principle capable of gluconeogenesis
In animal models of MS, the concentration of and glucose release. Thus, the increased levels
several metabolites was altered in the CSF. As an of β-hydroxybutyrate may reflect a perturbation
example, significantly lower levels of arginine of astrocytic gluconeogenesis potentially due to
were observed during the early stage of experi- the presence of inflammatory plaques or due to
mental autoimmune encephalomyelitis (EAE), reduced cerebral blood flow as a result of a pertur-
which is one of the most commonly used MS ani- bation of microcirculation.
mal models. Arginine is the main substrate for Another important metabolic factor playing a
nitric oxide (NO) synthesis, and its reduction role in MS pathogenesis is nitric oxide (NO). NO
likely results from increased activity of inducible products are significantly raised in the CSF of MS
NO synthase (iNOS) in activated immune cells patients [10]. NO competitively inhibits the bind-
and microglia. This NO can react with the free ing of oxygen to mitochondrial respiratory com-
radical superoxide O2−, arising from oxidative plex, and, thus, its increase perturbs ATP synthesis
phosphorylation in the mitochondria to create per- [11]. This condition, in which oxygen is in princi-
oxynitrite anion, a very reactive oxidizing agent, ple available but cells are unable to use it, mimics
capable of inducing cell death through multiple hypoxia and is called histotoxic or metabolic
pathways. Thus, lowered levels of arginine might hypoxia. Again, subsequent mitochondrial respira-
be an indirect indicator of cell stress and death. tory dysfunction may cause cell death and, in con-
Furthermore, levels of alanine and branched- sequence, demyelination and neurodegeneration.
chain amino acids (leucine, isoleucine, and valine) Elevation of Glu levels in CSF, a known CNS
are decreased in early EAE and likely MS. These neurotoxic trigger, compounded by low levels of
amino acids are utilized as a source of pyruvate for oxaloacetate (an inhibitor of neuronal cell death,
energy metabolism; thus, decreased levels indicate Fig. 1) may contribute to axonal loss and repre-
increased cell turnover. As the onset of EAE is sents an area for further study [12].
associated with maximum infiltration of the CNS
by blood monocytes and T cells, the observed
decrease may suggest these metabolites are uti- Treatment of Multiple Sclerosis
lized for energy metabolism by invading cells [8].
Human MS patients additionally show Despite tremendous scientific efforts, to date, MS
increased levels of lactate in the CSF correlating has no cure. Treatment usually focuses on strategies
with disease activity in the brains of patients with to treat acute MS attacks, to lower attack frequency,
CIS [9]. Increased levels of lactate likely arise and to reduce progression (i.e., progression of
from increased anaerobic glycolysis, an attempt clinical disability).
Multiple Sclerosis 51
Corticosteroids are mainly used to reduce the α4 and reduces the ability of inflammatory
inflammation that spikes during a relapse. These immune cells to pass through the BBB.
drugs inhibit lymphocyte proliferation, synthesis Teriflunomide belongs to a class of drugs called
of pro-inflammatory cytokines, and expression of pyrimidine synthesis inhibitors. Its ability to
cell surface molecules required for immune func- inhibit the mitochondrial enzyme dihydroorotate
tion (see chapter “Overview” under part “Immune dehydrogenase, which is relevant for the de novo
system”). Furthermore, it is believed that cortico- synthesis of pyrimidine, is believed to exert the
steroids stabilize the blood-brain barrier (BBB), most important therapeutic effect. By inhibiting
for example, by decreasing the expression of dihydroorotate dehydrogenase and diminishing
angiopoietin-1 and vascular endothelial growth DNA synthesis, teriflunomide has a cytostatic
factor A (VEGFA), both well known to regulate effect on proliferating B and T cells.
the permeability of the BBB (see chapters Dimethyl fumarate is a lipophilic, highly
“Overview” under part “Brain” and “Stroke”). mobile molecule in human tissue. As a electro-
Alternatively, plasmapheresis (meaning removal philic compound, dimethyl fumarate is rapidly
of blood components) might be applied to help attacked by the detoxifying agent glutathione
combat severe symptoms of relapses in patients (GSH). GSH depletion and subsequent induction
who are not responding to corticosteroids. of the anti-inflammatory stress protein HO-1 is
Disease-modifying drugs are prescribed with thought to be one of the mechanisms responsible
the aim to reduce relapse frequency. Currently, for the immunomodulatory actions of dimethyl
this group includes β-interferons (Avonex, fumarate. Other postulated mechanisms of action
Betaseron, Extavia, and Rebif), fingolimod include direct cytoprotective effects through
(Gilenya), glatiramer acetate (Copaxone), mito- upregulation of nuclear factor (erythroid-derived
xantrone (Novantrone), natalizumab (Tysabri), 2)-like 2 (Nrf2) and subsequent induction of an
teriflunomide (Aubagio), and dimethyl fumarate antioxidant response.
(Tecfidera or BG-12).
β-interferons balance the expression of pro-
and anti-inflammatory agents in the brain and Influence of Treatment
reduce the number of inflammatory cells that on Metabolism
cross the BBB.
Fingolimod, which is in vivo converted to its There is some evidence that the metabolic
active form fingolimod phosphate, suppresses changes in MS can be ameliorated by the admin-
lymphocyte egress from lymphoid tissues into istration of disease-modifying drugs. For exam-
the circulation. ple, CIS patients who received glatiramer acetate
Glatiramer acetate is a mixture of random or interferon beta 1b showed improvement in
polymers of four amino acids, which mimics the brain neuroaxonal integrity, as indicated by an
antigenic properties of the myelin basic protein, a increased NAA/creatine ratio [13, 14]. However,
component of the myelin sheath of nerves with our knowledge about the efficacy of disease-
which it competes for presentation to T cells. modifying drugs to modulate metabolic changes
Mitoxantrone is a type II topoisomerase inhib- in MS is in its infancy and warrants further stud-
itor; it disrupts DNA synthesis and DNA repair in ies. One has to point out that currently available
both healthy cells and cancer cells. Hence, it sup- immune-directed therapies have been shown to
presses the proliferation of T cells, B cells, and decelerate the inflammatory process in MS and,
macrophages (see chapter “Overview” under part thus, restore acute clinical deficits, which occur
“Immune system”), impairs antigen presentation, during a relapse. However, such therapy is less
and decreases the secretion of pro-inflammatory effective in preventing the progression of the dis-
cytokines. ease and neurodegeneration, which appear to be
Natalizumab is a humanized monoclonal anti- at least in part independent from inflammatory
body against the cell adhesion molecule integrin attacks.
52 M. Kipp
mitochondrial DNA can initiate a series of molec- of and hypersensitivity to IFN-γ have been linked
ular events leading to activation of apoptosis to the presence of two IFN receptor genes on
[12]. In this regard, reduced mitochondrial activ- chromosome 21 [16]. IFN-γ inhibits TSP-1 gly-
ity in DS appears to represent an adaptation to cosylation and reduces its cellular levels and
prevent cellular damage and preserve basic cellu- secretion [17, 18].
lar functions. In fact, upon stimulation, DS mito- Endocrine dysfunction is another prominent
chondria possess the capacity to increase ATP medical feature of Down syndrome. In particular,
production [13]. However, sustained increase of the function of the thyroid gland is often compro-
mitochondrial activity leads to lipid peroxidation mised. The latter secretes several hormones, i.e.,
and increased cell death. Interestingly, down- thyroxine (T4), triiodothyronine (T3), and calcito-
regulation of mitochondrial activity to prevent nin, which regulate metabolism, heart rate, and
oxidative damage has been observed in different growth. Alterations in their balance can lead to
organisms and cell types [14]. short stature, skin problems, and intellectual dis-
DS neurons and astrocytes also show a reduc- ability. It has been hypothesized that the develop-
tion in thrombospondin-1 (TSP-1) expression and ment of thyroid dysfunction in DS is influenced by
secretion contributing to dendritic spine abnor- oxidative stress [19] or deregulation of genes on
malities [15]. TSP-1 is an astrocyte-secreted chromosome 21 that participate in the immune
protein involved in the formation of excitatory response [20]. Individuals with DS are likely to
synapses. Deficits in TSP-1 lead to defects in have congenital hypothyroidism or develop thyroid
learning and memory in mice (M. Torres and dysfunction later in adulthood. The incidence of
J. Busciglio unpublished data). A possible expla- hypothyroidism in individuals with DS ranges
nation is that reduced TSP-1 levels are linked to from 3 to 54 %, and recent studies suggest that the
interferon (IFN) hypersensitivity. Overexpression prevalence increases after the age of 40 [21].
Down Syndrome 55
Hypothyroidism results in decreased T4 and T3, and preventing lipid peroxide-induced DNA
which are important for physical and intellectual damage (in conjunction with vitamin E) [26].
development by affecting protein synthesis and Recent work indicates that Coenzyme Q10 sup-
increasing metabolic rate, bone growth, and sensi- plementation restores the antioxidant/oxidant
tivity to catecholamines. Symptoms of hypothy- balance in plasma in children with DS [27].
roidism further include hypotonia, enlarged tongue, Considering the high prevalence of Alzheimer’s
small stature, skin problems, constipation, and disease (AD) in DS individuals, some interven-
lethargy [22]. Because many of the characteristics tions directed at treating AD have been tested.
involving hypothyroidism overlap with features of However, acetylcholinesterase inhibitors and the
DS, it is difficult to get an initial diagnosis. NMDA receptor antagonist memantine (common
Thyroid dysfunction is normally diagnosed AD treatments; see chapter “Alzheimer’s dis-
through blood analysis of thyroid stimulating ease”) have been unsuccessful or inconclusive
hormone (TSH). As part of a feedback loop, when applied to DS patients [28].
decreased T4 leads to increased levels of TSH to Hypothyroidism in general and in DS is easily
help stimulate more T4 production. Ultimately, controlled with T4 replacement therapy. However,
early diagnosis of hypothyroidism is critical for artificial elevation of T4 levels reduces TSH (see
preventing deterioration of physical and mental above), which can lead to significant side effects.
development in DS individuals. Individuals who Because TSH stimulates production of thyroid hor-
develop thyroid autoimmune disease are more mones, reduction of TSH leads to decreased hor-
likely to develop other endocrine disorders mone secretion affecting hormones such as
including diabetes mellitus (see chapter “Diabetes calcitonin. Calcitonin is important for preventing
mellitus”). Thus, proper endocrine screening Ca2+ loss (see chapter “Overview” under part “Teeth
should be routine in individuals with DS. and bones”), and synthetic replacement of T4 has
been associated with increased osteoporosis (see
chapter “Osteoporosis”) [29]. Nutritional therapies
Treatment of Down Syndrome such as iodine, L-tyrosine, and zinc have also been
and Its Influence on Metabolism suggested for treatment of hypothyroidism [30].
Anatomy and Physiology of the Eye gen to the photoreceptors. Both are separated by
Bruch’s membrane, an elastin- and collagen-rich
Vision is our dominant sense. The eyes, special- structure [2].
ized for the detection of light, are our most impor- Due to its function, the eye has to cope with
tant sensory organs, providing approximately special problems. Retinal cells are the only
70–80 % of our total sensory information. The neurons exposed to light. Bright illumination
optical apparatus projects an image of our envi- can result in the generation of free radicals that
ronment onto the back of the eye covered by the damage the retinal cells (see below). As pho-
retina. The retina is a neuronal tissue originating toreceptors (like most other central neurons)
from the brain during embryonic development and cannot be replaced, the eye has developed sev-
is, thus, a true part of the central nervous system. eral mechanisms of protection. The optical
The retina is a well-layered, appr. 200 μm thick apparatus absorbs high-energy ultraviolet light,
tissue and can be divided into an outer part that which would otherwise damage the retina [3].
harbors the light-sensitive cells – the rod and Moreover, in the center of the retina, protective
cone photoreceptor cells – and an inner part that pigments are embedded that absorb light of short
comprises a neuronal network [1]. This network wavelengths, giving this area a yellowish appear-
performs the first steps of information processing ance, called macula lutea (Latin: yellow spot) or
before the signal is relayed by the retinal ganglion briefly macula (Fig. 1a). Finally, the light-sensi-
cells to the brain via the optic nerve. A human tive segments of the rod and cone photoreceptors
retina harbors around 120 million rod and 6 mil- are continuously renewed.
lion cone photoreceptor cells. Rods are highly The eyeball is well protected in a cavity of the
sensitive, can respond to single light quanta, and skull called orbit. The frontal part of the human
provide vision during night and at twilight. Cones eye can be covered by the eyelids. The surface
are less sensitive and provide color vision during of the eye is moisturized by tears produced by
daylight. Behind the retina, two more layers are the lacrimal gland (situated in the upper outer
located: the retinal pigment epithelium (RPE) and part of the orbit). Tears are drained by the lac-
the choroid (see Fig. 1), a dense network of blood rimal puncta in the inner corner of the eyelids
capillaries, which provides nutrients and oxy- via the lacrimal sac into the nose (see chapter
“Glaucoma”). Most of the eyeball is covered by
A. Mataruga • F. Müller (*) the tough white sclera (Fig. 1a). In the front, the
Institute of Complex Systems 4, Zelluläre Biophysik sclera changes over to the transparent cornea, the
(ICS-4), Forschungszentrum Jülich GmbH,
first and most refractive part of the optical appa-
Leo-Brandt-Straße, Geb.15.1, 52425 Jülich, Germany
e-mail: a.mataruga@fz-juelich.de; ratus. The iris is the colored part of the eye. It is
f.mueller@fz-juelich.de a pigmented muscle tissue situated between the
Sclera
Ciliary epithelium
Posterior chamber
Anterior chamber
Lens
Pigment epithelium
Fig. 1 Schematic cross section of an eye. The different regeneration of the photopigment and the phagocytosis of
layers perform important tasks: the choroid is a layer of the photoreceptors’outer segments. The vitreous body is a
blood vessels important for photoreceptor supply. The jellylike transparent substance that maintains the eye in its
retina is a neuronal tissue comprising the photoreceptor spherical shape. Inset: Structures responsible for the con-
cells, a network of neurons, and the retinal ganglion cells trol of aqueous humor. The ciliary epithelium secrets
as output neurons that relay the information to the brain; aqueous humor into the posterior chamber. The trabecular
it also contains the macula lutea with the fovea, the central meshwork is a spongy tissue, which drains the aqueous
part of the retina with the highest visual acuity. The retinal humor from the anterior chamber together with Schlemm’s
pigment epithelium, a monolayer of pigmented cells that canal
forms part of the blood-retinal barrier, is involved in the
cornea and lens. Depending on the brightness of intraocular pressure, is slightly elevated, keeping
ambient light, the iris can contract or expand, thus the eyeball spherical.
changing the diameter of the pupil and control-
ling the amount of light falling into the eye. The
lens is suspended by the zonula fibers attached Metabolic and Molecular Pathways
to the ciliary muscles. Humans can adjust their and Processes in the Eye
focus to different viewing distances by contract-
ing the ciliary muscles, which ultimately leads Production of Aqueous Humor
to changes in the shape of the lens. For their
function, the cornea and lens must be transpar- The aqueous humor is secreted into the posterior
ent and, therefore, devoid of blood vessels. They chamber of the eye by a part of the ciliary epithe-
are nourished by diffusion from the aqueous lium situated close to the region where the zonula
humor, a transparent, jellylike fluid located in the fibers are attached (Fig. 1b). The composition of
anterior and posterior chamber of the eye. The aqueous humor is relatively similar to blood plasma.
compartment between the lens and retina is filled However, its protein concentration is low (less
with the jellylike vitreous body. The pressure of than 1 %), whereas ascorbate is up to 50 times
both aqueous and vitreous humor, the so-called higher than in blood plasma. Oxygen is derived
Overview 61
by diffusion from the cornea and from the vascu- called discs (Fig. 2b). The latter contain a high con-
lature of the iris [4]. The aqueous humor flows centration of the photopigment rhodopsin in their
from the posterior chamber through the pupil into membranes (Fig. 2c). Altogether 50–150 million
the anterior chamber (Fig. 1b) and drains away at rhodopsin molecules are found within a photo-
the angle between the cornea and iris, where it receptor cell. Rhodopsin belongs to the family of
passes through a porous tissue – the trabecular G-protein-coupled receptors (see below). It consists
meshwork – into a collecting channel (Schlemm’s of a protein part (the opsin) and a light-absorbing
canal), which empties into veins and thus into the cofactor, the aldehyde form of vitamin A, retinal
bloodstream. In the healthy eye, the delicate bal- (Fig. 2c, d).
ance between aqueous fluid production, circula- Retinal can exist in two different conforma-
tion, and drainage must be maintained in order to tions. The folded 11-cis-retinal is covalently
keep the intraocular pressure at a constant level. bound within the opsin molecule (Fig. 2c).
Slow drainage of aqueous humor or overproduc- Absorption of a light quantum causes 11-cis-
tion may lead to an increase in intraocular pres- retinal to switch to the elongated all-trans-retinal
sure that can result in the death of retinal ganglion (Fig. 2d), inducing a conformational change in
cells – a disease called glaucoma (see chapter the rhodopsin molecule. This conformational
“Glaucoma”). change activates the G-protein transducin, which
in turn activates phosphodiesterase 6 (PDE6).
The latter hydrolyzes cGMP, which acts as a sig-
Retinal Metabolism nal transducer, amplifier, and molecular switch.
In the dark, due to an elevated cGMP concen-
The retina is inverse, i.e., before light reaches the tration, cGMP-dependent ion channels (called
photoreceptors, it has to pervade the different cyclic nucleotide-gated ion channels) in the outer
retinal layers: three layers of somata (termed gan- segments are open, leading to an influx of Na+ and
glion cell layer, inner nuclear layer, and outer Ca2+, depolarization of the membrane potential,
nuclear layer), separated by two synaptic layers and transmitter release. Upon illumination and
(i.e., inner and outer plexiform layer). The gan- cGMP hydrolysis via PDE6, cGMP-dependent
glion cells are the output neurons of the retina. ion channels close. As fewer Na+ and Ca2+ enter
Their axons form the optic nerve (Fig. 1a). As all the cell, the membrane potential becomes more
neurons, retinal cells conduct information by negative. Thus, during illumination, the cells are
generating electrical signals at their plasma mem- more hyperpolarized, and fewer transmitter mol-
brane (see chapter “Overview” under part ecules are released from the synapse. This kind
“Brain”). Inside the cell, there is a high concen- of membrane potential modulation, also termed
tration of K+ ions and large polyanions (such as graded potentials, controls the activity of pho-
proteins and nucleic acids), while outside the Na+ toreceptor cells, like that of most retinal cells.
ion concentration is high resulting in a resting Graded potentials induce variations in the site
membrane potential of −70 mV. of membrane potential in contrast to the “all-or-
Photoreceptor cells can be divided into two nothing” action potentials. To shut off the signal-
compartments (Fig. 2a). The inner compartment ing cascade, rhodopsin becomes phosphorylated
comprises the cell body, the axon with the synaptic [5] and then sealed by arrestin, which ultimately
region, as well as the biochemical machinery with stops the interaction with transducin.
the mitochondria and ribosomes for routine cell The photoreceptor information is relayed syn-
metabolism. The outer segment harbors all pro- aptically via the bipolar cells to the ganglion cells.
teins to absorb light, to amplify the signal, and to Along this path, lateral neuronal interactions and
generate an electrical signal in response to light. feedback loops are provided by horizontal cells in
Rod outer segments are effective light catchers. the outer and by amacrine cells in the inner plexi-
The outer segment of a human rod contains a stack form layer. As retinal output neurons, ganglion
of up to 800 flat, hollow membrane compartments, cells communicate via action potentials – short
62 A. Mataruga and F. Müller
a b
Plasma
Blood membrane
capillaries
(Choroid)
Disc
Bruch‚s
membrane
RPE
cell c Cytoplasm
Outer
segment
Disc
interior
Inner
segment
d 11-cis-retinal all-trans-retinal
Carbon
Soma
Axon
Synaptic
ending Hydrogen Oxygen
Light
Fig. 2 Rod photoreceptor and rhodopsin. (a) Schematic micrograph of the region indicated in (a), showing an
overview of a rod photoreceptor and its surrounding lay- outer segment of a photoreceptor cell with its membra-
ers. The blood capillaries of the choroid provide nour- nous discs. (c) Schematic of a disc membrane harboring
ishment and oxygen to the photoreceptors. The retinal the light-sensitive pigment rhodopsin, a G-protein-
pigment epithelium (RPE) cells fulfill many functions coupled receptor with seven transmembrane helices
(e.g., retinal metabolism and blood-retinal barrier). Note (left). Two helices are removed to reveal the retinal-
that the center of the eye is towards the bottom. The binding pocket (right). (d) Chemical structure of free
outer segments of the photoreceptor cells contain light- 11-cis- and all-trans-retinal. Light converts 11-cis-reti-
absorbing discs. The inner segments contain cell body nal into all-trans-retinal
and normal metabolic machinery. (b) Shows an electron
(1–2 ms) stereotyped changes in membrane poten- the photoreceptors through open cGMP-
tial that propagate in an all-or-none fashion along dependent ion channels in the outer segment [7].
the axons of neurons (chapter “Overview” under As during illumination the ion flux into the pho-
part “Brain”). toreceptor outer segment decreases, energy con-
The physiology of photoreceptors is extraor- sumption by the Na+/K+-ATPase drops. However,
dinary in the sense that a large ionic current in the the energy expenditure for the subsequent phos-
dark is switched off in the light. Therefore, the phorylation of rhodopsin and the regeneration of
energy consumption of the retina is four times 11-cis-retinal increases.
higher in the dark than during illumination [6]. In Photoreceptor cells produce ATP from glu-
the dark, about 50 % of the energy is used by the cose mainly via oxidative phosphorylation and to
Na+/K+-ATPase to pump out excess Na+ that enter a lesser extent via glycolysis [8], and thus large
Overview 63
mitochondria are found densely packed in the molecule to oxygen, reactive oxygen species
photoreceptor inner segments. Glucose and oxy- (e.g., singlet oxygen) can be created. Those can
gen are supplied from the capillary network of break molecular bonds or induce photooxidation.
the choroid that lies close to the photoreceptors Accumulation of such events can ultimately lead
(Figs. 1a and 2a). The oxygen consumption of the to damage of the outer segments. Therefore, pho-
retina is appr. 20 % higher than the oxygen con- toreceptor outer segments must be constantly
sumption reported for the brain [5]. renewed. Around sunrise, the tips of the outer
segments are shed off and are phagocytosed by
RPE cells, while new discs are added at the bases
The Role of the Retinal Pigment of the outer segments [11]. Complete renewal of
Epithelium the rod outer segment takes approximately 10
days. Due to the high amount of material, phago-
Together with the retina, the RPE is among the cytosis in RPE cells is metabolically demanding.
most metabolically active tissues in the body. The Some of the breakdown products may be recy-
RPE serves many functions. First, melanin in cled, while others are discharged into the chorio-
RPE cells absorbs light that has passed through capillaries. Some undigested proteins, lipids, and
the retina in order to prevent light scattering and retinoids remain as an aggregation complex
to reduce light-induced damage. Second, the called lipofuscin [9]. Chemical reactions between
tight junctions between RPE cells form a barrier these components lead to the formation of
between the choroid and photoreceptors [9]. retinoid-lipid complexes in lipofuscin, the so-
Analogous to the blood-brain barrier, this blood- called bisretinoids [12]. Lipofuscin can absorb
retinal barrier controls exchange between blood light, shows autofluorescence, and is susceptible
and retina and thus maintains the specialized to photochemical changes. Lipofuscin accumula-
environment of the photoreceptors. The barrier tion is thought to contribute to the development
function of the RPE is physically supported by of age-related macular degeneration (see chapter
Bruch’s membrane that acts as a semipermeable “Age-related macular degeneration”).
molecular sieve [2]. At the same time, RPE cells
utilize glucose transporters that allow passive
transport of glucose from the choroid to the pho- Inside-Out: Signals from the Eye
toreceptors [10]. Third, the RPE is involved in Affecting Other Organs and Tissues
the regeneration of 11-cis-retinal. All-trans-
retinal (see above) detaches from the opsin and is The impact of the eye on other organs results
enzymatically reduced to all-trans-retinol. mainly from the projection of the retinal output
Retinoid binding proteins shuttle the retinol from neurons, the ganglion cells, which relay the sig-
the outer segments to the RPE, where the rest of nals from the retina via their axons to the brain.
the retinal metabolism takes place. Here, all- Most of the ganglion cell output provides the
trans-retinol is first esterized with palmitate, then basis for visual information processing that
isomerized to 11-cis-retinol, and finally, oxidized involves at least 30 % of the cerebral cortex.
to 11-cis-retinal. The latter is transported back to Recently, a class of ganglion cells has been
the outer segment, where it spontaneously reacts described that serves an entirely different function.
with opsin to regenerate rhodopsin, thus complet- These ganglion cells express their own photo-
ing the visual cycle. pigment called melanopsin, which is distantly
Finally, the RPE is of utmost importance for related to rhodopsin. This cell class provides input
the regeneration of the photoreceptor outer to the suprachiasmatic nucleus (SCN) in the brain
segments. The strong illumination of the outer (together forming the retinohypothalamic tract).
segments in a high-oxygen environment can lead The SCN functions as pacemaker, responsible for
to photochemical damage. If the energy from a the generation of the circadian clock. Retinal input
photon is transferred from a light-absorbing from the melanopsin-containing ganglion cells
64 A. Mataruga and F. Müller
resets the clock in the SCN every day [13]. SCN barrier. Consequences are bleedings into the
cells project to the paraventricular nucleus of the retina and vitreous as well as scar formation and
hypothalamus – a site of hormone production. The detachment of the retina. Diabetic retinopathy
projection from the SCN to the pineal gland con- may ultimately lead to blindness.
trols the release of melatonin, the “hormone of the
night” that is involved in the regulation of our
sleep-wake cycle. Circadian rhythms also influ- Final Remarks
ence body temperature, blood pressure, and heart
frequency (see chapters “Migraine and cluster The main functions of the eye are to provide
headache” and “Rheumatoid arthritis”). visual information about our environment and to
synchronize our internal clock to the day/night
cycle. Partial or total blindness can be induced by
Outside-In: Signals and Metabolites several mechanisms, including the destruction of
retinal ganglion cells and optic nerve due to an
Affecting the Function of the Eye
increase in intraocular pressure, as in glaucoma
Vitamin A, the precursor of retinal, is an essential (see chapter “Glaucoma”), or the loss of photore-
vitamin [14]. It is stored in the liver (see chapter ceptor cells triggered by photochemical damage
“Overview” under part “Liver”) and transported or other factors, such as in age-related macular
in the blood (see chapter “Overview” under part degeneration (see chapter “Age-related macular
“Blood”) by retinoid binding proteins. RPE cells degeneration”).
absorb vitamin A from the choroidal circulation
and convert it to retinal to supply the photorecep-
tors. As retinal is pivotal for rhodopsin function, References
lack of vitamin A may lead to night blindness.
1. Masland R (2012) The neuronal organization of the
Diabetes (see chapter “Diabetes mellitus”) retina. Neuron 76:266–280
can affect the performance of the eye in two 2. Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen
major ways. First, in the lens, glucose can be AA (2010) The dynamic nature of Bruch’s mem-
brane. Prog Retin Eye Res 29:1–18
converted into sorbitol, which is later – but more
3. Hunter JJ, Morgan JI, Merigan WH, Sliney DH,
slowly – converted into fructose [15]. Under nor- Sparrow JR, Williams DR (2012) The susceptibility
mal conditions, only small amounts of sorbitol of the retina to photochemical damage from visible
are synthesized. However, unphysiologically light. Prog Retin Eye Res 31:28–42
4. Shui YB, Fu JJ, Garcia C, Dattilo LK, Rajagopal R,
high blood glucose levels cause excess sorbitol
McMillan S, Mak G, Holekamp NM, Lewis A, Beebe
production, which results in osmotic swelling DC (2006) Oxygen distribution in the rabbit eye and
of the lens (as sorbitol and fructose cannot leave oxygen consumption by the lens. Invest Ophthalmol
the lens and thus are highly osmotic) that can Vis Sci 47:1571–1580
5. Yau KW, Hardie R (2009) Phototransduction motifs
ultimately lead to lens clouding, i.e., cataract.
and variations. Cell 139:246–264
Second, diabetes triggers pathological changes 6. Okawa H, Sampath AP, Laughlin SB, Fain GL (2008)
in retinal blood vessels. In early diabetic reti- ATP consumption by mammalian rod photorecep-
nopathy (the so-called non-proliferative stage), tors in darkness and in light. Curr Biol 18:
1917–1921
retinal blood vessels become blocked, which
7. Ames A 3rd, Li YY, Heher EC, Kimble CR (1992)
results in reduced nourishment and oxygen sup- Energy metabolism of rabbit retina as related to func-
ply. In response to the hypoxic state, in a second tion: high cost of Na+ transport. J Neurosci 12:
phase (called proliferative diabetic retinopathy), 840–853
8. Wong-Riley M (2010) Energy metabolism of the
new blood vessels are formed. These vessels are
visual system. Eye Brain 2:99–116
thinner, mechanically less stable and their endo- 9. Cunha-Vaz JG (1976) The blood-retinal barriers. Doc
thelial cells form a less effective blood-retinal Ophthalmol 41:287–327
Overview 65
10. Senanayake P, Calabro A, Hu JG, Bonilha VL, Darr and oxidative stress in the aging brain. Int J Biochem
A, Bok D, Hollyfield JG (2006) Glucose utilization by Cell Biol 36:2376–2391
the retinal pigment epithelium: evidence for rapid 13. Berson D (2003) Strange vision: ganglion cells as cir-
uptake and storage in glycogen, followed by glycogen cadian photoreceptors. Trends Neurosci 26:314–320
utilization. Exp Eye Res 83:235–246 14. D’Ambrosio DN, Clugston RD, Blaner WS (2011)
11. Kevany BM, Palczewski K (2010) Phagocytosis of Vitamin A metabolism: an update. Nutrients 3:
retinal rod and cone retinal. Physiology (Bethesda) 63–103
25:8–15 15. Kinoshita JH (1965) Pathways of glucose metabolism
12. Keller JN, Dimayuga E, Chen Q, Thorpe J, Gee J, in the lens. Invest Ophthalmol 4:619–628
Ding Q (2004) Autophagy, proteasomes, lipofuscin,
Age-Related Macular
Degeneration
Introduction to Age-Related under the RPE. The late stages of AMD are sub-
Macular Degeneration divided into an exudative and a non-exudative
form. The exudative form is characterized by the
Age-related macular degeneration (AMD) is the formation of choroidal neovascularizations
leading cause of irreversible blindness in the (CNV) with concomitant extracellular fluid accu-
elderly population of industrialized countries [1]. mulation, RPE detachment, and/or hemorrhages.
Based on a meta-analysis, the prevalence of early- The non-exudative late stage, termed “geographic
stage AMD is estimated to be 6.8 % and for the atrophy” (GA), is characterized by cell death of
late stages 1.5 % [2]. Prevalence, incidence, and all affected cell layers. It has been speculated that
progression of all forms of AMD rise with increas- GA is the natural end stage of AMD, if the dis-
ing age. Thirty percent of all probands aged ≥75 ease does not convert into CNV [6]. The exuda-
years were found to have early AMD and 7.1 % tive and non-exudative forms are not mutually
suffered from late stages of the disease [3, 4]. exclusive, as these may develop in the same eye.
Various cell layers are involved in the disease
process: the choriocapillaris (i.e., the layer of capil-
laries adjacent to Bruch’s membrane in the choroid),
Bruch’s membrane, the retinal pigment epithelium Pathophysiology of Age-Related
(RPE), and photoreceptors (see chapter “Overview” Macular Degeneration and
under part “Eye”). AMD typically affects the central Metabolic Alterations
retina (macula including the fovea) as the area with
the highest resolution. Untreated, the disease results The pathogenesis of AMD is incompletely under-
in severe loss of vision. stood. As a complex, multifactorial disease, it is
Different stages and phenotypic manifesta- thought to be affected by numerous systemic,
tions of the disease have been categorized [5]. genetic, and environmental factors, e.g., smoking.
The early and intermediate dry forms of the dis- Aging processes appear to play a major role in
ease are characterized by the so-called drusen the pathogenesis of AMD, and it is presumed that
and pigmentary alterations. Drusen are extracel- everybody would develop AMD if only a high
lular deposits located within Bruch’s membrane enough age would be reached.
During AMD, changes in Bruch’s membrane
are observed and accompanied by activation of
M. Fleckenstein • F.G. Holz (*) the complement system. Deposition of molecules
Department of Ophthalmology, University of Bonn,
within Bruch’s membrane leads to formation of
Ernst-Abbe-Straße 2, 53127 Bonn, Germany
e-mail: monika.fleckenstein@ukb.uni-bonn.de; drusen, a characteristic of early- and late-stage
frank.holz@ukb.uni-bonn.de AMD. Accumulation of lipofuscin and reactive
oxygen species (ROS) damage the RPE and like- [17], such as (1) high oxygen consumption by the
wise contribute to the progression of AMD. retina and RPE compared to many other tissues, (2)
Considerable structural changes in Bruch’s high levels of cumulative irradiation, and (3) abun-
membrane occur due to aging processes [7]. As a dance of photosensitizers within the neurosensory
result of calcification, loss of its elastin layer, and retina and RPE. Furthermore, photoreceptor outer
formation of cross-links such as advanced glyca- segment membranes are rich in polyunsaturated
tion end products (AGEs), the membrane fatty acids, which are readily oxidized and thus can
becomes more brittle. Furthermore, it increases initiate a cytotoxic chain reaction.
in thickness due to the lifelong entrapment of Accumulation of lipofuscin granules in post-
molecules and cellular debris, particularly lipids. mitotic RPE cells apparently due to incomplete
These accumulations of proteins and lipids are lysosomal degradation of photoreceptor outer
called drusen. Structural changes and accumula- segments further contributes to AMD progression
tion of material within Bruch’s membrane may [7]. Lipofuscin is a photosensitizer generating a
reduce the free flow of molecules between the range of ROS. Furthermore, the photoreactivity of
choroid and the photoreceptors and, eventually, individual lipofuscin granules increases with age.
in the most severe cases, lead to cellular atrophy. Exposure of lipofuscin-containing RPE cells to
Altered immune responses with complement blue light results in lipofuscin-dependent lipid
system activation are thought to be further involved peroxidation, protein oxidation, loss of lysosomal
in AMD [8], as complement proteins are found integrity, mitochondrial DNA damage, and retinal
within the drusen, and contain rise allows of com- pigment epithelium (RPE) cell death (Fig. 1).
plement jensen are associater with the disease. The The interaction of these metabolic and struc-
complement system belongs to the innate immune tural alterations with genetic and environmental
system (see chapter “Overview” under part risk factors is thought to induce pathological
“Immune system”) and can be activated via three changes promoting the development of pheno-
different pathways, i.e., the classic, lectin, and typic AMD changes and resulting in an earlier
alternative ones. Whereas the classical and lectin onset of the disease. They also form the basis for
pathways are activated via antibodies and opso- therapeutic rationales, e.g., targeting oxidative
nins, respectively, which are bound to the surface stress with prophylactic and interventional phar-
of a pathogen, the alternative complement path- macological measures (see below).
way is continuously active at a low level and In exudative AMD, vascular endothelial growth
becomes activated by the absence of complement factor-A (VEGF-A, or VEGF, in brief) has been
regulatory proteins on the surface of most micro- identified as a major factor inducing ocular neo-
bial pathogens. In each pathway, a proteolytic cas- vascularizations [18]. Further, VEGF plays a role
cade is amplified, and effectors such as in inflammatory processes, immunity, and wound
anaphylatoxins, the membrane attack complex, healing; it acts as a survival factor for endothelial
and opsonins may be activated. It has been sug- cells and as a neuroprotectant for neurons in the
gested that aging causes an increased activation of central nervous system and the retina. The angio-
the alternative complement system in the blood genic cascade and vascular permeability induced
[9]. The role of the alternative complement path- by VEGF [18] play an essential role in the thera-
way in AMD pathogenesis has been exemplified peutic concept of VEGF inhibition (Fig. 2).
by the discovery of the gene for complement fac-
tor H (CFH) [10–12], an inhibitor of the alterna-
tive pathway, as well as other risk loci in this Treatment of Age-Related
pathway [13–15]. Specific polymorphisms in Macular Degeneration
these genes are thought to be associated with
abnormal complement activation [16]. So far, a number of different approaches have been
Furthermore, the retina provides an ideal envi- tried to prevent the development of the late stages
ronment for the generation of ROS due to its of AMD. However, with the exception of small
specific anatomical and metabolic characteristics effects of dietary supplements, efficacious
Age-Related Macular Degeneration 69
Fig. 1 Lipofuscin-dependent
Light
reactive oxygen species
(ROS) generation – a
metabolic pathway presumed
to contribute to the age-
related macular degeneration
(AMD) disease process. POS
photoreceptor outer segments,
RPE retinal pigment POS
epithelium
Loss of Mitochondrial
lysosomal integrity DNA damage
Ranibizumab Pegaptanib
Fab antibody fragment, Oligonucleotide aptamer,
Neutralizing all VEGF-A isoforms Binding specificity for
VEGF-A isoforms 165, 189, 201
Aflibercept
Fusion protein consisting of key
domains of VEGF-R1 and VEGF-R2
coupled to Fc part of IgG,
High affinity for all VEGF-A and -B Bevacizumab
Fig. 2 Anti-vascular isoforms and placental growth factor VEGF Full antibody against VEGF-A
endothelial growth factor-A
(VEGF-A) strategies
currently used in the
treatment of exudative
age-related macular VEGF-R1 VEGF-R2 Endothelial cell
degeneration (AMD). The
angiogenic cascade and
vascular permeability [18] Angiogenesis Vascular permeability
play an essential role in
VEGF inhibition. IgG
immunoglobulin G
70 M. Fleckenstein and F.G. Holz
measures are currently lacking. Only recently it has tanib sodium was the results of studies showing
been achieved to treat exudative AMD successfully that VEGF-A-165 plays an important role in the
using anti-VEGF compounds injected into the vit- neovascularization process [22]. The complete
reous at regular intervals. In clinical practice, this blockage of all VEGF-A isoforms was thought to
treatment strategy for exudative AMD has replaced impair physiological functions [23]. Efficacy of
angio-occlusive therapies such as laser photocoag- pegaptanib in clinical studies was limited.
ulation and verteporfin photodynamic therapy. Ranibizumab is a Fab antibody fragment neu-
For the non-exudative late stage of AMD, tralizing all VEGF-A isoforms. It is well toler-
there is no treatment available yet to slow or to ated and shows a favorable safety profile.
halt GA progression. A number of preclinical and Monthly injected ranibizumab has been shown to
clinical trials are currently carried out to find a stabilize or to improve vision in over 90 % of
treatment for this form of AMD manifestation. patients and significantly improve vision in over
30 % of patients [24–26].
Aflibercept is a fusion protein, consisting of
Influence of Treatment the key domains of the human VEGF receptors 1
on Metabolism and 2, coupled to the Fc part of a human IgG mol-
ecule. It has a high affinity for all VEGF-A and
Nutritional Supplementation VEGF-B isoforms as well as placental growth
to Prevent Development factor [27], and theoretical models as well as tri-
of Late-Stage AMD als [28] indicate a longer duration of action com-
pared with current treatments. In the studies with
Alleviation of oxidative stress is thought to be a intravitreal aflibercept, no increase in ocular or
critical step to prevent the conversion from early to systemic adverse events was noted, despite the
late AMD stages. Nutrients that may reduce oxida- increased affinity of aflibercept for all VEGF-A
tive damage include vitamins, carotenoids, and and VEGF-B isoforms [28].
trace elements. The AREDS (Age-Related Eye Bevacizumab, a full antibody against VEGF-A,
Disease Study) trial demonstrated that a combina- has originally been developed as a cancer thera-
tion of vitamins C and E, β-carotene, and zinc oxide, peutic. It is also used for the intravitreal treatment
reduces the risk of late-stage AMD in patients with of exudative AMD. However, the drug has not
intermediate risk of conversion [19]. A recent been approved for this indication and, therefore,
update suggested lutein and zeaxanthin as appropri- represents an off-label therapy.
ate substitutes for β-carotene, which increased the Intravenous administration of anti-VEGF com-
incidence of lung cancer in former smokers [20]. pounds in the treatment of cancer has been associ-
Due to their high number of double bonds, these ated with increased risks of stroke (see chapter
macular carotenoids/pigments can quench ROS, “Stroke”), venous thromboembolism, congestive
limiting oxidative stress, increasing membrane sta- heart failure, and bleeding. However, results across
bility, and may also act as filters for blue light and studies with differing methodologies provide some
thus limit retinal photo-stress [21]. reassurance that the widespread use of injections
of VEGF inhibitors within the vitreous to treat
exudative AMD has not resulted in significant
Anti-VEGF Therapy in the Treatment increases of systemic adverse events [29].
of Exudative AMD
as prevention of progression from early to late 9. Hecker LA, Edwards AO, Ryu E, Tosakulwong N,
Baratz KH, Brown WL, Charbel Issa P, Scholl HP,
AMD stages represent an unmet need and are,
Pollok-Kopp B, Schmid-Kubista KE, Bailey KR,
therefore, in the focus of current research activi- Oppermann M (2010) Genetic control of the alterna-
ties. While anti-VEGF therapy represents a tive pathway of complement in humans and age-
breakthrough in the therapy of neovascular related macular degeneration. Hum Mol Genet
19:209–215
AMD, repeated, sometimes lifelong, administra-
10. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson
tion of the drug is an enormous burden for the LM, Gallins P, Spencer KL, Kwan SY, Noureddine M,
patients and health systems. Long-acting drug Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel
delivery systems would therefore be desirable. EA, Pericak-Vance MA (2005) Complement factor H
variant increases the risk of age-related macular
As of yet, there is no treatment available to slow
degeneration. Science 308:419–421
or to halt progression of the dry late form of AMD, 11. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS,
i.e., GA. However, various preclinical and clinical Haynes C, Henning AK, SanGiovanni JP, Mane SM,
trials are currently ongoing. Targets for this pheno- Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C,
Hoh J (2005) Complement factor H polymorphism in
type address various pathways including inflam-
age-related macular degeneration. Science 308:385–389
mation, complement system, trophic factors, 12. Edwards AO, Ritter R 3rd, Abel KJ, Manning A,
oxidative stress, reduction of retinal toxins, and Panhuysen C, Farrer LA (2005) Complement factor H
improvement of choroidal blood flow [30]. polymorphism and age-related macular degeneration.
Science 308:421–424
13. Maller J, George S, Purcell S, Fagerness J, Altshuler
D, Daly MJ, Seddon MJ (2006) Common variation in
three genes, including a noncoding variant in CFH,
References strongly influences risk of age-related macular degen-
eration. Nat Genet 38:1055–1059
1. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY 14. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber
(2012) Age-related macular degeneration. Lancet AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile
379:1728–1738 GR, Smith RT, AMD Genetics Clinical Study Group,
2. Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Hageman GS, Dean M, Allikmets R (2006) Variation
Klein BE, Hofman A, Jensen S, Wang JJ, de Jong PT in factor B (BF) and complement component 2 (C2)
(2001) Risk factors for age-related macular degeneration: genes is associated with age-related macular degen-
Pooled findings from three continents. Ophthalmology eration. Nat Genet 38:458–462
108:697–704 15. Maller JB, Fagerness JA, Reynolds RC, Neale BM,
3. Klein R, Klein BE, Linton KL (1992) Prevalence of Daly MJ, Seddon JM (2007) Variation in complement
age-related maculopathy. The Beaver Dam Eye Study. factor 3 is associated with risk of age-related macular
Ophthalmology 99:933–943 degeneration. Nat Genet 39:1200–1201
4. Klein R, Klein BE, Jensen SC, Meuer SM (1997) The 16. Nitsch D, Douglas I, Smeeth L, Fletcher A (2008)
five-year incidence and progression of age-related Age-related macular degeneration and complement
maculopathy: the Beaver Dam Eye Study. Ophthalmology activation-related diseases: a population-based case–
104:7–21 control study. Ophthalmology 115:1904–1910
5. Ferris FL 3rd, Wilkinson CP, Bird A, Chakravarthy U, 17. Beatty S, Koh H, Phil M, Henson D, Boulton M
Chew E, Csaky K, Sadda SR (2013) Clinical classifi- (2000) The role of oxidative stress in the pathogenesis
cation of age-related macular degeneration. of age-related macular degeneration. Surv Ophthalmol
Ophthalmology 120:844–851 45:115–134
6. Sarks SH (1976) Ageing and degeneration in the macular 18. Grisanti S, Lüke J, Peters S (2013) Anti-VEGF ther-
region: a clinico-pathological study. Br J Ophthalmol apy: basics and substances. In: Holz FG, Pauleikhoff
60:324–341 P, Spaide RF, Bird AC (eds) Age-related macular
7. Boulton M (2013) Ageing of the retina and retinal degeneration. Springer, Heidelberg/New York/
pigment epithelium. In: Holz FG, Pauleikhoff D, Dordrecht/London, pp 225–232
Spaide RF, Bird AC (eds) Age-related macular degen- 19. Age-Related Eye Disease Study Research Group
eration. Springer, Heidelberg/New York/Dordrecht/ (2001) A randomized, placebo-controlled, clinical
London, pp 45–63 trial of high-dose supplementation with vitamins C
8. Hageman GS, Luthert PJ, Victor Chong NH, Johnson and E, beta carotene, and zinc for age-related macular
LV, Anderson DH, Mullins RF (2001) An integrated degeneration and vision loss: AREDS report no. 8.
hypothesis that considers drusen as biomarkers of Arch Ophthalmol 119:1417–1436
immune-mediated processes at the RPE-Bruch’s 20. Chew EY, Clemons TE, Agrón E, Sperduto RD,
membrane interface in aging and age-related macular Sangiovanni JP, Kurinij N, Davis MD (2013) Long-
degeneration. Prog Retin Eye Res 20:705–732 term effects of vitamins C and E, beta-carotene, and
72 M. Fleckenstein and F.G. Holz
zinc on age-related macular degeneration: AREDS Ranibizumab versus verteporfin for neovascular age-
report no. 35. Ophthalmology 120:1604–1611 related macular degeneration. N Engl J Med 355:
21. Loane E, Kelliher C, Beatty S, Nolan JM (2008) The 1432–1444
rationale and evidence base for a protective role of 26. Mitchell P, Foran S (2013) Anti-VEGF therapy for
macular pigment in age-related maculopathy. Br J AMD: results and guidelines. In: Holz FGPD,
Ophthalmol 92:1163–1168 Pauleikhoff D, Spaide RF, Bird AC (eds) Age-related
22. Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, macular degeneration. Springer, Heidelberg/New
Ogura Y, Hida T, Oguchi Y, Ambati J, Miller JW, York/Dordrecht/London
Gragoudas ES, Ng YS, D'Amore PA, Shima DT, 27. Ohr M, Kaiser PK (2012) Aflibercept in wet age-
Adamis AP (2003) VEGF164-mediated inflammation related macular degeneration: a perspective review.
is required for pathological, but not physiological, Ther Adv Chronic Dis 3:153–161
ischemia-induced retinal neovascularization. J Exp 28. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser
Med 198:483–489 PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y,
23. Usui T, Ishida S, Yamashiro K, Kaji Y, Poulaki V, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo
Moore J, Moore T, Amano S, Horikawa Y, Dartt D, Y, Anderesi M, Groetzbach G, Sommerauer B,
Golding M, Shima DT, Adamis AP (2004) Sandbrink R, Simader C, Schmidt-Erfurth U (2012)
VEGF164(165) as the pathological isoform: differen- Intravitreal aflibercept (VEGF trap-eye) in wet age-
tial leukocyte and endothelial responses through related macular degeneration. Ophthalmology 119:
VEGFR1 and VEGFR2. Invest Ophthalmol Vis Sci 2537–2548
45:368–374 29. Campbell RJ, Bell CM, Campbell Ede L, Gill SS
24. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser (2013) Systemic effects of intravitreal vascular endo-
PK, Chung CY, Kim RY (2006) Ranibizumab for neo- thelial growth factor inhibitors. Curr Opin Ophthalmol
vascular age-related macular degeneration. N Engl 24:197–204
J Med 355:1419–1431 30. Mata NL, Vogel R (2010) Pharmacologic treatment of
25. Brown DM, Kaiser PK, Michels M, Soubrane G, atrophic age-related macular degeneration. Curr Opin
Heier JS, Kim RY, Sy JP, Schneider S (2006) Ophthalmol 21:190–196
Glaucoma
transport in the retinal ganglion cells, as well as cause fluid accumulation in the intraocular space,
degeneration of neuronal processes resulting in thus increasing IOP [12].
apoptotic cell death. To date, the mechanisms Systemic hypertension increases ciliary capil-
underlying these changes are not well understood. lary pressure and can increase AH filtration through
the ciliary body of the eye [14]. In a mechanism
similar to that described for fat deposits and blood
Pathophysiology of Glaucoma viscosity, increased blood volume associated with
and Metabolic Alterations elevated systemic blood pressure can increase epi-
scleral and ciliary vein resistance [15]. This resis-
An association between glaucoma and metabolic tance opposes flow through the drainage canals and
conditions has long been postulated and debated. ultimately increases IOP [16]. However, other
Early studies have shown an increased preva- studies have associated low blood pressure with
lence of acute closed-angle glaucoma among increased likelihood of developing glaucoma [17].
patients with metabolic disorders, such as homo- In this case, reduced ocular perfusion pressure (the
cystinuria, and Lowe’s syndrome [6]. However, difference between IOP and systemic blood pres-
the focus of most research in this area has been sure—opposing pressures that determine blood
on the putative relationship between glaucoma flow to optic tissues) results in decreased blood
and diabetes mellitus (see chapter “Diabetes mel- flow to the retina or optic nerve head [17]. As the
litus”)—and whether each of the respective con- retina is one of the most metabolically demanding
ditions serves as a risk factor for the other. While tissues in the body, even relatively subtle declines
diabetic retinopathies are well described, the rea- in oxygen and nutrient supply may directly blunt
sons for the increased incidence of glaucoma in retinal function and/or raise vulnerability to insult
diabetic patients are poorly understood [7]. through increased oxidative stress, calcium dys-
Closed-angle glaucoma is likely associated regulation, and abnormal neuronal signaling [5].
with diabetes since abnormal glucose responses,
shallow anterior chambers of the eye, and dys-
function of the autonomic nervous system seem to Treatment of Glaucoma
be related. Open-angle glaucoma is even more
widely studied but also less understood [8]. Although the dysfunction and degeneration of reti-
Interestingly, obesity [9], hypertension [8], and nal ganglion cells and their projections are what
insulin resistance (symptoms of metabolic syn- cause blindness in glaucoma, existing therapies tar-
drome, see chapter “Metabolic syndrome”) have a get lowering IOP through medication or surgery
stronger relationship to increased IOP than diabe- [18]. Currently, first-line treatment for glaucoma is
tes itself [10]. This could be explained by several the topical use of eyedrops to reduce IOP [19].
factors (Fig. 1). Fat deposits around the eye and There are five main classes of IOP-lowering drugs,
blood viscosity are often increased among obese all of which either reduce the production of AH (by
individuals—the latter being due to elevated lev- reducing activity of the ciliary body) or increase
els of hematocrit, lipids, fibrinogen, and immuno- AH outflow (by action on the drainage canals in the
globulins as well as changes in red blood cell iridocorneal angle, Table 1). Interestingly, lowering
rigidity [11]. Both fat deposits and high blood IOP often slows the progression of vision loss even
viscosity can increase resistance of the episcleral in patients with normal IOP [20].
vein, which in turn impedes AH outflow [12]. The AH production can be reduced with drugs tar-
accumulation of AH in an environment that geting the adrenergic system, antagonizing β- and
restricts its exit can ultimately lead to a net activating α-receptors (e.g., timolol or brimoni-
increase in IOP [13]. dine, respectively), or with carbonic anhydrase
While the mechanisms are less clear, insulin inhibitors (e.g., dorzolamide), presumably by
resistance and associated elevated blood glucose slowing the formation of bicarbonate ions with
are suggested to alter the osmotic gradient to subsequent reduction in Na+ and fluid transport.
Glaucoma 75
Retinal blood
IOP
flow
OPP
RGC damage
Fig. 1 Relationship between conditions associated with retinal function and leads to retinal ganglion cell (RGC)
metabolic syndrome, diabetes, and glaucoma. Different damage and degeneration through specific (Ca2+-activated
factors act to (1) increase intraocular pressure (IOP) or (2) degenerative cascades) and nonspecific (oxidative stress-
reduce blood flow to the retina (due to either low blood induced damage) mechanisms. Another major factor in
pressure or microvascular changes). Either of these effects glaucoma is age. Terms highlighted in framed boxes
will reduce ocular perfusion pressure (OPP), leading to a change with age in a way that age increases the prevalence
decrease in retinal blood supply. Ultimately, this impairs and severity of the disease
Eyedrops
b-BLOCKERS Lacrimal puncta
Heart rate
Blood pressure
Bronchospasm
Airway obstruction
LDL
[LPL] Serum triglycerides
HDL
Fig. 2 Effects of topical β-blocker treatment (eyedrops) heart rate, lower blood pressure, impair respiratory func-
on systemic function. Eyedrops travel through the lacri- tion, and produce unfavorable blood lipid profiles through
mal puncta and enter systemic circulation through the inhibition of lipoprotein lipase (LPL) in heart, muscle,
nasolacrimal duct. Common intraocular pressure-lower- and adipose tissue. LDL low-density lipoprotein, HDL
ing drugs that inhibit the adrenergic system can decrease high-density lipoprotein
agents used for the treatment of glaucoma Metabolic syndrome as a risk factor for high-ocular
tension. Int J Obes (London) 34:1209–1217
(although some of the existing IOP-lowering
11. Guiraudou M, Varlet-Marie E, Raynaud de Mauverger
drugs such as brimonidine are thought to have E, Brun JF (2013) Obesity-related increase in whole
neuroprotective effects). Researchers are cur- blood viscosity includes different profiles according to
rently exploring a number of avenues—some of fat localization. Clin Hemorheol Microcirc 55:63–73
12. Newman-Casey PA, Talwar N, Nan B, Musch DC,
which could potentially have effects on metabo-
Stein JD (2011) The relationship between compo-
lism—such as drugs affecting hemodynamics, nents of metabolic syndrome and open-angle glau-
mitochondrial function, or Ca2+ dynamics. With a coma. Am Acad Ophthalmol 118:1318–1326
projected increase in glaucoma prevalence, this 13. Bulpitt CJ, Hodes C, Everitt MG (1975) IOP and sys-
temic blood pressure in the elderly. Br J Ophthalmol
avenue represents one of the best hopes for reduc-
59:717–720
ing disease burden in the future. 14. Oh SW, Lee S, Park C, Kim DJ (2005) Elevated IOP
is associated with insulin resistance and metabolic
syndrome. Diabetes Metab Res Rev 21:434–440
15. Cherecheanu AP, Garhofer G, Schmidl D,
References Werkmeister R, Schmetterer L (2013) Ocular perfu-
sion pressure and ocular blood flow in glaucoma. Curr
1. Quigley HA, Broman AT (2006) The number of peo- Opin Pharmacol 13:36–42
ple with glaucoma worldwide in 2010 and 2020. Br J 16. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC
Ophthalmol 90:262–267 (1995) Hypertension, perfusion pressure, and primary
2. Gordon MO, Beiser JA, Brandt JD, Heuer DK, open-angle glaucoma. A population-based assess-
Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, ment. Arch Ophthalmol 113:216–221
Parrish RK 2nd, Wilson MR, Kass MA (2002) The 17. Leske MC (2009) Ocular Perfusion pressure and glau-
ocular hypertension treatment study: baseline factors coma: clinical trial and epidemiologic findings. Curr
that predict the onset of primary open-angle glau- Opin Ophthalmol 20:73–78
coma. Arch Ophthalmol 120:714–720 18. McKinnon SJ, Goldberg LD, Peeples P, Walt JG,
3. Shields MB (2008) Normal-tension glaucoma: is it Bramley TJ (2008) Current management of glaucoma
different from primary open-angle glaucoma? Curr and the need for complete therapy. Am J Manag Care
Opin Ophthalmol 19(2):85–88 14:S20–S27
4. Sommer A (1989) Intraocular pressure and glaucoma. 19. Taniguchi T, Kitazawa Y (1997) The potential sys-
Am J Ophthalmol 107:186–188 temic effect of topically applied beta-blockers in glau-
5. Crish SD, Calkins DJ (2011) Neurodegeneration in coma therapy. Curr Opin Ophthalmol 8:55–58
glaucoma: progression and calcium-dependent intra- 20. Sommer A, Tielsch J (2008) Blood pressure, perfusion
cellular mechanisms. Neuroscience 176:1–11 pressure, and open-angle glaucoma. Arch Ophthalmol
6. Wilson WA (1969) Ocular findings in several meta- 126:741, author reply 741–742
bolic diseases. Calif Med 111:446–449 21. Monane M, Bohn RL, Gurwitz JH, Glynn RJ,
7. Mapstone R, Clark CV (1985) Prevalence of diabetes Choodnovskiy I, Avorn J (1994) Topical glaucoma
in glaucoma. BMJ 291:93–95 medications and cardiovascular risk in the elderly.
8. Jonas JB, Grundler AE (1998) Prevalence of diabetes Clin Pharmacol Ther 55:76–83
mellitus and arterial hypertension in primary and 22. Huerta C, García Rodríguez LA, Möller CS, Arellano
secondary open-angle glaucomas. Graefes Arch Clin FM (2001) The risk of obstructive airways disease in
Exp Ophthalmol 236:202–206 a glaucoma population. Pharmacoepidemiol Drug Saf
9. Tan GS, Wong TY, Fong CW, Aung T (2009) 10:157–163
Diabetes, metabolic abnormalities, and glaucoma. 23. Kirwan JF, Nightingale JA, Bunce C, Wormald R
Arch Ophthalmol 127:1354–1361 (2002) Beta blockers for glaucoma and excess risk of
10. Imai K, Hamaguchi M, Mori K, Takeda N, Fukui M, airways obstruction: population based cohort study.
Kato T, Kawahito Y, Kinoshita S, Kojima T (2010) BMJ 325:1396–1397
Part III
Teeth and Bones
Overview
Anatomy and Physiology of Teeth processes [2]. In addition to these three principal
and Bones hard tissues, the roots of the teeth are covered by
cementum, a bone-like tissue (Fig. 1a).
Bone and teeth comprise the mineralized hard The tooth is essential for mastication and also
tissues of the human body. They have evolved important for proper speech and aesthetics [2],
from a hard external skeleton in early vertebrates while bone constitutes the skeleton, which sup-
that led eventually to bony plates, teeth, and ports and protects our body and enables move-
scales as well as to the internal skeleton that char- ment. In addition, bone is critical to the homeostasis
acterizes modern jawed vertebrates [1]. Bone and of calcium and phosphate [3–5]. In the following,
teeth form in organic extracellular matrix. The growth of bone and teeth is briefly explained.
mineral component essentially consists of
hydroxyapatite (i.e., a special calcium phosphate,
Ca10(PO4)6(OH)2) with various potential substi- Bone Growth
tutes, such as fluoride, replacing hydroxide (see
chapter “Dental caries”). The organic constitu- Bone can develop by two mechanisms, i.e.,
ents vary in different tissues [1]. Bone consists of intramembranous ossification or endochondral
~65 % (w/w) minerals, 25 % organic matrix ossification [3, 4], in which cartilage is not pres-
(~95 % of which are collagen fibrils), and water. ent or serves as a model, respectively. In intra-
The tooth consists of a bulk of dentin covered membranous ossification, mesenchymal cells
with enamel on the crown (Fig. 1a). Dentin is proliferate and condense. Some of these cells dif-
similar to bone in proportion of mineral (~70 % ferentiate into osteoblasts, which secrete organic
w/w) and collagen fibrils, but includes different matrix of bone. As osteoblasts secrete the bone
non-collagenous proteins. Unlike bone and den- matrix, some become entrapped within the
tin, enamel is a highly mineralized (~97 % w/w), matrix. These cells are referred to as osteocytes.
virtually inorganic tissue; its initial organic Intramembranous bones grow appositionally by
matrix is removed through specific maturation recruiting newly differentiated osteoblasts. It
takes place in most bones of the skull. In con-
trast, endochondral ossification uses a cartilage
model. The cartilage model grows interstitially
by proliferation and differentiation of chondro-
K. Kawasaki • K.M. Weiss (*) cytes, with the old cartilage model progressively
Department of Anthropology, Pennsylvania
getting replaced by endochondral bone. During
State University, 409 Carpenter Building,
University Park, PA 16802-3404, USA this process, mineralized portions of cartilage
e-mail: kuk2@psu.edu; kenweiss@psu.edu are partially resorbed by chondroclasts (similar
a Tooth
Saliva
Enamel
Demineralization
Dentin Pulp Dentin
Pi
Ca 2+
Cementum Remineralization
Pulp Ca 2+ , P i, F -
Odontoblast Odontoblast
process body Bone
Dentin Enamel Saliva
b Bone
OPG Maturation
Sealing zone
Fig. 1 Tooth-specific (a) and bone-specific (b) metabolic arrow represents acid, e.g., produced by cariogenic bac-
pathways. (a) A sagittal section of a tooth is illustrated teria. (b) Bone remodeling progresses through (i) bone
in the middle showing the different zones and structures resorption and (ii) bone formation, driven by osteoclasts
in a human tooth. The pulp-dentin border is enlarged and osteoblasts, respectively (left). Principal regulatory
on the left. In the right enlargement, flows of calcium mechanisms in these processes are illustrated on the right.
(Ca2+), phosphate (Pi), and fluoride (F−) during demin- RANK receptor activator of nuclear factor-κB, RANKL
eralization and remineralization are shown. The yellow RANK ligand, OPG osteoprotegerin
life, and the pulp space reduces progressively inducing their maturation and subsequent bone
with age. resorption, as well as promoting the survival of
Enamel matrix is secreted by ameloblasts that osteoclasts. The RANKL-RANK interaction can
overlay the forming enamel surface. Before tooth be interrupted by antagonistic binding of osteo-
eruption, ameloblasts fuse with the oral epithe- protegerin (OPG) to RANK. OPG is a soluble
lium and the cells covering the top of the crown receptor, secreted by osteoblast-lineage cells.
subsequently degenerate, leaving mature enamel Thus, the local RANKL/OPG ratio determines
acellular. The enamel is highly mineralized and the activity of RANK signaling that induces bone
wear resistant, but this tissue is brittle and frac- remodeling.
tures by the forces of mastication. However, the For bone formation, osteocytes play an essen-
enamel is supported by underlying dentin, which tial role [4]. Osteocytes represent osteoblast-
is more resilient and compensates for the brittle- derived cells that are embedded in bone (Fig. 1b).
ness of enamel. Osteoblasts that do not differentiate to osteocytes
Humans have two complete sets of dentition. either line the surface of quiescent bone or
The deciduous teeth are replaced by the perma- undergo apoptosis. In bone, osteocytes lie in
nent successors with additional permanent molars lacunae and extend cell processes through cana-
erupting behind the deciduous tooth row. During liculi. These processes form a network with other
tooth replacement, dentin and cementum of osteocytes and osteoblasts present on the bone
deciduous teeth are resorbed, and the jaw bone is surface (Fig. 1b). It is thought that osteocytes
remodeled. sense mechanical strain as shear stress in intersti-
tial fluid filling the lacuna-canalicular system.
In response to mechanical loading, osteocytes
Calcium and Phosphate Metabolism suppress expression of the sclerostin gene [3].
and Physiological Reactions in Bone Sclerostin antagonizes Wnt/β-catenin signaling
and Tooth that induces differentiation of preosteoblasts to
osteoblasts and the production of bone matrix
Bone Remodeling (Fig. 1b). Furthermore, mechanical loading may
cause microdamage and osteocyte apoptosis near
Bone remodeling progresses through bone the damage site. However, surviving osteocytes
resorption and bone formation (Fig. 1b) [3]. For activate the production of RANKL and suppress
resorption, preosteoclasts, derived from the OPG production, thus inducing bone resorption
hematopoietic lineage, first mature into multinu- (Fig. 1b). Subsequent bone formation would
cleated osteoclasts, which adhere to the bone sur- eventually repair the microdamage.
face and form a closed compartment. The bone remodeling cycle ends when
Into this sealing zone, osteoclasts secrete resorbed bone is completely replaced by new
acid (protons) and proteolytic enzymes, includ- bone. Imbalance of bone resorption and bone for-
ing cathepsin K. The acid dissolves hydroxyapa- mation may lead to a loss of bone mass and
tite, whereas cathepsin K digests collagens and strength, that is, osteoporosis (see chapter
other organic bone constituents. Following bone “Osteoporosis”). In addition to replacement,
resorption, osteoclasts probably produce signals bone remodeling is important for homeostasis of
for new bone formation, although the details calcium and phosphate, and bone serves as the
remain unclear. reservoir of these ions. Bone is thus highly vascu-
The receptor activator of nuclear factor-κB larized, which is essential for the transport of cal-
ligand (RANKL), a membrane-bound cytokine cium and phosphate, as well as oxygen and
that is presented by various cells in the osteoblast nutrients (common to teeth). A rich vasculature
lineage, plays a critical role for differentiation of also facilitates the circulation of various hor-
osteoclasts [3] (Fig. 1b). RANKL binds its recep- mones that regulate bone remodeling (see below).
tor, RANK, on osteoclast precursor cells, thereby Another important function of bones is to provide
84 K. Kawasaki and K.M. Weiss
the space for the bone marrow, in which various bone and teeth as hydroxyapatite crystals, primar-
blood cells develop from hematopoietic stem ily providing the rigidity of these structures. Thus,
cells. The bone marrow is crucial for the hemato- metabolically more active bone is considered as the
poietic system (see chapter “Overview” under reservoir of calcium and phosphate. The homeosta-
part “Blood”) and immune system (see chapter sis of calcium and phosphate is regulated in a
“Overview” under part “Immune system”). dynamic equilibrium accomplished by intestinal
absorption, renal excretion, and bone remodeling
through hormonal controls, largely by parathyroid
Calcium Metabolism in Teeth hormone (PTH) and calcitriol (Fig. 2) [3, 5].
Calcitriol is the active form of vitamin D3; vitamin
Unlike bone that undergoes dynamic remodeling, D3 (cholecalciferol) is synthesized in the skin or
teeth are less metabolically active, resorbed only dur- ingested with the food and sequentially hydroxyl-
ing replacement in normal physiological conditions. ated initially to calcidiol in the liver and then to
Yet, the superficial layer of enamel repeats deminer- calcitriol in the kidney.
alization and remineralization (Fig. 1a) [2], espe- Changes in the calcium concentration within
cially when challenged (see chapter “Dental caries”). the extracellular fluid are detected by the calcium
Remineralization occurs by deposition of calcium, sensing receptor (CaR) in the parathyroid glands
phosphate, and fluoride, supplied by saliva. Fluoride- [3]. There, a rise in calcium concentration leads
substituted hydroxyapatite is more acid resistant, and to suppression of the synthesis and secretion of
fluoride selectively remains in enamel. A similar pro- PTH (Fig. 2). Conversely, a decrease in calcium
cess is known as posteruptive maturation. Shortly concentration enhances PTH secretion.
after eruption of the developing tooth, the enamel is PTH binds its receptor (parathyroid hor-
more permeable and susceptible to acid dissolution. mone 1 receptor; PTH1R) in the kidney, which
Incorporation of calcium, phosphate, and fluoride leads to calcium reabsorption, phosphate excre-
into such enamel from saliva increases surface hard- tion, and hydroxylation of calcidiol to calcitriol
ness and resistance to demineralization. (Fig. 2) [3, 5]. In the small intestine, calcitriol
If demineralization dominates remineraliza- increases absorption of calcium and phosphate.
tion in enamel, dental caries progresses (see chap- Furthermore, PTH induces bone resorption (see
ter “Dental caries”). When caries process reaches below). These mechanisms cooperatively increase
dentin, odontoblasts respond by inductive miner- the calcium concentration in the extracellular
alization in two principal ways, tubular sclerosis fluid. The increased concentrations of calcium and
and tertiary dentin formation. Tubular sclerosis phosphate could cause their pathological precipi-
represents mineralization of dentinal tubules that tation. However, such precipitation is prevented by
enclose odontoblast processes. Tertiary dentin phosphate excretion mediated by PTH. Calcitriol
forms in the pulp by preexisting odontoblasts or suppresses PTH gene expression in the parathy-
newly differentiated odontoblast-like cells. roid glands, acting as a negative feedback regula-
tor. The interplay of PTH and calcitriol is essential
for calcium and phosphate homeostasis (Fig. 2).
Bone and Tooth: Roles in Calcium- PTH also affects bone, causing an increase
Phosphate Homeostasis in bone resorption (triggered, e.g., by calcium-
deficient diet) [3, 5]. PTH binds PTH1R on osteo-
In adult humans, 5–10 % of bone is remodeled blast-lineage cells, thereby activating RANKL
each year. Such high rates of bone turnover are expression and suppressing OPG expression. This
essential for the homeostasis of calcium and phos- induces bone resorption (Fig. 1b). Paradoxically,
phate in the extracellular fluid (mostly blood intermittent administration of PTH at low doses
plasma and interstitial fluid) to ensure physiological increases bone formation probably through sup-
activities [4, 5]. Approximately 99 % of calcium pression of the sclerostin gene and enhancing
and 80 % of phosphate in our body are located in Wnt/β-catenin signaling (Fig. 1b).
Overview 85
Calcitriol Ca2+
Pi
Excretion
Kidney
It has been postulated that calcitriol also mastication. Yet, even though the tooth surface is
induces bone resorption by activating RANKL acellular, it repeats demineralization and remin-
and suppressing OPG production directly in eralization. Similarly, bone is constantly remod-
osteoblast-lineage cells [3]. However, this action eled by osteoblasts and osteoclasts to adapt to
has been only detected by administration of cal- changing needs (of the skeleton), repair damage,
citriol at pharmacological doses. At physiologi- and regulate mineral metabolism. An imbalance
cal doses, calcitriol reduces bone resorption of calcium and phosphate metabolism in teeth
partly by suppressing PTH production (Fig. 2). and bone may result in potentially life-threat-
ening conditions including caries (see chapter
“Dental caries”) and osteoporosis (see chapter
Final Remarks “Osteoporosis”), respectively.
Colin Robinson
a b
Ca 2+ II Ca 2+ II Ca 2+ II Ca 2+ II
HCO3− Pi
Pi
Ca 2+ I Ca 2+ I Ca 2+ I Ca 2+ I
Ca 2+ II F- Mg 2+
Ca 2+ II OH − Ca 2+ II
CO32− Pi
Pi Pi
Sr2+ Ca 2+ I
Ca 2+ I
Pb 2+
Ca 2+ II Ca 2+ II
Zn 2+ Ca 2+ II Ca 2+ II
c HO −
HO −
F−
−OH
−OH
Fig. 1 Chemical composition of hydroxyapatite. (a) View substitutes. A fluoride (F−) ion is shown in the centre posi-
of a regular, non-distorted hexagonal unit cell of hydroxy- tion. Close fit and high electronegativity of fluoride ions
apatite in the tooth down the long c-axis. One layer of a unit confer stability on the crystal with regard to acid. Distortions
crystal is shown. The positions of inner (Ca2+ I) and outer due to carbonate (CO32−) and magnesium (Mg2+) ions are
(Ca2+ II) calcium ions, as well as phosphate ions (Pi), are indicated resulting in less well-ordered crystals and greater
shown. Please note that outer Ca2+ ions also “belong” to acid solubility. Locations of other substituent ions are
two neighbouring apatite crystals (shown with dotted shown, e.g. Sr2+, Pb2+, Zn2+. HPO42− and HCO3− can also be
lines). A hydroxyl ion (OH−) is shown in the centre. For a present. Charge balance is maintained by loss of calcium or
complete hydroxyapatite unit cell, a second layer must be hydroxyl ions. (c) View of hydroxyapatite crystal showing
added, rotated by 60°, so that Ca2+ will be placed atop Pi, the long c-axis with a fluoride substituting for one hydroxyl
resulting in the chemical formula of Ca2+10(PO43−)6)(OH−)2. ion. The orientation of hydroxyl ions is altered such that the
(b) View of a substituted, distorted hydroxyapatite hexago- hydroxyl protons are oriented towards the fluoride ion. This
nal unit cell down the long c-axis showing possible increases stability of the crystals towards acid [13]
the lesion front advances relatively quickly, the Histological studies of caries lesions reveal
lesion surface appears to remain intact due to pores, which progressively increase in size until
reprecipitation of dissolved crystals facilitated by mechanical breakdown occurs. These are visible as
high surface levels of fluoride [12–14]. a series of zones (Fig. 2a) [12]. Initial dissolution
Fig. 2 Pathophysiology of dental caries. (a) Overview faces starts. Subsequent reprecipitation of dissolved mineral
image of an affected tooth indicating the section shown in occurs in the dark zone (dark areas in c). Dissolution contin-
(b). (b) Section through an interproximal (white spot) caries ues even of this stable reprecipitated mineral (lesion body) as
lesion of enamel showing histological zones of the lesion. (c) pH falls towards the plaque biofilm on the enamel surface.
Schematic drawing of pore structure and changes in crystal The surface zone contains a range of poorly defined/bulky
appearance, due to dissolution, at each stage with the earliest calcium phosphate materials. (e) Ionic alterations in different
stage to the right: translucent zone (1 % mineral loss) through zones of a caries lesion showing relative changes of impor-
the dark zone (5 % mineral loss) to the body of the lesion tant ions and conditions (arbitrary units). Whereas the fluo-
(20–50 % mineral loss). Pore size increases at each stage ride content is relatively low in sound enamel, it continuously
with additional small pores indicating crystal regrowth/rem- rises along the lesion progression, with a steep rise during the
ineralisation in the dark zone indicated by darker areas, later body and highest concentration on the enamel surface.
dissolved in the lesion body. (d) Graphical illustration of Calcium and phosphate are also high at the surface and in
chemical changes to enamel crystals (hexagons) at each sound enamel. Their minimal concentration can be found in
stage of lesion development (from right to left). Intact prisms the body of the lesion. Carbonate and magnesium ions are
and crystals are present in healthy teeth (sound enamel). maximal in sound enamel and drop continuously towards the
Large, selective loss of carbonate and magnesium ions and surface. Similarly, pH is highest in sound enamel and con-
increase in fluoride occurs during the first stage (translucent tinuously drops towards the surface [13]
zone), where dissolution of prism boundaries and crystal sur-
Dental Caries 89
a b c
Body of
Caries lesion lesion
Section shown in b
Dentine
Surface Enamel Dentin
Translucent
d Surface Body Dark zone zone Sound enamel
Calcium and
phosphate
Ion concentration
Carbonate and
magnesium
pH
Lesion progression
90 C. Robinson
of crystal surfaces produces the translucent zone, raises issues of bacterial resistance and the pos-
with ~1 % mineral loss (Fig. 2b). This is succeeded sibility of long-term effects on oral soft tissues.
by the dark zone [15] with larger pores and ~5 % Inclusion of buffers in toothpastes and mouth-
mineral loss. The dark appearance is due to the addi- washes to correct pH has a limited effect due to
tional generation of much smaller pores, which do their relatively short half-life in the mouth.
not admit media such as quinoline, which has the Mineral ions can be supplemented to the lesion
same refractive index as apatite crystals. Importantly site to promote remineralisation [18]. Fluoride in
this indicates some closing up of existing pores by particular is remarkably effective, reducing the dis-
regrowth of existing crystals and new crystal precip- ease by 50–70 %. Originally thought to increase
itation, i.e. remineralisation. Some accumulation of enamel resistance via incorporation into crystals
organic material has also been reported. This remin- during development, later emphasis shifted towards
eralisation, via calcium and phosphate from saliva, is a topical remineralising effect on the lesion itself
facilitated by the massive loss of carbonate and mag- [19]. Fluoride can be supplied to the tooth surface
nesium, which are crystal growth inhibitors because via the diet, drops or tablets entering the saliva
of their destabilising effect on apatite crystals and an directly or via the bloodstream. Topical application
increase in the crystal growth promoter fluoride. The via toothpastes and mouthwashes is also effective
subsequently formed body of the lesion with even [20, 21]. Why continuous supply of fluoride is nec-
larger pores (20–30 % mineral loss) represents con- essary is not perfectly understood but is likely
tinued dissolution of even the reprecipitated material related to maintenance of a concentration gradient
as more acid penetrates from the plaque [13]. into the lesion through the plaque biofilm [22].
Demineralisation and remineralisation can Fluoride inhibition of plaque acid production may
thus occur at the same time in the same lesion also contribute. More generally, removal of biofilm
depending on concentration gradients of fluoride, by flossing and toothbrushing twice daily for about
carbonate, magnesium and pH [13]. 2 min is also effective by removing acid generating
bacteria and lowering the overall bacterial load.
crystal development is impaired and porosity in 4. Kay MI, Young RA, Posner AS (1964) Crystal struc-
ture of hydroxyapatite. Nature 204:1050–1052
enamel results, which increases in severity with
5. Elliott JC, Holcomb DW, Young RA (1985) Infrared
fluoride concentration. In extreme cases bone can determination of the degree of substitution of hydroxyl
be affected. Several mechanisms may operate here, by carbonate ions in human dental enamel. Calcif
including increased apatite-protein binding to crys- Tissue Int 37:372–375
6. Terpstra RA, Driessens FCM (1986) Magnesium in
tal growth sites limiting crystal growth [23] and
tooth enamel and synthetic apatites. Calcif Tissue Int
more recently alterations in cytoskeletal behaviour 39:348–354
in the enamel forming ameloblasts [24]. This may 7. Moreno EC, Kresak M, Zahradnik RT (1974)
inhibit removal of proteins and/or access of cal- Fluoridated hydroxyapatite, solubility and caries for-
mation. Nature 247:64–65
cium phosphate to the growing crystals. Several
8. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhurst FE
guidelines have been published with regard to opti- (2005) Defining the normal bacterial flora of the oral
mal dietary fluoride levels [25]. cavity. J Clin Microbiol 43:5721
9. Van Nieuw Amerongen A, Bolscher JG, Veerman EC
(2004) Salivary proteins: protective and diagnostic
value in cariology? Caries Res 38:247–253
Perspectives 10. Wood SR, Kirkham J, Marsh PD, Shore RC, Nattress
B, Robinson C (2000) Architecture of intact natural
The most effective current anticaries therapy is human plaque biofilms studied by confocal laser scan-
ning microscopy. J Dent Res 79:21–27
fluoride. Administration via the drinking water
11. Kleinberg I (2002) A mixed – bacterial ecological
is extremely effective and is relatively inex- approach to understanding the role of the oral bacteria
pensive. However, interpreted as mass medica- in caries causation: an alternative to the Streptococcus
tion and with the risk of fluorotic changes, this mutans and specific plaque hypothesis. Crit Rev Oral
Biol Med 13:108–125
route is still somewhat controversial. Topical
12. Darling AI (1961) The selective attack of caries on the
oral application remains the most effective and dental enamel. Ann R Coll Surg Engl 29:354–369
acceptable treatment but depends on individual 13. Robinson C, Kirkham J, Shore RC, Brookes SJ, Wood
compliance. More recently, attempts have been SR, Strafford SM (2000) The chemistry of enamel
caries. Crit Rev Oral Biol Med 11:481–495
made to encourage remineralisation by supply-
14. Weatherell JA, Deutsch D, Robinson C, Hallsworth
ing additional calcium to tooth surfaces using AS (1977) Assimilation of fluoride by enamel through
a calcium-protein complex and via administration the life of the tooth. Caries Res 11(Suppl 1):85–115
of peptides, which nucleate the deposition of new 15. Silverstone LM (1967) Observations on the dark zone
in early enamel caries and in artificial caries-like
hydroxyapatite crystals. New approaches to diag-
lesions. Caries Res 1:261–274
nosing very early chemical changes in the enamel 16. Hope CK, Wilson M (2004) Analysis of the effects of
surface, driving fluoride deep into the lesion more chlorhexidine on oral biofilm vitality and structure
effectively together with disruption of plaque and based on viability profiling and an indicator of mem-
brane integrity. Antimicrob Agents Chemother 48:
specific targeting of bacterial acid production
1461–1468
seem the most promising way forward. 17. van Loveren C, Buijs JF, Ten Cate JM (2000) The
effect of triclosan toothpaste on enamel demineralisation
in a bacterial demineralisation model. J Antimicrob
Chemother 45:153–158
References 18. Pearce EI, Schamschula RG, Cooper MH (1983)
Increases in fluoride, calcium and phosphate in dental
1. Oral health means more than just good teeth. www.oral- plaque resulting from the use of a mineralising mouth-
healthplatform.eu. As available on 1 Aug 2013 wash containing urea and monofluorophosphate.
2. Johansen E (1965) Comparison of the ultrastructure J Dent Res 62:818–820
and chemical composition of sound and carious 19. Cochrane NJ, Cai F, Huq NL, Burrow MF, Reynolds
enamel from human permanent tooth. In: Stack MV, EC (2010) New approaches to enhanced remineralisa-
Fearnhead RW (eds) Tooth enamel, its composition, tion of tooth enamel l. J Dent Res 89:1187–1197
properties, and fundamental structure. John Wright & 20. Featherstone JD (1999) Prevention and reversal of
Sons Ltd., Bristol, pp 177–181 dental caries: role of low level fluoride. Community
3. Boyde A (1989) Enamel. In: Oksche A, Vollrath L Dent Oral Epidemiol 27:31–40
(eds) Handbook of microscopic anatomy, vol V/6, 21. Marinho VC, Higgins JP, Sheiham A, Logan S (2003)
Teeth. Springer, Berlin, p 309 Fluoride toothpastes for preventing dental caries in
92 C. Robinson
children and adolescents. Cochrane Database Syst 24. Li Y, Decker S, Yuan ZA, DenBesten PK, Aragon
Rev (1):CD002278 MA, Jordan-Sciutto K, Abrams WR, Huh J,
22. Watson PS, Pontefract HA, Devine DA, Shore RC, McDonald C, Chen E, MacDougall M, Gibson CW
Nattress BR, Kirkham J, Robinson C (2005) (2005) Effects of fluoride on the actin cytoskele-
Penetration of fluoride into natural plaque biofilms. ton of murine ameloblasts. Arch Oral Biol 50:
J Dent Res 84:451–455 681–688
23. Robinson C, Connell S, Kirkham J, Brookes SJ, Shore 25. Fawell J, Bailey K, Chikton E, Dahi E, Fewtrell L,
RC, Smith AM (2004) The effect of fluoride on the Magara Y (2006) Fluoride in drinking water. WHO,
developing tooth. Caries Res 38:268–276 IWA Publishing, London, Seattle
Osteoporosis
Fracture risk
formation and suppresses calcium (Ca2+) absorp- nuclear factor-κB ligand (RANKL, see chapter
tion), malabsorption, idiopathic hypercalciuria “Overview” under part “Teeth and bones”) in
(excess of urine calcium excretion without an bone marrow cells, whereas estrogens stimu-
apparent underlying etiology, due to genetic late the production of its soluble decoy receptor
causes), or endocrine diseases, such as primary osteoprotegerin in osteoblasts. Estrogen defi-
hyperparathyroidism or hyperthyroidism (all ciency also stimulates bone resorption by indirect
related to an imbalance of hormones affecting effects, in particular via cells of the immune sys-
bone metabolism). tem and proinflammatory cytokines (see below).
Moreover, estrogens modulate Ca2+ absorption
and excretion.
Endocrine Factors These effects are often exacerbated by vitamin
D insufficiency (calcidiol <50 nmol/l), which
Ca2+ and phosphate (PO43−, Pi) are essential compo- induces secondary hyperparathyroidism (mean-
nents for bone mineral formation and their avail- ing increased PTH). Impaired vitamin D synthe-
ability is mainly regulated by parathyroid hormone sis in skin and reduced renal hydroxylation in old
(PTH, increasing bone resorption) and vitamin D age lead to low calcitriol levels.
(increasing Ca2+ and Pi absorption, see chapter Renal synthesis of calcitriol is regulated not
“Overview” under part “Teeth and bones”). only by PTH but also by insulin-like growth
One major cause of osteoporosis is the decline factor-1 (IGF-1). IGF-1 is produced in the liver
in estrogens after menopause but also in men, in response to growth hormone (somatotro-
resulting in a negative balance in bone remode- pin) from the pituitary (see chapter “Overview”
ling. Estrogens control bone remodeling by under part “Brain”) and dietary animal protein
estrogen receptors on osteoblasts and osteoclasts. intake, as a diet rich in amino acids is a com-
Estrogen deficiency promotes osteoclastogen- mon inducer of growth. IGF-1 is an important
esis by upregulating the receptor activator of regulator of muscle and bone growth, acting as
Osteoporosis 95
falls, mechanical stimuli targeting osteocytes, monoclonal antibody that selectively inhibits the
and muscle strength. Mechanical loading also RANKL. The only bone anabolic agent (promot-
prevents the expression of sclerostin, a negative ing bone formation) for the treatment of osteopo-
regulator of bone formation produced by osteo- rosis is truncated or full-length PTH. Teriparatide,
cytes, inducing new bone formation. the first 34 amino acids of human PTH, was the
first anabolic agent based on the effects of PTH
on bone turnover that depend on the pattern and
Anti-osteoporotic Drugs duration of its elevation. While hyperparathy-
roidism is associated with increased bone resorp-
The primary objective of all anti-osteoporotic tion, daily administration of teriparatide results
drugs is to reduce fracture risk, by improving in upregulation of bone formation on the skele-
bone strength. Except for hormone replace- ton. Strontium ranelate reduces fracture risk both
ment therapy (HRT), the efficacy of all drugs by inhibiting bone resorption and stimulating
was tested in patients receiving a combination bone formation, through various mechanisms not
of Ca2+ and vitamin D (Table 1) [11]. HRT was yet fully elucidated.
commonplace in the treatment or prevention of
osteoporosis, but its indication is now reduced
because of an increased risk of breast cancer (see Perspectives
chapter “Breast cancer”), cardiovascular disease
(see chapter “Atherosclerotic heart disease”), Osteoporosis is a common disorder associated
and stroke (see chapter “Stroke”) induced by the with high morbidity and increased mortality,
estrogens [12]. which can be easily diagnosed based on clinical
Most of the more recent drugs (Table 1) risk factors and BMD assessment. Its prevention
decrease bone resorption: bisphosphonates, is feasible by cost-effective strategies targeting
denosumab, and SERMs (selective estrogen- risk factors or drugs modifying bone turnover.
receptor modulators). With population aging and increased life expec-
Bisphosphonates were the first of these and tancy, long-term treatment of osteoporosis needs
are still the most common treatment. They inhibit to consider sequential therapeutic strategies.
osteoclastic resorption. Selective estrogen- Promising drugs currently under investigation
receptor modulators, nonsteroidal agents that include an oral drug that inhibits the bone resorp-
bind to estrogen receptors (see chapter “Breast tion enzyme cathepsin K (odanacatib) and anti-
cancer”), act as estrogen agonists on bone. More sclerostin monoclonal antibodies (romosozumab)
recently, denosumab was developed, a humanized that stimulate bone formation by osteoblasts.
Table 1 Pharmacological agents preventing fracture risk used in postmenopausal osteoporosis
Drug class Drug molecules Bone targets and mechanism Effects on Bone remodeling Side/off-target effects and adverse effects
of action Bone resorption Bone formation
Osteoporosis
Bisphosphonates Alendronate, Inhibitors of bone resorption: Oral: low bioavailability due to low absorption in
risedronate, Inhibit osteoclast activity Induce gastrointestinal (<1 %)
ibandronate, osteoclast apoptosis Long-lasting remanent protection of bone
zoledronate, Oesophageal irritation
Flu-like symptoms after intravenous injection
Osteonecrosis of the jaw in patients receiving high doses
Atypical fractures of the femur with long-term use
SERMs Raloxifene, Inhibitors of bone resorption: Risk of invasive breast cancer due to estrogen antagonist
bazedoxifene Nonsteroidal agents that bind to effects
the estrogen receptor and act as Deep venous thromboembolism
estrogen agonists on bone
Anti-RANKL Denosumab Inhibitors of bone resorption: Possible adverse immune effects (dermatological side
monoclonal Humanized monoclonal antibodies effects and skin infection)
antibodies binding to RANKL. Prevent the Hypocalcemia
effect of RANKL on osteoclasts Possibly associated with osteonecrosis of the jaw and
differentiation, activation, and atypical fractures of the femur
survival
PTH Teriparatide Activators of bone formation: Contraindicated in conditions with abnormally increased
Number and activity of bone turnover, in patients with prior radiation therapy to
osteoblasts the skeleton, skeletal malignancies, or bone metastases
Limited to 24 months (risk of osteosarcoma)
Strontium ranelate Mixed effect on bone resorption Venous thromboembolism risk
and formation: Inhibits bone Isolated cases of drug rash with eosinophilia and systemic
resorption and stimulates bone symptoms
formation
SERM selective estrogen-receptor modulator, RANKL receptor activator of nuclear factor-κB ligand
97
98 E. Biver and R. Rizzoli
Anatomy and Physiology of Joints range of movement. The ends of the opposing
skeletal elements in synovial joints are covered
Joints Classification with articular cartilage. The spaces between the
bones in synovial joints are filled with synovial
Joints are locations at which two or more bones fluid, which helps to lubricate and protect the car-
come together. They are often constructed to tilage and nourishes the tissues. The joint is sur-
allow movement and provide mechanical support. rounded by the synovial membrane and held
Joints can be classified functionally based on the together by the fibrous joint capsule (that insulates
amount of movement allowed: “synarthroses” are the joints from surrounding tissues) and ligaments
immovable, “amphiarthroses” are slightly mov- (that hold the skeletal elements in place) [1].
able, and “diarthroses” are freely movable. Synovial joints can be distinguished again into
Joints can also be classified structurally, six different types depending on the mobility and
describing how the bones connect to each other, as type of movement they allow for: gliding, hinge,
fibrous, cartilaginous, and synovial. Synarthroses pivot, condyloid, saddle, “ball and socket,” and
are fibrous joints that connect bones without compound joints.
allowing any movement and are found, for exam- The following passages will describe the dif-
ple, in the skull and pelvis and at the union of the ferent structures of synovial joints, with special
spinous processes and vertebrae. In cartilaginous emphasis on biochemical processes that play a
joints (amphiarthroses), the bones are attached by role during joint homeostasis.
cartilage, and they allow for only a little move-
ment, such as in the spine or ribs. Synovial joints,
also called diarthroses, are of crucial importance Joint Formation
for the skeletal function, as they permit a wider
A process called endochondral ossification medi-
ates the formation of long bones and thereby the
formation of articular joints in arms and legs (see
J. Bertrand (*)
Institute of Experimental Musculoskeletal chapter “Overview” under part “Teeth and
Medicine IEMM, University Hospital Muenster, bones”). During the differentiation of mesenchy-
Domagkstrasse 3, Muenster 48149, Germany mal cells into chondrocytes, the expression pat-
e-mail: bertrand@uni-muenster.de
tern of extracellular matrix proteins changes.
J. Hubert While the expression of collagen I decreases,
Klinik und Poliklinik für Orthopädie,
chondrocytes start producing collagens II, IX, and
Universitätsklinikum Hamburg-Eppendorf,
Martinistrasse 52, Hamburg 20246, Germany XI as well as proteoglycans like aggrecan, link
e-mail: j.hubert@uke.de protein, and matrix Gla protein [2]. At the ends of
the bones, this composition of cartilage matrix is remodeling in both physiological and pathologi-
retained, and the chondrocytes do not differentiate cal conditions. Canonical Wnt signaling pro-
any further and form the articular cartilage. motes differentiation of osteoblast precursor cells
In the bone-forming parts of the embryonic (Fig. 1) [8, 9]. Additionally, this pathway sup-
cartilage, chondrocytes differentiate further and presses bone resorption by shifting the RANKL/
become hypertrophic. As part of their hypertro- OPG ratio towards OPG in mature osteoblasts
phic differentiation, they start to express collagen [10]. However, the activation of the noncanonical
X. With beginning bone formation, cartilage pathway enhances the RANKL-induced osteo-
undergoes vascularization [2, 3], and the extra- clast formation [11].
cellular matrix gets mineralized. Subsequently, a
continuous cycle of bone remodeling starts,
driven by resorbing osteoclasts and bone-forming Cartilage
osteoblasts (see chapter “Overview” under part
“Teeth and bones”). Cartilage is a flexible form of connective tis-
During osteoarthritis (see chapter sue. The predominant form is hyaline cartilage,
“Osteoarthritis”), however, articular chondrocytes named after its glassy, translucent appearance.
also undergo prehypertrophic to hypertrophic It is commonly associated with the skeletal
maturation. This differentiation is accompanied system, as it covers the bones and represents
by an increase in expression of certain marker the articular cartilage in joints. It is also found
genes, such as alkaline phosphatase [4] and col- between the ribs and the sternum or breast-
lagen X [5], with subsequent mineralization of the plate, in the trachea and bronchi of the lungs,
diseased cartilage [5]. in the ear, and in the larynx or voice box.
Macroscopically, articular cartilage can be
divided into the superficial zone, the transi-
Joint-Specific Pathways tional zone, the radial zone, and the calcified
and Processes cartilage zone, where the cartilage interfaces
with the bone (Fig. 1) [12]. These zones are
Bone characterized by a distinct organization of the
collagen network, as well as by differences in
The aforementioned balance between bone forma- the amounts and types of proteoglycans. Type
tion and resorption is regulated by macrophage II collagen is the principal molecular compo-
colony-stimulating factor (M-CSF) and receptor nent in healthy articular cartilage, but colla-
activator of nuclear factor-κB ligand (RANKL) [6, gens III, VI, IX–XII, and XIV all contribute in
7]. M-CSF is constitutively expressed in osteo- smaller amounts to the mature matrix [13–15],
blasts and binds to receptors on monocytes, mac- whereas the collagens IX, X, and XI are spe-
rophages, and osteoclasts, thereby inducing cific for cartilage tissue. The main proteoglycan
osteoclast maturation and differentiation. RANKL, is aggrecan. It is important for the biomechani-
however, is mainly expressed in osteoblasts in cal properties of articular cartilage because it
response to factors that stimulate bone resorption, builds a hydrated gel structure due to its inter-
such as parathyroid hormone and calcitriol. action with hyaluronan and link protein. Due to
RANKL binds to its receptor on osteoclast precur- these properties of aggrecan, the cartilage is a
sors, initiating their maturation. Bone resorption rigid and reversibly deformable tissue that has
induced by RANKL can be blocked by osteoprote- the ability to resist compression.
gerin (OPG), which is also secreted by osteoblasts The only cells found in cartilage are chondro-
and osteogenic stromal stem cells (see chapter cytes. In adult cartilage, the chondrocytes remain
“Overview” under part “Teeth and bones”). resting in a non-proliferating state, but display
The Wnt signaling pathways (canonical moderate metabolic activity and the ability to
and noncanonical) play a central role in bone maintain the surrounding matrix.
Overview 103
Patella
Femur
Tenocytes
Cartilage
Calcified zone
Subchondral bone
Radial
Ligaments
Transitional
Superficial
Meniscus Cartilage zones
Synovial Wnt
membrane
Osteoblast RANKL
OPG
Fibula
Osteoclast
Tibia
Bone
Fig. 1 Macroscopic and microscopic diagram of the the right depict magnifications of important structures and
anatomy of the human knee. The knee is a synovial joint; tissue-specific pathways showing, from top to bottom,
its anatomical structures, bones (patella, femur, fibula, tendon, cartilage, and bone. Please note that the cartilage
and tibia), ligaments, and meniscus are shown (to the left), zones do not extend along the cartilage but into it, toward
including the different cell compartments. The inserts to the femur, as indicated by the small gray box
Ligaments and Tendons Tendons are responsible for the power trans-
mission as well as for the stabilization of joints
Tendons and ligaments are tough, fiber-rich con- and skeletal elements. In tendons the collagenous
nective tissues characterized by their excellent fibers, which are parallel and oriented in tensile
tensile strength. Both consist of fibroblasts (in direction, are divided by septa of loose connec-
tendons called tenocytes), which have long tive tissue (peritendineum) to separate bundles.
extensions that are located in rows in between On the outside, the tendon is enveloped by a
the collagen fibrils, and the proteoglycan matrix white fibrous sheath called epitendineum, which
that is synthesized by the fibroblasts into the merges into the perimysium, the connective tis-
intercellular space (Fig. 1). The collagen fibrils sue surrounding the muscle.
consist primarily of collagen type I and very Ligaments mediate the guidance of joints and
small amounts of elastin and other collagens skeletal elements. They are coarse, fiber-rich
(types II–V, IX, and X). connective tissues that connect different skeletal
104 J. Bertrand and J. Hubert
Synovial fluid
Production of:
Collagen I
Hyaluronan
Fibronectin
Type B
synoviocytes
Lining layer
Phagocytosis
Sublining layer
Blood vessels
Type A Activation
synoviocyte Cytokines
Fig. 2 Schematic view of the synovial membrane (or functions of these cell types are shown in black. The dif-
synovium) and its cell types. Type A synoviocytes are ferent layers of the synovium are labeled on the right side.
resident macrophages, which are rare in healthy synovium, As depicted, the sub-lining is extensively vascularized
and type B synoviocytes are fibroblast-like cells. Basal
elements and have mainly stabilizing functions. four to five cell layers thick and has no basement
The histological structure of the ligament is very membrane, which makes it differ significantly from
similar to the structure of tendons. regular epithelium. The composition of the
Damage of these structures due to a trauma com- synovium is very variable, but mostly has two lay-
monly leads to an impairment of the joint function ers: the superficial layer of the synovium is called
and may possibly result in changes of its biomechani- lining layer and can be separated histologically
cal properties and subsequent osteoarthritis (see from the more loose network of fibroblast under-
chapter “Osteoarthritis”) [16]. Inflammatory pro- neath, which is called sub-lining (Fig. 2). It consists
cesses, like in rheumatoid arthritis (see chapter of two cell types, fibroblasts and macrophages,
“Rheumatoid arthritis”), can cause a chronic damage which both differ from similar cells in other tissues.
to the tendons, tendon sheaths, the articular capsule, The (resident) macrophages are called type A syn-
and the ligaments, thus deforming the joints [17]. oviocytes and are rare in healthy synovium. Their
main function is phagocytosis of undesirable sub-
stances from the synovial fluid, such as cell debris
Synovium and dead cell tissues. The fibroblast-like type B syn-
oviocytes provide the synovial cavity with lubricat-
The synovial membrane (or synovium, Fig. 2) is ing factors and produce components of the
specific to synovial joints and seals the synovial extracellular matrix, including hyaluronan, colla-
fluid from the surrounding tissue. It is only about gens, and fibronectin. The superficial layer is called
Overview 105
lining layer. This layer of cells lacks the basement tissue. Due to these inflammatory conditions,
membrane and thereby facilitates the rapid exchange there is an increase in vascularization of the sub-
of nutrients between blood and the synovium. lining, facilitating the accumulation of immune
The sub-lining is intensely vascularized, cells and perpetuating possible autoimmune pro-
providing nutrients to the synovium and the avas- cesses. These processes together lead to hyper-
cular cartilage. During rheumatoid arthritis, type plasia of the synovial membrane, and the resulting
B synoviocytes undergo stable activation, mean- tissue is called pannus tissue [21].
ing that they proliferate more and produce proin-
flammatory cytokines (see chapter “Rheumatoid
arthritis”). Final Remarks
8. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, hyaline cartilages of the pig. Biochem J 151:
Glass DA 2nd, Hartmann C, Li L, Hwang TH, Brayton 595–602
CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1- 15. Burgeson RE, Hebda PA, Morris NP, Hollister DW
independent decrease in osteoblast proliferation, (1982) Human cartilage collagens. Comparison of
osteopenia, and persistent embryonic eye vascularization cartilage collagens with human type V collagen.
in mice deficient in Lrp5, a Wnt coreceptor. J Cell J Biol Chem 257:7852–7856
Biol 157:303–314 16. Fleming BC, Hulstyn MJ, Oksendahl HL, Fadale PD
9. Clement-Lacroix P, Ai M, Morvan F, Roman-Roman (2005) Ligament injury, reconstruction and osteoar-
S, Vayssière B, Belleville C, Estrera K, Warman ML, thritis. Curr Opin Orthop 16:354–362
Baron R, Rawadi G (2005) Lrp5-independent activa- 17. Ash Z, McGonagle D (2011) Joint appendages: the
tion of Wnt signaling by lithium chloride increases structures which have historically been overlooked in
bone formation and bone mass in mice. Proc Natl arthritis research and therapy development. Best Pract
Acad Sci U S A 102:17406–17411 Res Clin Rheumatol 25:779–784
10. Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel 18. Dreier R (2010) Hypertrophic differentiation of chon-
MS, Clevers H, Taketo MM, Long F, McMahon AP, drocytes in osteoarthritis: the developmental aspect
Lang RA, Karsenty G (2005) Canonical Wnt signal- of degenerative joint disorders. Arthritis Res Ther
ing in differentiated osteoblasts controls osteoclast 12:216
differentiation. Dev Cell 8:751–764 19. Mayan MD, Carpintero-Fernandez P, Gago-Fuentes
11. Tu X, Joeng KS, Nakayama KI, Nakayama K, R, Martinez-de-Ilarduya O, Wang HZ, Valiunas V,
Rajagopal J, Carroll TJ, McMahon AP, Long F (2007) Brink P, Blanco FJ (2013) Human articular chondro-
Noncanonical Wnt signaling through G protein-linked cytes express multiple gap junction proteins: differential
PKCdelta activation promotes bone formation. Dev expression of connexins in normal and osteoarthritic
Cell 12:113–127 cartilage. Am J Pathol 182:1337–1346
12. Wong M, Carter DR (2003) Articular cartilage func- 20. Smith MD, Barg E, Weedon H, Papengelis V, Smeets
tional histomorphology and mechanobiology: T, Tak PP, Kraan M, Coleman M, Ahern MJ (2003)
a research perspective. Bone 33:1–13 Microarchitecture and protective mechanisms in
13. Poole AR, Kojima T, Yasuda T, Mwale F, Kobayashi synovial tissue from clinically and arthroscopically
M, Laverty S (2001) Composition and structure of normal knee joints. Ann Rheum Dis 62:303–307
articular cartilage: a template for tissue repair. Clin 21. Neumann E, Lefevre S, Zimmermann B, Gay S,
Orthop Relat Res 391(Suppl):S26–S33 Muller-Ladner U (2010) Rheumatoid arthritis pro-
14. Eyre DR, Muir H (1975) The distribution of different gression mediated by activated synovial fibroblasts.
molecular species of collagen in fibrous, elastic and Trends Mol Med 16:458–468
Osteoarthritis
Osteoarthritis (OA) is the most common form of OA is a multifactorial disease resulting in the fail-
arthritis, affecting 13.9 % of US adults aged 25 ure of the articular tissues to maintain a homeo-
and older, totaling 26.9 million [1]. OA is charac- static balance between matrix synthesis and
terized by degradation and loss of articular carti- degradation. An initial phase of cartilage remod-
lage, hypertrophic bone changes with osteophyte eling is characterized by edema, followed by deg-
formation (bony projections along the joint mar- radation and loss of this tissue. These alterations
gin), subchondral bone remodeling, and inflam- are associated with synovial inflammation and
mation of the synovial membrane. Other tissues subchondral bone remodeling (Fig. 1).
of the joint including the muscles and ligaments In cartilage, there is only one type of cell, the
are also altered during the OA process. chondrocyte, which is responsible for the mainte-
OA can be triggered by external factors such nance of this tissue’s extracellular matrix (ECM,
as trauma and endogenous predisposing factors see chapter “Overview” under part “Joints”).
including age, genetics, and high body mass Early during the OA process, increased biome-
index. It results in pain, reduced quality of life, chanical stress and/or biochemical stimuli can
and disability necessitating joint replacement in activate the anabolic function of chondrocytes to
end-stage disease. repair early cartilage damage. Over time, this
Important advances have been made in under- anabolic attempt fails and leads to an imbalance
standing its pathological processes, and promis- favoring degradation. This degradation will
ing new disease-modifying OA drugs (DMOADs) induce a vicious circle, in which the degradative
are being developed that will slow the progres- fragments of ECM proteins (e.g., fibronectin and
sion of the disease and improve the current symp- collagen) induce synovial membrane inflamma-
tomatic treatment. tion, which in turn will produce catabolic and
inflammatory factors [2, 3], thus aggravating the
OA process. Increasing evidence suggests that in
OA there is a cross talk between the cartilage,
synovial membrane, and subchondral bone,
C. Roubille • J. Martel-Pelletier • J.-P. Pelletier (*)
Osteoarthritis Research Unit, which sustains the catabolic process [4, 5].
University of Montreal Hospital Synovial inflammation, which is suggested to be
Research Centre (CRCHUM), secondary to the release of cartilage products into
900 Saint-Denis, Tour Viger, Montreal,
the synovial fluid, and subchondral bone remod-
QC H2X 0A9, Canada
e-mail: camille.roubille@gmail.com; eling by its release of soluble mediators, affects
jm@martelpelletier.ca; dr@jppelletier.ca the cartilage by sustaining its degradation. The
Education
Weight loss
Osteophytes
Subchondral bone
remodeling
Fig. 1 A model of global pathophysiology of knee osteo- reduced quality of life. Current osteoarthritis management
arthritis and of current multimodal management. consists of education (on osteoarthritis, its progression,
Osteoarthritis can be triggered by external factors includ- and its risk factors), weight loss (if necessary), prevention
ing trauma and endogenous predisposition factors such as of injury, exercise, and pharmacological symptomatic
age, genetics, and high body mass index (BMI). After an treatment. Common treatments include acetaminophen
initial phase of cartilage edema, cartilage damage and loss (paracetamol), nonsteroidal anti-inflammatory drugs
occurs, which is associated with synovial inflammation, (NSAIDs), opioids, intra-articular (IA) administration of
osteophyte formation, and subchondral bone remodeling. hyaluronate and corticosteroids, and symptomatic slow-
These structural changes generate pain, disability, and acting drugs (SYSADOA)
chondrocytes (autocrine pathway) and synovio- inhibitors of MMPs (TIMPs) and proinflamma-
cytes (see chapter “Overview” under part tory cytokine inhibitors including the IL-1β
“Joints”) in the synovial membrane (paracrine receptor antagonist (Fig. 2). Additionally, in OA,
pathway) release catabolic and proinflammatory the loss of integrity of the osteochondral junction
substances. These include proteinases, e.g., is associated with microcracks and the invasion
matrix metalloproteinases (MMPs) and aggreca- of articular cartilage by vascular channels origi-
nases, and inflammatory cytokines, including nating from the subchondral bone, supporting the
interleukin (IL)-1β and tumor necrosis factor α molecular cross talk between the subchondral
(TNFα), which enhance the synthesis of protein- bone and the cartilage. Continued ECM degrada-
ases and other catabolic factors to degrade the tion in the articular tissues results, preventing the
ECM of the articular tissues. Soon, these factors cartilage from withstanding normal mechanical
overwhelm endogenous inhibitors, such as tissue factors.
Osteoarthritis 109
Anti-bone remodeling
Anti-IL-1b Synovial
inflammation
Anti-TNFa
Subchondral bone
remodeling IL-1β
BMPs TNFα
BML Osteophytes TGF-β Cytokines
BML IGF-1
Aggrecanases Stably activated
TIMPs
Anti-MMPs/ type B
MMPs
-aggrecanases IL-1Ra synoviocyte
BML Anti-cytokine Cytokines
Anabolism,
Anti-NO NO Repair
Degradation/
Inflammation
BMP-7 injection
MMPs
Aggrecanases
Activated
Proteases
chondrocyte
Cartilage
Anti-NF-kB NF-kB degradation
Anti-p38 MAPK (p38) Cartilage
debris
Incomplete
repair
Fig. 2 A model of cross talk between cartilage, synovial inflammation. The attempt to repair, which could occur
membrane, and subchondral bone leading to an imbalance via growth factors such as bone morphogenetic proteins
favoring articular tissue degradation in knee osteoarthri- (BMPs) and transforming growth factor β (TGF-β), fails
tis. Excessive production of proteases such as matrix to achieve a complete repair of the extracellular matrix.
metalloproteinases (MMPs) and aggrecanases, nitric Disease-modifying osteoarthritis drugs, such as inhibitors
oxide (NO), and inflammatory cytokines, such as of MMPs and aggrecanases, anti-cytokine therapy, anti-
interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) bone remodeling, anti-nuclear factor-κB (NF-κB), and
by the chondrocyte contributes to the degradation of artic- anti-mitogen-activated protein kinase (MAPK), have been
ular tissue including the cartilage. This induces a vicious developed, which aim to inhibit these factors and path-
circle in which the cartilage fragments activate synovio- ways. BML bone marrow lesion, IGF-1 insulin-like
cytes (see chapter “Overview” under part “Joints”), result- growth factor 1, IL-1Ra interleukin-1β receptor antago-
ing in enhanced cartilage degradation and synovial nist, TIMPs tissue inhibitors of metalloproteinases
Diarrhea is the most frequent adverse event, hand [22] and knee OA [23], but the results are
which likely occurs due to prostaglandin synthe- still controversial [24].
sis induced by rhein, the active metabolite of dia-
cerein, leading to an increase in gut motility.
Treatment with avocado-soybean unsaponifi- Targeting Subchondral Bone
ables reduces pain in knee and hip OA persis- Remodeling
tently, and the effect is prolonged even after
treatment discontinuation [17, 18]. Inhibition of Strontium ranelate inhibits bone resorption
IL-1β and MMPs has been proposed as potential in subchondral bone [25]. This results from
mechanisms of action. decreased differentiation and resorptive activity
of osteoclasts and increased osteoclast apoptosis
[26]. Strontium ranelate reduces the progression
Disease-Modifying of spinal [27] and knee OA, as assessed in a
Osteoarthritis Drugs Phase III trial by both X-rays [28] and MRI [29].
Risedronate, a bisphosphonate with anti-
Currently, several classes of DMOADs are in resorptive properties, preserves the structural
development or tested in clinical trials (Fig. 2). integrity of the subchondral bone [30], but in a
Phase III clinical trial, no significant effect was
found on the Western Ontario and McMaster
Targeting Cartilage Catabolism Universities Arthritis Index (WOMAC) or radio-
and Anabolism graphic progression in knee OA [31].
In vitro, calcitonin reduces collagen degrada-
MMP inhibitors aim to block ECM degrada- tion by inhibiting the expression and activity of
tion. One such drug, doxycycline, showed only MMPs in chondrocytes [32]. Oral and nasal
a minimal structural benefit and no effect on applications of this thyroid hormone involved in
pain in a clinical trial [19]. An inhibitor of calcium homeostasis are currently being tested
inducible NO synthase (cindunistat) revealed a [33]. Recently, a Phase III clinical trial was ter-
reduction in joint space narrowing in mild OA minated early, probably due to an imbalance in
in the first year [20]. Finally, intra-articular prostate cancer events in male subjects [34].
injection of growth factors such as bone mor- Vitamin D supplementation in one study did
phogenetic protein 7 (BMP7) aims to repair OA not show any symptom or DMOAD benefits [35].
cartilage. However, another clinical trial evaluating whether
vitamin D supplementation can slow knee OA
progression is ongoing [36].
Targeting Synovial Inflammation A Phase III study evaluating the recombinant
by Anti-cytokine Therapy human FGF-18 in patients with knee OA is also
currently underway [37].
Blockade of inflammatory cytokines focuses on
IL-1β and TNFα. Other potential targets include
IL-6, nuclear factor-κB (NF-κB), and mitogen- Perspectives
activated protein kinase (MAPK), as they are
part of the inflammation cascade in OA. Intra- OA management is based on a wide spectrum of
articular administration of the IL-1β receptor therapeutic options to relieve pain and to try to
antagonist anakinra shows controversial results delay progression. The focus is now on the devel-
with regard to symptoms [21], probably due to opment of DMOADs that could be associated with
the short half-life of the drug and the protocol conventional therapy to provide a more effective
used for the clinical studies so far. Moreover, treatment, which remains a huge unmet medical
two antibodies against TNFα (adalimumab, inf- need worldwide given that OA prevalence is likely
liximab) were shown to relieve symptoms of to increase with the aging population.
112 C. Roubille et al.
22. Fioravanti A, Fabbroni M, Cerase A, Galeazzi M 31. Bingham CO 3rd, Buckland-Wright JC, Garnero P,
(2009) Treatment of erosive osteoarthritis of the hands Cohen SB, Dougados M, Adami S, Clauw DJ, Spector
by intra-articular infliximab injections: a pilot study. TD, Pelletier JP, Raynauld JP, Strand V, Simon LS,
Rheumatol Int 29:961–965 Meyer JM, Cline GA, Beary JF (2006) Risedronate
23. Maksymowych WP, Russell AS, Chiu P, Yan A, Jones decreases biochemical markers of cartilage degrada-
N, Clare T, Lambert RG (2012) Targeting tumour tion but does not decrease symptoms or slow radio-
necrosis factor alleviates signs and symptoms of graphic progression in patients with medial
inflammatory osteoarthritis of the knee. Arthritis Res compartment osteoarthritis of the knee: results of the
Ther 14:R206 two-year multinational knee osteoarthritis structural
24. Verbruggen G, Wittoek R, Vander Cruyssen B, arthritis study. Arthritis Rheum 54:3494–3507
Elewaut D (2012) Tumour necrosis factor blockade 32. Sondergaard BC, Wulf H, Henriksen K, Schaller S,
for the treatment of erosive osteoarthritis of the inter- Oestergaard S, Qvist P, Tanko LB, Bagger YZ,
phalangeal finger joints: a double blind, randomised Christiansen C, Karsdal MA (2006) Calcitonin
trial on structure modification. Ann Rheum Dis 71: directly attenuates collagen type II degradation by
891–898 inhibition of matrix metalloproteinase expression and
25. Tat SK, Pelletier JP, Mineau F, Caron J, Martel-Pelletier activity in articular chondrocytes. Osteoarthritis Cartilage
J (2011) Strontium ranelate inhibits key factors affect- 14:759–768
ing bone remodeling in human osteoarthritic sub- 33. Esenyel M, Icagasioglu A, Esenyel CZ (2013) Effects
chondral bone osteoblasts. Bone 49:559–567 of calcitonin on knee osteoarthritis and quality of life.
26. Martel-Pelletier J, Wildi LM, Pelletier JP (2012) Future Rheumatol Int 33:423–427
therapeutics for osteoarthritis. Bone 51:297–311 34. Nordic Bioscience A/S; Novartis. Efficacy and safety
27. Bruyere O, Delferriere D, Roux C, Wark JD, Spector of oral salmon calcitonin in patients with knee osteoar-
T, Devogelaer JP, Brixen K, Adami S, Fechtenbaum J, thritis (OA 2 Study). In: ClinicalTrials.gov [Internet].
Kolta S, Reginster JY (2008) Effects of strontium Bethesda (MD): National Library of Medicine (US).
ranelate on spinal osteoarthritis progression. Ann 2000- [cited 2014 Mar 5]. Available from http://
Rheum Dis 67:335–339 clinicaltrials.gov/show/NCT00704847NLMIdentifier:
28. Reginster JY, Badurski J, Bellamy N, Bensen W, NCT00704847
Chapurlat R, Chevalier X, Christiansen C, Genant H, 35. McAlindon T, LaValley M, Schneider E, Nuite M,
Navarro F, Nasonov E, Sambrook PN, Spector TD, Lee JY, Price LL, Lo G, Dawson-Hughes B (2013)
Cooper C (2013) Efficacy and safety of strontium Effect of vitamin D supplementation on progression
ranelate in the treatment of knee osteoarthritis: results of knee pain and cartilage volume loss in patients with
of a double-blind, randomised placebo-controlled symptomatic osteoarthritis: a randomized controlled
trial. Ann Rheum Dis 72:179–186 trial. JAMA 309:155–162
29. Pelletier J-P, Roubille C, Raynauld JP, Abram F, Dorais 36. Cao Y, Jones G, Cicuttini F, Winzenberg T, Wluka A,
M, Delorme P, Martel-Pelletier J (2013) Disease modi- Sharman J, Nguo K, Ding C (2012) Vitamin D supple-
fying effect of strontium ranelate in the Phase III knee mentation in the management of knee osteoarthritis:
osteoarthritis study SEKOIA using quantitative mag- study protocol for a randomized controlled trial.
netic resonance imaging: reduction in bone marrow Trials 13:131
lesions protects against cartilage loss. Ann Rheum Dis. 37. EMD Serono; Nordic Bioscience Clinical Development
doi: 10.1136/annrheumdis-2013-203989 AS, Herlev Denmark. A study to investigate the safety
30. Buckland-Wright JC, Messent EA, Bingham CO 3rd, and effectiveness of different doses of sprifermin
Ward RJ, Tonkin C (2007) A 2 yr longitudinal radio- (AS902330) in patients with osteoarthritis of the knee
graphic study examining the effect of a bisphospho- (FORWARD). In: ClinicalTrials.gov [Internet]. Bethesda
nate (risedronate) upon subchondral bone loss in (MD): National Library of Medicine (US). 2000- [cited
osteoarthritic knee patients. Rheumatology (Oxford) 2014 Mar 5]. Available from http://clinicaltrials.gov/
46:257–264 show/NCT01919164NLMIdentifier:NCT01919164
Rheumatoid Arthritis
IL-6
Androstenedione A
[17β-HSD]
TNF-α E
IL-1
IL-6
Macrophage
IgG A
Estrone Estradiol
E
B lymphocyte
Estrogens (E) Synovial
Androgens (A) inflammation IL-2
Synovial tissue INFγ DHEAS A
E
Synovial tissue
T lympho-
cyte
Testosterone
Th2
Fig. 1 Sex hormone synthesis pathways and their influence Effects of estrogens and androgens on the immune cells and
on cytokine expression in synovial cells. Left side: their cytokine production. Estrogens (E) may exert stimula-
Androgens (such as testosterone) and estrogens (such as tory effects on some activities of macrophages and T-helper
estrone and estradiol) originate from common precursors 2 (Th2) cells in producing inflammatory cytokines and
(see chapter “Overview” under part “Reproductive sys- induce B lymphocytes to secrete IgGs (immunoglobulins
tem”). Proinflammatory cytokines promote peripheral (incl. G). Androgens (A) have an inhibitory effect on the same
synovial) conversion of estrogens to androgens by acting on cells. TNFα tumor necrosis factor α, IL Interleukin, INFγ
the respective enzymes (light gray boxes). Right side: Interferon γ, 17β-HSD 17β-Hydroxysteroid dehydrogenase
cytotoxic T-helper type (Th1) to a humoral synovial tissue), convert peripheral androgens into
T-helper type 2 (Th2) immune reaction (see chap- proinflammatory estrogen metabolites. Fluctuation
ter “Overview” under part “Joints”). They also of symptoms in female RA patients during the
inhibit the production of proinflammatory cyto- menstrual cycle supports an important role of ste-
kines implicated in RA (see above). roid hormones in clinical RA manifestations [12].
Whereas an acute stimulus of the HPA axis More specifically, estrogens trigger the release of
triggers a physiological response to cope with proinflammatory cytokines (such as TNFα, IL-1,
stress, chronic stress, e.g., chronic inflammatory and IL-6) from macrophages and T lymphocytes
diseases or altered psychological status (see chap- via estrogen receptors A and B (Fig. 1, and see
ter “Major depressive disorder”), impairs and chapters “Overview” under part “Reproductive
reduces HPA axis activation and compensatory system” and “Breast cancer”). Effectively, this cre-
physiological actions [9]. The lack of HPA axis ates a vicious circle that aggravates RA [13, 14].
hormones (mainly cortisol and adrenaline), or the
reduced adrenal response to acute inflammation,
is frequent in RA and other chronic inflammatory The Vitamin D Endocrine System
conditions and contributes to disease progression.
The inhibition (or exhaustion) of the HPA axis The secosteroid vitamin D3 is generated from the
finally results in chronically elevated levels of backbone of cholesterol or ingested with the diet.
proinflammatory cytokine levels [10]. Therefore, Its inactive form cholecalciferol is created in the
depression and stressful life events are now recog- skin and further converted into the active forms
nized as main risk factors in chronic inflamma- calcidiol and calcitriol (in the liver and kidney,
tory/autoimmune diseases, notably in RA and respectively, see chapter “Overview” under part
systemic lupus erythematosus [11]. “Teeth and bones”). Too low levels of serum cal-
cidiol are a risk factor for developing autoimmune
diseases, such as RA, type 1 diabetes mellitus (see
The Hypothalamic- chapter “Diabetes mellitus”), and others [15, 16].
Pituitary-Gonadal Axis Vitamin D3 acts as an immune-modulatory mol-
ecule by binding to vitamin D receptors in immune
The hypothalamic-pituitary-gonadal (HPG) axis cells. Indeed, several of these cells (e.g., macro-
includes hypothalamic production of gonadotropin- phages) can even synthesize calcitriol themselves.
releasing hormone, subsequent secretion of folli- The latter can inhibit the differentiation of B
cle-stimulating hormone (FSH) and luteinizing lymphocytes into plasma cells and class-switched
hormone (LH) from the anterior lobe of the pitu- memory B cells and can downregulate Th1-
itary gland, and resultant synthesis of sex hor- dependent immune responses (see chapters
mones (estrogens and androgens) in female or “Overview” under part “Joints” and “Overview”
male gonads (see chapter “Overview” under part under part “Gastrointestinal tract”) [17]. In con-
“Reproductive system”). As sex hormones are ste- clusion, vitamin D3, cortisol, and sex hormones
roids, they arise from cholesterol and are structur- regulate both innate and adaptive immunity and
ally related to glucocorticoids, thus influencing thus influence RA development [18].
inflammatory cells [11]. Most importantly, andro-
gens generally prevent the release of proinflamma-
tory cytokines (such as TNFα, IL-1, and IL-6) Circadian Rhythms and the Immune
from immune cells (within the synovial tissue), System
whereas estrogens trigger their release (Fig. 1).
Sex hormones can also be created by peripheral Several clinical symptoms in immune-mediated
steroidal conversion (intracrine metabolism) from rheumatic diseases (such as RA) are aggravated in
precursors. Interestingly, aromatases, which are the early morning (particularly joint stiffness), since
increased in inflammatory tissues (like RA proinflammatory cytokines (such as IL-1, IL-6, and
118 M. Meroni et al.
Normal subjects
Anti-inflammatory
Cortisol
Inflammation
Melatonin
Night Pro-inflammatory
21:00 00:00 03:00 05:00 05:00
RA Patients
Steroid replacement
Anti-inflammatory
Cortisol
Inflammation
Melatonin
Night Pro-inflammatory
21:00 00:00 03:00 05:00 05:00
Fig. 2 Relatively impaired cortisol secretion in rheumatoid α (TNFα), interleukin (IL-)1, and IL-6 mediators at around
arthritis (RA) patients compared to healthy subjects. The 5 a.m. In healthy subjects the cortisol secretion is propor-
cortisol nadir at midnight and the parallel increase of the tional to melatonin levels, whereas in RA patient it is
immune-stimulatory hormone melatonin drive the increase impaired in relation to melatonin, thus favoring immune-
of nightly proinflammatory mediators (not shown). This inflammatory stimulation. This is the reason why steroid
triggers a delayed expression/release of cortisol, which replacement is mandatory as etiological treatment in RA
suppresses the surge in inflammatory tumor necrosis factor patients and in other inflammatory diseases
awakes in the morning at a time when joint stiff- 2. Hench PS, Slocumb CH, Holley HF, Kendall EC
(1950) Effect of cortisone and pituitary adrenocorti-
ness is already at a maximum. However, this is
cotropic hormone (ACTH) on rheumatic diseases.
not optimal. In fact, glucocorticoid administra- J Am Med Assoc 144:1327–1335
tion at 2–3 am is recommended, showing a more 3. Straub RH (2007) The complex role of estrogens in
marked and significant effect on morning stiffness inflammation. Endocr Rev 28:521–574
4. Webster JI, Tonelli L, Sternberg EM (2002)
and serum IL-6 decrease [22].
Neuroendocrine regulation of immunity. Ann Rev
Consequently, traditional drugs such as pred- Immunol 20:125–163
nisone (a synthetic corticosteroid with anti- 5. Engelmann M, Landgraf R, Wotjak C (2004) The hypo-
inflammatory effects and a short half-life) are thalamic-neurohypophysial system regulates the hypo-
thalamic-pituitary-adrenal axis under stress: an old
now administered considering circadian rhythms,
concept revisited. Front Neuroendocrinol 25:132–149
to optimize clinical efficacy (Fig. 2) [23]. This 6. Cutolo M, Straub RH, Chrousos GP (2007) Stress and
tailored administration has the advantage of min- autoimmunity. Neuroimmunomodulation 2006, 1st
imizing steroid treatment-related side effects, edn. Karger, Switzerland
7. Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010)
like systemic hypertension, hyperglycemia,
Energy regulation and neuroendocrine-immune con-
tachycardia, insomnia, osteopenia/osteoporosis, trol in chronic inflammatory diseases. J Intern Med
and, especially, HPA inhibition due to negative 267:543–560
feedback [24]. 8. Labrie F (1991) Intracrinology. Mol Cell Endocrinol
78:C113–C118
Finally, circannual supplementation therapy
9. Kanik KS, Chrousos GP, Schumacher HR, Crane ML,
with vitamin D (mainly at winter and spring Yarboro CH, Wilder RL (2000) Adrenocorticotropin,
time), in addition to release-modified glucocorti- glucocorticoid, and androgen secretion in patients
coids, seems to represent an effective NEI treat- with new onset synovitis/rheumatoid arthritis: rela-
tions with indices of inflammation. J Clin Endocrinol
ment strategy in RA management [25, 26].
Metab 85:1461–1466
The role of steroid hormone deficiency in the 10. Straub RH, Paimela L, Peltomaa R, Schölmerich J,
transition from chronic inflammation to cancer is Leirisalo-Repo M (2002) Inadequately low serum lev-
currently under investigation [27, 28] in particu- els of steroid hormones in relation to IL-6 and TNF in
untreated patients with early rheumatoid arthritis and
lar since RA patients seem at higher risk of devel-
reactive arthritis. Arthritis Rheum 46:654–662
oping cancer (see chapter “Overview” under par 11. Straub R, Buttgereit F, Cutolo M (2011) Alterations of
“Cancer”). the hypothalamic-pituitary-adrenal axis in systemic
immune diseases – a role for misguided energy regu-
lation. Clin Exp Rheumatol 29:S15–S23
12. Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson
Perspectives AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood
CS (2009) Identification of a regulatory loop for the
The action of different steroid hormones, influ- synthesis of neurosteroids: a steroidogenic acute
regulatory protein-dependent mechanism involv-
enced by the products of activated immune cells,
ing hypothalamic-pituitary-gonadal axis receptors.
triggers the immune-inflammatory response, tar- J Neurochem 110:1014–1027
gets the organs-specific microenvironments, and 13. Walker SE, Jacobson JD (2000) Roles of prolactin
influences the rhythms (circadian and circannual) and gonadotropin-releasing hormone in rheumatic
diseases. Rheum Dis Clin North Am 26:713–736
of several other hormones. New therapeutic strat-
14. Cutolo M, Pizzorni C, Sulli A (2011) Vitamin D endo-
egies are based on circadian/circannual rhythms crine system involvement in autoimmune rheumatic
and on the recent knowledge of the complex NEI diseases. Autoimmun Rev 11:84–87
system that is under such rhythm control. 15. Adams JS, Hewison M (2008) Unexpected actions of
vitamin D: new perspectives on the regulation of
innate and adaptive immunity. Nat Clin Pract
Endocrinol Metab 4:80–90
References 16. Cutolo M (2013) Further emergent evidence for the
vitamin D endocrine system involvement in autoim-
1. Hench PS (1938) The ameliorating effect of preg- mune rheumatic disease risk and prognosis. Ann
nancy on chronic atrophic (infectious, rheumatoid) Rheum Dis 72:473–475
arthritis, fibrositis, and intermittent hydrarthrosis. 17. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky
Proc Staff Meet Mayo Clin 13:161–167 PE (2007) Modulatory effects of 1,25 dihydroxyvitamin
120 M. Meroni et al.
D3 on human B cell differentiation. J Immunol release versus standard prednisone to reduce duration
179:1634–1647 of morning stiffness of the joints in rheumatoid arthri-
18. Cutolo M, Plebani M, Shoenfeld Y, Adorini L, Tincani tis (CAPRA-1): a double-blind, randomised con-
A (2011) Vitamin D endocrine system and the trolled trial. Lancet 371:205–214
immune response in rheumatic diseases. Vitam Horm 23. Cutolo M (2012) Chronobiology and the treatment of
86:327–351 rheumatoid arthritis. Curr Opin Rheumatol 24:
19. Straub RH, Cutolo M (2007) Circadian rhythms in 312–318
rheumatoid arthritis: implications for pathophysiol- 24. Cutolo M (2011) Rheumatoid arthritis: circadian and
ogy and therapeutic management. Arthritis Rheum circannual rhythms in RA. Nat Rev Rheumatol 7:
56:399–408 500–502
20. Cutolo M, Straub RH, Buttgereit F (2008) Circadian 25. Villaggio B, Soldano S, Cutolo M (2012)
rhythms of nocturnal hormones in rheumatoid arthri- 1,25-dihydroxyvitamin D3 downregulates aromatase
tis: translation from bench to bedside. Ann Rheum expression and inflammatory cytokines in human
Dis 67:905–908 macrophages. Clin Exp Rheumatol 30:934–938
21. Crofford LJ, Kalogeras KT, Mastorakos G, Magiakou 26. Cutolo M (2010) Hormone therapy in rheumatic dis-
MA, Wells J, Kanik KS, Gold PW, Chrousos GP, eases. Curr Opin Rheumatol 22:257–263
Wilder RL (1997) Circadian relationships between 27. Cutolo M (2012) The challenges of using vitamin D in
interleukin (IL)-6 and hypothalamic- pituitary-adrenal cancer prevention and prognosis. Isr Med Assoc J
axis hormones: failure of IL-6 to cause sustained hyper- 14:637–639
cortisolism in patients with early untreated rheumatoid 28. Cutolo M, Sulli A, Straub RH (2014) Estrogen’s
arthritis. J Clin Endocrinol Metab 82:1279–1283 effects in chronic autoimmune/inflammatory diseases
22. Buttgereit F, Doering G, Schaeffler A, Witte S, and progression to cancer. Expert Rev Clin Immunol
Sierakowski S, Gromnica-Ihle E, Jeka S, Krueger K, 10(1):31–39. doi:10.1586/1744666X.2014.863149.
Szechinski J, Alten R (2008) Efficacy of modified-
Part V
Gastrointestinal Tract
Overview
Stomach
Churn and mix
Protein digestion
Liver
Acid production:
Bile acids
Aids protein digestion
(aid lipid digestion)
Antimicrobial
First-pass organ of
Intrinsic factor
ingested metabolites
Iron reduction
Duodenum
Neutralization Pancreas
Protein, lipid, Digestive enzymes
carbohydrate digestion
Absorption:
Nutrients
Electrolytes and Jejunum
metal ions Digestion
Water Absorption:
Electrolyte-rich fluid
Ileum
Absorption:
Colon
Bile acids
Absorption:
Vitamin B12
Water
Role in immunity
Electrolytes
Bacterial metabolism
Fatty acid metabolism
Fig. 1 Overview of the gut with summary of main func- physiology is determined by the specialized cells lining
tions demonstrating absorption of water and electrolytes, the epithelium with absorption of different molecules in
carbohydrate, lipid, proteins, vitamins, and minerals. Gut different parts of the gut
the gastric mucosa binds to dietary cobalamin, Intestinal epithelial cells contribute to digestion
protecting it from digestion and enabling absorp- by secreting enzymes such as lactase (see chap-
tion in the terminal ileum (Fig. 1). ter “Lactose intolerance”) that are bound to
their surface and express in their cell mem-
branes protein transporters that enable nutrients
The Small Intestine: Duodenum, to pass from the lumen of the intestine into the
Jejunum, and Ileum epithelial cell and then out of the cell and into
the lymphatic and vascular circulation (lipo-
The small intestine is differentiated along its philic and hydrophilic substances, respec-
length, with distinct functions occurring in duo- tively). In addition, epithelial cells absorb elec-
denum, jejunum, and ileum. Acidic chyme from trolytes and metallic trace elements such as
stomach is released gradually into the duodenum, Na+, K+, Ca2+, Mg2+, Zn2+, Cu2+, and water.
where it is mixed with alkaline bile and pancre- Paracellular movement of water and electro-
atic secretions rich in HCO3–. The duodenal lytes also occurs, and the direction, either into
mucosa is specialized for absorption. or out of the lumen, depends on osmotic and
The pancreas produces the bulk of digestive ionic gradients. Tight junctions between epithe-
enzymes for carbohydrates, lipids, and proteins, lial cells are more effective distally, and para-
and bile acids contribute to the formation of cellular transport in the healthy intestine plays
mixed micelles of lipid, aiding their digestion. only a minor role.
Overview 125
Digestion and absorption continue in the jeju- essential fatty acids. Tight junctions between
num, where much of the electrolyte-rich fluid colonic epithelial cells prevent salt and water loss
that is secreted by the stomach, pancreas, and from the interstitial tissue space and limit the
duodenum is reabsorbed. Without this reabsorp- translocation of bacteria and toxins from the
tion, total body water, Na+, K+, and Mg2+ are rap- colonic lumen into the circulation.
idly depleted, presenting a clinical problem for The practical importance of reabsorption is
patients who undergo intestinal resection leaving illustrated by patients who have undergone exten-
them with a jejunostomy or proximal ileostomy. sive resection of the small intestine. When they
The terminal ileum is particularly important have a proximal jejunostomy or ileostomy, loss
for the absorption of bile acids and Vitamin B12. of salt and water means that they require regular
As a consequence, disease of the ileum can cause intravenous supplementation, even when absorp-
vitamin B12 deficiency and diarrhea caused by tion of dietary carbohydrate, fat, and protein is
loss of the enterohepatic circulation of bile salts sufficient. In such cases, anastomosis of the small
(see chapter “Overview” under part “Liver”), intestine to the colon typically reverses depen-
with consequent excess of these in the colon, dence on intravenous fluids.
where they cause secretion of water and electro- Colonic bacteria contribute metabolically to the
lytes [1]. The ileum also acts as a barrier between host. Food residue in the colon is fermented, yield-
the large and small intestine, with effects on bac- ing gases such as methane (CH4), H2, and CO2 and
terial populations, and intestinal motility. Finally, short chain fatty acids (SCFAs), such as acetate,
the ileum plays a prominent role for the immune butyrate, and propionate. However, fermentation
system (see below) [2]. can also produce toxic metabolites (see below).
Absorption of carbohydrates requires digestion Butyrate is a major energy source for colonic epi-
of complex carbohydrates into monosaccharides, thelial cells and its absence can result in inflamma-
as polysaccharides and disaccharides cannot be tion (see also chapter “Colorectal cancer”).
absorbed. Lactose, a disaccharide of galactose Moreover, the mix of colonic bacterial spe-
and glucose, is the main sugar in bovine and cies, termed the microbiome, varies between
human milk and is digested by lactase, which is individuals. This variation may be associated
produced by intestinal epithelial cells. Lack of with diseases including obesity and autoim-
lactase causes lactose intolerance, in which munity [3].
colonic bacteria digest lactose to produce fermen-
tation by-products, which, with the lactose,
increases the osmotic gradient and results in diar- Inside-In: Metabolites of the
rhea (see chapter “Lactose intolerance”). Gastrointestinal Tract Affecting
Furthermore, excess lactose may alter colonic Itself
bacteria. Avoiding dietary dairy can lead to Ca+
deficiency and potentially osteomalacia (Fig. 2). Regulation of digestive processes involves struc-
tures in the hypothalamus (see chapters
“Overview” under part “Brain”, “Diabetes mel-
The Large Intestine: Cecum, litus”, and “Overview” under part “Brain”), yet it
Colon, and Rectum also occurs to a major part within the gastrointes-
tinal tract, starting with the amount of food intake
The main function of the specialized colonic epi- sensed by chewing and stomach filling. Most
thelium is to reabsorb H2O from the 3–6 l/day of importantly, the stomach releases hormones,
fluid that enters the cecum, so that approximately such as gastrin, cholecystokinin (CCK), and
200 ml is excreted as fecal waste. Reabsorbed secretin, which in turn promote the release of
water is accompanied by electrolytes, particu- HCl, stimulate contraction of the gallbladder, and
larly Na+, K+, and Mg2+. Colonic bacteria metab- promote secretion from the pancreatobiliary sys-
olize fats and contribute to the provision of tem, while enhancing intestinal propulsion.
126 S. Keshav and P. Allan
Carbohydrates Carbohydrates
Lipid
Goblet cell
Mucus
Differentiation Enteroendocrine cell
Paneth cells
Protection
Support cells Villus
Colonic crypt
Enterocyte
absorptive cell
Goblet cell
Water Water
Stem cells
Replication
Fig. 2 Diagram of the microscopic appearance of a stylized crypt-villus unit and colonic crypt, showing specialized
cells, enzymes, absorption, secretion, and immune functions
Overview 127
Small Intestine
Small Intestine
Additionally, the gastrointestinal tract, more spe-
There are several examples how circulating hor- cifically the small intestine, can act as an endo-
mones and neural signals can regulate intestinal crine organ secreting incretins, which act on
absorption [4]. However, a detailed discussion is pancreatic β-cells causing an increase in insulin
not within the scope of this chapter. secretion even before blood glucose is elevated or
Iron transporters particularly are concentrated delay gastric emptying (see chapters “Overview”
proximally, where the majority of iron is absorbed. under part “Pancreas” and “Diabetes mellitus”).
As an example, iron absorption is inhibited by the
circulating hormone hepcidin, levels of which are
increased by infection and inflammation contribut- Colon
ing to the anemia seen in many chronic diseases.
The small intestine is also highly relevant to the Fermentation by colonic bacteria can produce
interaction with endogenous material and anti- toxic metabolites that can be absorbed into the
gens. Thus, intestinal lymphoid tissue is concen- circulation to exert systemic effects (see chapter
trated in the ileum, with many prominent Peyer’s “Cirrhosis”). There is therefore now a concerted
patches, and specialized cells that form part of the research effort aimed at understanding how the
innate immune system (see chapter “Overview” microbiome interacts with the intestine and the
under part “Immune system”), such as Paneth whole body in health and disease.
cells, are most abundant in the ileum [2]. Paneth
cells and goblet cells, among others, produce
many antibacterial proteins such as α and β defen- Typical Pathology of the
sins, regenerating (REG) proteins, and cathelici- Gastrointestinal Tract
dins. Innate and adaptive immune mechanisms, as
well the effects of constant propulsion along the Stomach and Small Intestine
intestinal tract, and chemical and mechanical bar-
rier functions of glycosaminoglycan-rich mucus Vomiting causes loss of acid. This loss results in
maintain near sterility of the small intestine, with concomitant K+ loss in the urine to favor retention
approximately 105–107 bacteria/ml of luminal of hydrogen (H+) ions (see chapter “Overview”
128 S. Keshav and P. Allan
Introduction to Peptic Ulcer Disease possible pathogenetic factors associated with this
rare peptic ulceration are older age, multimorbid-
Peptic ulcer disease (PUD) is defined as a defect ity, recent surgery, underlying sepsis, and medi-
in the lining of the gastrointestinal mucosa, with cation (other than NSAIDs ulcerogenic drugs).
appreciable depth or involvement of the submu- Peptic ulcer is typically localized in the stom-
cosa [1]. The development of peptic ulceration is ach (gastric ulcer) and duodenum (duodenal
a result of an imbalance between factors poten- ulcer), most commonly in the duodenal bulb
tially damaging the gastric mucosa (aggressive) (the part of the duodenum closest to the stom-
and protective (defensive) factors. The former ach) due to the high exposure to gastric acid.
include endogenous factors (e.g., gastric acid Small areas of the duodenum colonized by Hp,
and pepsin) and exogenous factors including called duodenal gastric metaplasia, may addi-
chronic Helicobacter pylori (Hp) infection, use tionally contribute to the pathogenesis of PUD
of nonsteroidal anti-inflammatory drugs in duodenum [3].
(NSAIDs), consumption of alcohol, smoking, The most common symptoms of PUD are
and exposure to stress [2]. The latter comprise abdominal pain, vomiting, hematemesis (vom-
pre-epithelial defense (secretion of mucus and iting of blood), and melena (the passage of dark
bicarbonates), epithelial defense (epithelial res- stools stained with altered blood). In contrast,
titution and replication, extracellular buffers older patients (>80 years) often lack abdomi-
including bicarbonates), and post-epithelial nal pain. Pain occurs typically during the night,
defense (mucosal microcirculation, tissue acid- when gastric acidity is increased (due to cir-
base balance). cadian changes) and buffering food intake is
Sometimes the definitive cause of the ulcer minimal [4].
cannot be established (“idiopathic ulcer”). The Complications of PUD include bleeding, per-
foration of stomach or duodenum, and gastric
outlet obstruction (i.e., an obstructed pylorus)
that could be fatal if untreated [5]. More often,
P.C. Konturek (*)
Second Department of Internal Medicine, gastric outlet obstruction is caused by neoplasia,
Thuringia Clinic Saalfeld, however.
Rainweg 68, Saalfeld/Saale 07318, Germany Duodenoscopy is the current standard for
e-mail: pkonturek@thueringen-kliniken.de
diagnosis of PUD revealing its localization and
S.J. Konturek possible complications (especially bleeding).
Institute of Physiology,
In addition, endoscopy allows obtaining biop-
Jagiellonian University Cracow,
Grzegorzecka Str. 16, Krakow 31-525, Poland sies from gastric mucosa for detection of Hp
e-mail: mpkontur@cyf-kr.edu.pl infection [6].
Etiology Symptoms
Aggressive
Diagnosis
Biopsy Endoscopy
Treatment
Hp+ Hp-
Eradication therapy of Hp for 7−10 days Antisecretory therapy for 4–8 weeks
Endoscopic therapy of bleeding Discontinuation of NSAIDs, Smoking, Alcohol
Reinforcement of mucosal defence
Fig. 1 Pathogenesis of peptic ulcer disease (PUD). PUD ulcer. Additionally, biopsies are taken to determine the
develops due to an imbalance between aggressive and presence (Hp+) or absence (Hp–) of Helicobacter pylori
protective factors within the gastric mucosa and com- infection resulting in eradication therapy or treatment
monly causes vomiting, loss of appetite, anemia, and with anti-secretory drugs, respectively. Drugs reinforcing
upper gastrointestinal bleeding. It is diagnosed by esopha- mucosal defense can be used instead of anti-secretory
gogastroduodenoscopy (upper endoscopy), which allows drugs. Alcohol and smoking should be avoided
localization and treatment (endoscopic hemostasis) of the
Gastrin Gastrin
H2RA
ACh
Anticholinergics
H2
M3
Histamine [AC]
2+
Ca
ECL cell Parietal cell
CCK 2
K+
Apical cell surface PPI Gastrin receptor
Basolateral cell surface inhibitors
[H+/K+-ATPase]
Stomach lumen H+
Antacids
Fig. 2 Working mechanism of anti-secretory drugs. Anticholinergics block acetylcholine (ACh) effects via
Anti-secretory drugs prevent the release of gastric acid the M3 receptors, decreasing intracellular Ca2+. Similarly,
by acting on the H+/K+-ATPase. Histamine H2 receptor blockade of gastrin receptors (CCK2) reduces intracellular
(H2R) antagonists (H2RA) competitively and reversibly Ca2+ but also decreases histamine release from enterochro-
block H2R, inhibiting signaling via adenylate cyclase maffin (ECL) cells. However, these drugs are currently not
(AC) to reduce cAMP levels and thus H+ secretion. PPIs used in PUD. Antacids directly neutralize acid within the
(proton pump inhibitors) directly inhibit the ATPase. gastrointestinal tract
mucosa (such as gastric acid) or at reinforcement stomach epithelium (see chapter “Overview”
of the mucosal defense mechanisms. Inhibition under part “Gastrointestinal tract”) to inhibit this
of aggressive factors includes (1) compounds transporter and thus acid secretion. PPIs show
neutralizing acid, called antacids; (2) inhibi- improved peptic ulcer healing and faster pain
tors of acid and pepsin secretion, such as anti- relief compared to H2RAs [23]. Pharmacological
cholinergics, histamine H2 receptor antagonists strategies to reinforce the mucosal defense mech-
(H2RA), and proton pump inhibitors (PPIs); and anisms increase protective factors (PGE, EGF),
(3) compounds eliminating potentially cytotoxic gastric mucus and alkaline secretion, and gastric
elements in the gastroduodenal secretions like mucosal blood flow, trigger or facilitate repara-
bile acids or lecithin (Fig. 2). tive mechanisms, and decrease ROS [24].
H2RAs block the stimulatory effect on acid Bleeding remains an important complication
secretion of histamine, released from entero- of PUD with a high mortality rate (5–15 %),
chromaffin cells (ECL). PPIs covalently bind to especially in the elderly due to increased use of
the H+/K+-ATPase on parietal cells within the low-dose aspirin for prevention of cardiovascular
Peptic Ulcer Disease 133
diseases. Management of bleeding includes mul- directly. Aluminum additionally increases synthe-
timodal endoscopic techniques to stop the gastro- sis of PGE2 and gastric mucosal microcirculation,
intestinal bleeding (endoscopic hemostasis) yet it may cause constipation. Magnesium can
followed by pharmacological acid suppression cause diarrhea. Due to their adsorptive capacity,
with PPI or H2RA. Moreover, high doses of these antacids may hinder intestinal absorption of
intravenously administered PPIs are recom- concurrent medication. Moreover, antacids con-
mended to reduce risk of re-bleeding after endo- taining sodium bicarbonate, magnesium hydrox-
scopic hemostasis [25]. If repeated endoscopies ide, and calcium carbonate are contraindicated in
fail or perforation (of the gastrointestinal wall) is patients with renal insufficiency [30].
present, surgical therapy is indicated, the exact Anticholinergics (e.g., pirenzepine or telenze-
type of which is controversial, ranging from pine) speed up the healing of peptic ulcers due to
oversewing to partial gastrectomy [26]. their inhibitory effect on gastric acid secretion.
However, side effects include visual disturbances,
photophobia, and dryness of the mouth, limiting
Influence of Treatment on their use, especially in patients with glaucoma
Metabolism and Consequences (see chapter “Glaucoma”), enlarged prostate, or
for Patients stenosis of the pylorus sphincter [31].
H2RAs (e.g., cimetidine, ranitidine, famoti-
Therapy of Hp+ PUD dine, nazatidine, roxatidine) competitively and
reversibly block the H2R on the basolateral
The commonly used first-line standard triple ther- membrane of the parietal cells inhibiting mainly
apy includes two antibiotics, such as clarithromy- basal and partially meal-stimulated gastric acid
cin or metronidazole, and amoxicillin along with secretion. Possible side effects of H2RAs include
a PPI, such as omeprazole, lansoprazole, panto- the development of tolerance and rebound acid
prazole, rabeprazole, or esomeprazole, and is hypersecretion (a temporary increase in gastric
given for 7–14 days. Sequential therapy, which acid secretion after the abrupt withdrawal of
shows significantly higher eradication rates [27], H2RA) [32].
generally consists of PPI and amoxicillin for the PPIs (e.g., omeprazole, lansoprazole, panto-
first 5 days, followed by PPI along with clarithro- prazole, and rabeprazole) inhibit acid secretion
mycin and metronidazole for 5 days. by the parietal cell [33]. Although gastric acid
Second-line treatment adds bismuth salts or a inhibition is very effective, prolonged suppres-
fluoroquinolone-based antibiotic (e.g., levofloxa- sion favors small intestinal bacterial overgrowth
cin or moxifloxacin) to PPI and the other antibiot- and concomitant malabsorption and facilitates
ics. If second-line therapy fails, further eradication enteric infections (especially with Clostridium
depends on the antibiotic susceptibility [28]. difficile), as bacteria are no longer effectively
In patients with antrum-predominant gastritis, eliminated in the stomach [34]. Additionally,
eradication of Hp restores impaired gastrin- osteoporosis (due to parathyroid hyperplasia, see
somatostatin link, decreases basal and stimulated chapter “Osteoporosis”) and hyperplasia of
acid secretion in the stomach, and restores acid enterochromaffin cells (due to chronic hypergas-
load in the duodenum. However, the atrophy of trinemia) can develop (Fig. 2) [35].
gastric mucosa does not reverse after successful To enhance mucosal defense, initially, miso-
eradication of Hp [29]. prostol, a prostaglandin E1 analogue, was used.
Unfortunately, its use was limited by abdominal
pain and diarrhea due to its stimulatory effect on
Therapy of Hp− PUD intestinal motility [36]. Sucralfate exerts protec-
tive action by increasing the synthesis of muco-
Most antacids are inorganic salts (magnesium and/ sal growth factors, mucosal microcirculation,
or aluminum hydroxide and/or bicarbonate, and and by angiogenic actions [37]. Colloidal bis-
calcium carbonate), which neutralize gastric acid muth subcitrate accelerates ulcer healing by the
134 P.C. Konturek and S.J. Konturek
formation of occlusive complexes and the accu- invasive procedure in the era of non-invasive testing.
Dig Liver Dis 40(7):497–503
mulation of epidermal growth factor (EGF) in the
7. Schwarz K (1910) Über penetrierende Magen- und
ulcer crater [38]. Jejunalgeschwüre. Beitr Klin Chir 67:96–128
Rebamipide is cytoprotective and enhances 8. Tarnawski AS, Ahluwalia A, Jones MK (2012) The
gastric mucus production, stimulates the release mechanisms of gastric mucosal injury: focus on
microvascular endothelium as a key target. Curr Med
of endogenous prostaglandins, and inhibits the
Chem 19(1):4–15
generation of ROS [39]. 9. Graham DY, Lew GM, Klein PD, Evans DG, Evans
DJ Jr, Saeed ZA, Malaty HM (1992) Effect of treat-
ment of Helicobacter pylori infection on the long-
term recurrence of gastric or duodenal ulcer. A
Perspectives randomized, controlled study. Ann Intern Med
116(9):705–708
Thanks to a declining prevalence of Hp infection 10. Marshall BJ (1995) The 1995 Albert Lasker Medical
and introduction of effective anti-Hp therapies, Research Award. Helicobacter pylori. The etiologic
agent for peptic ulcer. JAMA 274(13):1064–1066
PUD frequency is decreasing [40], and NSAIDs-
11. Konturek PC, Konturek SJ, Bobrzynski A, Kwiecien
induced ulcers now emerge as the most important N, Obtulowicz W, Stachura J, Hahn EG, Rembiarz K
cause of PUD. (1997) Helicobacter pylori and impaired gastric secre-
With regard to the increasing resistance rate tory functions associated with duodenal ulcer and
atrophic gastritis. J Physiol Pharmacol 48(3):
of Hp and rising frequency of Hp− ulcers, novel
365–373
therapies to strengthen the mucosal defense are 12. McColl KE, El-Omar E, Gillen D (2000) Helicobacter
urgently needed. New candidates to reinforce pylori gastritis and gastric physiology. Gastroenterol
the mucosal defense include melatonin, probiot- Clin North Am 29(3):687–703
13. Malfertheiner P, Leodolter A, Peitz U (2000) Cure of
ics, H2S, NO, and CO [41]. Melatonin enhances
Helicobacter pylori-associated ulcer disease through
gastric microcirculation and exerts antioxidative eradication. Baillieres Best Pract Res Clin
effects on the gastric mucosa, independently of Gastroenterol 14(1):119–132
prostaglandin synthesis [42]. Some probiot- 14. Takeuchi K (2012) Pathogenesis of NSAID-induced
gastric damage: importance of cyclooxygenase inhi-
ics increase production of mucosal growth fac-
bition and gastric hypermotility. World J Gastroenterol
tors and reduce proinflammatory cytokines [43]. 18(18):2147–2160
Finally, H2S, NO, and CO were shown to increase 15. Chan FKL, Leung WK (2002) Peptic ulcer disease.
protective prostaglandins in gastroduodenal Lancet 360:933–941
16. Gisbert JP, Calvet X (2009) Review article:
mucosa and inhibit the generation of proinflam-
Helicobacter pylori-negative duodenal ulcer. Aliment
matory cytokines [44]. Pharmacol Ther 30:791–815
17. Maity P, Biswas K, Roy S, Banerjee RK,
Bandyopadhyay U (2003) Smoking and the pathogen-
esis of gastroduodenal ulcer-recent mechanistic
References update. Mol Cell Biochem 253(1–2):329–338
18. Franke A, Teyssen S, Singer MV (2005) Alcohol-
1. Malfertheiner P, Chan FK, McColll KE (2009) Peptic related diseases of the esophagus and stomach. Dig
ulcer disease. Lancet 374:1449–1461 Dis 23(3–4):204–213
2. Konturek PC (1997) Physiological, immunohisto- 19. Shimamoto T, Yamamichi N, Kodashima S, Takahashi
chemical and molecular aspects of gastric adaptation Y, Fujishiro M, Oka M, Mitsushima T, Koike K
to stress, aspirin and to H. pylori-derived gastrotoxins. (2013) No association of coffee consumption with
J Physiol Pharmacol 48:3–42 gastric ulcer, duodenal ulcer, reflux esophagitis and
3. Tytgat GNJ (2011) Ethiopathogenetic principles non-erosive reflux disease: a cross-sectional study of
and peptic ulcer disease classification. Dig Dis 29: 8,013 healthy subjects in Japan. PLoS One 8(6):
454–458 e65996
4. Choung RS, Talley NJ (2008) Epidemiology and clin- 20. Selgrad M, Malfertheiner P (2011) Treatment of
ical presentation of stress-related peptic damage and Helicobacter pylori. Curr Opin Gastroenterol 27(6):
chronic peptic ulcer. Curr Mol Med 8(4):253–257 565–570
5. Milosavljevic T, Kostić-Milosavljević M, Jovanović I, 21. Chan FK, Ching JY, Suen BY, Tse YK, Wu JC,
Krstić M (2011) Complications of peptic ulcer Sung JJ (2013) Effects of Helicobacter pylori infec-
disease. Dig Dis 29:491–493 tion on long-term risk of peptic ulcer bleeding in
6. Graham DY, Kato M, Asaka M (2008) Gastric low-dose-aspirin users. Gastroenterology 144(34):
endoscopy in the 21st century: appropriate use of an 528–535
Peptic Ulcer Disease 135
22. Malfertheiner P, Megraud F, O’Morain C, Bazzoli F, 35. Abraham NS (2012) Proton pump inhibitors: poten-
El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, tial adverse effects. Curr Opin Gastroenterol 28(6):
Kuipers EJ (2007) Current concepts in the manage- 615–620
ment of Helicobacter pylori infection: the Maastricht 36. Reskin JB, White RH, Jackson JE, Weaver AL,
III Consensus Report. Gut 56(6):772–781 Tindall EA, Lies RB, Stanton DS (1995) Misoprostol
23. Sachs G, Shin JM, Hunt R (2010) Novel approaches dosage in the prevention of non-steroidal anti-
to inhibition of gastric acid secretion. Curr inflammatory drug-induced gastric and duodenal
Gastroenterol Rep 12(6):437–447 ulcers: a comparison of three regimens. Ann Intern
24. Holle GE (2010) Pathophysiology and modern treat- Med 123:344–350
ment of ulcer disease. Int J Mol Med 25(4):483–491 37. Konturek SJ, Brzozowski T, Majka J, Szlachcic A,
25. Holster IL, Kuipers EJ (2011) Update on the endo- Bielanski W, Stachura J, Otto W (1993) Fibroblast
scopic management of peptic ulcer bleeding. Curr growth factor in the gastroprotection and ulcer heal-
Gastroenterol Rep 13:525–531 ing: interaction with sucralfate. Gut 34(7):881–887
26. Lee CW, Sarosi GA Jr (2011) Emergency ulcer sur- 38. Hall DW (1989) Review of the modes of action of col-
gery. Surg Clin North Am 91(5):1001–1013 loidal bismuth subcitrate. Scand J Gastroenterol
27. Ford AC, Delaney BC, Forman D, Moayyedi P (2006) Suppl 157:3–6
Eradication therapy for peptic ulcer disease in 39. Song KH, Lee YC, Fan DM, Ge ZZ, Ji F, Chen MH,
Helicobacter pylori positive patients. Cochrane Jung HC, Bo J, Lee SW, Kim JH (2011) Healing
Database Syst Rev (2):CD003840 effects of rebamipide and omeprazole in Helicobacter
28. Graham DY, Calvet X (2012) Guide regarding choice pylori-positive gastric ulcer patients after eradication
of second-line therapy to obtain a high cumulative therapy: a randomized double-blind, multinational,
cure rate. Helicobacter 17:243–245 multi-institutional comparative study. Digestion
29. McColl KE (1997) Helicobacter pylori and acid 84:221–229
secretion: where are we now? Eur J Gastroenterol 40. Konturek PC, Bielanski W, Konturek SJ, Hahn EG
Hepatol 9(4):333–335 (1999) Helicobacter pylori associated gastric pathol-
30. Konturek SJ (1993) New aspects of clinical pharma- ogy. J Physiol Pharmacol 50(5):695–710
cology of antacids. J Physiol Pharmacol 44(3 41. Al-Jiboury H, Kaunitz JD (2012) Gastroduodenal
Suppl 1):5–21 mucosal defense. Curr Opin Gastroenterol 28(6):
31. Warner CW, McIsaac RL (1991) The evolution of 594–601
peptic ulcer therapy. A role for temporal control of 42. Celinski K, Konturek SJ, Konturek PC, Brzozowski T,
drug delivery. Ann N Y Acad Sci 618:504–516 Cichoz-Lach H, Slomka M, Bielanski W, Reiter RJ
32. Huang JQ, HRH (2001) Pharmacological and phar- (2011) Melatonin or L-tryptophan accelerates healing
macodynamic essentials of H2-receptor antagonists of gastroduodenal ulcers in patients treated with
and proton pump inhibitors for the practising physi- omeprazole. J Pineal Res 50(4):389–394
cian. Best Pract Res Clin Gastroenterol 15(3): 43. Konturek PC, Sliwowski Z, Koziel J, Ptak-Belowska
355–370 A, Burnat G, Brzozowski T, Konturek SJ (2009)
33. Mössner J, Caca K (2005) Developments in the inhi- Probiotic bacteria E. coli Nissle 1917 attenuates acute
bition of gastric acid secretion. Eur J Clin Invest gastric lesion induced by stress. J Physiol Pharmacol
35(8):469–475 60(Suppl 6):41–48
34. Williams C, McColl KE (2006) Review article: proton 44. Wallace JL (2012) Hydrogen sulphide: a rescue mol-
pump inhibitors and bacterial overgrowth. Aliment ecule for mucosal defence and repair. Dig Dis Sci
Pharmacol Ther 23(1):3–10 57(6):1432–1434
Gastroenteritis
Liver Stomach
Pancreas
Duodenum
Large intestine
Small intestine
III. Symptoms
Diarrhea VI. Outcomes
Vomiting Usually self-limiting in
Stomachache 3−4 days, unless parasitic
Malaise Severe cases may be
Nausea Rectum
life-threating without
Fever intervention
Anus
Fig. 1 Overview of acute infectious gastroenteritis. major metabolic disorders include maldigestion and mal-
Acute gastroenteritis is a disease affecting the stomach absorption due to impaired intestinal mucosal surfaces
and small and large intestine (central panel). Causes with consequences of hypotonic dehydration and meta-
of infectious gastroenteritis include bacterial, viral, bolic acidosis, which can have severe complications (IV).
and/or parasitic pathogens (I). These pathogens can Rehydration with proper electrolytes is critical for treat-
be invasive and cause cell damage and produce toxins. ment. Antidiarrheals and antiemetics may provide relief
Alternatively, the pathogens are noninvasive and dam- from symptoms. Antibiotics are only used for bacterial
age mainly occurs through enterotoxin production (II). and parasitic pathogens (V). Gastroenteritis is usually
The resulting mucosal damage increases permeability self-limiting in 3–4 days. Parasitic gastroenteritis may
and peristaltic movement and impairs intestinal absorp- last longer. Life-threatening cases occur mostly in young
tion, resulting in diarrhea and other symptoms (III). The children and the elderly (VI)
Noninvasive bacteria cause similar symptoms which results in more chloride ions in the lumen
by adhering to the gut wall followed by produc- of the small intestine and causes water to move
tion of enterotoxins, such as Vibrio cholerae and into lumen, known as osmotic diarrhea [8].
enterotoxigenic strains of Escherichia coli. Toxin Finally, some bacterial toxins, such as entero-
production results in secretory diarrhea with a toxins A to E from S. aureus, present in con-
large volume of watery diarrhea characterized taminated food [9] may cause symptoms similar
by excessive mucosal secretion due to adenylate to those of noninvasive bacteria, as enterotox-
cyclase induction resulting in impaired intestinal ins are heat resistant and thus not destroyed by
absorption [7]. In addition, cholera toxins bind cooking. Nausea and vomiting may occur more
to channel proteins, opening chloride channels, frequently with this form of gastroenteritis
Gastroenteritis 139
due to excessive gas formation and the body’s to maldigestion and malabsorption, similar to
response to purge the toxins. bacterial gastroenteritis. In addition, infected
In all forms of bacterial gastroenteritis, inflam- epithelial cells induce villus ischemia and acti-
mation as the host’s immune response to toxins vation of the enteric nervous system that further
or pathogens combined with variable entero- and exaggerate the disease [15]. Recent studies of
cytotoxic effects can lead to mucosal cell damage RV showed that the viral nonstructural protein 4
and result in overall dysfunction of the gut with (NSP4) could act as an enterotoxin, the first iden-
maldigestion of food and malabsorption of nutri- tified in viral infections. NSP4 binds integrins
ents. In addition, overgrowth of some pathogenic α1β1 and α2β1 [14] and appears to trigger epi-
bacterial strains may further exacerbate these thelial cell chloride secretion by increasing intra-
effects on metabolism [10]. cellular Ca2+ through phospholipase C activation
On average, the symptoms of bacterial gastro- [16]. NSP4 also disrupts tight junctions, which is
enteritis infections last between 2 and 10 days. believed to be a new mechanism of pathogenesis
Since patients are unable to reabsorb lost fluid, leading to malabsorption and dehydration via
dehydration is the most common severe compli- increased permeability [17]. Symptoms related to
cation of acute gastroenteritis [11]. Thus, hospi- viral gastroenteritis usually last 1–3 days and are
talization is sometimes required in the pediatric most often self-limiting. However, severe cases
and geriatric populations, although generally can be life-threatening due to severe dehydration
infections are self-limiting. [12].
Viruses Parasites
Acute viral gastroenteritis is one of the top 5 The most common parasites responsible for gas-
causes of death worldwide. The major viral gas- troenteritis are Giardia and Cryptosporidium.
troenteritis pathogens include rotavirus (RV), Like bacteria, they can invade the intestinal
norovirus (NoV), astrovirus, and enteric adeno- mucosa or adhere to the gut wall. Subsequent
virus [12]. RV is the leading cause of severe inflammation and disruption of the gut mucosa
diarrhea in children under 5 years with signifi- lead to watery diarrhea, inadequate digestion of
cant mortality in developing nations, although food, and malabsorption of nutrients [18]. The
NoV also contributes [13]. In developed nations, course of parasitic gastroenteritis is longer than
NoV infections commonly occur in adults and both bacterial and viral gastroenteritis with symp-
are responsible for major outbreaks of acute toms lasting up to 4 weeks, even if the infection is
gastroenteritis. These viral pathogens are typi- cleared. It usually resolves without intervention.
cally invasive, infecting enterocytes, and cause Due to the longer duration of symptoms, weight
cell death or toxic effects disturbing the normal loss due to malabsorption, fatigue, and dehydra-
function of the gut. Unfortunately, the precise tion are commonly observed [11].
pathogenic mechanisms of most of these viruses
remain unknown [12]. RV uses sialic acid, several
integrins, and heat shock cognate protein 70 as Treatment of Gastroenteritis
cell surface receptors, which facilitate virus pen-
etration through the mucosal surface and infec- In most cases of acute gastroenteritis, the infec-
tion [14]. This may cause structural changes, tions resolve on their own. However, severe cases
including villus shortening, which decreases the with serious dehydration such as those caused by
function of the small bowel mucosa, along with RV infection can be life-threatening. Thus, the
inflammation and mononuclear cell infiltration in most important aspects of symptom management
the lamina propria (inner layer of the gut mucosa). are rehydration and prevention of electrolyte
These changes combined with cell damage lead loss. In developing countries where intravenous
140 C. Quigley and X. Jiang
Table 1 Antibiotic treatment guidelines for bacterial and iting release of acetylcholine and prostaglandins,
parasitic gastrointestinal infections
thereby reducing peristalsis and increasing intes-
Pathogen Treatment tinal transit time [21]. Although this may allow
Bacterial increased water and electrolyte absorption, dehy-
Campylobacter sp. Erythromycin, if administered dration is still a risk and fluids should continue
<4 day after symptom onset
to be administered. The antiemetic ondansetron
Clostridium difficile Avoid antibiotic (may prolong
infection)
(Zofran) appears to decrease vomiting during
Oral Metronidazole may be acute gastroenteritis by inhibiting serotonin bind-
administered ing to 5-hydroxytryptamine (5-HT) receptors in
Escherichia coli Avoid antibiotic (may prolong the small intestine [22]. Probiotics, which consist
infection or cause hemolytic- of nonpathogenic strains of bacteria, are consid-
uremic syndrome)
ered during acute gastroenteritis to help rebuild
Salmonella sp. Antibiotic treatment not
recommended for non-typhoid
normal bacterial flora in the gut [23].
strains, except for To combat the infection, feeding of human
immunocompromised patients milk is recommended for breastfeeding infants
Ampicillin may be used, but [24], as it may contain antibodies against many
for resistant strains, third- bacterial and viral pathogens, which may reduce
generation Cephalosporins,
Fluoroquinolones (not in the infection [25]. In addition, human milk con-
children), or Trimethoprim- tains many carbohydrate glycans that may serve
Sulfamethoxazole may be as decoy receptors for bacterial and viral patho-
effective gens that require a carbohydrate receptor to initi-
Shigella sp. Antibiotics not recommended
ate infection [26].
for mild cases
Some bacterial and parasitic infections may
Ampicillin may be used for
moderate to severe cases require antibiotic intervention by ciprofloxacin
Trimethoprim- or metronidazole, respectively, for clearance
Sulfamethoxazole for resistant (Table 1). The WHO also recommends antibiot-
strains ics for young children with bloody diarrhea and
Fluoroquinolones for highly fever [27]. It is not generally recommended, how-
resistant strains
ever, as viruses remain unaffected.
Staphylococcus aureus Antibiotics ineffective (toxin
present in contaminated food) Bismuth subsalicylate is used to treat diarrhea,
Vibrio cholera Antibiotic selection is based since it may reduce secretions [28], bind free
on resistance bacterial toxins [29], and exert topical effects on
Parasitic gut mucosa [4].
Cryptosporidium Antibiotic dependent on age Finally, vaccination is a potential key to pre-
parvum and general immune status vention. Two vaccines are available to prevent
Giardia intestinalis Commonly: Metronidazole,
RV, which are highly recommended for children,
Paromomycin
while vaccines for NoV and others are under
development.
rehydration is difficult to access, oral rehydration
is strongly recommended [19]. The World Health
Organization (WHO) recommendations include Influence of Treatment
glucose electrolyte solutions or rice-based solu- on Metabolism
tions, since they are easily accessible [20]. Other
treatments to prevent dehydration include antidi- Prompt rehydration is key to stop continued dete-
arrheal over-the-counter medications or pre- rioration of the gut and restore normal metabo-
scription antiemetics if vomiting is severe [3]. lism. Without proper reabsorption of lost fluid
Antidiarrheal medications, such as loperamide due to mucosal damage, overall fluid deficit
(Imodium), bind opiate receptors in the gut, inhib- can rapidly lead to dehydration, which can lead
Gastroenteritis 141
to hypovolemic shock, where the heart can- and prevention. Current research on NoV and
not efficiently pump blood through the body RV recognition of human blood group antigens
due to severe fluid deficits and even death [30]. may shed new light on mechanisms of virus/host
Because dehydration is accompanied by loss of interactions, particularly for mucosal infection,
electrolytes, rehydration with proper solutions potentially revealing new treatment approaches.
containing sufficient electrolytes is important. Further studies aim to understand the protec-
Insufficient electrolytes can alter neurologic tion of some pathogens from disinfection proce-
and myocardial functions, while severe sodium dures, such as UV, γ-irradiation, and high pressure.
excess (due to decreased water in dehydration) Although research of viral pathogens causing gas-
can lead to cerebrovascular damage, hemorrhage, troenteritis remains difficult due to the inability to
and death [31]. Rehydration plus some antidiar- cultivate them in vitro, virus surrogates (replace-
rheal treatment will restore the body’s normal ments from other species closely related to human
functions allowing it to heal damaged mucosal pathogens) provide an important new tool.
surfaces of the gut. Proper digestion of food and Most likely, cases of acute infectious gastro-
absorption of nutrients also may help to restore enteritis will continue to occur despite our best
the overall conditions of the gut, including normal efforts to prevent them. Our hope is that increased
bacterial flora. However, antidiarrheal treatments availability to clean water sources and improved
are contraindicated if symptoms include fever sanitary conditions in developing nations will
and/or bloody stool, as they can prolong or decrease worldwide infection rates. New and
exacerbate bacterial infections [19]. Since anti- improved vaccines may also decrease infection
motility agents increase bowel stasis, bacteria rates and/or hospitalizations, especially for viral
may proliferate, creating additional toxins and infections. The constantly evolving knowledge
exacerbating gastroenteritis [32]. Antibiotic and understanding of ideal treatment procedures
intervention also has limitations; because many will hopefully decrease mortality rates and fre-
prescribed antibiotics cannot distinguish between quency of complications due to acute infectious
pathogenic bacteria and normal gut flora, treat- gastroenteritis.
ment may also destroy endogenous bacteria and
prolong maldigestion and malabsorption. Thus,
more specific antibiotics showing a narrow spec- References
trum (e.g., erythromycin against Campylobacter
infections) are recommended [33]. 1. World Health Organization (2013) Diarrhoeal disease.
Available from: http://www.who.int/mediacentre/fact-
sheets/fs330/en/index.html. Accessed 21 June 2013
2. Kosek M, Bern C, Guerrant RL (2003) The global
Perspectives burden of diarrhoeal disease, as estimated from stud-
ies published between 1992 and 2000. Bull World
Prevention and rehydration are the keys for con- Health Organ 81:197–204
trol of pathogenic acute gastroenteritis. Oral 3. Aranda-Michel J, Giannella RA (1999) Acute diar-
rhea: a practical review. Am J Med 106(6):670–676
rehydration is critical for patients with severe
4. Thielman NM, Guerrant RL (2004) Clinical practice.
symptoms and a large volume of body fluid loss. Acute infectious diarrhea. N Engl J Med 350(1):38–47
Washing of hands after toilet use and before 5. Hao W-L, Lee Y-K (2004) Microflora of the gastroin-
meals is the most important hygiene practice to testinal tract. Methods Mol Biol 268:491–502
6. Festi D, Schiumerini R, Birtolo C, Marzi L, Montrone
prevent spread of these diseases. Most diarrheal
L, Scaioli E, Di Biase AR, Colecchia A (2011) Gut
pathogens are resistant to environmental condi- microbiota and its pathophysiology in disease para-
tions and are carried by food and water. digms. Dig Dis 29(6):518–524
Research on the mechanisms these pathogens 7. Navaneethan U, Giannella RA (2008) Mechanisms
of infectious diarrhea. Nat Clin Pract Gastroenterol
use to persist in the environment and the pro-
Hepatol 5(11):637–647
cedures to prevent contamination of food and 8. Sellin JH (2001) The pathophysiology of diarrhea.
water are important areas for disease control Clin Transplant 15(Suppl 4):2–10
142 C. Quigley and X. Jiang
9. Le Loir Y, Baron F, Gautier M (2003) Staphylococcus Antiemetic activity of ondansetron in acute gastroen-
aureus and food poisoning. Genet Mol Res 2(1):63–76 teritis. Aliment Pharmacol Ther 11(1):185–191
10. Schiller LR (2007) Evaluation of small bowel bacte- 23. Preidis GA, Hill C, Guerrant RL, Ramakrishna
rial overgrowth. Curr Gastroenterol Rep 9(5):373–377 BS, Tannock GW, Versalovic J (2011) Probiotics,
11. McClarren RL, Lynch B, Nyayapati N (2011) Acute enteric and diarrheal diseases, and global health.
infectious diarrhea. Prim Care 38(3):539–564 Gastroenterology 140(1):8–14
12. Clark B, McKendrick M (2004) A review of viral gas- 24. King CK, Glass R, Bresee JS, Duggan C, Centers for
troenteritis. Curr Opin Infect Dis 17(5):461–469 Disease Control and Prevention (2003) Managing
13. Ramani S, Kang G (2009) Viruses causing childhood acute gastroenteritis among children: oral rehydra-
diarrhoea in the developing world. Curr Opin Infect tion, maintenance, and nutritional therapy. MMWR
Dis 22(5):477–482 Recomm Rep 52(RR-16):1–16
14. López S, Arias CF (2004) Multistep entry of rotavirus 25. Hayani KC, Guerrero ML, Morrow AL, Gomez HF,
into cells: a Versaillesque dance. Trends Microbiol Winsor DK, Ruiz-Palacios GM, Cleary TG (1992)
12(6):271–278 Concentration of milk secretory immunoglobulin A
15. Ciarlet M, Gilger MA, Barone C, McArthur M, Estes against Shigella virulence plasmid-associated anti-
MK, Conner ME (1998) Rotavirus disease, but not gens as a predictor of symptom status in Shigella-
infection and development of intestinal histopatho- infected breast-fed infants. J Pediatr 121(6):852–856
logical lesions, is age restricted in rabbits. Virology 26. Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang
251(2):343–360 X, Guerrero ML, Meinzen-Derr JK, Farkas T,
16. Dong Y, Zeng CQ-Y, Ball JM, Estes MK, Morris Chaturvedi P, Pickering LK, Newburg DS (2004)
AP (1997) The rotavirus enterotoxin NSP4 mobi- Human milk oligosaccharides are associated with
lizes intracellular calcium in human intestinal cells protection against diarrhea in breast-fed infants. J
by stimulating phospholipase C-mediated inositol Pediatr 145(3):297–303
1,4,5-trisphosphate production. Proc Natl Acad Sci 27. Singh A (2010) Pediatric emergency medicine prac-
94(8):3960–3965 tice acute gastroenteritis — an update. Emerg Med
17. Lorrot M, Vasseur M (2007) How do the rotavirus Pract 7
NSP4 and bacterial enterotoxins lead differently to 28. Gyles C, Zigler M (1978) The effect of adsorbant and
diarrhea? Virol J 4(1):31 anti-inflammatory drugs on secretion in ligated seg-
18. Huston CD (2004) Parasite and host contributions to ments of pig intestine infected with Escherichia coli.
the pathogenesis of amebic colitis. Trends Parasitol Can J Comp Med 42(3):260–268
20(1):23–26 29. Ericsson CD, Evans DG, DuPont HL, Evans DJ,
19. Guerrant RL, Van Gilder T, Steiner TS, Thielman Pickering LK (1977) Bismuth subsalicylate inhibits
NM, Slutsker L, Tauxe RV, Hennessy T, Griffin PM, activity of crude toxins of Escherichia coli and vibrio
DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, cholerae. J Infect Dis 136(5):693–696
Reller LB, Osterholm MT, Bennish ML, Pickering 30. Kreimeier U (2000) Pathophysiology of fluid imbal-
LK (2001) Practice guidelines for the management of ance. Crit Care 4(Suppl 2):S3–S7
infectious diarrhea. Clin Infect Dis 32(3):331–351 31. Hirschhorn N (1980) The treatment of acute diarrhea
20. Practice parameter: the management of acute gas- in children. An historical and physiological perspec-
troenteritis in young children. American Academy tive. Am Journal Clin Nutr 33(3):637–663
of Pediatrics, Provisional Committee on Quality 32. Church J, Fazio V (1986) A role for colonic stasis in
Improvement, Subcommittee on Acute Gastroenteritis the pathogenesis of disease related to Clostridium dif-
(1996) Pediatrics 97(3):424–435 ficile. Dis Colon Rectum 29(12):804–809
21. Sandhu BK, Tripp JH, Candy DC, Harries JT (1981) 33. Ternhag A, Asikainen T, Giesecke J, Ekdahl K
Loperamide: studies on its mechanism of action. Gut (2007) A meta-analysis on the effects of antibiotic
22(8):658–662 treatment on duration of symptoms caused by infec-
22. Cubeddu LX, Trujillo LM, Talmaciu I, Gonzalez V, tion with campylobacter species. Clin Infect Dis
Guariguata J, Seijas J, Miller IA, Paska W (1997) 44(5):696–700
Lactose Intolerance
Introduction to Lactose Intolerance disease and ulcerative colitis) [4], and thus should
be taken into account when diagnosing and
Lactose intolerance is a biochemical condition treating these patients [5].
caused by the inability to digest fully the sugar in Lactose, galactose-1,4-β-glucose, is only
milk, i.e., lactose [1]. The condition of lactose found naturally in significant amounts in mamma-
intolerance is better described as “lactose sensi- lian milk (cow’s milk 49 g/l; human milk 70 g/l).
tivity,” as everyone can tolerate some lactose, Lactose is one sixth as sweet as sucrose and pro-
although this amount varies considerably between vides some 40 % of the energy requirements of
individuals [2]. It is essential to distinguish lac- a suckling infant. However, adults do not need
tose intolerance from an allergy to milk proteins lactose. Disaccharides (e.g., lactose, sucrose, and
as there are major differences in the management isomaltose) cannot be absorbed directly in the
of these two conditions and allergy occurs in intestine, requiring an enzyme to cleave them into
3–5 % of infants. Some four billion people monosaccharides. Lactose is cleaved by lactase
around the world express low lactase levels (see (lactase-phlorizin hydrolase), which occurs in
below) and are thus potentially sensitive to lac- the small intestinal microvilli. Galactose and glu-
tose, suffering a range of gut and systemic symp- cose are subsequently absorbed into the entero-
toms (Fig. 1), unless diagnosed and then managed cyte via the sodium-activated glucose transporter
correctly. Lactose sensitivity is associated with 1 (SGLUT1, also called SGLT1). Glucose and
two common gut conditions [3], irritable bowel galactose are then taken up into the blood by the
syndrome (IBS, a disease characterized by transporter GLUT2. Galactose is converted to glu-
abdominal pain, diarrhea, or constipation or both cose mainly by the Leloir pathway, where galac-
alternating) and inflammatory bowel disease tose is converted to UDP-glucose, particularly in
(IBD, a group of inflammatory conditions affect- the liver via galactose 1-phosphate (Gal-1-P) and
ing small intestine and colon, including Crohn’s UDP-galactose. Alternatively, humans can use the
De Ley-Doudoroff pathway. Inherited mutations
of enzymes in the Leloir pathway cause galactose-
A.K. Campbell (*) mias, affecting 1 in 55,000 individuals. For exam-
School of Pharmacy and Pharmaceutical Sciences, ple, galactosemia type 1 (galactose-1-phosphate
Cardiff University, Redwood Building, uridylyltransferase deficiency) is seen in suckling
King Edward VII Avenue, Cardiff CB10 3NB, UK
infants causing severe illness, including not want-
e-mail: campbellak@cardiff.ac.uk
ing to drink, vomiting, jaundice, hypoglycemia,
S.B. Matthews
enlarged liver (hepatomegaly), enlarged spleen
Welston Court Science Centre, Milton,
Pembrokeshire SA70 8PS, UK (splenomegaly), proximal tubulus kidney damage,
e-mail: matthewss6@cf.ac.uk cataract, mental retardation, and failure to thrive.
Ingestion of lactose
[Lactase]
SGLT1
Generation of gases and metabolic toxins
Absorption of glucose by gut bacteria and archaea
and galactose
Absorption Colon
Gut pain
Flatulence Hearing Fertility
loss
Constipation
Diarrhea Allergies
Muscle and
Headache joint pain
Cognitive dysfunction
Fatigue Heart
palpitations
Fig. 1 Main metabolic changes in lactose intolerance. Under side), lactose is transferred to the large intestine and metabo-
healthy conditions, lactose is digested by lactase and incor- lized to metabolic toxins. The metabolic toxin groups are
porated causing an increase in blood glucose and galactose shown, with the respective gut and systemic symptoms.
levels (left side). In patients who cannot hydrolyze lactose SGLT1 sodium-activated glucose transporter 1, GLUT2 glu-
fully in the small intestine (lactose intolerant/sensitive, right cose transporter 2, H2 hydrogen, CH4 methane
Galactose synthesis occurs mainly in the A further problem is the increasing preva-
mammary gland, via the reversible conversion of lence of sensitivity to fructose. There is an
UDP-glucose to UDP-galactose. UDP-galactose increased use of fructose as a sweetener in many
then reacts with glucose to form lactose, though foods and drinks, and sensitivity to fructose can
65 % of galactose for lactose comes from the lead to similar symptoms to those of lactose
blood. Galactose can also be synthesized de novo intolerance. Fructose is absorbed into the
from glycerol. Galactose has an important role in enterocyte by GLUT5. Like, glucose and galac-
cerebrosides. tose, fructose is transferred into the blood by
SGLT1 is inhibited by tri- and tetrasaccha- GLUT2.
rides (e.g., raffinose and stachyose) found in root In diagnosis, hypolactasia is often overlooked
vegetable, pulses, and soya. People who eat a lot and not tested for if the patient only complains of
of these can exhibit symptoms similar to hypo- systemic symptoms, as opposed to gut symptoms.
lactasia (lack or reduced amounts of lactase). Yet, in many hypolactasia/lactose intolerant
Lactose Intolerance 145
patients, systemic symptoms can be more signifi- The loss after weaning correlates with two
cant than those in the gut. polymorphisms – C/T13910 and G/A22018 – occur-
Interestingly, the symptoms that affected ring within introns of a helicase, upstream from
Charles Darwin for 50 years match exactly those the lactase gene on the long arm of chromosome
of lactose intolerance [6]. Yet, he was never diag- 2 [8]. There is close correlation between the
nosed because his doctors did not understand the level of lactase and the C and G genotypes, those
link between the gut and the peripheral tissues. with CC and GG having the lowest levels. The
Lactose intolerance is often confused in babies molecular basis of this correlation is unknown.
with allergy to milk proteins, particularly αS1- But, the key is the number of cells expressing
casein, as symptoms are similar [1]. Protein allergy lactase rather than the level of lactase in each
usually disappears by 3 years, whereas lactose cell [2]. In Chinese, the loss of lactase can be
intolerance can get worse with age. The allergy >90 % by the age of 5 years, but in other races it
severity ranges from mild to anaphylactic (see may take until teenage before the nadir of lactase
chapter “Allergies”). Depending on the allergen, is reached [1].
changing the origin of the milk, e.g., to goat’s milk, Hypolactasia causes a maldigestion of lactose
can be effective, though this is not always the case. in the small intestine. Lack of lactose uptake does
Additionally, many patients suffering from not cause severe symptoms as the human body
lactose intolerance are also sensitive to other sub- does not require lactose as such and can synthe-
stances in foods, the most common being wheat. size galactose in some non-mammary cells if
required. However, undigested lactose is trans-
ported to the colon where it is subject to degrada-
Pathophysiology of Lactose tion by bacteria or archaeans forming gases such
Intolerance and Metabolic as hydrogen or methane and metabolic toxins
Alterations such as methylglyoxal and other alcohols, diols,
aldehydes, ketones, and acids [9]. Due to the
There are five causes of hypolactasia: (1) congen- variable tolerance of lactose between individuals
ital loss (very rare); (2) inherited loss on weaning, [3] and the different degradation products, the
very common; (3) gut infections, such as rotavi- resulting symptoms vary in type and severity
rus and Giardia (a monocellular parasite; see (Fig. 1) [10].
chapter “Gastroenteritis”); (4) damage to the villi Gas in the large intestine causes gut symp-
in the small intestine caused by radiotherapy or toms, like distension, borborygmi, and flatulence.
bacterial overgrowth; and (5) hormonal distur- Moreover, the metabolic toxins affect the balance
bance (e.g., thyroid), menopause, and aging. of microflora in the gut and cause diarrhea or
The first two of these are irreversible. In con- constipation. This surprising difference between
trast, the last three potentially are reversible [1], diarrhea or constipation in particular patients
after recovery from the gut infection, repair of reflects whether the bacterial metabolic toxins act
damage to the villi, or treatment of the hormonal to block smooth muscle contraction, and thus
disturbance. Almost all mammals lose lactase cause constipation, or act in an analogous way to
after weaning [7]. Thus, inherited hypolactasia is cholera or enterotoxin to signal fluid secretion
very common, being as high as 90 % in Chinese into the large intestine. After absorption into the
and >80 % in Asians [1]. In evolution, apes would blood, the bacterial metabolic toxins result in a
never see milk after coming off the mother’s multitude of systemic symptoms in peripheral
breast. Lactase persistency in adult humans is tissues, ranging from fatigue, headache, cogni-
only present in some ethnic groups, such as tive dysfunction, muscle and joint pain to heart
Bedouins and Northern Europeans (in which it palpitations, exacerbation of allergies [11] (see
reaches 90 %). Sensitivity to lactose generally chapter “Allergies”), and liver and kidney prob-
increases with southern origins. lems (see chapters “Overview” under the part
146 A.K. Campbell and S.B. Matthews
“Liver” and “Overview” under the part “Kidney”). Treatment of Lactose Intolerance
These symptoms are the result of direct effects of
the toxins on ionic signaling in peripheral tissues Treatment depends on the reason for the hypolac-
[9]. Most prominently, methylglyoxal reacts with tasia. Failure to treat correctly may leave patients
hormones (e.g., insulin) and neurotransmitters with long-term damage to the intestine or other
(e.g., serotonin and dopamine), inactivating them tissues and also other conditions, such as IBD or
[9], a biochemical process called Pictet-Spengler celiac disease.
reaction. Methylglyoxal also acts on neurons As congenital loss and loss after weaning can-
directly, causing pain. not be “reactivated,” avoidance of lactose in the
Lactose intolerance is associated with IBS [5] diet is, in general, inevitable (Fig. 2) [2]. This is
and IBD [4]. The symptoms in IBS are a result of difficult, however, because lactose is “hidden” in
poor lactose digestion and sugar absorption in the many foods and drinks, not normally associated
small intestine. In IBD, it is not clear whether with milk (e.g., chocolate, bread, biscuits, pro-
lactose intolerance is a cause or consequence of cessed meat) [3]. It is used in processed foods
the intestinal inflammation. Although there are because it improves shelf life, browning, mouth
endogenous mechanisms capable of inactivating feel, and flavor. As filler, lactose bulks up expen-
bacterial toxins, their role in lactose intolerance, sive ingredients and often replaces fat removed
IBS, and IBD is as yet unknown. from products in low-fat alternatives.
IBS
Removal of lactose Surgery for IBD
(including hidden lactose) Laxatives
Anti-motility
Anti-spasmodic Exclusion of protein
Avoidance of tri- and Anti-depressant allergy in babies and
tetra-saccharides children
IBD
Probiotics Steroids Complimentary therapies
Azothiaphrine
Monitoring of calcium Infliximab
Cognitive behavioral
and vitamin D status
therapy
Other systemic symptoms
Exclusion of other (fatigue, allergy, palpitations,
food sensitivities cyclic vomiting)
(e.g. wheat)
Anti-histamines
Asthma inhalers
Anti-depressants
Headache Topical steroids Muscle and joint pain
β-blockers
NSAIDs Vitamins and minerals Pain relief
Migraine treatment Triptans Anti-inflammatories
Fig. 2 Influence of disease treatments on disease. Three be helpful, as well. Comorbidities and symptoms are
general types of treatment are available for the various often targeted using specific drugs. Cognitive behavioral
symptoms in lactose-sensitive patients: (1) dietary manip- therapy involves discussions with a psychologist, using
ulation, particularly lactose exclusion; (2) drugs, which standard psychological methods. Complimentary thera-
are often not very effective, if at all; and (3) nondrug ther- pies involve acupuncture, reflexology, and exercise. IBS
apy. The most effective and common treatment is removal irritable bowel syndrome, IBD inflammatory bowel dis-
of lactose from the diet. Other dietary restrictions might ease, NSAIDs nonsteroidal anti-inflammatory drugs
Lactose Intolerance 147
Labeling of added lactose is poor as it is little or no consistent effect on the gut and sys-
commonly part of “flavorings” or “added sugar,” temic symptoms caused by lactose. Nondrug
being described as “natural.” It is possible to treatments of IBS include cognitive behavioral
take the equivalent of a liter of milk in “hidden” therapy; stress management; complementary
lactose, for example, after starting a weight loss therapies, including acupuncture and reflexol-
regime using meal substitute drinks high in lac- ogy; and exercise.
tose. Symptoms of lactose intolerance are often Lactose sensitivity is commonly seen in IBD
aggravated by tri- and tetrasaccharides inhibit- [4]. IBD treatment involves aminosalicylates,
ing SGLUT1 (see above) and leading to unab- corticosteroids, and immunosuppressants. These
sorbed sugars reaching the bacteria in the large are used to reduce the effect of inflammation in
intestine. the intestine, but do not alleviate the symptoms
Natural yogurt is often tolerated, since the lac- caused by lactose.
tose content is much reduced. Substitutes, such
as lactose-free cow’s milk or soya milk, are gen-
erally useful, if soya intolerance is excluded. Influence of Treatment
Symptoms caused only by lactose can disap- on Metabolism and Consequences
pear within a few days after removing lactose for Patients
from the diet.
Alternatively, the enzyme marketed as “lac- Removal of lactose from the diet or uptake of
tase,” actually β-galactosidase, taken before eat- digesting enzymes does not have adverse
ing lactose, may alleviate symptoms, as it is effects on the patient’s metabolism. It is vital
supposed to digest lactose similar to the endoge- to ensure calcium and vitamin D levels when
nous enzyme. β-galactosidase also hydrolyses milk, their major dietary source, is avoided.
lactose to galactose and glucose and is expressed Advice on the possible use of probiotics is also
in many bacteria and several molds. Yet, it has no required. However, dietary removal of lactose
sequence similarity to mammalian lactase, con- may not solve all the problems, if the patient is
tains only one active center for lactose, and can- intolerant to other foods. These need to be
not hydrolyze cerebrosides (also known as identified and treated, most commonly by
monoglycosylceramides) as lactase does. The dietary means.
use of β-galactosidase is not routinely recom- The systemic symptoms of lactose intolerance
mended, as most of the enzyme is degraded in the lead to unnecessary drug usage. Headaches are
stomach. Timing and dose are critical to be treated by regular analgesics and the risk of over-
effective. use is high. Migraine and cyclical vomiting syn-
Despite the best therapeutic approach of a lac- drome can be controlled by regular β-blockers
tose-free diet being drug free, many drugs are pre- and triptans (see chapter “Migraine and cluster
scribed, or bought over the counter by people with headache”). Other commonly used drugs are
lactose sensitivity, in an attempt to alleviate gut antihistamines, anti-inflammatories, steroids, and
and systemic symptoms, the most common being asthma inhalers, taken to alleviate allergic symp-
IBS. toms (see chapter “Asthma”). Yet, unknown to
Treatment of IBS includes antispasmodics most asthmatics, many inhalers also contain sig-
(e.g., mebeverine); bulk laxatives; antimotility nificant amounts of lactose.
drugs (e.g., loperamide); antidepressants (e.g., Drug interaction from polypharmacy is a seri-
the tricyclic amitriptyline or a serotonin reup- ous potential risk, especially as many of the drugs
take inhibitor), which reduce pain and cramps; are self-prescribed. There is also a danger of drug
and analgesics. Probiotics can also reduce overuse. Furthermore, there can be an iatrogenic
symptoms [12]. Patients often also take antac- problem of taking too much lactose in drugs, as it
ids and proton pump inhibitors to reduce stom- is often included in pills, which then contributes
ach acidity and reflux. However, these have to morbidity [13].
148 A.K. Campbell and S.B. Matthews
Perspectives References
In diagnosis, the gold standard [5] for a patient 1. Campbell A, Jenkins-Waud J, Matthews S (2005) The
molecular basis of lactose intolerance. Sci Prog 92:
presenting with unexplained gut and systemic 241–287
symptoms should first be to test for the polymor- 2. Campbell AK, Matthews SB (2005) Tony’s lactose
phism C/T13910. All CC should immediately free cookbook: the science of lactose intolerance and
change to a lactose-free diet, whereas CT or TT how to live without lactose. The Welston Press,
Pembrokeshire, p 204
patients should undergo a hydrogen and methane 3. Matthews SB, Waud JP, Roberts AG, Campbell AK
breath test after lactose ingestion, together with a (2005) Systemic lactose intolerance: a new perspec-
record of symptoms. A significant number of tive on an old problem. Postgrad Med J 81:167–173
patients show no positive hydrogen or methane 4. Eadala P, Matthews SB, Waud JP, Green JT, Campbell
AK (2011) Association of lactose sensitivity with
breath test, but will exhibit symptoms after lac- inflammatory bowel disease – demonstrated by analy-
tose ingestion. Hypolactasia caused by infec- sis of genetic polymorphism, breath gases and symp-
tions, e.g., Giardia or rotavirus, which damage toms. Aliment Pharmacol Ther 34:735–746
the lactase-containing intestinal villi (see chapter 5. Waud JP, Matthews SB, Campbell AK (2008)
Measurement of breath hydrogen and methane,
“Overview” under the part “Gastrointestinal together with lactase genotype, defines the current
tract”), or hormonal imbalance, which can reduce best practice for investigation of lactose sensitivity.
lactase levels, should be investigated, if there is Ann Clin Biochem 45:50–58
no evidence of family history. If the breath hydro- 6. Flatz G (1987) Genetics of lactose digestion in
humans. Adv Hum Genet 16:1–77
gen or methane is increased, together with induc- 7. Enattah NS, Sahi T, Savilahti E, Terwilliger JD,
tion of symptoms by lactose, the patient should Peltonen L, Jarvela I (2002) Identification of a variant
change to a lactose-free diet. All patients with a associated with adult-type hypolactasia. Nature Genet
significant increase in symptoms after the lactose 30(2):233–237
8. Campbell AK, Matthews SB, Vassell N, Cox C,
load should undergo a supervised trial to deter- Naseem R, Chaichi MJ, Holland IB, Wann KT (2010)
mine their lactose threshold. Every patient should Bacterial metabolic ‘toxins’: a new mechanism for
be followed up in 12 weeks for a definitive diag- lactose and food intolerance, and irritable bowel syn-
nosis, based on clinical improvement, following drome. Toxicology 278(3):268–276
9. Matthews SB, Campbell AK (2000) When sugar is
lactose removal from the diet. not so sweet. Lancet 355(9212):1330
Lactose sensitivity, and the production of met- 10. Grimbacher B, Peters T, Peter HH (1997) Lactose
abolic toxins by gut bacteria and archaeans, pro- intolerance may induce severe chronic eczema. Int
vides a new mechanism linking the gut to other Arch Allergy Immunol 113(4):516–518
11. Zuccotti G (2008) Probiotics in clinical practice: an
illnesses, such as type 2 diabetes (see chapter overview. J Int Med Res 36(1):1–53
“Diabetes mellitus”), Parkinson’s disease (see 12. Eadala P, Waud JP, Matthews SB, Green JT, Campbell
chapter “Parkinson’s disease”), Alzheimer’s dis- AK (2009) Quantifying the ‘hidden’ lactose in drugs
ease (see chapter “Alzheimer’s disease”), some used for the treatment of gastrointestinal conditions.
Aliment Pharmacol Ther 29(6):677–687
cancers (see chapter “Overview” under the part 13. Campbell AK, Matthews SB (2005) Darwin’s
“Cancer”), and periodontal disease. The molecu- illness revealed. Postgrad Med J 81(954):
lar mechanisms responsible for the production of 248–251
bacterial metabolic toxins are a good target for
drug discovery in developing a new treatment for
these conditions.
Colorectal Cancer
Polyp
Proteolytic
Protein BCFA, Indoles, Phenols, Amines
fermentation
Red meat
Processed meat NOC, PAH, HCA, Heme, Iron
Animal fat Primary bile acids Secondary bile acids
Colon cancer
Chronic infection/Inflammation
Toxins
ROS H 2S
Pro-neoplastic factors
SRB
Fiber Saccharolytic
Resistant starch SCFAs, CO2, H 2 Anti-neoplastic factors
fermentation
Complex carbohydrates
MA
Folate
Biotin
CH4
Fig. 1 Dietary factors and microbiotal metabolites fatty acids (SCFAs), whereas high dietary red meat and fat
mediating the risk of colorectal cancer. The balance promote production of proinflammatory proteolytic bacte-
between health-promoting and proinflammatory metabo- rial fermentation end products and carcinogenic second-
lites determines the risk of colorectal cancer (CRC). Their ary bile acids. MA methanogenic archaea, SRB
production is dependent on both food compositions and sulfate-reducing bacteria, BCFA branched-chain fatty
(food metabolizing) microbiota. High fiber and resistant acids, NOC N-Nitroso compounds, PAH polyaromatic
starch diet promote saccharolytic bacterial fermentation hydrocarbons, HCA heterocyclic amines, ROS reactive
and enhance production of anti-inflammatory short-chain oxygen species
microbiome, which holds a rich repertoire of based on dietary habits [13]. Whereas native
metabolic functions [10]. In a symbiotic relation- Africans consume a diet rich in indigestible fiber
ship, the microbiota are dependent on undigested and resistant starch and low in animal products,
food residues and in turn produces essential African Americans consume more animal pro-
metabolites (see below). tein, red meat, and saturated fat and lower amounts
The microbiota include ~800 different bacte- of complex carbohydrates, resulting in a ten times
rial species with over 7,000 strains. Recent higher CRC incidence [14].
advances in molecular identification and charac- Indigestible fiber, resistant starch, and com-
terization techniques have led to a better under- plex carbohydrates undergo saccharolytic fer-
standing of the microbiotal composition and mentation predominantly in the proximal colon
appreciation of their metabolic potential [10]. yielding SCFAs (acetate, propionate, and butyr-
Interestingly, microbial analyses revealed funda- ate), ethanol, and gases such as carbon dioxide
mentally different microbiomes among people of (CO2) and hydrogen (H2; Fig. 1) [15]. Acetate
different origins, which even allow categoriza- and propionate are the major (~85 %) fraction of
tion into human fecal enterotype categories [11]. SCFAs but are absorbed mostly into the systemic
While ~90 % of protein and carbohydrate are circulation, with acetate being taken up by the
digested and absorbed along the small intestine, liver for cholesterol synthesis and propionate par-
residual food is metabolized by the colonic ticipating in gluconeogenesis [16]. Butyrate, on
microbiota through fermentation, producing pro- the other hand, is the most important pluripotent
tective and vital metabolites, such as short-chain SCFA that exerts its principal actions locally in
fatty acids (SCFAs), or vitamins such as folate the colon serving as the chief energy source for
and biotin that are essential for DNA synthesis the colonocytes, regulator of the epithelial growth
and repair. However, the microbiota can also pro- and differentiation, and anti-inflammatory and
duce toxins and detrimental metabolites such as antineoplastic factor [17]. It causes hyperacety-
hydrogen sulfide (H2S), reactive oxygen species lation of histones by inhibiting histone deacety-
(ROS), and secondary bile acids (BAs) promot- lase and modulates transcription factors to
ing inflammation and neoplastic progression (see regulate gene expression and cell function [18].
below). Its actions are also mediated by signaling path-
Chronic inflammation is triggered and perpet- ways involving upregulation of peroxisome
uated by some microbiota through signaling proliferator-activated receptor-γ (PPARγ), sup-
pathways such as induction of Toll-like recep- pression of nuclear factor-κB (NF-κB) activation,
tors, upregulation of cyclooxygenase-2 (COX-2), and G-protein-coupled receptor signaling [16].
and activation of mitogen-activated protein Finally, butyrate plays a critical role in reinforc-
kinases (MAPKs) that promote proinflammatory ing the gut mucosal defense barrier by enhancing
cytokine release, cell proliferation, genetic muta- mucin gene expression and induction of trefoil
tion, and neoplastic transformation [12]. It is the factors (i.e., secretory proteins with a short trefoil
fine balance between the beneficial and harmful motif involved in mucosal stabilization, protec-
microbiota and their metabolites that determines tion, and regeneration), antimicrobial peptides,
the state of health versus disease (Fig. 1). A dis- and transglutaminase activity (that cross-links
turbed microbial composition and function result and stabilizes proteins) [19].
in a state of dysbiosis, a key predecessor of dis- On the contrary, undigested protein residues
eases such as diabetes (see chapter “Diabetes reaching the distal colon undergo proteolytic fer-
mellitus”), obesity (see chapter Metabolic syn- mentation by bacteria producing branched-chain
drome), inflammatory bowel disease, and CRC. fatty acids and inflammatory nitrogenous metab-
Indeed, diet is the cause of over 90 % of gas- olites such as phenolic and indolic compounds
trointestinal cancers, the risk differing significantly that have been shown to cause colonocyte DNA
152 K. Vipperla and S.J. O’Keefe
damage in experimental models (Fig. 1) [20]. of alcohol, avoidance of tobacco use, and, most
High consumption of red meat promotes proteo- importantly, dietary modifications (see below)
lytic fermentation by providing large amounts of can mitigate CRC risk.
undigested protein residues. Red meat is also
responsible for increasing CRC risk in several
other ways. Hydrogen (H2), produced during fer- Dietary Modifications for Minimizing
mentation, is generally excreted in the breath Risk of Colorectal Cancer
(directly or as methane). However, it can also be
converted to hydrogen sulfide (H2S) by sulfide- In light of the decisive influence of diet on CRC
reducing bacteria using methionine and cysteine risk, it is prudent to consume a balanced diet that
from animal protein [21]. H2S induces mucosal can modulate the microbial composition to pro-
hyperproliferation and free radical-mediated duce beneficial metabolites such as butyrate.
genotoxicity, effects that can be reversed by Enhancing butyrate production can mitigate the
butyrate [22]. Aromatic amino acids, which are mutagenic effects of secondary BAs, prolifera-
abundant in red meat, undergo bacterial decar- tive effects of H2S, and DNA damage induced by
boxylation and N-nitrosation resulting in forma- red meat [28]. Chlorophyll (present in green
tion of N-nitroso compounds (NOC) [23]. In a rat leafy vegetables) has been shown to ameliorate
model, dietary heme was shown to promote colo- the toxic effects of heme [29]. Increasing our
nocyte proliferation by causing epithelial injury, dietary fiber, resistant starch, and complex carbo-
inhibition of apoptosis, and crypt cell hyperpla- hydrate content and moderating red meat and ani-
sia, the precursors of carcinogenesis [24]. In mal fat portions seem to be a simple step for
addition, meat processing and cooking practices promoting colonic mucosal health. This diet is
that expose meat to very high temperatures also well tolerated even if patients are used to a more
result in formation of several mutagens (such as traditional diet. Reduction of red meat does not
NOC, polycyclic aromatic hydrocarbons, and disturb general metabolism. Our demand for
heterocyclic amines) that cause DNA base alkyl- dietary protein, important for our structural and
ation and formation of base adducts, biomarkers metabolic needs, can quite easily be met by con-
of chemical carcinogenesis [23, 25]. sumption of other protein-rich diets such as white
Finally, high dietary fat increases BA synthesis meat, fish, and legumes.
and consequently BA transition to the colon allow-
ing bacterial conversion to secondary BAs (such as
deoxycholic acid and lithocholic acid), which have Cancer Screening
strong inflammatory properties and cause oxida- and Chemoprevention
tive DNA damage and genomic instability of the
colonocytes [26]. High-fat diet also stimulates The adenoma-carcinoma sequence usually takes
delivery of sulfur-rich taurine conjugates to the 7–10 years offering an adequate window period
colon promoting certain detrimental bacterial to screen and intervene. At least 60 % of deaths
strains and inducing colitis by proinflammatory from CRC can be prevented by early detection of
Th1-mediated immune responses and bacterial by- precancerous polyps through diligent screening
products such as H2S and secondary BAs [27]. of people who are 50 years or older (or earlier in
case of higher risk) using high-sensitivity fecal
occult blood testing (meaning detection of blood
Treatment and Influence in the stool), flexible sigmoidoscopy (i.e., an
on Metabolism investigation of the rectum and last third of the
colon by insertion of a camera mounted on a flex-
Prevention ible scope into the anus and its guidance through
the rectum into the colon), and/or colonoscopy
In general, adopting a healthy lifestyle with (or coloscopy, i.e., an endoscopic examination of
increased physical activity, limited consumption the large bowel with a flexible tube inserted via
Colorectal Cancer 153
11. Arumugam M, Raes J, Pelletier E et al (2011) contribution to cancer of known exposures to NOC.
Enterotypes of the human gut microbiome. Nature Cancer Lett 93:17–48
473:174–180 24. De Vogel J, Van-Eck WB, Sesink AL, Jonker-Termont
12. Terzic J, Grivennikov S, Karin E, Karin M (2010) DS, Kleibeuker J, Van Der Meer R (2008) Dietary
Inflammation and colon cancer. Gastroenterology heme injures surface epithelium resulting in hyperp-
138:2101–2114 roliferation, inhibition of apoptosis and crypt hyper-
13. Doll R, Peto R (1981) The causes of cancer: quantitative plasia in rat colon. Carcinogenesis 29:398–403
estimates of avoidable risks of cancer in the United 25. Cross AJ, Ferrucci LM, Risch A et al (2010) A large
States today. J Natl Cancer Inst 66:1191–1308 prospective study of meat consumption and colorec-
14. O’Keefe SJ, Chung D, Mahmoud N et al (2007) Why tal cancer risk: an investigation of potential mecha-
do African Americans get more colon cancer than nisms underlying this association. Cancer Res 70:
Native Africans? J Nutr 137:175S–182S 2406–2414
15. Cummings JH, Englyst HN (1991) Measurement of 26. Bernstein C, Holubec H, Bhattacharyya AK et al
starch fermentation in the human large intestine. Can (2011) Carcinogenicity of deoxycholate, a secondary
J Physiol Pharmacol 69:121–129 bile acid. Arch Toxicol 85:863–871
16. Roy CC, Kien CL, Bouthillier L, Levy E (2006) 27. Devkota S, Wang Y, Musch MW et al (2012) Dietary-
Short-chain fatty acids: ready for prime time? Nutr fat-induced taurocholic acid promotes pathobiont
Clin Pract 21:351–366 expansion and colitis in Il10−/− mice. Nature 487:
17. Vipperla K, O’Keefe SJ (2012) The microbiota and its 104–108
metabolites in colonic mucosal health and cancer risk. 28. Fung KY, Cosgrove L, Lockett T, Head R, Topping
Nutr Clin Pract 27:624–635 DL (2012) A review of the potential mechanisms for
18. Davie JR (2003) Inhibition of histone deacetylase the lowering of colorectal oncogenesis by butyrate. Br
activity by butyrate. J Nutr 133:2485S–2493S J Nutr 108:820–831
19. Willemsen LE, Koetsier MA, Van Deventer SJ, Van 29. De Vogel J, Jonker-Termont DS, Van Lieshout EM,
Tol EA (2003) Short chain fatty acids stimulate epi- Katan MB, Van Der Meer R (2005) Green vegetables,
thelial mucin 2 expression through differential effects red meat and colon cancer: chlorophyll prevents the
on prostaglandin E(1) and E(2) production by intesti- cytotoxic and hyperproliferative effects of haem in rat
nal myofibroblasts. Gut 52:1442–1447 colon. Carcinogenesis 26:387–393
20. Hughes R, Magee EA, Bingham S (2000) Protein 30. Levin B, Lieberman DA, Mcfarland B et al (2008)
degradation in the large intestine: relevance to colorec- Screening and surveillance for the early detection of
tal cancer. Curr Issues Intest Microbiol 1:51–58 colorectal cancer and adenomatous polyps, 2008: a joint
21. Gibson GR, Macfarlane GT, Cummings JH (1993) guideline from the American Cancer Society, the US
Sulphate reducing bacteria and hydrogen metabolism Multi-Society Task Force on Colorectal Cancer, and the
in the human large intestine. Gut 34:437–439 American College of Radiology. Gastroenterology
22. Attene-Ramos MS, Wagner ED, Gaskins HR, Plewa 134:1570–1595
MJ (2007) Hydrogen sulfide induces direct radical- 31. Cunningham D, Atkin W, Lenz HJ et al (2010)
associated DNA damage. Mol Cancer Res 5:455–459 Colorectal cancer. Lancet 375:1030–1047
23. Mirvish SS (1995) Role of N-nitroso compounds 32. Siegel R, Desantis C, Virgo K et al (2012) Cancer
(NOC) and N-nitrosation in etiology of gastric, treatment and survivorship statistics, 2012. CA
esophageal, nasopharyngeal and bladder cancer and Cancer J Clin 62:220–241
Part VI
Pancreas
Overview
Anatomy and Physiology the pancreas into the duodenum of the small
of the Pancreas intestine [2]. On a cellular level, exocrine acinar
cells make up ~95 % of the pancreas and form
Ingestion of a meal stimulates the physiological flower-like clusters that connect with terminal
response to control the digestion, absorption, and ducts located at the tips of the ductal tree
assimilation of nutrients. The pancreas is integral (Fig. 1b, c). Centroacinar cells line the edges of
to this process, communicating with other organs the terminal ducts and create an interface between
through hormones and metabolites to efficiently duct and acinar cells (Fig. 1c) [2]. The endocrine
obtain and use energy sources [1]. Following the cells of the pancreas aggregate in clusters to form
intake of food, the exocrine compartment (made islets of Langerhans that make up ~1–2 % of the
up of acinar, duct, and centroacinar cells; Fig. 1) pancreas (Fig. 1b, d). Human islets are mainly
releases digestive fluid to facilitate the intestinal composed of four different hormone-secreting
breakdown and absorption of nutrients [2]. In cell types, α-cells (secreting glucagon; 20–30 %
contrast, pancreatic endocrine cells (α-, β-, δ-, of the cells in the islet), β-cells (secreting insulin;
and pancreatic polypeptide cells) release hor- 60–70 %), δ-cells (secreting somatostatin;
mones [3] that control how cells use and store <10 %), and pancreatic polypeptide cells (secret-
energy fuels (i.e., glucose, lipids, and proteins) ing pancreatic polypeptide; <3–5 %) (Fig. 1d)
during different metabolic transitions (i.e., feed- [6]. Ghrelin-expressing ε-cells are a fifth islet cell
ing, fasting, and exercise) [4]. type that are rare in the adult pancreas but found
Located in the abdominal region, the “head” primarily during gestational development [7, 8].
of the pancreas is nestled in the curve of the small These islet endocrine cells are the major source
intestine (Fig. 1a), while the “tail” is situated next of hormones responsible for regulating systemic
to the spleen [5]. The lobes of the pancreas sur- energy levels and require an extensive capillary
round a branching network of ducts that merge network to efficiently monitor, detect, and release
into one main tube that carries digestive enzymes hormones in a manner that accommodates the
(made by pancreatic acinar cells) and bicarbonate- changing energy needs of the body [3].
rich fluid (made by pancreatic duct cells) across
Pancreas-Specific Metabolic
A.E. Folias • M. Hebrok (*) Pathways and Processes
Department of Medicine, UCSF Diabetes Center,
513 Parnassus Avenue, HSW 1116, 0540,
Glucose is one of the three major metabolic fuels
San Francisco, CA 94143, USA
e-mail: afolias@diabetes.ucsf.edu; and is particularly important for satisfying quick
mhebrok@diabetes.ucsf.edu energy demands. To use glucose and other energy
a b
Ductal system
Tail of the pancreas
Duct
Acinar cell
e GLUT1
Centroacinar cell
Glucose-6-P ATP/ADP d
Glycolysis
& TCA cycle K+ α-cell
b-cell
Insulin granules Ca2+
δ-cell
Fig. 1 Anatomy of the pancreas. (a): Diagram showing the (insulin), δ-cells (somatostatin), and pancreatic polypeptide
head of the pancreas located adjacent to the small intestine (PP) cells (pancreatic polypeptide). (e): Schematic of glu-
and the pancreatic ductal system that transports digestive cose-stimulated insulin secretion in a β-cell. Glucose enters
enzymes into the duodenum of the intestine. (b): the cell via glucose transporter 1 (GLUT1) and is phosphor-
Microscopic image of the pancreas (stained with hematoxy- ylated by glucokinase and metabolized in glycolysis and the
lin and eosin) showing the separated exocrine (acinar, cen- tricarboxylic acid (TCA) cycle. This increases cellular ATP
troacinar, and duct cells) and endocrine (islet cells) and the ATP/ADP ratio inducing closure of the ATP-
compartments. (c): Schematic of digestive enzyme release sensitive K+ channels. Subsequent depolarization of the cell
from the flower-like structure formed by acinar cells into a causes voltage-gated Ca2+ channels to open and allows an
terminal duct lined with centroacinar cells. (d): Schematic influx of Ca2+ ions that stimulate the exocytosis of insulin
of the four main hormone-secreting endocrine cells that secretory granules
make up the islets of Langerhans: α-cells (glucagon), β-cells
sources, cells must first transport these nutrients and short-term (coma) complications can arise
from the bloodstream into the cell. The hormone from hyperglycemia (elevated blood glucose)
insulin (synthesized and released by β-cells) is and hypoglycemia (too little blood glucose),
one of the main drivers of glucose uptake by tis- highlighting the importance of regulating insulin
sues, and disruption in the synthesis, secretion, or release to maintain blood glucose levels within a
signaling of insulin can lead to the manifestation specific range [1, 4].
of diabetes (see chapter “Diabetes mellitus”) [4]. Insulin is released in response to nutritional
Both serious long-term (heart disease, blindness) and hormonal signals, with the primary regulator
Overview 159
being glucose. β-cells use the metabolism of glu- inhibitory ATP-binding site, while the SUR1
cose as a way to determine both the levels of glu- (sulfonylurea receptor 1) β-subunits can induce
cose present in the bloodstream and the closure of the channel independent of ATP levels
corresponding amount of insulin to release in a in response to antidiabetic sulfonylurea drugs
process known as glucose-stimulated insulin (see chapter “Diabetes mellitus”). In humans,
secretion (Fig. 1e) [9]. As glucose is metabo- elevated insulin release occurs with loss of func-
lized, ATP levels and thus the cellular ATP/ADP tion mutations in either SUR1 or Kir6.2, while
ratio increase, causing the ATP-sensitive K+ decreased insulin secretion is found in cases of
channels to close and a depolarization of the KATP activating mutations that hyperpolarize the β
membrane. This change in membrane potential cell [14]. Ultimately, the fine-tuned interactions
opens voltage-gated Ca2+-channels. Influx of Ca2+ between glucose transport and glucokinase activ-
then triggers the exocytosis of secretory granules ity and the characteristics of the ATP-sensitive K+
storing insulin (Fig. 1e). The released, active channels and voltage-gated Ca2+ channels con-
form of insulin is derived from the proteolytic tribute to the threshold triggering insulin release
cleavage of proinsulin that removes the C-peptide in response to high blood glucose.
portion to allow direct association of the A and B
chains via disulfide bonds [10].
To act as “glucose sensors,” β-cells can effi- Inside-In: Metabolites of the
ciently sample and metabolize a wide range of Pancreas Affecting Itself
glucose levels. Glucose is first transported into
the β-cell at levels proportional to the blood- The regulation of pancreatic hormone secretion
stream by a transporter with low-affinity/high- directly occurs within the islet itself, tailoring
capacity characteristics for glucose called glucose the release of insulin and glucagon to match the
transport protein 1 (GLUT1, Fig. 1e) [11]. diverse and fluctuating metabolic demands of
Glucose is subsequently phosphorylated to retain the body. The anatomical organization of cells
glucose inside the cell and allow entry into gly- within the islet (Fig. 1d) is considered to be
colysis. Hexokinase catalyzes this rate-limiting important for efficient function, allowing regula-
(slowest) step, acting as a regulator over the flux tion to occur intimately via cell-cell interactions.
of the pathway [12]. There are several isozymes Direct communication between β cells contrib-
of hexokinase that differ in amino acid sequence utes to appropriate insulin release by inhibiting
but catalyze the same reaction. Glucokinase is the basal release of insulin secretion but enhanc-
the form of hexokinase expressed in the liver and ing glucose-stimulated insulin secretion [15].
insulin-secreting β-cells (Fig. 1e). In addition to Additionally, as β-cells and α-cells are activated
tissue-specific expression, glucokinase also has a under different metabolic conditions, release of
very high Km (the substrate concentration that factors from β-cells (insulin, γ-amino butyric
produces half-maximal velocity) for glucose in acid, and zinc) [16, 17] can directly inhibit glu-
comparison to other hexokinases. This high Km cagon release from α-cells [18]. Lastly, the intra-
(10 mmol/l) allows the β-cell to metabolize and islet release of somatostatin from δ-cells can
“sense” a range of glucose levels without inhibit both α- and β-cell function, contributing
becoming saturated. Other tissues, such as the to the fine-tuning of endocrine response to exter-
brain, express a hexokinase with a significantly nal signals [19, 20].
lower Km (50 μmol/l) for glucose to ensure the While endocrine hormones (such as pancre-
glycolytic needs of the brain are satisfied even atic polypeptide released by δ-cells) impact exo-
during states of low blood glucose [13]. crine function, most of this regulation is believed
Additionally, characteristics of the subunits to be via indirect mechanisms. However, there is
that make up the KATP channel also impact how some evidence that endocrine hormones can
insulin is secreted. The Kir6.2 (K+ inward rectify- directly stimulate (insulin) or inhibit (somatosta-
ing) α-subunits of the KATP channel contain an tin) exocrine enzyme release [21].
160 A.E. Folias and M. Hebrok
a Fed b Fasted
Glucose Glucose
Lipids Lipids
AAs AAs
Pancreatic Pancreatic
β-cells α-cells
Insulin Glucagon
Fig. 2 How pancreatic metabolites affect other tissues. hormone glucagon released by α-cells counter-regulates
(a): The anabolic hormone insulin is secreted by β cells insulin by stimulating the mobilization of fuels, particu-
when nutrient levels are high (fed state) to promote the larly glucose, during states of low fuel availability (fast-
uptake and storage of energy sources. (b): The catabolic ing/exercise). AAs amino acids
acids (Fig. 2a). Insulin acts to promote the syn- and glucogenic amino acids) into glucose (gluco-
thesis of glycogen (the storage form of glucose neogenesis). Unlike the liver, the glucose yielded
found in the muscle and liver, glycogenesis) as from glycogen breakdown in the muscle is used
well as suppress glycogenolysis (glycogen break- only within the skeletal muscle. Additionally,
down). Additionally, fatty acid synthesis (lipo- glucagon also decreases processes that remove
genesis) and protein synthesis are increased by glucose from the bloodstream, including glyco-
insulin, while lipid breakdown (lipolysis) and genesis and glycolysis (Fig. 2b) [28].
protein breakdown are inhibited (Fig. 2a) [4].
Conversely, the catabolic hormone glucagon
counter-regulates insulin by stimulating the Final Remarks
mobilization of fuels, particularly glucose, dur-
ing states of low fuel availability (fasting/exer- Both the endocrine and exocrine compart-
cise, Fig. 2b) [27]. Glucagon elevates blood ments of the pancreas are vital to proper diges-
glucose levels by stimulating hepatic glucose tion, absorption, and assimilation of nutrients.
output via the breakdown of glycogen (glycoge- The exocrine compartment (acinar, duct, and
nolysis) as well as promoting the conversion of centroacinar cells) releases digestive enzymes
other carbon sources (pyruvate, lactate, glycerol, and bicarbonate fluid to aid in the intestinal
162 A.E. Folias and M. Hebrok
breakdown of lipids, carbohydrates, and proteins. 11. Matschinsky FM (2009) Assessing the potential of
glucokinase activators in diabetes therapy. Nat Rev
As these nutrients are absorbed, the endocrine
Drug Discov 8:399–416
cells of the islet (α-, β-, δ-, and pancreatic poly- 12. Matschinsky FM, Glaser B, Magnuson MA (1998)
peptide cells) release hormones that affect how Pancreatic beta-cell glucokinase: closing the gap
cells use and store these macronutrients. Insulin between theoretical concepts and experimental reali-
ties. Diabetes 47:307–315
release by β-cells controls the uptake and stor-
13. Murray RK, Granner DK, Mayes PA, Rodwell VW
age of nutrients following a meal, while gluca- (2000) Harper’s biochemistry, 25th edn. Appleton and
gon release by α-cells promotes mobilization of Lange, Stamford, pp 215–216
energy stores during times when food intake is 14. Jentsch TJ, Hübner CA, Fuhrmann JC (2004) Ion
channels: function unravelled by dysfunction. Nat
low. The importance of proper pancreatic func-
Cell Biol 6:1039–1047
tion is highlighted by conditions that can occur in 15. Konstantinova I, Nikolova G, Ohara-Imaizumi M,
cases of exocrine insufficiency (nutrient malab- Meda P, Kucera T, Zarbalis K, Wurst W, Nagamatsu
sorption) and impaired endocrine function (dia- S, Lammert E (2007) EphA-Ephrin-A-mediated beta
cell communication regulates insulin secretion from
betes, see chapter “Diabetes mellitus”).
pancreatic islets. Cell 129:359–370
16. Ishihara H, Maechler P, Gjinovci A, Herrera PL,
Wollheim CB (2003) Islet beta-cell secretion deter-
References mines glucagon release from neighbouring alpha-
cells. Nat Cell Biol 5:330–335
17. Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N,
1. Thompson JL, Manore MM, Vaughan LA (2008) The
Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB,
science of nutrition. Pearson Benjamin Cummings,
Braun M, Wang Q (2006) Intra-islet insulin sup-
San Francisco
presses glucagon release via GABA-GABAA recep-
2. Reichert M, Rustgi AK (2011) Pancreatic ductal cells
tor system. Cell Metab 3:47–58
in development, regeneration, and neoplasia. J Clin
18. Gromada J, Franklin I, Wollheim CB (2007) Alpha-
Invest 121:4572–4578
cells of the endocrine pancreas: 35 years of research
3. Murtaugh LC, Melton DA (2003) Genes, signals, and
but the enigma remains. Endocr Rev 28:84–116
lineages in pancreas development. Annu Rev Cell
19. Rutter GA (2009) Regulating glucagon secretion:
Dev Biol 19:71–89
somatostatin in the spotlight. Diabetes 58:299–301
4. Saltiel AR, Kahn CR (2001) Insulin signalling and the
20. Hauge-Evans AC, King AJ, Carmignac D, Richardson
regulation of glucose and lipid metabolism. Nature
CC, Robinson IC, Low MJ, Christie MR, Persaud SJ,
414:799–806
Jones PM (2009) Somatostatin secreted by islet delta-
5. Cummings DE, Overduin J (2007) Gastrointestinal
cells fulfills multiple roles as a paracrine regulator of
regulation of food intake. J Clin Invest 117:13–23
islet function. Diabetes 58:403–411
6. Cabrera O, Berman DM, Kenyon NS, Ricordi C,
21. Barreto SG, Carati CJ, Toouli J, Saccone GT (2010) The
Berggren PO, Caicedo A (2006) The unique cytoar-
islet-acinar axis of the pancreas: more than just insulin.
chitecture of human pancreatic islets has implications
Am J Physiol Gastrointest Liver Physiol 299:G10–G22
for islet cell function. Proc Natl Acad Sci U S A
22. Chandra R, Liddle RA (2012) Neurohormonal regula-
103:2334–2339
tion of pancreatic secretion. Curr Opin Gastroenterol
7. Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L
28:483–487
(2012) Ghrelin expression in the mouse pancreas
23. Williams JA (2010) Regulation of acinar cell function
defines a unique multipotent progenitor population.
in the pancreas. Curr Opin Gastroenterol 26:478–483
PLoS One 7:e52026
24. Keller J, Layer P (2005) Human pancreatic exocrine
8. Andralojc KM, Mercalli A, Nowak KW, Albarello L,
response to nutrients in health and disease. Gut
Calcagno R, Luzi L, Bonifacio E, Doglioni C, Piemonti
54(Suppl 6):1–28
L (2009) Ghrelin-producing epsilon cells in the devel-
25. Drucker DJ (2006) The biology of incretin hormones.
oping and adult human pancreas. Diabetologia
Cell Metab 3:153–165
52:486–493
26. Yip GC, Wolfe MM (2000) GIP biology & fat metab-
9. Muoio DM, Newgard CB (2008) Mechanisms of dis-
olism. Life Sci 66:91–103
ease: molecular and metabolic mechanisms of insulin
27. Habegger KM, Heppner KM, Geary N, Bartness TJ,
resistance and beta-cell failure in type 2 diabetes. Nat
DiMarchi R, Tschöp MH (2010) The metabolic
Rev Mol Cell Biol 9:193–205
actions of glucagon revisited. Nat Rev Endocrinol
10. Uchizono Y, Alarcón C, Wicksteed BL, Marsh BJ,
6:689–697
Rhodes CJ (2007) The balance between proinsulin
28. Jiang G, Zhang BB (2003) Glucagon and regulation
biosynthesis and insulin secretion: where can
of glucose metabolism. Am J Physiol Endocrinol
imbalance lead? Diabetes Obes Metab 9(Suppl 2):
Metab 284:E671–E678
56–66
Diabetes Mellitus
Obesity
HYPERGLYCEMIA
Fig. 1 Pathogenesis of type 2 diabetes mellitus. Two glucose (glucotoxicity) and an inflammatory response of
main pathophysiological features contribute to the mani- the adipose tissue (lipotoxicity), both leading to β-cell
festation of type 2 diabetes mellitus: insulin resistance (1) dysfunction (2). Thus, peripheral insulin resistance paves
and β-cell dysfunction (2). Both insulin resistance and the way for the onset of type 2 diabetes. TNFα tumor
β-cell dysfunction develop in the setting of genetic back- necrosis factor α, IL interleukin, NF-κB nuclear factor-κB,
ground and environmental factors. Initially, peripheral NEFA nonesterified fatty acids, FTO fat mass and obesity-
insulin resistance (1) can be overcome by an increased associated protein, TCF7L2 transcription factor 7-like 2,
insulin secretion. Over time, this compensatory mecha- IR insulin receptor, IRS IR substrate
nism can fail due to mild but progressive increase in blood
also correlates with a decline in circulating lev- toxicity are suggested to contribute to β-cell
els of anti-inflammatory adipokines such as dysfunction and death (Fig. 1). There is evi-
adiponectin, secreted frizzled-related protein 5 dence that glucotoxicity is likely mediated by
(SFRP5), visceral adipose tissue-derived serine an increased amount of reactive oxygen species
protease inhibitor (vaspin), and omentin-1 [10]. (ROS) following oxidative glucose metabolism
For instance, adiponectin acts as an insulin sen- in the β-cell [13]. Several genes and mutations
sitizer by suppressing hepatic gluconeogenesis, are also implicated in the development of T2DM.
enhancing glucose uptake in skeletal muscle, For example, variants of the gene encoding the
and inhibiting lipolysis [12]. fat mass and obesity-associated protein (FTO)
As exposure to high glucose concentrations associate with obesity and metabolic syndrome
is toxic to β-cells, both lipotoxicity and gluco- (see chapter “Metabolic syndrome”). Moreover,
166 A. Welters and E. Lammert
single nucleotide polymorphisms (SNPs) within disease”, “Overview” under the part “Blood ves-
the gene locus for the transcription factor 7-like 2 sels”, and “Stroke”) [20].
(TCF7L2), also known as transcription factor 4,
are linked to an approximately 1.5-fold increased
risk to develop T2DM. However, nongenetic fea- Diabetes Treatment and Its
tures such as a large waist circumference appear Influence on Metabolism
to have a better predictive value [14].
In general, obesity, insulin resistance, gluco- The main goal in the treatment of diabetes is to
toxicity, and lipotoxicity develop over several maintain the blood glucose level within a physi-
years and ultimately result in a decline of func- ological range, e.g., by decreasing insulin resis-
tional β-cell mass to 40–60 % of normal, thus tance, by activating endogenous insulin secretion,
leading to an overt T2DM [15]. or by exogenous administration of recombinant
insulin.
Of note, increasing endogenous insulin secre-
Complications tion requires yet functional β cells.
In T1DM, where the functional β-cell mass
Hyperglycemia is associated with acute life- is already significantly reduced once symp-
threatening complications, such as ketoacidosis toms occur, patients immediately require insulin
or hyperosmolar hyperglycemic state, and with replacement therapy.
serious long-term complications particularly Traditionally, exogenous insulin is adminis-
affecting the cardiovascular system (see chapters tered by subcutaneous injection. Today, insulin
“Atherosclerotic heart disease”, “Heart failure”, therapy is individualized and varies regarding
and “Stroke”). Cardiovascular disease accounts insulin preparation (rapid- and short-acting insulin
for approximately 70 % of all causes of death in vs. intermediate- and long-acting insulin), applica-
patients with T2DM [16]. tion system (pen vs. insulin pump), and regimen
Chronic hyperglycemia causes vascular com- (conventional vs. intensified regimen; see below).
plications in part via an increased formation To mimic physiological insulin secretion, an
of advanced glycation end products (AGEs), intensified regimen is recommended for T1DM
production of ROS, or activation of the renin- that combines the application of a long-acting
angiotensin-aldosterone system (RAAS, see insulin (e.g., insulin glargine or insulin detemir),
chapter “Overview” under the part “Kidney”) [17, mimicking basal insulin secretion, with premeal
18]. AGEs are formed by nonenzymatic glycosyl- bolus application of a rapid- or short-acting insu-
ation of proteins, lipids, and nucleic acids, which lin (e.g., insulin lispro or insulin aspart) adjusted
is accelerated in diabetes due to increased blood for the amount of carbohydrate intake and current
glucose concentrations. The activation of the blood glucose level.
receptor for AGE (RAGE) elicits oxidative stress By contrast, current treatment guidelines in
and vascular inflammation, thus leading to endo- T2DM recommend a stepwise approach starting
thelial and smooth muscle cell dysfunction [19]. with lifestyle changes, such as physical activity
Subsequently, an imbalance in vasoconstric- and weight reduction, and follow up with drug
tion and vasodilation, failure in the regulation treatment, typically with metformin (see below
of angiogenesis and blood flow, and changes in and Fig. 2). Initially, most patients can be treated
platelet function and coagulation contribute to with an oral glucose-lowering drug (see below
microvascular disease resulting in retinopathy and Fig. 2). However, over time, due to the pro-
(see chapter “Overview” under the part “Eye”), gressive nature of the disease, many patients
nephropathy (see chapter “Chronic kidney dis- require a combination of two or more antidia-
ease”), neuropathy, and macrovascular disease, betic drugs (Fig. 2). The benefit of glucose-low-
such as atherosclerosis, thrombosis, and throm- ering treatment is judged by the concentration
boembolism (see chapters “Atherosclerotic heart of glycosylated hemoglobin (called HbA1c)
Diabetes Mellitus 167
Lifestyle intervention
(weight loss, physical activity, diet)
+ If metformin is
Metformin contraindicated:
- α-Glucosidase inhibitor
1st step Hepatic glucose output - Meglitinide
Insulin resistance - Sulphonylurea
-Thiazolidinedione
(- Insulin)
Disease progression
(HbA1c >7 % after 3 months of treatment)
Combined therapy
+ Basal insulin + Sulphonylureas
(especially if HbA1c >8.5 %)
1st tier
Insulin secretion
Hyperglycemia
2nd step
Metformin + thiazolidinedione
2nd tier
Disease progression
(HbA1c > 7% after 3 months of treatment)
3rd step
Fig. 2 Long-term management of hyperglycemia in type certain drugs, some patients might require medications
2 diabetes mellitus. Treatment of type 2 diabetes mellitus other than metformin or sulfonylureas to achieve glyce-
(T2DM) generally starts with lifestyle intervention and an mic control (2nd step, 2nd tier). If the disease further pro-
oral antidiabetic drug, typically metformin (1st step). If gresses (as indicated by HbA1c measurement after 3
glycated hemoglobin (HbA1c) continues to be >7 % after months of therapy), a combination of metformin and an
3 months of therapy, treatment is intensified by addition of intensified insulin therapy is recommended (3rd step)
a second oral antidiabetic drug, typically a sulfonylurea, (Adapted from the American Diabetes Association/
or basal insulin therapy (2nd step, 1st tier). Importantly, European Association for the Study of Diabetes (ADA/
treatment of T2DM is individualized for each patient. EASD) consensus algorithm [26])
Depending on comorbidities and/or contraindications to
However, many approved antidiabetic drugs 4. American Diabetes Association (2012) Diagnosis
and classification of diabetes mellitus. Diabetes Care
can cause serious adverse effects, such as hypo-
35(Suppl 1):S64–S71
glycemia (insulin, sulfonylureas, meglitinides), 5. American Diabetes Association (2004) Gestational
weight gain (insulin, sulfonylureas, meglitinides, diabetes mellitus. Diabetes Care 27(Suppl 1):S88–S90
thiazolidinediones), gastrointestinal disturbances 6. Boitard C (2012) Pancreatic islet autoimmunity.
Presse Med 41:e636–e650
(α-glucosidase inhibitors, biguanides), peripheral
7. Peng H, Hagopian W (2006) Environmental factors
edema, fractures, and an increased risk for con- in the development of type 1 diabetes. Rev Endocr
gestive heart failure (see chapter “Heart failure”) Metab Disord 7:149–162
without an associated increase in mortality (pio- 8. Classen JB, Classen DC (2001) Vaccines and the
risk of insulin-dependent diabetes (IDDM): potential
glitazone), or severe lactic acidosis (biguanides)
mechanism of action. Med Hypotheses 57:532–538
[21, 22]. Incretin homologues have been shown 9. Kahn SE, Hull RL, Utzschneider KM (2006)
to induce pancreatitis and possibly pancreatic Mechanisms linking obesity to insulin resistance and
hyperplasia [23]. type 2 diabetes. Nature 444:840–846
10. Kwon H, Pessin JE (2013) Adipokines medi-
ate inflammation and insulin resistance. Front
Endocrinol 4:71
Perspectives 11. Coppari R, Bjorbaek C (2012) Leptin revisited: its
mechanism of action and potential for treating diabe-
tes. Nat Rev Drug Discov 11:692–708
Recently, SGLT-2 inhibitors have been developed
12. Stumvoll M, Goldstein BJ, van Haeften TW (2005)
to inhibit renal glucose reabsorption, thus lead- Type 2 diabetes: principles of pathogenesis and ther-
ing to increased glucose excretion and reduction apy. Lancet 365:1333–1346
of hyperglycemia [24]. Moreover, novel insulin 13. Robertson RP, Harmon J, Tran PO, Poitout V (2004)
Beta-cell glucose toxicity, lipotoxicity, and chronic
delivery systems are currently tested such as sen-
oxidative stress in type 2 diabetes. Diabetes 53(Suppl
sor-augmented insulin pumps or fully automated 1):S119–S124
closed-loop systems (also referred to as the “arti- 14. Siren R, Eriksson JG, Vanhanen H (2012) Waist cir-
ficial pancreas”) that continuously sense the blood cumference a good indicator of future risk for type
2 diabetes and cardiovascular disease. BMC Public
glucose level and automatically deliver insulin [25].
Health 12:631
Importantly, none of the current therapies is 15. Weir GC, Cavelti-Weder C, Bonner-Weir S (2011)
curative, necessitating lifelong diabetes treat- Stem cell approaches for diabetes: towards beta cell
ment. Thus, identification of a curative drug replacement. Genome Med 3:61
16. Laakso M (1999) Hyperglycemia and cardiovascular
taken for a short period of time to prevent β-cell
disease in type 2 diabetes. Diabetes 48:937–942
destruction and trigger β-cell regeneration is the 17. Yamagishi S (2011) Role of advanced glycation end
long-term goal of current diabetes research. A products (AGEs) and receptor for AGEs (RAGE)
more detailed understanding of the molecular in vascular damage in diabetes. Exp Gerontol
46:217–224
mechanisms leading to progressive β-cell death
18. Furukawa M, Gohda T, Tanimoto M, Tomino Y
and dysfunction in diabetes is therefore required (2013) Pathogenesis and novel treatment from
to develop such treatments. the mouse model of type 2 diabetic nephropathy.
Scientific World Journal 2013:928197
19. Sho-ichi Y (2010) Role of advanced glycation end
products (AGEs) and receptor for AGEs (RAGE)
in vascular damage in diabetes. Exp Gerontol 46:
References 217–224
20. Costa PZ, Soares R (2013) Neovascularization in
1. Bluestone JA, Herold K, Eisenbarth G (2010) diabetes and its complications. Unraveling the angio-
Genetics, pathogenesis and clinical interventions in genic paradox. Life sci 92:1037–1045
type 1 diabetes. Nature 464:1293–1300 21. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007)
2. WHO;IDF (2006) Definition and diagnosis of diabetes Pioglitazone and risk of cardiovascular events in
mellitus and intermediate hyperglycemia; Report of a patients with type 2 diabetes mellitus: a meta-analysis
WHO/IDF consultation; ISBN: 978-92-4-159493-6 of randomized trials. JAMA 298:1180–1188
3. Sherwin R, Jastreboff AM (2012) Year in diabetes 22. Black C et al (2007) Meglitinide analogues for type
2012: the diabetes tsunami. J Clin Endocrinol Metab 2 diabetes mellitus. Cochrane Database Syst Rev
97:4293–4301 18;(2):CD004654
Diabetes Mellitus 169
23. Butler AE et al (2013) Marked expansion of exo- 25. Yaturu S (2013) Insulin therapies: current and future
crine and endocrine pancreas with incretin therapy in trends at dawn. World J Diab 4:1–7
humans with increased exocrine pancreas dysplasia 26. Nathan DM et al (2009) Medical management of
and the potential for glucagon-producing neuroendo- hyperglycemia in type 2 diabetes: a consensus algo-
crine tumors. Diabetes 62:2595–2604 rithm for the initiation and adjustment of therapy:
24. Riser Taylor S, Harris KB (2013) The clinical effi- a consensus statement of the American Diabetes
cacy and safety of sodium glucose cotransporter-2 Association and the European Association for the
inhibitors in adults with type 2 diabetes mellitus. Study of Diabetes. Diabetes Care 32:193–203
Pharmacotherapy 33:984–999
Part VII
Liver
Overview
Dieter Häussinger
Bile canaliculi
PC
Hepatic venule
Portal venule
SEC KC
Glycogenolysis Glutamine
Gluconeogenesis synthesis
Fatty acid oxidation
Urea synthesis
Glycogen synthesis
Glycolysis
Lipogenesis
Biotransformation
Fig. 1 Acinar organization and metabolic zonation. The endothelial cells (SECs), and hepatic stellate cells (HSCs)
liver acinus is the functional unit of the liver and extends located in the space of Disse. PCs are polar cells and adja-
from the terminal portal venule to terminal hepatic ven- cent PCs form the bile canaliculus with their apical mem-
ule. Schematic presentation of the cells constituting the brane. Along the acinus, metabolic pathways show
acinus, i.e., parenchymal cells (PCs, also called hepato- gradients or are heterogeneously distributed (“metabolic
cytes), liver macrophages (Kupffer cells, KCs), sinusoidal zonation”)
the portal-venous blood, which mixes with blood localized in a small perivenous PC subpopulation,
from the hepatic artery in the inflow segment of the so-called perivenous scavenger cells, which
the acinus, passes 20–30 PCs. These are morpho- eliminate ammonia, eicosanoids, and other sig-
logically very similar but differ in their enzyme naling molecules with high affinity before the
and transporter equipment (the so-called PC het- sinusoidal blood enters the systemic circulation.
erogeneity or metabolic zonation) [3]. Metabolite,
hormone, and oxygen gradients but also signals
from neighboring cells are thought to be respon- iver-Specific Metabolic Pathways
L
sible for this metabolic zonation. Periportal PCs, and Processes
i.e., those located at the sinusoidal inflow, are pri-
marily engaged in gluconeogenesis, fatty acid Plasma Protein Synthesis
oxidation, and urea synthesis, whereas glycolysis,
lipogenesis, and biotransformation predominate Except for immunoglobulins, most circulating
in perivenous PCs (located at the sinusoidal plasma proteins are synthesized in the liver. These
outflow). Glutamine synthetase is exclusively
include albumin, which is responsible for transport
Overview 175
of some lipophilic substances (in the bloodstream) rea Synthesis and Acid-base
U
and regulation of oncotic pressure, and acute phase Homeostasis
proteins, which are synthesized and secreted by
PCs in response to cytokines such as tumor necro- One liver-specific pathway is urea synthesis [4]
sis factor α (TNFα), interleukin-1, and interleukin- from bicarbonate (HCO3−) and ammonium
6, which are produced by macrophages including (NH4+), which are generated in almost stoichio-
Kupffer cells, endothelial cells, and fibroblasts at metric amounts during complete amino acid oxi-
sites of injury. The plasma concentrations of acute dation. Urea synthesis can be viewed as an
phase proteins (such as C-reactive protein) can energy-driven neutralization of the strong base
increase within hours after a local inflammatory HCO3− by the weak acid NH4+:
reaction up to several hundredfold and apart from
opsonization (see chapter “ Overview” under the 2NH 4 + + 2HCO3− → urea + CO 2 + 3H 2 O
part “Immune system”); their role mainly resides
in a local restriction of inflammatory processes. Thus, the role of urea synthesis resides not
only in the removal of potentially toxic ammo-
nium ions but also in the removal of bicarbonate.
Nutrient Metabolism Through a pH-regulated partitioning of hepatic
ammonium disposal via either bicarbonate-
The liver is the central organ of glucose homeosta- consuming urea synthesis or via glutamine syn-
sis and acts as a “glucostat.” In the absorptive thesis (from glutamate and ammonium), the liver
phase, when plasma insulin levels increase, the can adjust the rate of bicarbonate disposal to the
liver synthesizes and stores glycogen from gluco- needs of systemic acid-base homeostasis. The
neogenic precursors in periportal PCs and from structural-functional organization of urea and
absorbed glucose in perivenous PCs, whereas glu- glutamine synthesis in the liver acinus allows for
cose becomes mobilized from glycogen in the this role: in periportal PCs, ammonium is dis-
postabsorptive state, when insulin levels are low posed of via urea synthesis, whereas downstream
and glucagon levels are high (see chapters perivenous scavenger cells maintain ammonia
“Overview” under the part “Pancreas” and homeostasis by high-affinity disposal via gluta-
“Diabetes mellitus”). After exhaustion of glycogen mine synthesis. In the kidney, ammonia is then
stores, gluconeogenesis mainly from glucogenic liberated from glutamine by renal glutaminase
amino acids, glycerol, and lactate is stimulated and excreted into the urine. Glutamine uptake,
through induction of enzymes of amino acid glutaminase, and carbonic anhydrase V in peri-
metabolism, gluconeogenesis, and the urea cycle, portal PCs are major sensitively acid-base regu-
whereas glycolytic enzymes become repressed in lated steps, which adjust flux through the
perivenous PCs. The shift from net glucose con- HCO3−-disposing urea cycle. Selective destruc-
sumption to net glucose output in the postabsorp- tion of perivenous scavenger cells or specific
tive state is therefore accomplished by increasing knockdown of glutamine synthetase in these cells
the flux through the periportal gluconeogenic path- triggers hyperammonemia.
way and a simultaneous decrease of glycolytic flux
in perivenous PCs [3]. The liver is also a major
organ for synthesis of triglycerides, cholesterol, ile Formation and Bile Acid
B
and sphingolipids and secretes very low-density Secretion
lipoproteins (see chapter “Hyperlipidemia”). In the
postabsorptive state, fatty acid oxidation provides Another liver-specific pathway is biliary excre-
energy for the liver; ketogenesis and ketone body tion of endo- and xenobiotics and bile formation
release from the liver can provide energy for other [5]. PCs are polar cells, in which the basolateral
organs, such as the brain (see chapter “Overview” (sinusoidal) membrane faces the bloodstream,
under the part “Brain”). whereas the apical (canalicular) membrane of
176 D. Häussinger
two adjacent PCs forms the bile canaliculus, p rotects sinusoidal endothelial cells and cholan-
which is sealed by tight junctions. Bile formation giocytes against BA-induced apoptosis, increases
is an osmotic process, which is driven by the bile flow through stimulation of Cl- secretion by
coordinated action of transport systems in the cholangiocytes, and ameliorates cytokine forma-
sinusoidal and canalicular membranes of the PC tion by Kupffer cells.
and subsequent water flow. PCs metabolize cho- A small fraction of BAs is reabsorbed from
lesterol to lipid-soluble, unconjugated BAs, the bile duct by the apical sodium-dependent bile
which are later conjugated to become water- salt transporter (ASBT), excreted into the blood
soluble. At the sinusoidal membrane, conjugated via the organic solute and steroid transporter αβ
BAs are taken up by the Na+-taurocholate (OSTαβ), and recirculated to the liver, a process
cotransporting protein (NTCP), whereas sinusoi- called cholehepatic shunting (Fig. 2).
dal uptake of unconjugated BAs, bilirubin (a
catabolite of heme), and other anions is accom-
plished by the organic anion transporting protein Detoxification
(OATP) family (Fig. 2). Canalicular secretion is
achieved by transport ATPases, such as the bile Detoxification of endo- and xenobiotics involves
salt export pump (BSEP), and the bilirubin- biotransformation of these compounds. Such
transporting multidrug resistance-related protein reactions convert lipophilic compounds into
(MRP2, Fig. 2). polar, water-soluble metabolites. In a first step
In addition to bilirubin and BAs, cholesterol, (biotransformation phase I), such compounds
phospholipids, and other substances are also become hydroxylated or N- or O-dealkylated by
secreted into the canaliculi via specific transport- cytochrome P450 enzymes and undergo oxida-
ers, such as the aminophospholipid transporter tive deamination or hydrolysis. Such reactions
FIC1 (from familial intrahepatic cholestasis), the introduce or expose reactive groups, which are
cholesterol transporter ABCG5/G8 (ATP-binding used in phase II of biotransformation for conju-
cassette G5/G8), and the multidrug resistance gation reactions, leading to the formation of
protein 1 and 3, the latter of which acts as a flip- hydrophilic compounds, which can be excreted
pase and transports phospholipids from the inner into the bile or urine. Such conjugation reactions
to the outer leaflet of the canalicular membrane include glucuronidation, sulfation, or coupling to
(Fig. 2). glutathione or amino acids such as glycine, tau-
The BSEP and MRP2 are regulated at the rine, or glutamine. Phase III of biotransformation
level of gene expression but also on short-term describes the excretion of such conjugates into
time scale by dynamic insertion/retrieval of the bile or blood via canalicular transporters (e.g.,
transporters into/from the canalicular membrane. MRP2) or sinusoidal OATPs, respectively.
High BA concentration (overload) in PCs acti- Phase I–III enzyme activities can be induced
vates the nuclear transcription factor farnesoid X by endo- and xenobiotics after their binding to
receptor (FXR), which upregulates the BSEP and nuclear receptors, such as constitutive androstane
MRP2 expression and downregulates expression receptor or the pregnane X receptor (also called
of NTCP and cholesterol-7α-hydroxylase, a rate- steroid and xenobiotic-sensing nuclear receptor).
controlling step of BA synthesis. In cholestasis, a After heterodimerization with the retinoid X
condition of impaired bile formation, compensa- receptor, these act as transcription factors induc-
tory BA efflux pathways via MRP3 and 4 located ing a variety of genes involved in biotransforma-
at the sinusoidal part of the PC membrane become tion, such as cytochrome P450 family 3A
activated (Fig. 2). These responses protect PCs (CYP3A), glutathione-S-transferases, or OATP2.
against intracellular BA accumulation, which is Aromatic hydrocarbons are sensed by the aryl
toxic and can lead to PC apoptosis [5]. hydrocarbon receptor (AHR), which together
In addition to FXR, bile acids can activate with the aryl hydrocarbon receptor nuclear trans-
TGR5, a G protein-coupled BA receptor in the locator (ARNT) acts as a ligand-activated tran-
plasma membrane of cholangiocytes, Kupffer scription factor, which regulates the expression of
cells, sinusoidal endothelial cells, and other cell phase I and II enzyme activities. Biotransformation
types. This triggers cAMP formation, which reactions can also give rise to toxic products. One
Overview 177
Conjugated Unconjugated
bile bile salts, Sinusoidal blood
salts bilirubin
BA BA Cyclic Basolateral,
nucleotides sinusoidal
Bilirubin conjugates Aminophospholipids cell surface
BA
MRP2 FIC1
Canaliculus
BSEP Apical,
BA Drugs
FXR canalicular
NTCP
BSEP MDR1 cell surface
MRP2 BA synthesis
HCO3- BA
AE−2
OSTαß
ASBT
BA TGR5 FXR
Lower GI tract
Fig. 2 Schematic representation of hepatobiliary transport liver (“cholehepatic shunting”). In the bile duct, cholangio-
systems, bile formation, and bile acid signaling. Conjugated cytes sense the bile acid concentration via the G protein-
and unconjugated bile acids (BAs) are taken up from the coupled bile acid receptor TGR5 causing an increase in
blood into the liver parenchymal cells (PCs) via Na+- chloride excretion into the lumen to increase bile flow. In
taurocholate cotransporting protein (NTCP) and organic the intestine, BAs can activate their receptors FXR and
anion transport protein (OATP), respectively. High levels of TGR5 in order to signal back to the liver and to secrete
BAs in the PC can activate the farnesoid X receptor (FXR) glucagon-like peptide-1 (GLP-1), respectively. GLP-1
to reduce the BA load (by reducing uptake and increasing increases glucose tolerance. The signal to the liver down-
excretion, left PC). Under conditions of cholestasis, BAs stream of FXR is relayed via fibroblast growth factor (FGF)
can be exported into the blood by means of multidrug resis- 15/19. This activates its receptor (FGF-R/β-Klotho) on PCs
tance-associated proteins 3–5 (MRP3-5, right PC). Both to repress further BA synthesis. Additionally, BAs are also
mechanisms help to prevent BA-induced liver damage. reabsorbed in the terminal ileum and transported back to
Biliary excretion of various substances is accomplished by the liver (“enterohepatic circulation of BAs”) BSEP bile
specific transport ATPases in the canalicular, apical mem- salt export protein, ABCG5/G8 ATP-binding cassette G5/
brane of the PC. In the bile duct, a small fraction of BAs is G8 cholesterol transporter, MDR multidrug resistance pro-
reabsorbed by the apical sodium-dependent bile salt trans- tein, FIC1 familial intrahepatic cholestasis aminophospho-
porter ASBT, excreted into the blood via the organic solute lipid transporter, CFTR cystic fibrosis transmembrane
and steroid transporter (OST) αβ and recirculated to the conductance regulator, AE-2 anion exchanger 2
178 D. Häussinger
example is the formation of genotoxic derivatives Failure of the liver to eliminate NH4+, which
of benzopyrene. Another example is paracetamol arises during intestinal and hepatic metabolism,
(acetaminophen) toxicity. This drug is partly con- can lead to hyperammonemia and ammonia tox-
verted to a highly toxic quinone derivative, which icity in the brain (hepatic encephalopathy; see
is immediately detoxified by S-conjugation with chapter “Cirrhosis”), which is characterized by a
glutathione. However, after depletion of glutathi- low-grade cerebral edema and an oxidative/nitro-
one stores, this highly reactive intermediate forms sidative stress response [10].
protein adducts, which can produce acute liver
necrosis.
utside-In: Metabolites of Other
O
Tissues Affecting the Liver
I nside-Out: Metabolites of the Liver
Affecting Other Tissues There are several ways how metabolites from
other tissues can affect liver function. These
BAs also serve as signaling molecules in other tis- include hormones and cytokines released from
sues because the bile acid receptors FXR and extrahepatic sites. For example, insulin from pan-
TGR5 are also found in extrahepatic tissues creatic β cells (see chapter “Overview” under the
(Fig. 2). TGR5 activation in enteroendocrine intes- part “Pancreas”) binds to insulin receptors on
tinal cells triggers release of glucagon-like pep- PCs in the postabsorptive state and increases
tide-1 (GLP-1) from the ileal L cells, thereby nutrient anabolism, such as glycogen synthesis.
stimulating insulin secretion from β cells (see In addition, nutrients and toxins directly affect
chapter “Overview” under the part “Pancreas”) liver function through alterations of PC hydra-
delaying gastric emptying and improving insulin tion. PC hydration is dynamic and is controlled
sensitivity, thus increasing glucose tolerance (see by a variety of transport systems in the plasma
chapter” Diabetes mellitus”) [6]. Activation of membrane of PCs, which can create or dissipate
FXR in the ileum by BAs triggers formation and osmotic gradients. For example, an increased
release of fibroblast growth factor 15/19, which amino acid load to the liver leads to an osmotic
returns to the liver and activates the fibroblast water shift into the PC due to cumulative amino
growth factor receptor/ß-Klotho complex to down- acid uptake driven by the transmembrane sodium
regulate hepatic de novo bile acid synthesis [7] and gradient. This increase of PC volume represents
to protect the liver during cholestasis [8] (Fig. 2). an independent signal regulating liver function.
Another example for inside-out signaling is PC swelling increases bile flow (choleresis),
the hepatorenal reflex, which is activated by inhibits protein and glycogen breakdown, stimu-
amino acids most likely through induction of PC lates protein and glycogen synthesis, and acts as
swelling and an increase of the sinusoidal blood an antiapoptotic and proliferative signal. Opposite
pressure and which triggers a decrease of glo- responses are triggered by PC shrinkage. Control
merular filtration rate (GFR) in the kidney (see of liver cell functions by fluctuations of PC
chapter “Overview” under the part “Kidney”) via hydration or PC volume is mediated by osmo-
the afferent vagal nerves and sympathetic effer- sensing and osmosignaling pathways [11].
ent nerves [9]. Renal water retention triggered by Integrins were identified as important osmosen-
this reflex may counteract splanchnic blood pool- sors in response to PC swelling, activating osmo-
ing in the absorptive state. The latter describes signaling pathways [12]. Conversely, cell
the circumstance that after a rich meal, a large shrinkage is sensed by an increased concentra-
volume of blood is diverted to the intestine to tion of intracellular chloride and involves endo-
facilitate digestion and absorption, resulting in somal acidification, ceramide formation,
postprandial hypotension. Thus, the hepatorenal activation of protein kinase Cζ and NADPH oxi-
reflex contributes to maintain sufficient blood dase with subsequent formation of reactive oxy-
pressure to perfuse vital organs, such as the brain. gen species and further signaling events.
Overview 179
In cirrhosis, intestinal transit time is prolonged pressin (also called antidiuretic hormone, ADH)
and the intestinal mucosa is often edematous due is secreted with consequent free water reabsorp-
to low oncotic pressure (as a consequence of tion, further fluid overload, and dilutional hypo-
hypoalbuminemia) and increased portal pressure. natremia that characterizes cirrhosis in its more
In addition, biliary secretion and gut luminal bili- advanced stages [9]. Moreover, the low vascular
ary content are reduced, so that bile acids no lon- resistances, fluid overload, and high cardiac out-
ger exert their antimicrobial effects or contribute put characterize the hyperdynamic circulatory
to the integrity of intestinal mucosa to a sufficient syndrome of cirrhosis. Hyperdynamic circulation
extent (see chapter “Overview” under the part is sustained by the persistent liver-gut inflamma-
“Liver”) [4]. This can lead to bacterial over- tory interactions, hyperactivation of neurohor-
growth and translocation [5]. The presence of monal systems, and reduced renal perfusion. The
bacterial products in the systemic circulation fur- overall effect is a further increase in portal inflow
ther activates the immune system, increasing the and portal hypertension, which maintains the
inflammatory response and leading to a functional vicious cycle [10].
immune paralysis that characterizes the typical
susceptibility of cirrhotic patients to infections
[6]. More specifically, endotoxins (such as lipo- Reduced Parenchymal Metabolic
polysaccharides, see chapter “Fever”) activate Function
inflammatory cells, which release cytokines
(such as tumor necrosis factor α, interleukins 1 The progressive decline of functional liver
and 6) and express specific enzymes such as parenchyma is accompanied by reduced albu-
inducible nitric oxide synthase (iNOS) and heme min synthesis. Hypoalbuminemia leads to low
oxygenase (HO) that produce high levels of nitric colloid-osmotic pressure and extravasation of
oxide and carbon monoxide, respectively [7]. fluid in the extravascular spaces or intersti-
Both of these molecules stimulate soluble gua- tium. Transport of endogenous (unconjugated
nylate cyclase. The resultant cGMP then acti- bilirubin, transferrin, apoproteins, lipid-soluble
vates protein kinase G and lowers intracellular hormones) and exogenous molecules (e.g., anti-
Ca2+ levels in smooth muscle cells (SMCs) thus biotics, diuretics, NSAIDS) in the blood is also
causing vasodilation. Consequently, the portal impaired. Moreover, albumin is the main extra-
pressure increases, whereas the systemic blood cellular source of reduced sulfhydryl groups, and
pressure decreases (see chapter “Overview” therefore, hypoalbuminemia is accompanied by
under the part “Blood vessels”). increased oxidative stress and inflammation [11].
As a compensatory response, the adrenergic In cirrhosis, the lipid profile is often abnormal
system and the renin-angiotensin-aldosterone due to low synthesis of apoproteins and choles-
system (RAAS) are activated (see chapter terol (see chapter “Hyperlipidemia”) [12].
“Overview” under the part “Kidney”). However, Hepatocytes are responsible for the first
despite high levels of catecholamines and other hydroxylation of inactive cholecalciferol to cal-
vasoconstrictors such as angiotensin II, the cidiol (see chapters “Overview” under the part
splanchnic and systemic vasodilation persist due “Teeth and bones” and “Osteoporosis”). During
to a vascular hyporesponse to the vasoconstric- cirrhosis, this step is impaired and vitamin D syn-
tors. Because of increased sodium and water thesis is reduced together with a low production
retention (initially driven by RAAS activity), of vitamin D-binding protein [13].
fluid volume is overall increased but inappropri- Moreover, in severe forms of cholestatic liver
ately distributed and pooled in the splanchnic disease (i.e., when bile cannot flow from the liver
compartment, in the interstitium, and eventually to the duodenum), e.g., as a result of primary bili-
in the peritoneal space (ascites), thus leading to ary cirrhosis (i.e., an autoimmune disease accom-
relative hypovolemia (i.e., decrease in blood panied by a progressive destruction of the small
plasma volume) [8] (Fig. 1). In response, vaso- bile ducts), vitamin D absorption is also impaired
Cirrhosis 183
Liver cirrhosis
Splanchnic inflow Intrahepatic vascular resistance
Systemic
Ascites relative hypovolemia Splanchnic pooling
Fig. 1 Pathophysiology of cirrhosis and associated com- ing bacterial translocation and therefore systemic inflam-
plications. Increased splanchnic inflow and hepatic vascu- mation. Intestinal bacterial overgrowth and reduced transit
lar resistance in cirrhosis lead to portal hypertension. time increase gut ammonia (NH3) production that is not
When the hepatic venous pressure gradient (HVPG) rises appropriately metabolized by the liver, skeletal muscle,
above 10 mmHg, portal-systemic collaterals reroute and kidney. Toxic plasma concentrations of NH3 can then
inflammatory cytokines, vasodilators, and gut-derived cross the blood-brain barrier causing hepatic encephalop-
bacterial products to the systemic circulation. Systemic athy. NO nitric oxide, CO carbon monoxide, SNS sympa-
inflammation leads to vasodilation and reduced systemic thetic nervous system, RAAS renin-aldosterone-angiotensin
vascular resistance (SVR) triggering a neurohormonal system, ADH antidiuretic hormone (vasopressin), LPS
response. Retained fluid pools in the splanchnic compart- lipopolysaccharide, CGRP calcitonin gene-related pep-
ment causing relative hypovolemia throughout the body tide, VIP vasoactive intestinal peptide
maintaining the vicious cycle. Ascites develops, aggravat-
(together with other lipid-soluble vitamins such as insulin receptors and may lead to glucose intoler-
A, E, and K). This depletion may severely affect ance and hepatogenous diabetes [14]. In contrast,
bone metabolism leading to osteopenia (i.e., a con- impaired gluconeogenesis or lack of glycogen
dition where bone mineral density is reduced) or stores characterizes overt liver failure and can
even osteoporosis (see chapter “Osteoporosis”). lead to hypoglycemia.
Hepatocyte dysfunction is associated with a Under physiological conditions, the nitroge-
reduced insulin clearance. Subsequent hyperin- nous products of amino acid catabolism are
sulinemia may contribute to downregulation of metabolized by the liver through the urea cycle
184 M. Rosselli and M. Pinzani
and glutamine synthesis (see chapter “Overview” vascular wall results, increasing the risk of
under the part “Liver”) [15]. However, in cirrho- vascular rupture. Nonselective β-blockers
sis, nitrogen homoeostasis is disrupted, either (NSBBs, Table 1) represent the first-line treat-
because ammonia production exceeds urea cycle ment to directly reduce portal pressure and to
capacity (mainly by increased gut bacterial allow unopposed α-adrenergic activity. This pro-
ammoniogenesis) or because the liver is unable duces mesenteric arterial vasoconstriction and
to metabolize ammonia due to parenchymal therefore reduces portal venous load. Moreover,
insufficiency and portal blood shunting [16]. The NSBBs reduce cardiac output and systemic blood
skeletal muscle and kidneys are also regulators of pressure contributing to a further decrease in
ammonia concentration (by ammonia uptake and portal flow.
excretion). However, during cirrhosis, their com- If bleeding occurs despite NSBBs and endo-
pensation progressively fails due to muscle wast- scopic banding of gastroesophageal varices, there
ing and renal impairment, and subsequently, the may be indication to decompress the portal sys-
blood-brain barrier is crossed by an excess of tem by positioning a transjugular intrahepatic
ammonia that accumulates within the astrocytes. portal-systemic shunt (TIPS) [17], i.e., an artifi-
The consequent osmotic and inflammatory dam- cial shunt between the (inflow) portal vein and
age as well as neurotransmission impairment one of the (outflow) hepatic veins. This invasive
characterize hepatic encephalopathy (HE), one of procedure is used as a rescue remedy only in
the most important expressions of metabolic dys- severe, selected cases showing complications
function in acute and chronic liver disease. such as recurrent bleeding, refractory ascites,
hydrothorax, and/or hepatorenal syndrome, as in
30–50 % of cases, the shunt leads to portal-
Treatment of Cirrhosis and Related systemic HE.
Complications
Treatment of chronic liver disease is manifold and Ascites and Spontaneous Bacterial
primarily aimed at counteracting the etiological Peritonitis
agent (e.g., a hepatitis virus or excessive alcohol
consumption) in order to reduce liver inflamma- Ascites is treated by reducing fluid retention via
tion, preventing the formation of scarring tissue anti-aldosterone and loop diuretics and by a salt
and nodular regeneration that characterize the restriction diet (<90 mmol/day, see also chapter
final and irreversible stages of cirrhosis. However, “Hypertension”). In poor responses to medical
due to delayed diagnosis, poor response, or low treatment, there is indication for paracentesis, a
compliance to treatment, progression to cirrhosis puncturing of the peritoneal cavity to relieve
is sometimes inevitable. When signs of clinically abdominal pressure. This fluid removal must be
significant PH occur, treatment is aimed to delay accompanied with albumin infusion to prevent
and counteract cirrhosis complications. In cases hypotension, especially in cases of large volume
of advanced cirrhosis, liver transplantation (>5 l) paracentesis [18].
remains the only option. Complications of anti-aldosterone diuretics
are hyperkalemia, whereas loop diuretics may
lead to hyponatremia, hypokalemia, and hyper-
Portal Hypertension ammonemia with related HE. A specific side
effect of some anti-aldosterones such as spirono-
The management of PH is aimed at preventing lactone is gynecomastia, the benign enlargement
further pressure increase and related complica- of breast tissue in males (see chapter “Prostate
tions, particularly gastroesophageal bleeding. cancer”).
When the hepatic venous pressure gradient rises Bacterial translocation, especially in patients
beyond 12 mmHg, a critical tension within the with tense ascites, may lead to infection of the
Cirrhosis 185
ascitic fluid and spontaneous bacterial peritonitis, losporin (see chapter “Urinary tract infections”),
a life-threatening complication that calls for and albumin infusion to improve circulatory
prompt treatment with antibiotics, such as oral function and reduce the risk of hepatorenal
norfloxacin or intravenous 3rd generation cepha- syndrome.
186 M. Rosselli and M. Pinzani
G. Schoiswohl • J. Aljammal • E.E. Kershaw (*) Adipose tissue is divided into two types: white
Division of Endocrinology and Metabolism, (WAT) and brown (BAT) (Fig. 1a). WAT is com-
Department of Medicine, University of Pittsburgh, posed of white adipocytes characterized by large,
200 Lothrop Street, Biomedical Science Tower
unilocular lipid droplets and sparse mitochondria.
E1140, Pittsburgh, PA 15261, USA
e-mail: gabriele.schoiswohl@uni-graz.at; The high ratio of fat to mitochondria gives WAT
aljammalj@upmc.edu; kershawe@pitt.edu its characteristic white appearance. WAT is
a Transmission Scanning
Tissue Immunofluorescence electron electron
microscopy microscopy
N
White
LD
M
Brown
LD
Fig. 1 Adipocyte morphology and metabolic pathways. FFA free fatty acid, FA-CoA fatty acyl-CoA, Glycerol-3-P
(a): Distinguishing features of white (WAT, top panel) and glycerol-3-phosphate; [1] = glycerol-3P acyltransferase,
brown (BAT, bottom panel) adipose tissue. Gross images LPA lysophosphatidic acid, [2] = LPA acyltransferase, PA
of murine WAT and BAT (1st image). Immunofluorescence phosphatidic acid, [3] = PA phosphatase, DAG diacylglyc-
images of WAT and BAT cross sections highlighting adi- erol, [4] = monoacyl glycerol acyltransferase, MAG mono-
pocyte size (2nd image), mitochondrial content (3rd acylglycerol, DGAT DAG acyltransferase, TG triglyceride,
image), and lipid droplet proteins (4th image). ATGL adipose triglyceride lipase, HSL hormone-sensitive
Transmission (5th image) and scanning (6th image) elec- lipase, MGL MAG lipase (Figure courtesy of Erin E.
tron microscopy of WAT and BAT. (b): Anabolic (fat syn- Kershaw and Donna B. Stolz, University of Pittsburgh’s
thesis or lipogenesis) and catabolic (fat breakdown or Center for Biological Imaging)
lipolysis) pathways in adipocytes. LPL lipoprotein lipase,
Overview 193
located throughout the body in “depots” but is primarily released into the systemic circulation
also spread within and around other tissues where for energy. In BAT, on the other hand, FFAs pri-
it exhibits location-specific characteristics. WAT marily enter the mitochondria for thermogene-
is highly specialized for storing large amounts of sis. These processes are critically important in
fat as TGs but also has several other critical func- adipose tissue, the main site of lipid storage and
tions including mechanical protection, thermal release, but are also present in virtually all cells
insulation, energy homeostasis, and endocrine of the body. Impaired regulation of these funda-
factor production. BAT, on the other hand, is com- mental processes contributes to metabolic
posed of brown adipocytes characterized by diseases.
small, multilocular lipid droplets surrounded by
copious large mitochondria. The high ratio of
mitochondria to fat gives BAT its characteristic Inside-In: Metabolites of Fat Tissue
brown appearance. BAT, the presence of which Affecting Itself
has recently been confirmed in humans, is primar-
ily located along the axial skeleton [7]. In contrast Adipose tissue consists not only of adipocytes
to WAT, BAT is highly specialized for fat combus- but also a variety of other cell types including
tion to generate heat (thermogenesis). Recently, stromal cells (i.e., fibroblasts, stem cells), vascu-
adipocytes with mixed characteristics (“beige” lar cells (i.e., endothelial cells, smooth muscle
adipocytes) have been identified, suggesting that cells), and immune cells (i.e., macrophages).
specialized adipocytes may interconvert between These cell types interact with each other in an
pro-storage and pro-thermogenic phenotypes [8]. autocrine and paracrine manner [10]. Adipocytes
These characteristics make adipose tissue a focus and other cells within adipose tissue secrete bio-
of intense investigation for the treatment of obe- active substances known as “adipokines”
sity and metabolic disease. (adipocyte-derived cytokines) including cyto-
Adipose tissue is exquisitely designed for the kines (interleukin 6, tumor necrosis factor α),
regulated storage and release of lipid substrates complement-like factors (i.e., adiponectin), che-
and possesses all the cellular machinery for both mokines (i.e., monocyte chemotactic protein 1),
fat synthesis (lipogenesis) and fat breakdown acute phase reactants (i.e., angiotensin, plasmin-
(lipolysis, Fig. 1b). In the setting of energy ogen activator inhibitor 1), growth factors (i.e.,
excess (i.e., after a meal), energy substrates (i.e., vascular endothelial growth factor A), adhesion
glucose or fatty acids) enter the cell where they molecules (i.e., vascular cell adhesion molecule
are converted into fatty acyl-coenzyme As 1), hormones (i.e., leptin), and other proteins/
(FA-CoAs). These FA-CoAs are then sequen- peptides (i.e., retinol-binding protein 4, resistin).
tially esterified to a glycerol backbone by acyl- Adipocytes also express a variety of receptors for
transferases to form TGs. TGs are stored in lipid factors derived from both local and distant
droplets. Importantly, lipid droplets are highly sources [3]. This intra- and intercellular commu-
dynamic organelles that are associated with a nication influences numerous processes ranging
variety of lipid droplet proteins such as those of from adipocyte metabolism and development
the perilipin family [9]. For example, perilipin 1 (adipogenesis, maturation, and death) to whole
is primarily found in adipocytes where it is inte- adipose tissue dynamics (i.e., angiogenesis,
grally involved in lipolysis, whereas perilipin 5 inflammation). For example, under normal physi-
is primarily found in oxidative tissues such as ological circumstances, adipocyte hypertrophy
BAT where it is integrally involved in lipid oxi- promotes release of the adipocyte factors leptin
dation [9]. In the setting of increased energy and monocyte chemotactic protein 1 (MCP-1).
demand (i.e., fasting, exercise), free fatty acids Leptin activates receptors on adipocytes and else-
(FFA) are sequentially released from TGs by the where (i.e., the central nervous system, see chap-
lipolytic enzymes adipose triglyceride lipase ter “Overview” under the part “Brain”) to directly
(ATGL), hormone-sensitive lipase (HSL), and or indirectly restrict further adipocyte expansion.
monoglyceride lipase (MGL). In WAT, FFAs are MCP-1 promotes recruitment and activation of
194 G. Schoiswohl et al.
macrophages that dispose of excess FFAs and promoting insulin resistance, glucose intolerance
dead/dysfunctional adipocytes [11]. Under path- (see chapter “Diabetes mellitus”), atherosclerosis
ological circumstances, such as severe or pro- (see chapter “Atherosclerotic heart disease”), and
longed nutritional oversupply, macrophage- or other disease processes [12]. In addition to adipo-
adipocyte-derived inflammatory factors (i.e., kines, adipose tissue-derived FFAs serve as essen-
interleukin 6 and tumor necrosis factor α) lead to tial substrates for energy, signaling, and membrane
a vicious cycle of chronic inflammation, adipo- synthesis throughout the body. When present in
cyte lipolysis, and adipocyte dysfunction. This excess, however, FFAs accumulate in non-adipose
loss of adipose tissue homeostasis and the result- tissues where they cause lipid-induced toxicity.
ing changes in adipokines and fatty acids inter- This “lipotoxicity” contributes to insulin resis-
fere with numerous metabolic processes such as tance, diabetes, dyslipidemia, and other features
insulin signaling, thereby, causing insulin resis- of the metabolic syndrome (see chapters
tance, glucose intolerance, and other features of “Hyperlipidemia”, “Diabetes mellitus”, and
the metabolic syndrome (see chapter “Metabolic “Metabolic syndrome”). Thus, the endocrine
syndrome”) [12]. Thus, the autocrine and para- functions of adipose tissue are essential for main-
crine functions of adipose tissue are essential for taining whole-body metabolic homeostasis.
maintaining adipose tissue homeostasis but can
lead to disease when overwhelmed.
Outside-In: Metabolites of Other
Tissues Affecting Fat Tissue
Inside-Out: Metabolites of Fat
Tissue Affecting Other Tissues Other tissues influence adipose tissue by regulat-
ing its production, distribution, metabolism, and
Adipose tissue also interacts with the rest of the function (Fig. 2, right). Adipocytes and other
body to orchestrate essential physiological pro- cells within adipose tissue express traditional
cesses including energy homeostasis, reproduc- endocrine hormone receptors (i.e., insulin, gluca-
tive function, inflammatory responses, and gon, and growth hormone receptors), nuclear
vascular hemodynamics (Fig. 2, left). Adipose tis- hormone receptors (i.e., glucocorticoid, vitamin
sue communicates with these distant sites through D, thyroid hormone, androgen, and estrogen
secretory factors – making it one of the largest receptors), gut hormone receptors (i.e., gastrin
endocrine organs in the body. Numerous adipo- and glucagon-like peptide-1 receptors), cytokine
kines have been identified as noted above and are receptors (i.e., leptin, interleukin 6, and tumor
reviewed elsewhere [3]. For example, leptin is a necrosis factor α receptors), catecholamine
cytokine-like adipokine that signals the adequacy receptors, peptide receptors (i.e., angiotensin II
of adipocyte energy stores to the hypothalamus receptors), and FFA receptors (i.e., Toll4 recep-
where it acts to decrease energy intake, increase tors) [3]. In this way, distant sites communicate
energy expenditure, and regulate reproductive with adipose tissue to integrate physiological sig-
function through complex central nervous system nals. For example, in the setting of increased
circuits that control both neural (i.e., sympathetic energy requirements, catecholamines (i.e., epi-
and parasympathetic) and endocrine (i.e., gonadal, nephrine) from the central nervous system or
adrenal, and thyroid axes) output to the whole adrenal medulla act on adipocyte adrenergic
body [13]. Adiponectin is a multimeric comple- receptors to stimulate lipolysis (Fig. 1b).
ment-like adipokine that signals a healthy state of Conversely, in the setting of increased energy
adipose tissue and acts at multiple sites via mul- availability, insulin from the pancreas (see chap-
tiple mechanisms to improve cardiometabolic risk ter “Overview” under the part “Pancreas”) acts
[14]. Conversely, the adipose tissue-derived che- on adipocyte insulin receptors to facilitate glu-
mokines and cytokines have systemic inflamma- cose uptake and fat synthesis while simultane-
tory effects that increase cardiometabolic risk by ously inhibiting fat breakdown and promoting
Overview 195
Inside-out Outside-in
Fig. 2 Interactions between adipose tissue and other tissues (Figure courtesy of Erin E. Kershaw and Gianna Paniagua)
adipogenesis (Fig. 1b). Interestingly, just as the particularly responsive to glucocorticoids from
spectrum of adipocyte-secreted factors varies the adrenal glands. On the other hand, BAT is
across adipose tissue depots, so does adipose tis- particularly responsive to temperature (i.e.,
sue responsiveness to systemic signals [15]. For increasing thermogenesis in response to cold).
example, subcutaneous and breast adipose tissue Thus, adipose tissue is a highly adaptive tissue
is particularly responsive to estrogens from the that responds to both global and local needs of
ovaries, whereas visceral adipose tissue is the body.
196 G. Schoiswohl et al.
18. O'Rahilly S (2009) Human genetics illuminates the 21. McAllister EJ, Dhurandhar NV, Keith SW, Aronne
paths to metabolic disease. Nature 462:307–314 LJ, Barger J, Baskin M, Benca RM, Biggio J,
19. Magkos F, Yannakoulia M, Chan JL, Mantzoros CS Boggiano MM, Eisenmann JC, Elobeid M, Fontaine
(2009) Management of the metabolic syndrome and KR, Gluckman P, Hanlon EC, Katzmarzyk P,
type 2 diabetes through lifestyle modification. Annu Pietrobelli A, Redden DT, Ruden DM, Wang C,
Rev Nutr 29:223–256 Waterland RA, Wright SM, Allison DB (2009) Ten
20. Grun F, Blumberg B (2009) Endocrine disrupters as putative contributors to the obesity epidemic. Crit Rev
obesogens. Mol Cell Endocrinol 304:19–29 Food Sci Nutr 49:868–913
Metabolic Syndrome
Cardiovascular
diseases
Since dyslipidemia, hyperglycemia and hyper- to abnormalities in glucose and lipid metabolism,
tension are common disorders, these risk factors and endothelial dysfunction in MetS.
sometimes gather even in a lean individual with- Another pathogenetic condition in visceral
out visceral fat accumulation. However, MetS is obesity is a dysfunction of adipocytes, especially
different from a condition randomly clustering abnormalities of adipocyte-derived factors, so-
multiple risk factors (Fig. 1). called adipokines (see chapter “Overview” under
the part “Fat tissue”) [10]. Oxidative stress and
relative hypoxia due to insufficient blood sup-
Pathophysiology of the Metabolic ply are postulated to cause dysfunction of and
Syndrome damage to hypertrophied adipocytes. The latter
secrete various inflammatory adipokines includ-
Visceral Obesity ing monocyte chemotactic protein-1 (MCP-1) as
an alarm signal, which recruits macrophages into
Visceral adipose tissue is present in the mes- the adipose tissue. Macrophages surround and
entery and omentum, where innumerable ves- remove the damaged adipocytes and produce pro-
sels run from the digestive tract to the liver. In inflammatory cytokines, such as tumor necrosis
response to energy demand, visceral adipose tis- factor α (TNFα), thus triggering a chronic inflam-
sue rapidly hydrolyzes triglycerides and delivers matory process in the adipose tissue. In addition,
the products, free fatty acids (FFA) and glycerol, hypoxia induces hypoxia-inducible factor 1α, a
to the liver via the portal vein, which resynthe- transcription factor that enhances the expression
sizes energy substrates (triglycerides and glu- of plasminogen activator inhibitor 1 in adipocytes.
cose) for distant tissues (see chapters “Overview” Importantly, in MetS, these proinflammatory and
under the part “Liver” and “Overview” under prothrombotic adipokines spread from the adi-
the part “Fat tissue”) [9]. When the visceral fat pose tissue to the whole body via the bloodstream,
accumulates, large amounts of FFA are trans- triggering insulin resistance in muscle [11] and
ferred to liver and systemic circulation, leading thrombus formation in arteries [12].
Metabolic Syndrome 201
7. Matsuzawa Y, Fujioka S, Tokunaga K, Tarui S (1992) 13. Matsuzawa Y, Funahashi T, Kihara S, Shimomura
Classification of obesity with respect to morbidity. I (2004) Adiponectin and metabolic syndrome.
Proc Soc Exp Biol Med 200:197–201 Arterioscler Thromb Vasc Biol 24:29–33
8. Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita 14. Kadowaki T, Yamauchi T (2011) Adiponectin recep-
M, Shimamoto K, Daida H, Biro S, Hirobe K, tor signaling: a new layer to the current model. Cell
Funahashi T, Yokote K, Yokode M (2008) Metabolic Metab 13:123–124
syndrome. J Atheroscler Thromb 15:1–5 15. Ouchi N, Walsh K (2012) Cardiovascular and meta-
9. Maeda N, Funahashi T, Shimomura I (2008) bolic regulation by the adiponectin/C1q/tumor
Metabolic impact of adipose and hepatic glycerol necrosis factor-related protein family of proteins.
channels aquaporin 7 and aquaporin 9. Nat Clin Pract Circulation 125:3066–3068
Endocrinol Metab 4:627–634 16. Turer AT, Scherer PE (2012) Adiponectin: mecha-
10. Funahashi T, Matsuzawa Y (2007) Metabolic syn- nistic insights and clinical implications. Diabetologia
drome: clinical concept and molecular basis. Ann 55:2319–2326
Med 39:482–494 17. Kishida K, Funahashi T, Matsuzawa Y, Shimomura
11. Hotamisligil GS, Shargill NS, Spiegelman BM I (2012) Visceral adiposity as a target for the man-
(1993) Adipose expression of tumor necrosis factor- agement of the metabolic syndrome. Ann Med
alpha: direct role in obesity-linked insulin resistance. 44:233–241
Science 259:87–91 18. Inoue K, Maeda N, Kashine S, Fujishima Y,
12. Shimomura I, Funahashi T, Takahashi M, Maeda Kozawa J, Hiuge-Shimizu A, Okita K, Imagawa
K, Kotani K, Nakamura T, Yamashita S, Miura M, A, Funahashi T, Shimomura I (2011) Short-term
Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y effects of liraglutide on visceral fat adiposity, appe-
(1996) Enhanced expression of PAI-1 in visceral fat: tite, and food preference: a pilot study of obese
possible contributor to vascular disease in obesity. Nat Japanese patients with type 2 diabetes. Cardiovasc
Med 2:800–803 Diabetol 10:109
Part IX
Lung
Overview
Anatomy and Physiology upper and lower respiratory tract, also called
of the Lung upper and lower airways (Fig. 1a). The upper air-
ways comprise nasal cavity, pharynx, and larynx.
The lung is the human body’s respiratory organ, Their role is to warm and moisten the inhaled air
responsible for supply of all tissues and organs and to protect from noxious agents, mainly
with vital oxygen (O2) and for disposal of carbon filtering them via the nasal turbinates. The nasal
dioxide (CO2), the end product of internal respi- cavity also allows smelling. The pharynx is part of
ration and of several metabolic pathways. both digestive and respiratory systems (see chap-
The lung, located in the upper thorax, consists ter “Overview” under the part “Gastrointestinal
of two parts, the right lung further comprising tract”) and offers an alternate route of air supply
three lobes and the left lung comprising two. Left via the mouth. The larynx contains the vocal cords
and right lungs are individually surrounded by a (vocal folds), necessary for human speech. It con-
pleural cavity, which consists of two pleurae and tinues into the lower respiratory tract.
the cavity in between. The parietal pleura lines The lower respiratory tract consists of the tra-
the rib cage, whereas the visceral pleura covers chea and the lungs. The trachea bifurcates first
the surface of the lungs. The space between the into primary bronchi, subsequently into bronchi-
pleurae is filled with pleural fluid. The pleurae oles, and finally into terminal and respiratory
are critically important for breathing motions bronchioles, which ultimately give rise to alveolar
(see below). ductus and sacs (Fig. 1b). In total, the lower
The lungs represent the functional anatomical respiratory tract branches up to 20 times.
part of the respiratory system consisting of the The main function of the lung is to allow gas
exchange with the blood, which takes place in
respiratory bronchioles and subsequent lung
M. Zeeb (*) regions and is most pronounced in the alveoli.
Cardiometabolic Diseases Research, On a cellular level, the wall of the conducting
Boehringer Ingelheim Pharma GmbH & Co KG,
airways (trachea, bronchia, and bronchioles) con-
Birkendorfer Straße 65,
88400 Biberach (Riss), Germany sists of mucosa, submucosa, and adventitia. The
e-mail: martin.zeeb@boehringer-ingelheim.com mucosa contains a mucus layer (see below) and
A. Schnapp • M.-P. Pieper pseudostratified columnar, ciliated epithelium
Respiratory Diseases Research, with mucus-secreting goblet cells, columnar
Boehringer Ingelheim Pharma GmbH & Co KG, cells, and basal cells. Underneath, the lamina pro-
Birkendorfer Straße 65,
pria is located, a layer of connective tissue, which
88400 Biberach (Riss), Germany
e-mail: andreas.schnapp@boehringer-ingelheim.com; harbors large amounts of elastin (Fig. 1c). The
michael_paul.pieper@boehringer-ingelheim.com submucosa contains submucosal glands, which
Columnar cell
a b Goblet cell
Airway lumen
Mucus
Lower Upper respiratory tract
respiratory tract Lung
epithelium
Trachea
Basal cell
Bronchus Bronchioles
Basement
Lung membrane
Ribs
Pleurae
Smooth
muscle cells
Alveoli
c Bronchioles d
Pulmonary
vein
CO 2
O2
Pulmonary
artery
O2
CO 2
Fig. 1 Anatomy of the respiratory system. (a): the muscle layer transiently increases. (c): Anatomy of an
Macroscopic overview of upper and lower respiratory alveolar sack showing the approximate arrangement of
tract. (b): Magnification of a section through a bronchial individual alveoli and the surrounding dense capillary net-
wall showing the mucosa and the underlying tunica mus- work. Note that in the lung vasculature, arteries carry
cularis. In the mucosa, basal, ciliated columnar cells, and oxygen-deficient blood, whereas veins carry oxygen-rich
mucus-secreting goblet cells are shown. A submucosal blood (shown in blue and red, respectively). (d): Detailed
gland is not included due to space constraints albeit the view of a section through an alveolar wall showing thin
glands are present in bronchia. Whereas goblet cells, respiratory surface, movement of gases, and an alveolar
glands, and elastic fibers decrease in number concomitant macrophage
with the length of the cilia towards the smaller airways,
are connected to the mucosa and also contribute As the bronchi decrease in diameter, a gradual
to mucus secretion. In addition, this submucosal transition in the architecture of the epithelium
layer includes fibroblasts, dendritic cells, and can be observed. The epithelial layer transforms
neutrophils, the latter two of which participate in from pseudostratified, columnar epithelium
host defense. The adventitia, a fibroelastic con- towards a ciliated, simple columnar and finally
nective tissue layer, confines the airways towards simple cuboidal epithelium (the shape of a typi-
the outside. C-shaped rings of hyaline cartilage cal respiratory epithelium). Concomitantly, a
provide a semirigid outside support to prevent gradual decrease in the number of goblet cells as
collapse of the airway during inspiration. well as submucosal glands is seen, whereas Clara
Overview 209
cells emerge. Clara cells, although their function effectively hinders lung expansion and thus inha-
is not completely understood, are thought to play lation (pneumothorax). In contrast, exhalation
a role in the secretion of surfactant proteins (see occurs mainly passively as the lung has the intrin-
below). Furthermore, the amount of elastic tissue sic tendency to retract due to surface tension in
decreases and a muscularis mucosae begins to the alveoli and distension of its elastic fibers in the
take shape between the lamina propria and the lung tissue. The total lung capacity can amount up
submucosa. The cartilage skeleton is also absent to 6 l of air. Yet, even after maximal exhalation, a
from the bronchioles and smaller airways. residual volume of 1.25 l will remain, reflecting
Alveoli (Fig. 1c, d) feature an extremely thin the volume of the conducting airways, which do
wall of specialized respiratory epithelium to not participate in gas exchange [1].
facilitate gas exchange. Most of the alveolar epi- Any change leading to an obstruction of the
thelium is covered by small, squamous-like type airways, like those in asthma and COPD (see
I pneumocytes. It also includes larger cuboidal chapters “Asthma” and “COPD”) will have detri-
type II pneumocytes that produce surfactant (see mental effects. Ventilation deficiencies can be
below) and are thought to be stem cells for both divided into restrictive and obstructive disorders.
types of pneumocytes. Alveolar macrophages in The former describes a disturbed expansion of the
the alveolar lumen scavenge particulate matter airways (accompanied by reduced total capacity),
and microorganisms. whereas the latter describes difficulties in conduc-
In order to perform its function, the lung is tion and increased inflow or outflow resistance.
extensively vascularized; the alveoli are sur- Ventilation, diffusion, and convection (blood
rounded by a dense capillary network (Fig. 1c) flow) are of central importance to gas exchange,
that can be compared to a columnar hallway. Due meaning a constant delivery of fresh air, passive
to its potential volume and sophisticated regula- gas exchange with the blood, and ongoing propul-
tion, the pulmonary capillaries can act as a large sion of the oxygenated blood to keep a stable gra-
blood reservoir. dient over the alveolar membrane (see below) [2].
The ~300 mio alveoli, each 0.2–0.3 mm in It should be noted that gas exchange with the
diameter, sum up to a functional area of gas blood never reaches complete equilibration.
exchange of up to 140 m2. The alveolar wall, con- Whereas the inhaled gas mixture contains 21 % O2
sisting of alveolar epithelium, minimal interstitium, and around 0.05 % CO2, the exhaled gas mixture
and endothelium (Fig. 1d), totals to less than 1 μm. still contains 14–16 % O2 and around 4 % CO2.
The respiratory quotient is the relation
between exhaled CO2 and inhaled consumed O2
Mechanism of Breathing (CO2/O2). It is indicative of the primary meta-
bolic fuel (carbohydrates or fatty acids) at the
Breathing can be initiated by two similar actions, moment of measurement. As fatty acids require
upward rib movement (chest breathing) or down- more oxygen for complete oxidation of a single
ward movement of the diaphragm (abdominal carbon atom, preferential metabolism of fatty
breathing). As the outer pleura is physically con- acids decreases the respiratory quotient [3].
nected to both, it will follow the movement pas-
sively. Consequently, during inspiration, the
existing low pressure (below atmospheric pres- Lung-Specific Metabolic/Molecular
sure) in the intrapleural cavity is further decreased Pathways and Processes
and will cause the inner pleura and eventually the
lung tissue to follow (as interpleural fluid cannot Mucus Production
be expanded). This effectively increases the lung
volume and results in an inward movement of air. Mucus is secreted from goblet cells and submu-
Puncturing of the pleura is extremely dangerous cosal glands in the bronchial epithelium as a
as lack of the negative intrapleural pressure viscous fluid containing mucins, water, ions, and
210 M. Zeeb et al.
antimicrobial substances such as immunoglobu- by Fick’s law of diffusion. According to the law,
lin A (IgA, see also chapter “Overview” under a large exchange area, short diffusion distance,
the part “Immune system”) and lysozyme. and a constant gradient of substances (across the
Mucins are heavily glycosylated proteins of high membrane) facilitate diffusion. All these prereq-
molecular weight. uisites are provided by the unique setup of the
Mucus is essential to trap inhaled particles and alveoli (Fig. 1c, d). Nature of the gas also influ-
microorganisms and prevent them from reaching ences diffusion rate, with CO2 diffusing more
and damaging the respiratory epithelium (Fig. 1). freely over the alveolar membrane than O2.
Mucus containing bacteria, debris, and inflamma- The substance gradient is expressed by the
tory cells and products is referred to as phlegm. partial pressure of gases (pO2, pCO2) in the alve-
Rhythmic upward propulsion by the cilia on the olar lumen and in the blood. In order to provide a
bronchial epithelium transports mucus and cap- constant gradient that is as steep as possible, con-
tured particles towards the larynx, where most of it stant and coordinated ventilation and perfusion
is swallowed or expectorated. Cough is a physio- are of utmost importance. The ratio between ven-
logical reflex that aids to eject particles and mucus tilation and perfusion, called the ventilation-
or phlegm that would otherwise damage or block perfusion coefficient, is relatively constant
the airways. Consequently, damage to cilia causes (0.8–1) among healthy subjects to secure a proper
accumulation of mucus and increased ventilatory partial pressure gradient and thus gas exchange
resistance resulting in obstructive pathology. but can change significantly in some pathologies,
e.g., when pulmonary shunts are created by per-
fusion of non-ventilated alveoli (see chapter
Surfactant Production and Function “Community-acquired pneumonia”).
Hemoglobin helps to maintain the gradient
Alveoli are subject to dramatic surface tension by binding of O2 and thus effectively remov-
resulting from the attraction between the molecules ing it from the pool of free O2. Interestingly,
of the fluid film that covers the alveolar cell sur- the binding capacity of hemoglobin for O2 is
face. This force supports exhalation but would dependent on pO2, with the high partial pressure
drive all liquids within the airways to retract, the in the lungs increasing its binding affinity (see
lung to collapse, and the alveoli to merge into larger chapter “Overview” under the part “Blood”).
vesicles (prohibiting functional gas exchange). Consequently, the contact time of 0.3–0.7 s
However, the stability of the alveoli is ensured by a between an individual erythrocyte and the alve-
surface-active agent (surfactant) decreasing surface olar wall is already sufficient for saturation of
tension and lubricating the alveolar epithelium. hemoglobin with O2.
Surfactant is a mixture of proteins and lipids,
mainly consisting of lecithin derivatives. Its main
lipid components are dipalmitoylphosphatidylcho- Outside-In: Metabolites of Other
line (DPPC) molecules that tend to repel each Tissues Affecting the Lung
other, thus counteracting the surface tension of the
fluid film on the alveolar cell surface; surfactant Regulation of Breathing
also contains ∼ 40 % of other phospholipids and
~5 % surfactant-associated proteins and is secreted Regulation of breathing is mediated primarily via
by type II alveolar epithelial cells. the sympathetic and parasympathetic nervous
system. Sympathetic activity causes relaxation of
smooth muscle cells and thus bronchodilation
Gas Exchange aiding in inspiration. Parasympathetic activity
can constrict the airways, a feature used during
Gas exchange across the alveolar wall occurs by exhalation. Overactivation of the parasympathi-
passive diffusion; a process that can be described cus often causes pathological constriction.
Overview 211
However, constriction is more commonly caused deep and more frequent breathing (to incorporate
by local inflammation, as occurs during asthma sufficient O2). However, this effectively lowers
and COPD (see chapters “Asthma” and “COPD”, pCO2 in the blood causing decreased breathing,
respectively). which again causes hypoxemia, or even apnea
The central nervous control center of breathing (lack of breathing). The resulting periodic breath-
is represented by neural oscillators located in the ing pattern is known as Cheyne-Stokes breathing.
medulla oblongata, called the ventral respiratory Decreased atmospheric pressure at high alti-
group. These neurons trigger breathing autono- tudes can cause pulmonary edema. If the intra-
mously but are adjustable and react to systemic pulmonary pressure is too low compared to the
need and metabolism (as indicated by the blood blood pressure, plasma fluid leaks into the alve-
gas status). Detection of the blood gas status oli. More frequently, left ventricular heart failure
occurs mainly by arterial chemosensors located in results in pulmonary edema, which is character-
the carotid artery (called glomus caroticum) and ized by superficial breathing.
also by central chemoception in the brainstem. In contrast, hypercapnia (abnormally incre-
Among the three prime indicators triggering ased pCO2 in the blood) and acidosis are charac-
breathing (i.e., reduced pO2, increased pCO2, and terized by extremely deep breathing called
increased H+/decreased pH), increased pCO2 is Kussmaul breathing (see below).
the most important signal. There is an almost lin-
ear correlation between pCO2 and breathing
induction. At high concentrations, however, CO2 Breathing and Treatment
acts narcotic and may reduce breathing.
The tight chemosensation of pCO2 has impor- It should be noted that drug delivery via the
tant metabolic implications. Upon hyperventila- lungs, e.g., using inhalation devices, offers great
tion (increased/frequent breathing), pCO2 can be therapeutic potential, not only for treatment of
drastically reduced, reducing or even completely asthma and COPD. Inhaled drug delivery har-
inhibiting further breathing. The latter can lead to nesses immediate contact to mucosal surfaces
hypoxemia (reduced pO2 in the blood) and might and easy translocation to the blood across the
remain undetected until unconsciousness occurs. alveolar membrane [6].
Additionally, hypoxemia-induced breathing low-
ers pCO2, which will in turn decrease breathing
activity more efficiently than required based on Inside-Out: Metabolites of the Lung
pO2 status. Dramatic alterations of blood gases Affecting Other Tissues
can occur in divers or at high altitudes [4, 5].
Increased H+ is compensated by hyperventila- Function Under Extreme Conditions
tion, causing an increased exhalation of CO2. By
this mechanism, the lung is a major regulator of Hypercapnia not only increases breathing but
blood pH along with the kidneys (see below). also causes arousal and initiates head turning
Again, the expected response to high H+ is sty- during sleep. It can be caused by lung function
mied by the “more effective” response to altered deficits (as in several lung diseases), breathing
pCO2. depression, inhalation of increased concentra-
tions of CO2 (as in rebreathing), and long-term
artificial respiration. It is often accompanied by
Breathing and Pathologies respiratory acidosis due to the formation of car-
bonic acid (H2CO3) and subsequent dissociation
Observation of breathing patterns can hint at spe- to H+ and bicarbonate (HCO3−).
cific underlying pathologies and disturbances. Respiratory acidosis (blood pH <7.35) causes
For example, in altitude sickness, reduced pO2 clinical symptoms, such as blue, cyanotic lips;
in the atmosphere causes increased heart rate and increased heart rate (tachycardia); and pulmonary
212 M. Zeeb et al.
hypertonia (Fig. 2). Respiratory acidosis is hypoxia-inducible factor (HIF)-1α. This increases
commonly corrected by H+ excretion in the kid- production of hemoglobin and thus facilitates
ney (see chapter “Overview” under the part oxygen transport (see chapter “Overview” under
“Kidney”). the part “Blood”), e.g., during adaptation to high
Acidosis can also occur due to increased altitudes [7].
anaerobic glycolysis (causing increased lactic
acid concentrations) and ketone body synthesis
resulting in ketoacidosis (due to increased aceto- Other Functions
acetic acid and 2-hydroxybutyric acid concentra-
tions). This metabolic acidosis occurs during Finally, the lung also performs functions differ-
shock or, more commonly, deregulated diabetes ent from gas exchange. For example, lung endo-
(coma diabeticum, see chapter “Diabetes melli- thelium synthesizes angiotensin-converting
tus”). Other forms of metabolic acidosis originate enzyme (ACE) that converts angiotensin I to
from decreased H+ excretion (as occurs in kidney angiotensin II (Fig. 2). This conversion is of criti-
disease, see chapter “Chronic kidney disease”), cal importance to blood pressure homeostasis
increased HCO3− excretion, or acid intoxication (see chapters “Overview” under the part “Kidney”
(e.g., by acetylsalicylic acid). and Hypertension) and a protective role of ACE
If acidosis exceeds the buffer capacity of the in the lung has been reported [8].
blood, it can be fatal. In general, metabolic dereg-
ulation is antagonized by respiratory mecha-
nisms, and vice versa. Thus, severe metabolic Coordination with Other Organs
acidosis is characterized by Kussmaul breathing,
a deep and gasping breathing pattern, which is a The function of the lung needs to be coordinated
sign of life-threatening conditions. with other organs in particular with the cardio-
Prolonged reduced oxygen levels (hypox- vascular system. For example, increased breath-
emia) trigger release of erythropoietin (EPO) via ing is only useful if heart rate and blood
Overview 213
Mast
cell
Eosinophil
TSLP/IL-25/IL-33/GM-CSF
Dendritic cell B-cell
IgE
Chronic
inflammation
Group 2 innate IL-4/IL-5/IL-9/IL-13
lymphoid cells
Basophil
Naive
Th2 Fibroblast Smooth muscle cell
T-cell
Th2
Fibrosis Hypertrophy/Hyperplasia
Fig. 1 Type 2 immune responses in asthma. In the classi- muscle cells). In another pathway, allergens directly act
cal pathway, dendritic cells (DCs) take up allergens and on epithelial cells, inducing production of epithelial cyto-
present allergen-derived peptides to naive T cells (lower kines, such as thymic stromal lymphopoietin (TSLP),
left). T cells differentiate into Th2 cells (bottom center), IL-25, IL-33, and granulocyte macrophage-colony-stimu-
which secrete type 2 cytokines such as interleukin (IL-)4, lating factor (GM-CSF). TSLP, IL-25, and IL-33 act on
(IL-)5, (IL-)9, and (IL-)13. These cytokines activate DCs or group 2 innate lymphoid cells enhancing type 2
immune cells (B cells, mast cells, and eosinophils) and/or immune responses. Basophils enhance Th2 development
nonimmune cells (epithelial cells, fibroblasts, and smooth
Recognizing this heterogeneity is important in and efficacy of inhaled corticosteroids are invariant
evaluating the efficacy of inhaled glucocortico- in these two groups [17]. As a result of application
steroids, the most effective agents currently avail- of many phenotypes for clustering asthma patients,
able [1]. Inhaled corticosteroids are ineffective for age at disease onset (early vs. late) and associa-
5–10 % of asthma patients, and the medical costs tion of Th2 response (Th2 type vs. non-Th2 type)
of these patients account for 50 % of the overall are well accepted as useful stratification (Fig. 2)
cost of treating asthma [18, 19]. Understanding [17]. Early-onset Th2-type asthma includes mild to
the varying types of asthma will allow stratifica- severe patients and is associated with other allergic
tion of asthma patients and better treatment. diseases. Inhaled corticosteroids are effective, and
Although the concept of extrinsic (allergic) vs. Th2-targeted agents (e.g., anti-immunoglobulin E
intrinsic (nonallergic) asthma was proposed before, (IgE) antibody, anti-IL-5 antibody, and IL-4/IL-13
it has been shown that expression of Th2 cytokines antagonists) will be useful. Late-onset Th2-type
218 K. Izuhara et al.
Early-onset Late-onset
Exercise-induced
Fig. 2 Categorization of asthma patients (Adapted from corticosteroids and Th2-targeted agents. Late-onset Th2
Wenzel [17]). Asthma patients are categorized by disease type (center) is often severe, associated with sinusitis and
onset (early vs. late) and association of Th2 response (Th2 nasal polyps, and refractory for inhaled corticosteroids
type vs. non-Th2 type). Most early-onset patients are Th2 but responsive for Th2-targeted agents. Exercise-induced
type (left column). This type is mild to severe, associated asthma is included in this type. Late-onset non-Th2 type
with other allergic diseases, and responsive for inhaled contains obesity-related or neutrophilic asthma
asthma affects patients more severely than early- elucidate the heterogeneity of asthma to establish
onset types. Sinusitis or nasal polyps are often a better treatment of the patients in each.
observed in this type. Since inhaled corticosteroids
are less effective for this type, Th2-targeted agents
are more promising. The Th2 type is present in
up to 50 % of asthma patients. Exercise-induced References
asthma is included in this category. Fractional
1. GINA executive committee: Global strategy for
exhaled nitric oxide (FeNO), sputum eosinophils, asthma management and prevention updated 2012.
and serum periostin can be biomarkers for Th2- http://ginasthma.org/2012
type asthma. FeNO is produced by inducible nitric 2. Vercelli D (2008) Discovering susceptibility
genes for asthma and allergy. Nat Rev Immunol 8:
oxide synthase (iNOS) that is induced in airway
169–182
epithelial cells by IL-13. Periostin is a compo- 3. Moffatt MF, Kabesch M, Liang L et al (2007) Genetic
nent of thickened basement membranes of asthma variants regulating ORMDL3 expression contribute to
patients downstream of IL-4/IL-13 signals [20] the risk of childhood asthma. Nature 448:470–473
4. Moffatt MF, Gut IG, Demenais F et al (2010) A large-
and appears to be a promising surrogate biomarker
scale, consortium-based genomewide association
for high IL-13 expression [21]. study of asthma. N Engl J Med 363:1211–1221
Non-Th2-type asthma affects the remaining 5. Sleiman PM, Flory J, Imielinski M et al (2010)
50 % of patients and is mostly adult onset. This Variants of DENND1B associated with asthma in
children. N Engl J Med 362:36–44
type includes obesity-related or neutrophilic
6. Hirota T, Takahashi A, Kubo M et al (2011) Genome-
asthma (see above). wide association study identifies three new suscepti-
bility loci for adult asthma in the Japanese population.
Nat Genet 43:893–896
7. Tangye SG, Ma CS, Brink R et al (2013) The good,
Perspectives the bad and the ugly – TFH cells in human health and
disease. Nat Rev Immunol 13:412–426
Understanding of the pathogenesis of asthma has 8. Woodruff PG, Modrek B, Choy DF et al (2009)
increased along with an increased knowledge of T-helper type 2-driven inflammation defines major
subphenotypes of asthma. Am J Respir Crit Care Med
the immunological responses involved. Based on
180:388–395
this, several new drugs against asthma are now in 9. Holgate ST (2012) Innate and adaptive immune
development. For the future, it is important to responses in asthma. Nat Med 18:673–683
Asthma 219
10. Lambrecht BN, Hammad H (2012) The airway epi- 16. Meyer EH, Goya S, Akbari O et al (2006) Glycolipid
thelium in asthma. Nat Med 18:684–692 activation of invariant T cell receptor+ NK T cells is
11. Licona-Limon P, Kim LK, Palm NW et al (2013) sufficient to induce airway hyperreactivity indepen-
TH2, allergy and group 2 innate lymphoid cells. Nat dent of conventional CD4+ T cells. Proc Natl Acad Sci
Immunol 14:536–542 U S A 103:2782–2787
12. Nakae S, Suto H, Berry GJ et al (2007) Mast cell- 17. Wenzel SE (2012) Asthma phenotypes: the evolution
derived TNF can promote Th17 cell-dependent neu- from clinical to molecular approaches. Nat Med
trophil recruitment in ovalbumin-challenged OTII 18:716–725
mice. Blood 109:3640–3648 18. Adcock IM, Lane SJ (2003) Corticosteroid-insensitive
13. Yang XO, Chang SH, Park H et al (2008) Regulation asthma: molecular mechanisms. J Endocrinol 178:
of inflammatory responses by IL-17 F. J Exp Med 347–355
205:1063–1075 19. Sorkness RL, Bleecker ER, Busse WW et al (2008)
14. Kearley J, Barker JE, Robinson DS et al (2005) Lung function in adults with stable but severe asthma:
Resolution of airway inflammation and hyperreactiv- air trapping and incomplete reversal of obstruction
ity after in vivo transfer of CD4+CD25+ regulatory T with bronchodilation. J Appl Physiol 104:394–403
cells is interleukin 10 dependent. J Exp Med 202: 20. Takayama G, Arima K, Kanaji T et al (2006) Periostin:
1539–1547 a novel component of subepithelial fibrosis of bron-
15. Lewkowich IP, Herman NS, Schleifer KW et al chial asthma downstream of IL-4 and IL-13 signals.
(2005) CD4+CD25+ T cells protect against experi- J Allergy Clin Immunol 118:98–104
mentally induced asthma and alter pulmonary den- 21. Corren J, Lemanske RF, Hanania NA et al (2011)
dritic cell phenotype and function. J Exp Med Lebrikizumab treatment in adults with asthma. N Engl
202:1549–1561 J Med 365:1088–1098
Chronic Obstructive Pulmonary
Disease (COPD)
Molecular links have been established between cells, releasing multiple inflammatory mediators.
systemic oxidative stress, protein degradation, This leads to further recruitment of immune cells,
muscle and bone atrophy, cardiovascular and neu- airway epithelium proliferation, mucus hyper-
rological comorbidities, and inflammation (e.g., secretion, and airflow limitation. Combination
TNF-α, IL-6, and IL-8) [11]. of inflammation, imbalance in the protease-
In conclusion, exposure to inhaled toxic antiprotease system, and local tissue remodeling
agents leads to chronic irreversible inflammation, (fibrosis) results in alveolar wall destruction and
oxidative stress, and increased numbers of acti- emphysema. Based on their compromised lung
vated macrophages, neutrophils, and cytotoxic T anatomy and function, COPD patients are more
a Healthy COPD
Chronic bronchitis
Inflammation
Excess mucus
Airway obstruction
Emphysema
Alveolar wall destruction
Abnormal gas exchange
b
Tobacco smoke, toxic particles, and gases
Progressive inflammation
(Activation of epithelial and immune cells,
increased susceptibility to infections)
Infectious agents,
Epithelium Neutrophils Macrophages exacerbation
Fig. 1 Pathological hallmarks and implicated cell types in respectively. (b) Cellular components and molecular mech-
chronic obstructive pulmonary disease. (a) Comparison anisms of the inflammation and structural changes in the
between healthy and chronic obstructive pulmonary dis- COPD lung tissue. TGF-β transforming growth factor β,
ease (COPD) tissue in the upper (bronchi, above) and EGF epidermal growth factor, ROS reactive oxygen spe-
smaller airways (alveoli, below) and pathological manifes- cies, TNF-α tumor necrosis factor-α, IL interleukin, MCP-
tation of COPD – chronic bronchitis and emphysema, 1 monocyte chemotactic protein-1, LTB4 leukotriene B4
224 I. Konstantinova and A.C. Pearce
susceptible to exacerbations and often develop more effective approaches continue, e.g., non-
metabolic comorbidities. nicotinic drugs targeting neurotransmitter sys-
tems [14] and acetylcholine receptors [15].
Introduction to Treatment
and Influence on Metabolism Long-Acting Bronchodilators
COPD treatment aims to reduce the symptoms Long-acting β2 agonists (LABA, e.g., formoterol,
and exposure to risk factors. None of the existing salmeterol) improve lung function by binding to
COPD medical interventions (see Table 1 for the β2 adrenergic receptor on smooth muscle cells
most common examples) has been shown to con- (SMCs) surrounding the airways and inhibiting
clusively modify the long-term decline in lung their contraction. Treatment with LABA leads to
function [7]. reduced symptoms and improved FEV1, exercise
capacity, and health status [7]. This improvement
reflects the increased expiratory flow resulting
Smoking Cessation from widening of the obstructed airways. There
are some concerns about side effects of LABA
Smoking cessation is the only therapeutic inter- such as cardiac dysrhythmia and increased oxy-
vention so far shown to reduce disease progres- gen consumption, but lower doses are effective
sion [12]. However, the main problem with this and safe [12]. In addition to dilating the airways,
approach is the nicotine addiction. There are sev- LABA have some indirect effects on inflamma-
eral forms of nicotine replacement therapies, but tion leading to decreased neutrophil numbers and
their effectiveness is very low [13]. Efforts for IL-8 levels [16].
Table 1 Summary of the most common COPD treatments, outcomes, and side effects
Treatment Target Results Consequence Side effects
LABA β2-Adrenergic Bronchodilation due to Improved FEV1, Cardiac rhythm
Formoterol receptor (SMCs) inhibition of airway exercise capacity, disturbance,
Salmeterol SMC contraction general health status somatic tremor,
increased oxygen
consumption
LABA Acetylcholine Bronchodilation due to Improved FEV1, Dryness of the
Tiotropium bromide receptors (SMCs, inhibition of airway exercise capacity, mouth
submucosal gland SMC contraction and general health
cells) mucus secretion status; reduced
exacerbations
Inhaled Glucocorticoid Minimal effect on lung Reduced Oral infections,
corticosteroids receptor (multiple cell function exacerbations skin bruising,
Budesonide types) increased risk of
pneumonia
PDE4 inhibition PDE4 (inflammatory Reduced inflammation Improved FEV1, Nausea, reduced
Roflumilast and immune cells) due to inhibition of reduced appetite, abdominal
cAMP hydrolysis exacerbations pain, diarrhea,
headache, sleep
disturbance
LABA long-acting β2 agonists, SMC smooth muscle cell, FEV1 forced expiratory volume in 1 s, PDE4
phosphodiesterase-4
Chronic Obstructive Pulmonary Disease (COPD) 225
Tiotropium bromide binds to muscarinic ace- bances probably due to low specificity and high
tylcholine receptors on airway SMCs and submu- systemic availability. Therefore, more specific
cosal gland cells and inhibits contraction and PDE4 inhibitors (such as roflumilast [8]) and
mucus secretion. This bronchodilator effect inhaled approaches to retain the drug in the lung
translates into FEV1 increase and improved are being currently considered [7].
exercise capacity and health status [7]. Tiotropium
bromide is well tolerated with the only side effect
of mouth dryness [7]. There is some evidence Other Therapies
that tiotropium bromide is effective in reducing
exacerbations, although the mechanism is not Other therapies include use of antibiotics during
well understood [17]. exacerbations and oxygen therapy in patients
with chronic respiratory failure. There is a branch
of COPD therapy based on non-pharmacological
Corticosteroids approaches including pulmonary rehabilitation
(exercise and peripheral muscle training), nutri-
Corticosteroids act by binding to the ubiquitously tional supplementation (against weight loss,
expressed glucocorticoid receptor, which translo- skeletal muscle waste, and osteoporosis if the
cates to the nucleus and represses expression of respective comorbidities are present), and surgi-
inflammatory genes or induces expression of anti- cal treatment (lung transplantation or removal of
inflammatory genes. Eosinophils seem to be the part of the lung in order to increase effectiveness
most steroid-responsive immune cells, but in con- of respiratory muscles) [7].
trast to asthma, they are not prominent in COPD
[8]. In addition, alveolar macrophages from COPD
patients appear to be steroid resistant [12]. When Perspectives
inhaled, especially in combination with LABA,
corticosteroids (e.g., budesonide) have a modest Further research into the basic cellular, molecular,
effect on lung function decline and exacerbations. and genetic abnormalities of COPD is necessary. It
However, prolonged treatment increases the risk is important to identify the genes determining why
of infections (especially pneumonia) and skin only some heavy smokers develop significant
bruising [7]. COPD. This can lead to identification of novel tar-
gets and better patient stratification for therapy.
Current research is focused on inflammatory
Phosphodiesterase-4 Inhibitors mediator antagonists, e.g., inhibitors of lipids (e.g.,
leukotriene B4, prostaglandin E2), cytokines (e.g.,
Decrease of cellular cAMP levels activates TNF-α), and others. Antioxidants are considered
inflammatory cells such as neutrophils, T cells, as a potentially beneficial therapy. Based on the
macrophages, and structural cells such as epithe- imbalance of proteases and antiproteases, studies
lial cells, SMCs, fibroblasts, mucus gland cells, targeting neutrophil elastase, MMPs, and cysteine
and sensory neurons [12]. Phosphodiesterase-4 proteases are ongoing. Finally, there is a growing
(PDE4) antagonists reduce inflammation by interest in the potential use of stem cells for repair
inhibiting PDE4-mediated cAMP hydrolysis. of the damaged lung tissue [8].
Treatment leads to improved FEV1 in moderate In conclusion, improved COPD therapies are
to severe COPD patients [7]. PDE4 inhibitors urgently needed to provide long-term benefit in
have several side effects such as nausea, diarrhea, this common and important disease, for which no
headache, abdominal pain, and sleep distur- effective preventive therapy or cure exists.
226 I. Konstantinova and A.C. Pearce
suitable for patients with life-threatening CAP or contribute to an increased CAP risk. The presence
worsening pneumonia despite antimicrobial ther- of local immunoglobulins, particularly immuno-
apy. Urinary antigen determination may detect globulin A (IgA), complement, and normal flora
Legionella pneumophila and S. pneumoniae. also prevents colonization of the oropharynx by
Serum biomarkers like C-reactive protein (CRP) virulent organisms [6, 8, 9].
and procalcitonin (PCT) may be used as indica- Patients with pneumonia frequently show
tors of bacterial infection [11–13]. moderate to severe arterial hypoxemia (an abnor-
mally low O2 level in arterial blood), probably
due to pulmonary shunts (i.e., when ventilation
Pathophysiology of Community- fails to supply O2 to alveoli that receive normal
Acquired Pneumonia blood perfusion, which happens, e.g., when alve-
oli are filled with fluid), increased whole-body O2
The pathophysiology of CAP involves both uptake, ventilation-perfusion (VA/Q) mismatch-
host defense and microbial virulence factors. ing, and/or limited alveolar O2 diffusion into the
Constant exposure to contaminated air and blood [14].
frequent aspiration of nasopharyngeal flora Previous studies in animal models of pneu-
make lung parenchyma susceptible to virulent monia [15] and in humans [16] have demon-
microorganisms, commonly reaching the lower strated that the most common pattern of VA/Q
respiratory tract as inhaled and contaminated mismatching is a combination of both intra-
microdroplets. Mucociliary clearance and cough pulmonary shunt and mild to moderate areas
reflex are important initial defenses against of low ventilation-perfusion (VA/Q) ratios.
infection and can be inhibited by neurologic dis- Pulmonary hypoxia (i.e., low O2 levels in the
eases and conditions that impair the mucociliary lung) causes vasoconstriction to avoid perfu-
mechanism [6, 8]. sion of non-ventilated alveoli and redistribution
Most CAPs are bacterial in origin and often of the blood flow to better-ventilated lung areas.
follow brief viral upper respiratory tract infection. This response is often blunted in CAP patients
There are two main mechanisms to acquire (causing intrapulmonary increased shunts and
pneumonia. Firstly, inhalation causes pneumo- decreased VA/Q ratios) due to local release of
nia due to microorganisms that can remain sus- vasodilatory prostacyclins.
pended in air and evade local host defenses. In Prolonged systemic inflammation and bacte-
addition, aerosolization is the route of infection rial translocation to the blood cause sepsis (see
by intracellular bacteria such as Mycoplasma chapter “Sepsis”), a common consequence of
pneumoniae, Chlamydophila spp., Coxiella CAP. Impaired tissue oxygenation, as commonly
burnetii, and Legionella pneumophila [6, 8, 9]. occurs in CAP, is a major mechanism of organ
Secondly, aspiration of oropharyngeal flora can failure in sepsis [17, 18].
cause CAP. The ability of virulent bacteria such The host response to sepsis is characterized by
as Streptococcus pneumoniae, Staphylococcus both pro- and anti-inflammatory responses (see
aureus, Pseudomonas aeruginosa, and Klebsiella also chapter “Overview” under the part “Immune
pneumoniae to colonize the oropharynx is deter- system”). The extent and duration of these
mined by the interaction of specific microbial reactions are determined by host factors (age,
adhesins with cellular receptors. For example, comorbidities, medications, and genetic charac-
components of the extracellular matrix (ECM) teristics) and pathogen factors (microbial load
such as fibronectin in oral mucus promote the and virulence) [17, 19]. Proinflammatory reac-
adherence of viridans streptococci. In contrast, tions directed at eliminating invading pathogens
salivary fibronectin prevents colonization by are thought to be responsible for collateral tissue
Gram-negative bacilli, and decreased levels of damage. In contrast, anti-inflammatory responses
fibronectin due to alcoholism, diabetes, mal- are important to limit tissue injury, yet enhance
nutrition, and other severe comorbidities might susceptibility to secondary infections.
Community-Acquired Pneumonia 229
CAP treatment is still largely empirical because Microorganism Outpatient Hospital ICU
% % %
of the difficulties to detect the infective
Streptococcus pneumoniae 35 43 42
pathogen(s) from lung samples and should fol-
Atypical bacteria 36 16 14
low an approach according to the individual risk Mycoplasma pneumoniae 17 3 2
of mortality [6, 9]. Although the most common Coxiella burnetii 7 2 1
bacterium identified in CAP patients is S. pneu- Legionella pneumophila 6 8 8
moniae, other microorganisms (see above) are Chlamydophila 6 3 3
frequently involved, dependent on the place of pneumoniae
care (see Table 1). Respiratory virus 9 12 10
Eradication of the causative microorganism is Haemophilus influenzae 5 5 3
the most common and effective treatment option, Enteric Gram-negative 1 2 1
bacilli
and thus, antibiotic treatment should be initiated
Staphylococcus aureus 1 2 2
as soon as possible after diagnosis. In patients
Pseudomonas aeruginosa 1 4 5
with CAP and septic shock, delay must not be
Polymicrobial 9 13 22
more than 1 h after diagnosis [6, 11, 20]. The Others 4 3 6
severity of the disease implies a decision about
ICU intensive care unit
the most appropriate treatment setting (ambula-
tory, hospital ward, or ICU) and antibiotic used
according to European guidelines [20]. improve arterial oxygenation allowing to gain
In a responding patient, the duration of treat- time for the effect of antibiotics [24].
ment should generally not exceed 8 days, because
longer treatment days may increase bacterial
resistance. The serial use of serum biomarkers, Influence of Treatment on
particularly PCT, may guide even shorter treat- Metabolism and Consequences
ment duration, because PCT levels correspond to for Patients
response to treatment.
Multidrug resistance (MDR) represents Although the inflammatory response in CAP is
an emerging problem in CAP because of the compartmentalized to the lung, most cytokines
increasing number of residents living in health- can be detected in the systemic circulation, such
care facilities [21]. The empirical treatment of as interleukin (IL)-6, interleukin-8, and inter-
health-care-acquired pneumonia (HCAP) is still leukin-10 and tumor necrosis factor-α (TNF-α).
controversial. The current trend is to use risk However, they decline in the first 48 h of treat-
factors to suggest MDR or “different to treat ment (except TNF-α) [25], correlating with the
pathogens” as P. aeruginosa, S. aureus MR, or time to clinical defervescence (i.e., departure of
Enterobacteriaceae [22, 23]. fever).
Recently, it has been proposed that the use High levels on admission of IL-6 as well as
of aerosolized vasodilators may benefit patients. levels of IL-6 and IL-8 in the first 48 h were sig-
Inhaled nitric oxide (NO) has been shown to nificantly higher in patients requiring ICU admis-
improve pulmonary gas exchange in patients with sion and those who died [26]. CAP patients with
acute respiratory distress syndrome (ARDS) due pneumococcal infection receiving combination
to vasodilatation in ventilated lung areas where therapy, a β-lactam antibiotic plus a fluoroquino-
exogenous NO has easy access. As a result, blood lone antibiotic (e.g., a cephalosporin plus levo-
flow is redistributed from non-ventilated to ven- floxacin; see Table 2), show a faster decrease
tilated alveolar units, thereby reducing intrapul- in IL-6 [25, 26], recommending this treatment
monary shunts. Inhaled low doses of NO thus option.
230 S. Sialer et al.
Mortality in hospitalized pneumonia patients often used in patients with COPD to treat acute
is often associated with cardiac complications hypercapnic respiratory failure (meaning the fail-
such as cardiac insufficiency, arrhythmias, and ure to eliminate CO2 properly) [6, 20].
myocardial infarction [27]. The reasons for this Statins have pleiotropic effects (see chapter 43)
are still unclear, but could be explained by the showing immunomodulatory, anti-inflammatory,
persistent residual inflammation found in these antithrombotic, and direct antimicrobial action.
patients. Interestingly, patients receiving statins at the time
Additional therapies used in patients with CAP of CAP onset were less likely to develop sepsis
include adjunctive corticosteroids, low molecular and associated mortality. The beneficial effect of
weight heparin (LMWH), the use of noninvasive statins in CAP patients might also be attributed
ventilation (NIV), and statin drugs [20]. to their prevention of acute coronary syndrome
Corticosteroids are powerful inhibitors of and myocardial infarction, which are common in
inflammation, reducing the levels of TNF-α, CAP, yet further research on their mode of action
IL-1β, IL-8, and IL-6 and thus recruitment is needed.
of inflammatory cells into the alveolar space.
Additionally, they can ameliorate the insufficient
adrenal response in patients with severe CAP and Perspectives
septic shock [4, 6, 20].
LMWH should be given to patients with acute Although mortality of hospitalized CAP has
respiratory failure in order to inhibit coagulation decreased in recent years, further improvement is
(see chapter “Overview ” under the part “Blood”), required, especially in the area of clinical prac-
a major pathophysiological event in severe CAP. tice and pathophysiological research. To reduce
LMWH are used as prophylactic means to pre- hospital mortality, a system to quickly detect
vent pulmonary thromboembolism [20]. CAP, evaluate its severity, and identify infec-
The use of NIV (meaning ventilatory support tious microbes is required for quick intervention
through the patient’s upper airway using a mask and administration of adequate antibiotics. This
or similar device) is not yet the standard care, but is of particular importance in MDR pathogens
Community-Acquired Pneumonia 231
that already represent 6–10 % of cases of CAP. Thoracic Society consensus guidelines on the
management of community-acquired pneumonia in
Measurement of biomarkers, such as PCT and
adults. Clin Infect Dis 44(Suppl 2):S27–S72
pro-adrenomedullin, will be crucial to determine 12. Rello J, Bodi M, Mariscal D et al (2003)
severity and prognosis as well as to monitor Microbiological testing and outcome of patients
treatment. with severe community-acquired pneumonia. Chest
123:174–180
Research into the relationship between inflam-
13. Woodhead M (2011) New guidelines for the manage-
mation and cardiac complications in CAP will ment of adult lower respiratory tract infections. Eur
allow to set up appropriate therapeutic strategies Respir J 38(6):1250–1251
to decrease mortality and complications of CAP. 14. Rodriguez-Roisin R, Roca J (1996) Update ’96 on
pulmonary gas exchange pathophysiology in pneu-
Finally, better and careful follow-up of CAP
monia. Semin Respir Infect 11(1):3–12
patients after discharge will reduce long-term 15. Light RB, Mink SN, Wood LD (1981) Pathophysiology
mortality. of gas exchange and pulmonary perfusion in pneu-
mococcal lobar pneumonia in dogs. J Appl Physiol
Respir Environ Exerc Physiol 50(3):524–530
16. Gea J, Roca J, Torres A et al (1991) Mechanisms of
References abnormal gas exchange in patients with pneumonia.
Anesthesiology 75(5):782–789
1. Almirall J, Bolıbar I, Vidal J et al (2000) Epidemiology 17. Angus DC, van der Poll T (2013) Severe sepsis and
of community acquired pneumonia in adults: a septic shock. N Engl J Med 369(9):840–851
population-based study. Eur Respir J 15:757–763 18. Khardori R, Castillo D (2012) Endocrine and meta-
2. Ewig S, Birkner N, Strauss R et al (2009) New per- bolic changes during sepsis: an update. Med Clin
spectives on community-acquired pneumonia in North Am 96(6):1095–1105
388406 patients. Results from a nationwide manda- 19. Hotchkiss RS, Karl IE (2003) The pathophysiology
tory performance measurement program in healthcare and treatment of sepsis. N Engl J Med 348(2):138–150
quality. Thorax 64:1062–1069 20. Woodhead M, Blasi F, Ewig S, et al Joint Taskforce
3. Zalacain R, Torres A, Celis R et al (2003) Community- of the European Respiratory Society and European
acquired pneumonia in the elderly: Spanish multicen- Society for Clinical Microbiology and Infectious
tre study. Eur Respir J 21:294–302 Diseases (2011) Guidelines for the management of
4. Nair GB, Niederman MS (2011) Community acquired adult lower respiratory tract infections. Clin Microbiol
pneumonia: an unfinished battle. Med Clin North Am Infect 17(Suppl 6):E1–59
95:1143–1161 21. Rubinstein E, Kollef MH, Nathwani D (2008)
5. Gibson GJ, Loddenkemper R, Lundbäck B et al Pneumonia caused by methicillin-resistant
(2013) Respiratory health and disease in Europe: Staphylococcus aureus. Clin Infect Dis 46(Suppl 5):
the new European Lung White Book. Eur Respir J S378–S385
42(3):559–563 22. Ewig S, Welte T, Torres A (2012) Is healthcare-
6. Torres A, Barberán J, Falguera M et al (2013) associated pneumonia a distinct entity needing spe-
Multidisciplinary guidelines for the management of cific therapy? Curr Opin Infect Dis 25(2):166–175
community-acquired pneumonia. Med Clin (Barc) 23. Ewig S, Torres A (2011) Healthcare-associated pneu-
140(5):223e.1–223.e.19 monia: meeting the yeti. Eur Respir J 38(4):755–757
7. Almirall J, Bolíbar I, Serra-Prat M et al (2008) 24. Gómez FP, Amado VM, Roca J et al (2013) Effect
Community-Acquired Pneumonia in Catalan of nitric oxide inhalation on gas exchange in acute
Countries (PACAP) Study Group. New evidence severe pneumonia. Respir Physiol Neurobiol 187(2):
of risk factors for community-acquired pneumo- 157–163
nia: a population -based study. Eur Respir J 31(6): 25. Fernández-Serrano S, Dorca J, Coromines M et al
1274–1284 (2003) Molecular inflammatory responses measured
8. Cillóniz C, Ewig S, Polverino E et al (2012) in blood of patients with severe community-acquired
Community-acquired pneumonia in outpatients: aeti- pneumonia. Clin Diagn Lab Immunol 10(5):813–820
ology and outcomes. Eur Respir J 40(4):931–938 26. Padrones S, Garcia-Vidal C, Fernández-Serrano S
9. Cillóniz C, Ewing S, Polverino E et al (2011) et al (2010) Impact of antibiotic therapy on systemic
Microbial aetiology of community-acquired pneumo- cytokine expression in pneumococcal pneumonia. Eur
nia and its relation to severity. Thorax 66:340–346 J Clin Microbiol Infect Dis 29(10):1243–1251
10. Anevlavis S, Petroglou N, Tzavaras A et al (2009) A 27. Corrales-Medina VF, Musher DM, Wells GA et al
prospective study of the diagnostic utility of Sputum (2012) Cardiac complications in patients with
Gram stain in pneumonia. J Infect 59:83–89 community-acquired pneumonia: incidence, timing,
11. Mandell LA, Wunderink RG, Anzueto A et al (2007) risk factors, and association with short-term mortal-
Infectious Diseases Society of America/American ity. Circulation 125(6):773–781
Part X
Heart
Overview
Axel Gödecke
Fig. 1 Anatomic
features of the human
heart Aorta
CMs represent the major cell type in terms of Endothelial cells also form the inner cell layer
mass and dominate the structure of the myocar- of the cardiac chambers termed endocardium.
dium. CMs show a characteristic striated pattern Finally, the heart is surrounded by the pericar-
similar to skeletal muscle, which is due to the dium, protecting this vital organ.
parallel organization of the contractile actin and The heart is supplied by its own circulatory
myosin filaments. At their ends, CMs are con- system, which originates at the aortic root in the
nected via intercalated discs. These structures are form of two main coronary arteries. Since the
rich in gap junctions, which allow the spreading heart critically depends on aerobic metabolism,
of the electric excitation over the myocardium there is an extraordinary high capillary density
due to a direct electric coupling of CMs. A highly within the myocardium [2].
coordinated sequence of temporal and spatial
excitation and contraction of CMs leads to a con-
tinued cycle of ventricular contraction and relax- Cardiac Muscle Contraction
ation of the whole heart.
Interstitial and perivascular fibroblasts account The heartbeat is the consequence of a well-
for two thirds of cardiac cells in terms of numbers defined temporal and spatial sequence of excita-
[1]. Cardiac fibroblasts synthesize the extracellular tion and contraction of the cardiac muscle. The
matrix, which provides an extracellular protein origin of the electric excitation is the sinoatrial
scaffold for the attachment of CMs, fibroblasts, and node (SA node), which consists of specialized
endothelial cells. The amount and composition of CMs able to depolarize spontaneously and auton-
the cardiac extracellular matrix are important deter- omously. The SA node represents the primary
minants of myocardial stiffness. Therefore, activa- pacemaker of the heart, and upon its depolariza-
tion of cardiac fibroblasts and enhanced matrix tion, a wave of depolarization spreads over the
deposition which occur during aging but also in the atria. The atrioventricular plane which is assem-
context of heart failure (see chapter “Heart fail- bled by the heart valves insulates the ventricles
ure”) may lead to a reduced ventricular compli- from the atria. The only conducting connection is
ance, which impedes diastolic filling. the atrioventricular node (AV node), which is
Overview 237
located in the right atrial septum. The atrial exci- Ca2+-ATPase), which in a concerted manner gen-
tation passes the AV node and is then conducted erate the Ca2+ transients [3]. The periodic release
to all regions of the ventricular walls by the spe- and reuptake of Ca2+ are required for electrome-
cialized CMs forming the conduction system chanical coupling, linking cardiac action poten-
including the bundle of His, branches of Tawara, tials with contraction. When the membrane
and the Purkinje fibers. The final step of ventricu- potential of a CM reaches the threshold (−70 mV),
lar excitation involves the conduction between opening of voltage-gated sodium channels depo-
CMs via gap junctions. larizes the membrane potential to +30 mV fol-
Due to an unstable resting potential, SA nodal lowed by the opening of L-type Ca2+ channels
cells depolarize spontaneously, and the SA node which mediate an influx of Ca2+ from the intersti-
is able to initiate cardiac excitation autonomously. tial space. This Ca2+ current serves dual func-
However, the slope of this diastolic depolarization tions. First, it leads to a long-lasting (200–400 ms)
is increased by noradrenaline released by sympa- depolarization at a voltage around 0 mV before
thetic nerve fibers, which elevates heart rate K+ conductivity reverses the membrane potential
(positive chronotropy). Acetylcholine, the para- back to the diastolic values (−90 mV). Second,
sympathetic transmitter, reduces heart rate by flat- the Ca2+ influx gives rise to further Ca2+ release
tening the slope of diastolic depolarization. By from intracellular stores by opening the ryano-
similar mechanisms, sympathetic innervation of dine channel (Ryr2) in the membrane of the
the AV node increases the AV conduction time sarcoplasmic reticulum (SR). Finally, the intra-
(positive dromotropy) whereas acetylcholine cellular Ca2+ concentration increases to 10−5 mol/l
decreases it (negative dromotropy). (from initially 10−7 mol/l). Subsequent Ca2+ bind-
ing to troponin C displaces tropomyosin from
actin, enabling myosin to bind and to perform
Heart-Specific Metabolic/Molecular contraction. This is terminated by Ca2+ reuptake
Pathways and Processes into the SR and via export by the sarcolemmal
Na+/Ca2+ exchanger.
With more than three billion contractions, the heart Sympathetic nerve fibers also innervate the
pumps more than 200 million l of blood through myocardium. Norepinephrine increases Ca2+
the vasculature during a normal human life span. In influx, release from the SR, and accelerates reup-
order to continuously perform its function, the take into the SR leading to faster and increased
heart critically depends on oxidative phosphoryla- Ca2+ transients, which are the basis for enhanced
tion. Therefore, delivery of oxygen via coronary contractile force (positive inotropy).
perfusion must tightly match cardiac oxygen As only a minor part of the ATP is required for
demands even under high workload. As cardiac basal biochemical reactions, an experimentally
muscle contains only around 5 μmol ATP/g wet arrested heart consumes only 10 % of the oxygen
weight, all ATP would be consumed within 10 s if required to run a working heart. The high demand
oxidative ATP generation was stopped. for ATP of a beating heart even under resting
Almost 95 % of cardiac ATP generation conditions results in a high degree of oxygen
occurs through oxidative phosphorylation, which demand. The heart consumes 10 % of the whole-
represents the most efficient way to generate body oxygen, although it contributes only 0.5 %
ATP. This high level of oxidative phosphoryla- to whole-body mass. The high rate of oxygen
tion is reflected by a high mitochondrial content consumption leads to low PO2 values in cardiac
(30–35 Vol %) in the CMs. Glycolysis produces tissues. The resultant steep O2 gradient toward
most of the residual ATP (<5 %). the capillaries favors oxygen release from hemo-
Most ATP (60–70 %) is spent in CMs to gen- globin and results in a high oxygen extraction
erate mechanical work driving the circulation. (60–70 %) from the perfused blood already under
Another large part (30–40 %) is required to run basal conditions. Thus, the elevated oxygen
ion pumps (mostly sarco-/endoplasmic reticulum demand under conditions of high workload can
238 A. Gödecke
be covered only to a small part by an increase in rapidly mobilized by breakdown of glycogen [5].
oxygen extraction (+20 %). Instead, an increase Independent of its origin, most glucose enters the
in coronary flow (up to fivefold) largely ensures glycolytic pathway, leading to the formation of
cardiac oxygen supply to sustain the oxidative pyruvate.
generation of ATP. Lactate also contributes to cardiac ATP gen-
eration. It is taken up by the monocarboxylate
transporter and converted to pyruvate by the lac-
Cardiac Substrate Metabolism tate dehydrogenase reaction yielding NADH + H+.
The latter enters the respiratory chain, whereas
Cardiac substrate metabolism occurs in two pyruvate is oxidized to acetyl-CoA. Even under
major variants: The fetal heart depends to a large conditions of elevated workload, the heart rather
extent on glucose, whereas the adult heart prefers consumes than generates lactate. Thus, during
to consume fatty acids rather than glucose. exercise, the heart may use lactate produced by
However, the heart is also able to metabolize lac- anaerobic glycolysis in skeletal muscle.
tate and ketone bodies. Therefore, the adult heart
has often been named a “metabolic omnivore.”
All substrates may finally drain into the citric Inside-In: Metabolites of the Heart
acid cycle that is fueled by acetyl-CoA derived Affecting Itself
from glycolysis (glucose), β-oxidation (fatty
acids), lactate oxidation, and ketone bodies. A hallmark of cardiac metabolism is the ability to
Interestingly, in heart failure (see chapter “Heart switch between carbohydrates and fatty acids as
failure”), the adult heart may reduce fatty acid preferred carbon sources (metabolic flexibility).
oxidation in favor of glucose (termed metabolic Under conditions when oxygen is short, the heart
remodeling) [4]. uses more “oxygen-rich” glucose, which results
Fatty acids account for 50–70 % of total in a higher P/O ratio (ATP per oxygen) than the
cardiac energy supply in adults. Fatty acid uptake use of the “oxygen-poor” fatty acids.
into CMs is mediated to a large extent by fatty An important pathway is the Randle cycle
acid translocase (FAT/CD36). This protein is in [6, 7], also termed the glucose–fatty acid cycle,
part localized in storage vesicles in CMs, which which is substantially involved in regulating the
may fuse with the sarcolemma to enhance uptake relative contribution of fatty acid vs. carbohy-
of fatty acids (Fig. 2). Important stimuli of mem- drate utilization by the heart. Pyruvate, acetyl-
brane translocation are an increase in cardiac CoA, malonyl-CoA, and citrate are important
workload (contraction-mediated translocation) metabolic intermediates, which modulate sub-
and insulin. Fatty acids are further oxidized in the strate utilization (Fig. 2).
mitochondria during β-oxidation yielding high Fatty acid oxidation increases the mitochondrial
amounts of NADH + H+, FADH2, and CO2. acetyl-CoA/CoA and NADH/NAD+ ratios. These
Transport of acyl-CoA into the mitochondrion changes inhibit pyruvate dehydrogenase (PDH),
involves the carnitine shuttle system (Fig. 2). which determines the oxidation of the glycolytic
Glucose uptake by CMs may be stimulated pyruvate to acetyl-CoA. The activity of PDH is
under anabolic conditions by insulin via Akt controlled by PDH kinases and PDH phosphatases
(also called protein kinase B) and under catabolic (Fig. 2). In addition, citrate, leaving mitochondria
conditions by the AMP-dependent protein kinase. via citrate carriers, inhibits phosphofructokinases 1
Both stimulate translocation of the glucose trans- and 2 and therefore reduces glycolysis. However,
porter 4 (GLUT4) to the sarcolemma, enhancing cytoplasmic citrate can also be converted to acetyl-
glucose uptake (Fig. 2). In part, glucose is used to CoA (and oxaloacetate), which is further converted
synthesize glycogen, which serves as an energy to malonyl-CoA. Malonyl-CoA inhibits the carni-
store. Upon energy depletion and activation of tine shuttle system and thereby long-chain fatty
AMP-dependent protein kinase, glucose is acid uptake by mitochondria.
Overview 239
Translocation Translocation
[AKT] ATP/ADP
[AMPK] AMP
Gluc−6−P
Acyl−CoA
Malonyl−CoA
Lactate Fruc-1,6−bis−P
CoA
[ACC]
Carnitin
Citrate shuttle system
Pyruvate CPT I & II
Ca2+ PPP
[PD H] Citrate
Acyl-CoA
[PDP] [PDK 1,2,4] TCA
Fig. 2 Regulation of glucose and fatty acid metabolism in mean elevated cytoplasmic Ca2+ under β-adrenergic stim-
the heart. The basic principle of the glucose fatty acid ulation to elevated glucose oxidation. Lactate is also con-
cycle and its modulation by insulin and low energy is verted to pyruvate. Fatty acids are converted to acyl-CoA
shown. A low ATP/ADP ratio leads to formation of AMP, and transported to the mitochondrion via the carnitine
which activates AMP-dependent protein kinase (AMPK). shuttle system consisting of carnitine palmitoyltransferase
Insulin activates protein kinase B (AKT) via the insulin (CPT) I and II, in the outer and inner mitochondrial mem-
receptor. AKT and AMPK induce translocation of the glu- brane, respectively. Within the mitochondrion, acyl-CoAs
cose transporter 4 (GLUT4) and the long-chain fatty acid are degraded to acetyl-CoA during β-oxidation. Acetyl-
translocase (CD36) to the plasma membrane. Glucose is CoA is metabolized in the tricarboxylic acid cycle (TCA,
metabolized in glycolysis (left) to pyruvate, which is sub- also called citric acid cycle). Citrate from the TCA can be
sequently oxidized to acetyl-CoA by pyruvate dehydroge- exported to the cytosol, where it inhibits early steps of
nase (PDH) in the mitochondrion. PDH underlies product glycolysis and can be converted to malonyl-CoA. The lat-
inhibition by acetyl-CoA and NADH + H+ from the ter inhibits the carnitine shuttle system and thus fatty acid
β-oxidation. Additionally, they stimulate specific PDH oxidation. AMPK was shown to inhibit this conversion by
kinases (PDKs), which inhibit PDH by phosphorylation. blocking Acetyl-CoA carboxylase (ACC). Fruc-1,6-bis-P
PDH phosphatase (PDP) dephosphorylates and thus acti- fructose-1,6-bisphosphate, PFK1/2 phosphofructokinase
vates PDH. PDP is activated by pyruvate and Ca2+, linking 1/2
In the heart, the transport capacity of GLUT4 location (see above) elevates glycolytic flux and
transporters is almost saturated at physiological increases pyruvate, releasing the blockade of
plasma glucose levels limiting glucose inflow and PDH by PDH phosphatases (Fig. 2). In conse-
thus glycolytic flux. Stimulation of GLUT4 trans- quence, glucose metabolism is elevated despite
240 A. Gödecke
the presence of fatty acids. However, the precise Under hypoxic or ischemic conditions, ATP
interplay of metabolic factors directing cardiac breakdown may lead to the formation of adenos-
metabolism toward one or the other direction is ine. Adenosine released from the myocardium or
still not fully understood [8]. formed extracellularly from ATP is able to elevate
The extent of metabolic remodeling is cardiac perfusion by the activation of smooth
substantially modulated by comorbidities such as muscle cell A2A receptors and subsequent
diabetes, hypertension, hypercholesterolemia, enhancement of cAMP. cAMP in turn stimulates
etc. Thus, identification of the master switches PKA, which phosphorylates and thereby inhibits
directing cardiac metabolism toward a protective the regulatory myosin light chain kinase and stim-
program is of high medical importance. ulates MLC phosphatase, leading to relaxation.
Further important metabolites released by the Moreover, activation of KATP channels via PKA-
heart are nitric oxide (NO) and adenosine. Both of mediated phosphorylation may lead to hyperpo-
them are only short-lived and exert local functions. larization of smooth muscle cells and therefore
These include modulation of coronary vascular vasodilation. The cardiac release of adenosine is
tone and cardiac contractility (see below). minimal as long as oxygen supply is sufficient to
Moreover, NO and adenosine are able to keep match the demands [10]. Therefore, in contrast to
platelets and leukocytes in a quiescent state, acting NO, which is important for the setting of the basal
as antithrombotic and anti-inflammatory factors. vascular tone, adenosine-mediated vasodilation is
In the heart, NO, which is derived from L- more important under hypoxic conditions.
arginine, is synthesized in the coronary endothe-
lium by the endothelial NO synthase (type III
NOS). In CMs, the endothelial as well as the neu- Inside-Out: Metabolites of the Heart
ronal NO synthase (type I NOS) are constitu- Affecting Other Tissues
tively expressed. Under inflammatory conditions,
also the inducible NO synthase (type II NOS) In the context of inside-out signaling, peptide fac-
may be upregulated. NO modulates cardiac con- tors released by the heart act on other organs. The
tractile function, and depending on the NO con- natriuretic peptides (NPs), atrial and brain NP,
centrations, both positive as well as negative which are expressed predominantly in the atria
inotropic actions have been described. The and the ventricles, respectively, are released from
underlying mechanism appears to involve modu- the heart in response to mechanical signals such
lation of Ca2+ homeostasis as well as the avail- as stretch and elevated mechanical load, e.g., dur-
ability of cAMP due to the modulation of ing volume overload or exercise. They activate
phosphodiesterases. NO-mediated vasodilation membrane-bound guanylyl cyclase receptors,
involves a direct activation of the soluble guany- which elevate cGMP levels in target cells and
lyl cyclase, elevation of cGMP, and activation of regulate fluid homeostasis and reduce blood pres-
the cGMP-dependent protein kinase (PKG). PKG sure via increased Na+ excretion (see chapter
in turn activates the myosin light chain phospha- “Overview” under part “Kidney”). However,
tase by phosphorylation, which leads to a dephos- recent results indicate that natriuretic peptides
phorylation of the regulatory myosin light chain also have an important metabolic function. NP
in smooth muscle cells and the concomitant receptors are present on adipocytes and their acti-
reduction of vascular tone. vation stimulates lipolysis. Interestingly, the
Besides NO derived from NOS, recent studies potency of NP to enhance lipolysis is similar to
suggest that under hypoxic conditions, deoxy- that of β-adrenergic stimulation, which represents
genated hemoglobin and myoglobin reduce cir- the classical way. Whereas the latter is mediated
culating nitrite to NO. This interesting concept by the cAMP–PKA pathway, NPs exert their
provides a link between cardiac ischemia and the effects via cGMP and PKG. The physiological
vasodilatory and cardioprotective functions of role of this pathway can be seen in an elevated
NO [9]. supply of heart and skeletal muscle with fatty
Overview 241
acids during exercise, when mechanic forces Also, enhanced glucose levels can have detri-
stimulate the release of NP from the heart [11]. mental effects on cardiac function. For example,
It is well known that heart failure (see chapter hyperglycemia enhances diacylglycerol forma-
“Heart failure”) may be associated with the loss of tion and activation of PKC. Interestingly, in the
skeletal muscle. This interconnection of cardiac presence of high fatty acid levels, glucose oxida-
dysfunction and skeletal muscle wasting has been tion is blocked. Glucose is redirected to other
termed cardiac cachexia. Chronic heart failure leads pathways including the pentose phosphate path-
to upregulation of myostatin expression in cardiac way, which leads to synthesis of NADPH required
tissue. Myostatin, a cytokine of the transforming for the formation of glutathione, an important
growth factor (TGF)-β family, inhibits muscle antioxidant.
development and might be involved in cardiac
cachexia. Exercise reduces myostatin expression,
whereas physical inactivity may enhance it. The Final Remarks
mechanisms by which myostatin leads to atrophy of
skeletal muscle involves a reduced avtivation of The healthy heart is a metabolic omnivore, which
protein kinase B (AKT), which might diminish pro- is able to utilize carbon sources including glu-
tein synthesis via low mTOR activity or enhance cose, lactate, ketone bodies, and fatty acids for
protein degradation via induction of atrogin-1. oxidative generation of ATP. The hypertrophic
and failing heart, respectively, switch their
metabolism from the usually preferred fatty acids
Outside-In: Metabolites of Other to higher glucose consumption. Although still
Tissues Affecting the Heart not unambiguously clarified, many experimental
studies indicate that this metabolic remodeling is
Elevated levels of circulating free fatty acids (FFA) an important mechanism contributing to adapta-
may affect cardiac structure and function in several tion during the compensated state in heart failure
ways [4]. In rodent models, the elevated uptake of progression and encourage to develop metabolic
fatty acids, frequently associated with insulin resis- therapies to treat heart failure [13].
tance, leads to the development of cardiac lipotox-
icity characterized by contractile dysfunction, CMs
apoptosis, and fibrosis. An enhanced FFA uptake References
may increase the cardiac stores of triacylglycerol or
triglyceride (TG). Enhanced deposition of TG in 1. Camelliti P, Borg TK, Kohl P (2005) Structural and
the myocardium results in cardiac steatosis, i.e., the functional characterisation of cardiac fibroblasts.
Cardiovasc Res 65:40–51
ectopic deposition of surplus fatty acids in the form
2. Rakusan K, Flanagan MF, Geva T, Southern J, Van PR
of TG in CMs. The enhanced availability and (1992) Morphometry of human coronary capillaries dur-
metabolism of TG also elevate ceramide levels in ing normal growth and the effect of age in left ventricular
the heart. Ceramides have been shown to induce pressure-overload hypertrophy. Circulation 86:38–46
3. Stanley WC, Recchia FA, Lopaschuk GD (2005)
apoptosis of CMs by enhancing mitochondrial per-
Myocardial substrate metabolism in the normal and
meability. Moreover, ceramides inhibit Akt, which failing heart. Physiol Rev 85:1093–1129
are involved in cellular metabolism, growth, and 4. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS,
survival. On the other hand, elevated TGs also Stanley WC (2010) Myocardial fatty acid metabolism
in health and disease. Physiol Rev 90:207–258
enhance diacylglycerol known to activate conven-
5. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW,
tional and novel PKC isoforms [12], which may be Allard MF (2003) 5-Aminoimidazole-4-carboxamide
protective or pathologic. Among the latter, PKCβ1 1-beta -D-ribofuranoside (AICAR) stimulates myocar-
was shown to phosphorylate the β subunit of the dial glycogenolysis by allosteric mechanisms. Am J
Physiol Regul Integr Comp Physiol 284:R936–R944
insulin receptor as well as insulin receptor substrate
6. Hue L, Taegtmeyer H (2009) The Randle cycle revis-
1 (IRS1) on multiple serine/threonine residues thus ited: a new head for an old hat. Am J Physiol
contributing to insulin resistance. Endocrinol Metab 297:E578–E591
242 A. Gödecke
7. Randle PJ, Garland PB, Hales CN, Newsholme EA 10. Deussen A, Brand M, Pexa A, Weichsel J (2006)
(1963) The glucose fatty-acid cycle. Its role in insulin Metabolic coronary flow regulation–current concepts.
sensitivity and the metabolic disturbances of diabetes Basic Res Cardiol 101:453–464
mellitus. Lancet 1:785–789 11. Moro C, Polak J, Hejnova J, Klimcakova E, Crampes
8. Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, F, Stich V, Lafontan M, Berlan M (2006) Atrial natri-
Kulkarni A, Distefano A, Hwang YJ, Reznick RM, uretic peptide stimulates lipid mobilization during
Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI repeated bouts of endurance exercise. Am J Physiol
(2007) Continuous fat oxidation in acetyl-CoA carbox- Endocrinol Metab 290:E864–E869
ylase 2 knockout mice increases total energy expendi- 12. Geraldes P, King GL (2010) Activation of protein
ture, reduces fat mass, and improves insulin sensitivity. kinase C isoforms and its impact on diabetic compli-
Proc Natl Acad Sci U S A 104:16480–16485 cations. Circ Res 106:1319–1331
9. Lundberg JO, Weitzberg E, Gladwin MT (2008) The 13. Ashrafian H, Frenneaux MP, Opie LH (2007)
nitrate-nitrite-nitric oxide pathway in physiology and Metabolic mechanisms in heart failure. Circulation
therapeutics. Nat Rev Drug Discov 7:156–167 116:434–448
Atherosclerotic Heart Disease
and lymphocytes) activation [1]. Elevated concen- levels are strictly controlled and their increase,
trations of circulating LDL cholesterol facilitate subsequent to metabolic dysfunction, leads to
subendothelial ApoB lipoprotein retention espe- impaired CM contractility (Fig. 1) [4].
cially in arterial sites showing turbulent flow. Once Under physiological conditions, free fatty
in the arterial intima, LDL particles undergo oxi- acids (FFA) are the main source of energy, which
dation (e.g., by reactive oxygen species). Debris is more efficient than carbohydrate oxidation,
and cholesterol crystals accumulate in the vessel albeit at the expense of greater oxygen consump-
wall, associated with accumulation of different tion (see chapter “Overview” under part “Heart”).
leukocytes. Lipid peroxidation in the plaque A rapid increase in workload induces a shift from
enhances the expression of adhesion molecules FFA to glucose oxidation (metabolic switch).
that can in turn contribute to intimal leukocyte During myocardial ischemia, diminished perfu-
recruitment. Subsequent structural modifications sion leads to inadequate oxygen delivery that
progressively weaken the arterial wall. compromises oxidative phosphorylation and
Within the atheromatous plaque, several pro- therefore ATP generation. The diminished ATP
and anti-inflammatory cytokines and chemokines levels induce the loss of contractile force and
contribute to lesion growth, e.g., migration inhib- reduce the activity of ATP-dependent ion trans-
itory factor and type 1 interferons, are typically porters (Fig. 1). Even under hypoxic conditions,
overexpressed and exert proinflammatory and the myocardium continues to derive a large pro-
proatherogenic functions. Increased amounts of portion of its energy from FFA oxidation.
chemotactic chemokines recruit leukocytes and However, in order to supply more ATP, glycoly-
mediate transendothelial diapedesis. sis increases, prevailing over FFA oxidation. This
Within these initial lesions, known as “fatty leads to further metabolic changes, including
streaks,” recruited monocytes differentiate into intracellular acidosis, modified signaling,
macrophages, which ingest LDL. These lipid-laden increased saturated FFA oxidation, and possibly
monocytes turn into foam cells. Subsequently, a apoptosis [5].
necrotic core forms, surrounded by a fibrous cap After a severe ischemic event, CMs can
composed of collagen and smooth muscle cells. remain viable in the form of “stunned myocar-
Neutrophils and dendritic cells (DCs) are also dium” which describes a prolonged but reversible
involved in the progression of the atheroma. DCs LV dysfunction that initially persists despite the
take up lipids and further accumulate in clusters restoration of blood flow to the affected area.
with T cells in the so-called high-risk rupture plaque “Myocardial hibernation,” another form of myo-
region. In this region, T cells account for almost cardial oxygen deprivation and reduced ventricu-
20 % of the cells in the plaque. Their proinflamma- lar function, develops in response to a chronic
tory status further enhances leukocyte recruitment and substantial reduction of coronary blood sup-
and activation. Local inflammatory processes lead ply; in both hibernating and stunned myocar-
to the degradation of the collagen in the fibrous cap dium, cells are still alive but do not have enough
and the extracellular matrix weakening the fibrous energy to contract.
cap and compromise plaque stability. A thin fibrous In the short term, a reduced contractile
cap and continuous accumulation of lipids can cre- response to Ca2+ is present during hibernation.
ate a “high-risk” or “vulnerable” plaque. Through During prolonged hibernation, fetal genes are
the release of metalloproteinases, macrophages reactivated resulting in a switch from fat to glu-
have a pivotal role in plaque rupture [1, 3]. cose metabolism [6, 7]. On restoring artery
patency, FFA oxidation becomes active again,
prevailing over glucose oxidation.
Myocardial Ischemia and Heart Revascularization may improve or restore the
Metabolism functional capacity in the hibernated area.
Although the restoration of blood flow to isch-
Heart metabolism critically relies on the produc- emic myocardium is beneficial, on occasions, it
tion of sufficient ATP to allow muscle contrac- can lead to further cell damage, i.e., “myocardial
tion and Ca2+ cycling. The intracellular Ca2+ reperfusion injury” [8]. This is characterized by
Atherosclerotic Heart Disease 245
Normal Ischemia
Acyl-CoA ATP
Glycolysis
≥7x 2x
β-oxidation Acetyl-CoA Pyruvate
TCA
O2 ADP
NADH+H +
FADH2
H 2O ATP
Ca 2+ ATP ATP
Ca 2+ Ca 2+
ATPase ADP ADP ATPase
Ca 2+ Ca 2+
Na+/Ca 2+ Na+/Ca 2+
SR exchanger SR exchanger
3 Na+ 3 Na+ 3 Na+
Na +
2 K+ Ca 2+
1 Ca 2+ Ca 2+ 1 Ca 2+
Na+/K+ Ca 2+ ATPase Na+/K+ Ca 2+ ATPase
ATPase ATPase
Ca 2+
Na+ Na+
Na+/H+ Na+/H+
H+ exchanger H + exchanger
Fig. 1 Metabolic changes during myocardial ischemia. TCA, tricarboxylic acid cycle (also called citric acid
Upper part: Whereas fatty acid (FA) oxidation via cycle). Lower part: During ischemia, ATPase function is
β-oxidation is the preferred source of energy under nor- impaired as the ATP/ADP ratio is decreased. This leads to
mal oxygen supply, under hypoxic conditions (ischemia), an intracellular Ca2+ and Na+ overload, as Na+/H+
energy metabolism switches to glucose oxidation, which exchanger and Na+/Ca2+ exchanger remain active, whereas
requires less oxygen but also yields less ATP. Ischemia Na+/K+-ATPase and Ca2+-ATPase are dysfunctional. The
acts by reducing β-oxidation, increasing glycolysis, and resulting increase in Ca2+ further impairs myocardial
limiting the supply of O2 for oxidative phosphorylation. function. SR sarcoplasmic reticulum
Ca2+ overload and the release of cytotoxic reac- “Hypertension”), and diabetes mellitus (see
tive oxygen species induced by the sudden resto- chapter “Diabetes mellitus”), reduces ischemic
ration of blood flow [8]. events and long-term cardiovascular risk. A
healthy lifestyle, reduced oxidative stress, inflam-
mation, and improved cardiac metabolism repre-
Antianginal Treatment and sent useful measures to reduce cardiovascular
Influence of Treatment on Cardiac risk.
Metabolism Pharmacological agents available at present
act by reducing oxygen demand, increasing
First, appropriate management of modifiable risk coronary blood flow, or affecting myocardial
factors, i.e., obesity (see chapter “Metabolic syn- metabolism directly. Although medical treatment
drome”), smoking, dyslipidemia (see chapter in CSA patients often provides effective
“Hyperlipidemia”), hypertension (see chapter control of symptoms [9], some patients require
246 M. Slavich and J.C. Kaski
percutaneous coronary intervention (PCI), in required to protect and rescue damaged myocar-
which a balloon is inflated within the occluded dium. Nitrates improve oxygen supply (by vaso-
artery to improve coronary blood flow and pre- dilating activity) and reduce myocardial metabolic
vent recurrent ischemia [2]. Especially in acute demand (by reducing ventricular pre- and after-
ischemia, rapid restoration of coronary blood load). Diuretics and angiotensin converting
flow to the affected area with PCI results in enzyme inhibitors (see chapter “Hypertension”)
reduced mortality. are commonly used in order to reduce the ven-
Obstructive stenoses that reduce blood flow tricular loading, especially in patients with
and cause symptoms can be effectively treated advanced CAD and systolic dysfunction.
with bypass surgery or PCI and stenting. CAs act as vasodilators by preventing effec-
Deploying a stent restores coronary blood flow tive constriction of smooth muscle cells and
and results in symptom improvement. reducing the heart rate (negative chronotropic
effect). Non-dihydropyridine CAs have negative
inotropic effects, reducing heart contractility, as
Pharmacological Treatment higher level of Ca2+ in CMs is required for effec-
of Angina Pectoris tive contraction.
β-Blockers act on multiple levels to improve
Current pharmacological CAD treatment aims to disease progression and outcome, by blocking
(i) abolish or reduce symptoms and improve β-adrenergic receptors. They show negative ino-
quality of life, (ii) prevent ischemic episodes, (iii) tropic and chronotropic effects, acting on the
reduce CAD progression and the risk of acute heart directly providing a reduction of oxygen
coronary events, and (iv) improve survival. demand and preventing transient myocardial
Pharmacological antianginals act by reducing ischemia. Some classes (carvedilol) additionally
myocardial oxygen demand and/or improving have a direct metabolic effect, inducing a meta-
blood supply via peripheral and coronary vasodi- bolic shift to glucose utilization, reducing FFA
lation and reduction of blood pressure and heart uptake [11]. Finally, they enhance the bioavail-
rate. While for many years the treatment of CAD ability of NO, inducing vasodilation [12].
has been based on agents acting on hemodynamic Ivabradine is a novel drug, which only lowers
mechanisms, pharmacological agents are now the heart rate (negative chronotropic), without
available that beneficially affect the metabolic interfering with the inotropism, because of its
response of the ischemic heart and represent a selective inhibition of the funny current (a mixed
useful alternative or adjunct to conventional anti- sodium-potassium current) in the cardiac pace-
anginal agents [5]. Finally, agents that improve maker myocytes [13]. On the other side, drugs as
endothelial function are also useful. dopamine and epinephrine are able to increase
Identifying the prevailing mechanism respon- the inotropism and the chronotropism and are
sible for the development of myocardial ischemia effective especially in advanced CAD and in
is useful to design rational therapeutic strategies patients with severely impaired LV function.
to reduce symptoms and prevent ischemic epi- Trimetazidine and ranolazine directly modu-
sodes. In patients with angina triggered by coro- late CM metabolism and thus reduce heart energy
nary artery spasm leading to a primary reduction demand and loading conditions of the LV. This
of O2 supply, vasodilators are the first-line ther- modifies neurohormonal activation and delays
apy. In patients with obstructive CAD, drugs that the occurrence of cardiac remodeling (see chap-
reduce heart rate and blood pressure, such as ter “Heart failure” and Fig. 2). They have no
β-blockers and calcium channel blockers (CA), direct effects on blood pressure or heart rate and
are desirable. Negative chronotropic agents are are used as adjunctive therapy.
especially useful, as heart rate is a major determi- Trimetazidine inhibits the action of 3-ketoacyl
nant of energy expenditure and prognosis [10]. In coenzyme A thiolase, an enzyme implicated in the
developed CSA, different therapeutic options are β-oxidation [14]. The resulting switch from FFA to
Atherosclerotic Heart Disease 247
Nitrates
SMC spasm
Plaque CA and
b-blockers
Statins Cardiac
myocyte Ivabradine
Dopamine
Na+/Ca2+ Epinephrine
3 Na+ exchanger
1 Ca2+
Heart rate
Glucose
Ranolazine
ATP Contractility
β-Oxidation Loading
Fig. 2 Effects of treatment on cardiac metabolism. Statins contractility in late-stage and severe coronary artery disease
interfere with atheromatous plaque formation in blood ves- (positive chronotropy). Cardiac contractility can be increased
sels by reducing the available cholesterol. Nitrates stimulate by dopamine and epinephrine and depressed by CA and
vasodilation via a nitric oxide (NO)-dependent effect on β-blockers (positive and negative inotropy, respectively).
smooth muscle cells, increasing the blood supply to the car- Enhanced cardiac activity (heart rate, inotropism) requires a
diac myocytes (CMs). Ca2+ channel antagonists (CA) are lot of ATP and thus oxygen. Diuretics and angiotensin con-
effective in the regulation of spasm control, acting on vascu- verting enzyme inhibitor (ACE-I) reduce ventricular loading.
lar smooth muscle cells. Heart rate can be decreased (by Ranolazine and trimetazidine directly act on the metabolic
CAs, β-blockers, and ivabradine) to prevent excessive strain pathway of the CMs, by favoring glucose oxidation and
(negative chronotropy) and can be increased (by dopamine inhibiting β-oxidation. Ranolazine also reduces Ca2+ over-
and epinephrine) to prevent life-threatening reductions in load at the level of the Na+/Ca2+ exchanger
glucose oxidation optimizes cellular energy pro- oxidation. Moreover, it prevents calcium over-
cesses and enhances ATP production during isch- load during myocardial ischemia by inhibiting
emia, as glycolysis requires less oxygen [15]. In the Na+/Ca2+ exchanger. In CAD patients, the
this way, trimetazidine ensures the proper function- addition of ranolazine to standard therapy
ality of ion pumps, prevents CM apoptosis, and decreases angina recurrences and increases exer-
limits myocardial reperfusion injury [16], improv- cise tolerance [18].
ing the LV function and long-term survival [17]. In order to interfere with the plaque forma-
Ranolazine is a partial FFA oxidation inhibitor tion and progression, achieving normal choles-
and shifts ATP production from FFA to glucose terol levels is recommended. Statins inhibit
248 M. Slavich and J.C. Kaski
hydroxymethylglutaryl-CoA reductase, a key Fihn SD, Fraker TD Jr, Gardin JM, O’Rourke RA,
Pasternak RC, Williams SV (2003) ACC/AHA 2002
enzyme in cholesterol synthesis (see chapter
guideline update for the management of patients with
“Hyperlipidemia”), lowering the circulating cho- chronic stable angina. J Am Coll Cardiol 41:159–168
lesterol level thus acting on or preventing athero- 3. Dumitriu IE, Araguás ET, Baboonian C, Kaski JC
sclerotic lesions [19]. Since atherosclerotic (2009) CD4+ CD28 null T cells in coronary artery
disease: when helpers become killers. Cardiovasc Res
plaque disruption exposes the procoagulant
81:11–19
endothelial layer, antiplatelet agents are also 4. Neubauer S (2007) The failing heart–an engine out of
adopted in order to prevent thrombus formation. fuel. N Engl J Med 356:1140–1151
5. Lee L, Horowitz J, Frenneaux M (2004) Metabolic
manipulation in ischaemic heart disease, a novel
approach to treatment. Eur Heart J 25:634–641
Perspectives 6. Ferrari R, Ceconi C, Curello S, Benigno M, La Canna
G, Visioli O (1996) Left ventricular dysfunction due
Treatment of CAD aims to improve the patient’s to the new ischemic outcomes: stunning and hiberna-
tion. J Cardiovasc Pharmacol 28:S18–S26
life quality and to reduce serious cardiovascular
7. Cooper HA, Braunwald E (2001) Clinical importance
events that may lead to death or further morbid- of stunned and hibernating myocardium. Coron
ity. Despite the significant reduction in CAD Artery Dis 12:387–392
mortality and morbidity in recent years, several 8. Yellon DM, Hausenloy DJ (2007) Myocardial reper-
fusion injury. N Engl J Med 357:1121–1135
issues still need to be addressed, i.e., mechanisms
9. Weintraub WS, Spertus JA, Kolm P, COURAGE Trial
of atherosclerotic plaque progression, the early Research Group et al (2008) Effect of PCI on quality
identification of atheromatous plaques prone to of life in patients with stable coronary disease. N Engl
rupture, and the rational management of the dif- J Med 359:677–687
10. Fragasso G, De Cobelli F, Spoladore R, Esposito A,
ferent forms of ischemic heart disease.
Salerno A, Calori G, Montanaro C, Maranta F,
Early reperfusion strategies in myocardial Lattuada G, Margonato A, Del Maschio A, Perseghin
infarction have also resulted in a significant G (2011) Resting cardiac energy metabolism is
reduction of infarct size and mortality, but many inversely associated with heart rate in healthy young
adult men. Am Heart J 162:136–141
issues still remain unsolved, including how to
11. Wallhaus TR, Taylor M, DeGrado TR, Russell DC,
minimize reperfusion injury after acute coronary Stanko P, Nickles RJ, Stone CK (2001) Myocardial
revascularization. free fatty acid and glucose use after Carvedilol treat-
CSA affects a large proportion of individuals ment in patients with congestive heart failure.
Circulation 103:2441–2446
worldwide and its pharmacological treatment,
12. Vanhoutte PM, Gao Y (2013) Beta blockers, nitric
albeit effective in a large proportion of cases, is oxide, and cardiovascular disease. Curr Opin
far from ideal. The advent of newer antianginal Pharmacol. doi:10.1016/j.coph.2012.12.002
drugs that directly affect metabolic pathways in 13. Fox K, Ford I, Steg PG, Steg PG, Tendera M, Ferrari
R (2008) Ivabradine for patients with stable coronary
the myocardium has opened new avenues for
artery disease and left-ventricular systolic dysfunc-
CAD management. Notably, technical advances tion (BEAUTIFUL): a randomised, double-blind,
in the field of coronary revascularization with placebo-controlled trial. Lancet 372:807–816
new generations of biodegradable stents [20] are 14. Bertomeu-Gonzalez V, Bouzas-Mosquera A, Kaski
JC (2006) Role of trimetazidine in management of
expected to result in improved patient manage-
ischemic cardiomyopathy. Am J Cardiol 98:19J–24J
ment and less in-stent restenosis. 15. Fragasso G, Rosano G, Baek SH, Sisakian H, Di
Napoli P, Alberti L, Calori G, Kang SM, Sahakyan L,
Sanosyan A, Vitale C, Marazzi G, Margonato A,
Belardinelli R (2013) Effect of partial fatty acid
References oxidation inhibition with trimetazidine on mortality
and morbidity in heart failure: results from an interna-
1. Hansson GK (2005) Inflammation, atherosclerosis, tional multicentre retrospective cohort study. Int J
and coronary artery disease. N Engl J Med 352: Cardiol 163:320–325
1685–1695 16. Fragasso G, Palloshi A, Puccetti P, Silipigni C,
2. Gibbons RJ, Gibbons RJ, Abrams J, Chatterjee K, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato
Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, A (2006) A randomized clinical trial of trimetazidine,
Atherosclerotic Heart Disease 249
a partial free fatty acid oxidation inhibitor, in patients 19. Nissen SE, Tuzcu EM, Schoenhagen P (2005) Statin
with heart failure. J Am Coll Cardiol 48:992–998 therapy, LDL cholesterol, C-reactive protein, and
17. Fragasso G, Perseghin G, De Cobelli F, Esposito A, coronary artery disease. N Engl J Med 352:29–38
Palloshi A, Lattuada G, Scifo P, Calori G, Del 20. Haude M, Erbel R, Erne P, Erne P, Verheye S, Degen
Maschio A, Margonato A (2006) Effects of metabolic H, Böse D, Vermeersch P, Wijnbergen I, Weissman N,
modulation by trimetazidine on left ventricular func- Prati F, Waksman R, Koolen J (2013) Safety and per-
tion and phosphocreatine/adenosine triphosphate ratio formance of the drug-eluting absorbable metal scaffold
in patients with heart failure. Eur Heart J 27:942–948 (DREAMS) in patients with de-novo coronary lesions:
18. Nash DT, Nash SD (2008) Ranolazine for chronic 12 month results of the prospective, multicentre, first-
stable angina. Lancet 372:1335–1341 in-man BIOSOLVE-I trial. Lancet 381:836–844
Heart Failure
Cardiac injury
e.g. myocardial infarction
Contractility Digitalis
Diuretics
Fig. 1 Pathophysiology of heart failure and common vasoconstriction, however, puts even more load on the
treatments. Development and progression of heart failure challenged heart and promotes pathological remodeling.
by an injury such as myocardial infarction is mediated by SNS sympathetic nervous system, RAAS renin-angioten-
neurohumoral systems. A vicious circle of reduced car- sin-aldosterone system, ACE angiotensin-converting
diac output leads to the activation of neurohumoral sys- enzyme, AR angiotensin II receptor
tems. The subsequent increase in blood volume and
RAAS SNS
Natriuretic Angiotensin I Angiotensin II Catecholamines
peptides
ACE-inhibitor ß-blocker
Sarco- AR-blocker
lemma NPRA&B AR ß1-receptor
SERCA2a
Ryanodine receptor 2 K+ 3 Na+
Ca 2+ Na+
Na+/Ca 2+-
exchanger
Cardiac myocyte Contraction cycle with actin-myosin-troponin complex
Fig. 2 Cardiac myocyte signaling pathways involved in β1-receptor and associated Gs and adenylate cyclase (AC)
heart failure and current therapeutic targets. Natriuretic proteins. CaMKII and PKA increase leakage of Ca2+ from
peptides exert anti-apoptotic and anti-hypertrophic effects the sarcoplasmatic reticulum via ryanodine receptor ham-
via receptor-bound guanylate cyclase (rGC) increasing pering regular systolic contractions. PKA also activates
cGMP. The renin-angiotensin-aldosterone system (RAAS) L-type Ca2+-channels. All three (PKA, PKC, CaMKII)
or more specifically angiotensin II activates protein kinase negatively influence sarcoplasmatic/endoplasmic reticu-
C (PKC) and calcium-calmodulin-dependent protein lum Ca2+-ATPase (SERCA2a) via activation of its inhibitor
kinase II (CaMKII) via Gq downstream signaling of the phospholamban, thus hindering reuptake of Ca2+. Digitalis
angiotensin II receptor (AR). PKC and CaMKII show pro- is used to effectively increase intracellular Ca2+ via inhibi-
apoptotic effects. Catecholamines from the sympathetic tion of Na+/K+-ATPase. NPR natriuretic peptide receptor,
nervous system (SNS) increase intracellular cAMP via PP pyrophosphate, ACE angiotensin-converting enzyme
Initially, atrial and brain natriuretic peptides such as interleukin-6, tumor necrosis factor α
(see chapter “Overview” under part “Heart”) (TNFα), or insulin-like growth factors (Fig. 2).
counteract the detrimental effects by inhibiting Particularly, G protein-coupled receptors are
SNS and renin-angiotensin-aldosterone system activated, signaling via Gq in case of the angio-
and mediating anti-hypertrophic and anti- tensin II receptor and Gs in the case of β1 adreno-
apoptotic effects on a cellular level (via cGMP, receptors. The β1 adrenoreceptors activate
Fig. 2) [4, 7]. However, responsiveness to natri- adenylate cyclase to increase cAMP, which acts
uretic peptides decreases during HF progression, on protein kinase A (PKA) and thereby activates
favoring systems mediating adverse hemody- L-type calcium channels (Fig. 2). The angioten-
namics and remodeling processes. sin II receptor acts on phospholipase C and, sub-
Typically, remodeling processes in CMs sequently, PKC and Ca-calmodulin-dependent
are activated primarily by signaling pathways kinase II (CaMKII). Whereas CaMKII and PKA
induced by catecholamines and angiotensin II favor hypertrophic growth, CaMKII and PKC
and secondarily by cytokines or growth factors negatively influence cell survival (Fig. 2) [8].
254 R. Pfister and E. Erdmann
results [23], and additional targets are under 7. Gardner DG (2003) Natriuretic peptides: mark-
ers or modulators of cardiac hypertrophy? Trends
investigation such as adenylate cyclase and phos-
Endocrinol Metab 14:411–416
pholamban [2]. 8. Whelan RS, Kaplinskiy V, Kitsis RN (2010) Cell
An approach that is discussed controversially death in the pathogenesis of heart disease: mecha-
is myocardial regeneration therapy by stem cell nisms and significance. Annu Rev Physiol 72:
19–44
transplantation with the aim to replace CMs lost
9. Marks AR (2013) Calcium cycling proteins and HF:
to ischemia [24]. mechanisms and therapeutics. J Clin Invest 123:
Overall, the prevalence of HF is projected to 46–52
further increase during the next 20 years [25]. 10. El-Armouche A, Eschenhagen T (2009) Beta-
adrenergic stimulation and myocardial function in the
This is the result of demographic developments
failing heart. Heart Fail Rev 14:225–241
(increase of older individuals in the population), 11. Aronson D, Krum H (2012) Novel therapies in acute
an increase in prevalence of risk factors such as and chronic HF. Pharmacol Ther 135:1–17
diabetes and obesity, and improvements in treat- 12. Parissis JT, Rafouli-Stergiou P, Paraskevaidis I,
Mebazaa A (2009) Levosimendan: from basic science
ment of myocardial infarction and initial HF such
to clinical practice. Heart Fail Rev 14:265–275
that more patients survive to the stage of advanced 13. Malik FI, Hartman JJ, Elias KA, Morgan BP,
HF. According to the changing risk profiles, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee
HFpEF will likely increase, and thus a treatment KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard
M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu
needs to be found [1].
PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii
M, Suehiro I, Sylvester S, Tochimoto T, Valdez C,
Wang W, Katori T, Kass DA, Shen YT, Vatner SF,
References Morgans DJ (2011) Cardiac myosin activation: a
potential therapeutic approach for systolic HF.
Science 331:1439–1443
1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio
14. Koitabashi N, Kass DA (2012) Reverse remodeling in
A, Böhm M, Dickstein K, Falk V, Filippatos G,
HF–mechanisms and therapeutic opportunities. Nat
Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L,
Rev Cardiol 9:147–157
Lip GY, Maggioni AP, Parkhomenko A, Pieske BM,
15. Lowes BD, Gilbert EM, Abraham WT, Minobe WA,
Popescu BA, Rønnevik PK, Rutten FH, Schwitter J,
Larrabee P, Ferguson D, Wolfel EE, Lindenfeld J,
Seferovic P, Stepinska J, Trindade PT, Voors AA,
Tsvetkova T, Robertson AD, Quaife RA, Bristow MR
Zannad F, Zeiher A (2012) ESC Guidelines for the
(2002) Myocardial gene expression in dilated cardio-
diagnosis and treatment of acute and chronic HF
myopathy treated with beta-blocking agents. N Engl J
2012: the Task Force for the Diagnosis and Treatment
Med 346:1357–1365
of Acute and Chronic HF 2012 of the European
16. Reiken S, Wehrens XH, Vest JA, Barbone A, Klotz S,
Society of Cardiology. Developed in collaboration
Mancini D, Burkhoff D, Marks AR (2003) Beta-
with the Heart Failure Association (HFA) of the ESC.
blockers restore calcium release channel function and
Eur Heart J 33:1787–1847
improve cardiac muscle performance in human HF.
2. Braunwald E (2013) Heart failure. J Am Coll Cardiol
Circulation 107:2459–2466
HF 1:1–20
17. Parati G, Esler M (2012) The human sympathetic ner-
3. Jhund PS, MacIntyre K, Simpson CR, Lewsey JD,
vous system: its relevance in hypertension and HF.
Stewart S, Redpath A, Chalmers JW, Capewell S,
Eur Heart J 33:1058–1066
McMurray JJ (2009) Long-term trends in first hospi-
18. Lonn E, Shaikholeslami R, Yi Q, Bosch J, Sullivan B,
talization for HF and subsequent survival between
Tanser P, Magi A, Yusuf S (2004) Effects of ramipril
1986 and 2003: a population study of 5.1 million
on left ventricular mass and function in cardiovascular
people. Circulation 119:515–523
patients with controlled blood pressure and with pre-
4. Mudd JO, Kass DA (2008) Tackling HF in the twenty-
served left ventricular ejection fraction: a substudy of
first century. Nature 451:919–928
the Heart Outcomes Prevention Evaluation (HOPE)
5. van Berlo JH, Maillet M, Molkentin JD (2013)
Trial. J Am Coll Cardiol 43:2200–2206
Signaling effectors underlying pathologic growth
19. Fraccarollo D, Galuppo P, Hildemann S, Christ
and remodeling of the heart. J Clin Invest 123:
M, Ertl G, Bauersachs J (2003) Additive improve-
37–45
ment of left ventricular remodeling and neurohor-
6. Gandhi MS, Kamalov G, Shahbaz AU, Bhattacharya
monal activation by aldosterone receptor blockade
SK, Ahokas RA, Sun Y, Gerling IC, Weber KT (2011)
with eplerenone and ACE inhibition in rats with
Cellular and molecular pathways to myocardial
myocardial infarction. J Am Coll Cardiol 42:
necrosis and replacement fibrosis. Heart Fail Rev
1666–1673
16:23–34
Heart Failure 257
20. Hayashi M, Tsutamoto T, Wada A, Tsutsui T, Ishii C, Hajjar RJ (2011) Calcium upregulation by percutane-
Ohno K, Fujii M, Taniguchi A, Hamatani T, Nozato ous administration of gene therapy in cardiac disease
Y, Kataoka K, Morigami N, Ohnishi M, Kinoshita (CUPID): a phase 2 trial of intracoronary gene ther-
M, Horie M (2003) Immediate administration of apy of sarcoplasmic reticulum Ca2 + -ATPase in
mineralocorticoid receptor antagonist spironolac- patients with advanced HF. Circulation 124:304–313
tone prevents post-infarct left ventricular remodeling 24. Jeevanantham V, Butler M, Saad A, Abdel-Latif A,
associated with suppression of a marker of myocar- Zuba-Surma EK, Dawn B (2012) Adult bone mar-
dial collagen synthesis in patients with first ante- row cell therapy improves survival and induces
rior acute myocardial infarction. Circulation 107: long-term improvement in cardiac parameters: a sys-
2559–2565 tematic review and meta-analysis. Circulation 126(5):
21. Kapoor JR, Heidenreich PA (2012) Role of heart rate 551–568
as a marker and mediator of poor outcome for patients 25. Heidenreich PA, Albert NM, Allen LA, Bluemke
with HF. Curr Heart Fail Rep 9:133–138 DA, Butler J, Fonarow GC, Ikonomidis JS, Khavjou
22. Topkara VK, Mann DL (2010) Clinical applications O, Konstam MA, Maddox TM, Nichol G, Pham M,
of miRNAs in cardiac remodeling and HF. Per Med Pina IL, Trogdon JG (2013) Forecasting the impact
7:531–548 of HF in the United States: a policy statement from
23. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly the American heart association. Circ Heart Fail
DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, 6:606–619
Part XI
Blood Vessels
Overview
Anatomy and Physiology of Blood the blood toward the right heart. From the right
Vessels heart, blood flows into the pulmonary artery to
enter the pulmonary circulation, where it is reoxy-
The blood vessels conduct blood from the heart genated. The blood then returns to the left heart.
to the tissues and back, thus achieving continu- All large blood vessels are composed of three
ous supply of oxygen and nutrients, removal of layers: the tunica intima, tunica media, and tunica
waste products, and – when needed – delivery adventitia. The intima of healthy arteries is mainly
of leukocytes to the organs. In one overall cir- a continuous layer of endothelial cells (ECs),
culation cycle, the heart is passed two times in which prevents intravascular clotting of the blood,
order to pump the blood through the other tissues regulates fluid and solute transport from the blood
and lungs (see chapter “Overview” under part to the tissues and back, and controls leukocyte
“Heart”). Starting in the left ventricle of the heart, recruitment and vascular tone [1]. The media con-
oxygenated blood flows into the systemic circu- sists of multiple layers of smooth muscle cells
lation through the aorta, and then into the large (SMCs) embedded in collagen, alternated by lay-
conduit arteries, which subsequently divide into ers of elastin. The adventitia is a loose fibrous
smaller conduit arteries, resistance arteries, and tissue that contains fibroblasts as well as small
the microcirculation. There, arterioles branch out vessels (vasa vasorum) that nourish the outer cells
into capillaries, the smallest blood vessels and site of large arteries and can harbor leukocytes, mast
of solute and gas exchange. Capillaries merge into cells, and mesenchymal stem cells. At its outside,
venules, and those merge into veins, conducting it continues diffusely into a layer of perivascular
adipose tissue (PVAT) that provides vasoregu-
latory adipokines to the arteries and arterioles
V.W.M. van Hinsbergh (*) • E.C. Eringa (Fig. 1). In atherosclerotic arteries, the intima is
Department for Physiology, thickened by accumulation of lipoproteins and
Institute for Cardiovascular Research, lipid-laden cells underneath the endothelium (see
VU University Medical Center,
chapter “Atherosclerotic heart disease”).
Van der Boechorststraat 7,
Amsterdam 1081 BT, The Netherlands The aorta and large arteries are characterized
e-mail: v.vanhinsbergh@vumc.nl; e.eringa@vumc.nl by a thick layer of SMCs in their media, which
R. Meijer maintains a rather constant blood pressure. The
Department of Internal Medicine, elasticity (windkessel function) of arteries helps
Institute for Cardiovascular Research, not only to dampen the blood pulse generated by
VU University Medical Center,
each heart beat but also – by recoil – to continue
De Boelelaan, 7057,
Amsterdam 1007 MB, The Netherlands propelling the blood toward the tissues during
e-mail: r.meijer@vumc.nl diastole.
Nerve endings
PVAT
Adipokines Neurotransmitters
Adventitia
Media
Hormones
Intima
Vasoactive agents
Shear forces
Leukocytes
Fig. 1 External mediators acting on blood vessels. The interplay between endothelium and smooth muscle cells;
arterial wall consists of three main layers: the intima, shear forces influence the endothelial behavior; and leu-
which in healthy vessels mainly consists of the endothe- kocytes, platelets, and their products also interact with
lium; the media that harbors concentric smooth muscle the vessel wall. From the outside, sympathetic nerve end-
cells, alternated by collagen and elastin layers; and the ings release neurotransmitters and the perivascular adi-
adventitia. Many exogenous factors act on the wall of pose tissue (PVAT) releases adipokines that contribute to
arteries. From the luminal side, hormones and vasoac- vasoregulation
tive agents bind to cellular receptors and regulate the
The small arteries and arterioles are the major contact with pericytes and form a continuous
site of resistance to blood flow. The collective endothelium. However, in specific tissues, such
diameter of all resistance vessels together is a as liver and adrenal glands, they have large pores
main determinant of blood pressure (see chapter (so-called fenestrae) to allow rapid penetration
“Hypertension”), together with cardiac output. In of cholesterol-containing lipoproteins required
addition to regulation of blood pressure, these for bile and steroid production, respectively. In
“resistance vessels” determine and regulate the contrast, in the brain, a tight endothelial bar-
perfusion of the connected capillary bed, depend- rier known as the blood-brain barrier is formed
ing on the local demand, e.g., preferential perfu- by interplay between endothelium, pericytes,
sion through the skeletal muscle during exercise and astrocyte foot ends [3]. However, upon a
or to the splanchnic bed after meals. Neuronal thrombotic stroke, the site distal to the occluded
factors, hormones, and tissue-derived paracrine vessel becomes hypoxic and leaky (see chapter
factors modulate the perfusion of a tissue in order “Stroke”).
to meet its metabolic demand. The walls of postcapillary venules, which col-
Delivery of oxygen and nutrients as well as lect the blood from the capillaries, consist of
removal of waste products occurs in the capil- endothelium only and are the first to respond to
lary bed [2], as the surface area of the capil- vasoactive agents and noxious stimuli by tempo-
lary endothelium available for diffusion is large rarily allowing protein leakage to the interstitium
and transport distance from blood to the tissue and facilitating the first recruitment of phago-
is low. In most tissues, the capillary ECs are in cytes after injury or infection.
Overview 263
Walls of veins are considerably thinner than and inhibition of myosin light chain kinase
those of arteries, especially their media. Limb (MLCK) also leads to reduced actin-myosin
veins contain valves, facilitating conduction of the interaction. In contrast, endothelin-1 is secreted
blood back toward the heart despite a low blood by activated endothelium to stimulate vascular
pressure. No valves are encountered in the small- contraction (Fig. 2b).
est veins, the great collecting veins, and the veins The effects of NO and prostacyclin extend
of viscera and the brain. Veins are easily distended beyond SMC contraction. These mediators also
and contain the larger portion of blood in the cir- reduce the activation and aggregation of blood
culatory system. In chronically overdistended platelets (Fig. 2). Furthermore, NO reduces
veins in the legs, so-called varicose veins (see inflammatory activation (see below) in the healthy
chapter “Varicose veins”), the valves are no lon- arterial endothelium itself by interference with
ger competent to sustain blood movement toward nuclear factor κB signaling that is required for the
the heart, and, subsequently, a higher pressure on transcription of inflammation-specific genes [6].
the distal valves arises, creating a vicious cycle, SMCs also respond to pressure and radial
eventually resulting in stasis and ankle edema. strain, directly. Prolonged changes in blood pres-
sure can induce remodeling of SMCs and adapta-
tion of the vessel diameter. Another physical
Inside-In: Paracrine Signals Acting factor that affects vascular functioning is vascular
Within the Vessel stiffening. Calcification due to deposition of cal-
cium phosphate in arteries causes media stiffen-
SMC contraction occurs after stimulation of Ca2+ ing in conduit arteries of elderly people, by which
influx and subsequent activation of the enzyme the vessel wall becomes less compliant. However,
myosin light chain (MLC) kinase [4]. The phos- arterial stiffening can also be caused by forma-
phorylated MLC initiates movement of myosin tion of advanced glycation end products (see
along F-actin fibers leading to cell contraction. chapter “Diabetes mellitus”) that cross-link pro-
MLC phosphatase activity undoes MLC phos- teins within the vessel wall. Stiffening results in a
phorylation and prevents contraction [4]. reduced dampening of the pulse wave and thus a
Many vasoactive agents, such as norepineph- higher pulse pressure. This can promote vascular
rine and substance P released from neurons (see damage in brain and microvasculature of diabetic
below) and bradykinin (formed from a blood patients (see chapter “Diabetes mellitus”).
plasma protein), enhance cytoplasmic Ca2+ levels
in SMCs leading to contraction, when applied to
SMCs in the absence of endothelium. However, Inside-Out: Vascular Factors
when a healthy endothelium is present, these Affecting Other Tissues
vasoactive agents often also activate the endothe-
lium prompting the generation of nitric oxide In addition to local vasoregulation, ECs in spe-
(NO) by endothelial NO synthase (eNOS), cific organs can also affect distant tissues by
prostacyclin or prostaglandin E2 via cyclooxy- the conversion and catabolism of vasoactive
genase, and occasionally endothelium-derived agents [7]. In particular, the lung vasculature
hyperpolarization factor (Fig. 2a). These factors, plays an important role through the production
of which NO is the most potent one, cause of angiotensin-converting enzyme (ACE), which
“endothelium-dependent” relaxation of SMCs. converts angiotensin I into angiotensin II, thus
NO activates guanylate cyclase in SMCs and (the influencing systemic blood pressure and volume
resulting) cGMP activates protein kinase G, via the renin-angiotensin-aldosterone-system
which, among others, limits the influx of Ca2+ (see chapter “Overview” under part “Kidney”).
ions into the cytoplasm and subsequent contrac- The lung vasculature also inactivates bradyki-
tion of SMCs [5]. Prostacyclin and prostaglandin nin, an important vasodilator, and takes up and
E2 cause elevation of cellular cAMP level, which degrades serotonin, a vasoconstrictor terminating
by protein kinase A-mediated phosphorylation their effects.
264 V.W.M. van Hinsbergh et al.
a b
Healthy Endothelium Damaged/Activated Endothelium
Endothelium-induced SMC relaxation Insufficient generation of vasodilators
and prevention of platelet activation Enhanced Endothelin-1 production
Platelets
Norepinephrin, Norepinephrin,
Bradykinin Bradykinin
NO Prostacyclin
Endothelium
Endothelin-1
EDHF NO Prostacyclin
Smooth
muscle cell
Vasodilation Vasoconstriction
Fig. 2 Paracrine interaction between endothelium and contribute to vasodilation. Prostacyclin and NO also coun-
smooth muscle cells. (a) After stimulation with vasoactive teract platelet activation. (b) In disease, the production of
agents or neural factors (e.g., norepinephrine and bradyki- these vasodilating agents can decrease, while production
nin), the healthy endothelium releases nitric oxide (NO), of the protein endothelin-1 can increase. Additionally,
prostacyclin, and endothelium-derived hyperpolarization direct effects of vasoactive agents on smooth muscle cells
factor (EDHF), which counteract smooth muscle contrac- are no longer suppressed, inducing vasoconstriction
tion by various intracellular mechanisms and therewith
The endothelium of healthy vessels produces catalyzing enzyme. These antithrombotic activi-
several proteins that prevent thrombus formation ties ensure undisturbed circulation. If the balance
(see chapter “Overview” under part “Blood”) [8]. between pro- and antithrombotic/coagulant fac-
It interrupts the coagulation cascade by providing tors is disturbed, thrombus formation or bleeding
antithrombin III that neutralizes thrombin and will occur. While thrombus formation is required
by thrombomodulin-facilitated activation of the for limiting blood loss after wounding, it can also
anticoagulant protein C. It binds a metallopro- lead to adverse events, such as deep vein throm-
teinase called ADAMTS13 that proteolytically bosis or stroke (see chapter “Stroke”).
cleaves von Willebrand factor multimers limiting Inflammatory cells in atherosclerotic vessels
platelet adhesion and activation. Furthermore, (see chapter “Atherosclerotic heart disease”)
the endothelium reduces platelet activation produce cytokines, such as tumor necrosis
and aggregation (Fig. 2a). Finally, it releases factor-α (TNF-α), that alter the properties of ECs.
tissue-type plasminogen activator, a fibrinolysis- This results not only in a reduction of antithrom-
Overview 265
botic properties and activity of eNOS but also in act on blood vessels. For example, estrogens
the expression of leukocyte adhesion molecules, interact with an endothelial membrane-bound
such as vascular cell adhesion molecule-1 and estrogen receptor variant, which induces NO pro-
E-selectin, as well as chemo- and cytokines, such duction and vasodilation (see chapter “Overview”
as monocyte chemotactic protein-1 and interleu- under part “Reproductive system”) [11].
kin-8 that stimulate influx of various leukocyte The vessel wall is approached not only from
types [9]. Moreover, atherosclerotic arteries are its luminal side by endocrine mediators but also
associated with a subtle elevation of circulating from its outside by products of the surround-
C-reactive protein, reflecting a weak activation of ing PVAT acting in a paracrine fashion (Fig. 1).
the acute phase response in the liver (see chapter In obesity and type 2 diabetes (see chapters
“Overview” under part “Liver”). “Metabolic syndrome” and “Diabetes melli-
tus”, respectively), PVAT expands and becomes
inflamed. While lean PVAT produces adipokines
Outside-In: Factors from Other like adiponectin that facilitate vasodilation both
Tissues Affecting Conduit and in conduit arteries and insulin-stimulated resis-
Resistance Vessels tance arteries, the expanded fatty PVAT loses
this ability and shifts toward the production of
Neural factors, such as norepinephrine and sub- nonesterified fatty acids, the pro-inflammatory
stance P, and hormones, such as epinephrine, cytokine TNF-α, leptin, and other factors that
insulin, and estrogen, are important regulators of favor the contractile pathway induced by insulin
vascular tone (Fig. 1). However, the effect of a [12]. These events affect, for example, the white
specific factor can vary among the vascular beds adipose tissue and illustrate the mutual interrela-
of different organs because of different receptor tionship between metabolism, inflammation, and
isoforms, receptor sensitivities, or tissue-specific vessel functioning.
receptor distributions. In addition to primary
effects on the vasculature, inflammatory cyto-
kines and hypoxia can change gene expression in Final Remarks
ECs [9]. Furthermore, shear stress by laminar
flowing blood on arterial ECs causes a gene Blood vessels distribute fuel for metabolism,
induction pattern within these cells that reduces control tissue perfusion by vasoregulation, and
inflammatory activation, while disturbance of the deliver tissue products and leukocytes to the sites
laminar flow pattern in arteries alters endothelial where they are needed. Being critically important
functioning and contributes to atherosclerotic for the organism, blood vessels have a high
lesion generation [10]. capacity to adapt to various stresses and local
Hormones have to pass the endothelium to needs. This can occur by short-term responses,
reach tissue cells and usually also act directly on such as acute adaptation of the vessel tone or
blood vessels. In muscle or heart tissue, insulin release of factors that contribute to hemostasis, or
has to pass the endothelium, while activating by the induction of new genes, as in inflammation
insulin receptors on the endothelium simultane- or hypoxia. Normally, this response is temporary.
ously. Insulin receptor activation in the proximal However, this adaptability can be overstretched
resistance vessels of tissues that store nutrients by chronic activation or injury, leading to chronic
usually causes vasodilation by activation of or acute adverse responses. Within the book,
eNOS via a pathway that involves insulin recep- three frequently encountered clinically relevant
tor susbstrate-1, phosphatidylinositol-3-kinase, blood vessel-based diseases are covered: athero-
and Akt (also called protein kinase B). In obesity, sclerosis (see chapter “Atherosclerotic heart dis-
this effect is diminished, while endothelin-1 ease”), stroke (see chapter “Stroke”), and varicose
favors vascular contraction. Other hormones also veins (see chapter “Varicose veins”).
266 V.W.M. van Hinsbergh et al.
a b
stroke, excitotoxicity due to excess glutamate, designed to remove clots by aspiration and
inflammation, as well as release of free radicals extraction [17]. Treatment for hemorrhagic
induce stress to the cells. In response to this, stroke aims to stop the bleeding by surgical clip-
the hypothalamic-pituitary-adrenal system (see ping (closing the base of a leakage or aneurysm
chapter “Overview” under part “Brain”) triggers by constriction) or endovascular coiling (inser-
the release of neurohormones such as cortisol tion of a metallic coil into the site of leakage
and catecholamines [12]. This in turn promotes followed by blood clotting) and to drain the
glycogenolysis and gluconeogenesis in the liver blood (hematoma) that has accumulated in the
while inhibiting insulin sensitivity and glucose brain [18]. Apart from these, stroke treatment
uptake in the skeletal muscle [13]. They also also involves medications that control inflam-
stimulate lipolysis, resulting in accumulation of mation, brain swelling, blood pressure, hyper-
nonesterified fatty acids [13]. Hyperglycemia glycemia, and hypercholesterolemia (Table 1).
fuels anaerobic metabolism, lactic acidosis, and
free radical production, which then exert direct
membrane lipid peroxidation and cell lysis in the Influence of Treatment
metabolically challenged tissues [14]. Such posi- on Metabolism
tive feedback leads to a further derangement in
pH homeostasis, which can trigger the produc- Early phase damage in the brain can be reversed
tion of free radicals and affects the Ca2+ balance when the disrupted blood flow is restored in time
in neurons, possibly resulting in neuronal cell by medical interventions. Yet, reperfusion at the
death [15]. These free radicals can cause func- ischemic region can activate astrocytes, microg-
tional and morphological changes to the endothe- lia, and endothelial cells to produce cytokines
lium, thus increasing permeability of the BBB, and chemokines, which are potent mediators of
edema formation, as well as risk of hemorrhagic inflammatory responses. This results in activa-
transformation. tion of matrix metalloproteinases, which disrupt
the BBB by digesting extracellular matrix pro-
teins within the basal lamina, such as type IV col-
Treatment of Strokes lagen, laminin, and fibronectin. This consequently
causes BBB disruption, edema formation, and
Thrombolytic drugs such as alteplase and hemorrhagic transformation [19].
reteplase, which are synthetic enzymes with
similar function to the endogenously produced
tissue plasminogen activator (tPA), are the first Secondary Treatment Options
line of treatment against ischemic stroke [16].
tPA is a serine protease found on vascular endo- The majority of stroke patients have a combina-
thelial cells and is involved in the lysis of blood tion of medical disorders such as hypertension
clots (see chapter “Overview” under part (see chapter “Hypertension”), dyslipidemia (see
“Blood”). Although thrombolysis can improve chapter “Hyperlipidemia”), and diabetes (see
blood flow, these clot-dissolving drugs are only chapter “Diabetes mellitus”). Hence, treatment
effective within 4.5 h of stroke onset, after for stroke also includes the management of these
which they pose increased risk of hemorrhage. conditions. Antihypertensive drugs such as thia-
Hence, patients with hemorrhagic stroke or zide diuretics and Ca2+ channel blockers are pre-
severely elevated blood pressure are not eligible scribed to control blood pressure by reducing
for such treatment. A more invasive procedure, blood volume, systemic vascular resistance, and
mechanical thrombectomy, may be performed cardiac output (see chapter “Hypertension”).
to remove or break up the clot [17]. An alterna- Cholesterol-lowering drugs such as statins are
tive mechanical approach is the Penumbra used to control cholesterol synthesis in the liver
System, an embolectomy device specifically (see chapter “Hyperlipidemia”).
270 D.S. Karolina and K. Jeyaseelan
Insulin therapy is usually recommended for other drugs to reduce stroke complications is not
treating hyperglycemia in stroke patients. Besides always effective, and novel therapeutic agents are
lowering blood glucose levels, insulin also exerts necessary.
antioxidant and anti-inflammatory effects by sup- Recently, microRNAs (miRNAs) have gained
pressing several proinflammatory transcription attention in translational stroke research [21].
factors, such as nuclear factor-κB, early growth These endogenous gene regulators target several
response protein 1, and activator protein 1, as metabolic and biological processes that are
well as generation of reactive oxygen species, impaired in pathological conditions. For instance,
thereby minimizing stroke complications [20]. miR-320, a key player in edema formation, is
Moreover, insulin therapy has also been shown to upregulated in stroke conditions [22]. Hence,
significantly reduce systolic blood pressure and downregulation of miR-320 expression has been
improve stroke outcome [20]. associated with favorable outcomes in stroke
patients [23]. However, more and extensive studies
are needed before miRNAs could reach clinical tri-
Perspectives als in stroke therapy. Yet, the development of miR-
NAs as multi-target drugs holds great potential.
Pathogenesis of stroke involves multiple factors,
which coordinately impair the metabolic status of
the body. Recombinant or artificial tPAs, the only References
therapeutic arsenal available today, have several
1. Hademenos GJ, Massoud TF (1997) Biophysical
limitations such as short therapeutic window and mechanisms of stroke. Stroke 28:2067–2077
the risk of hemorrhagic transformation. Even 2. Qureshi AI, Mendelow AD, Hanley DF (2009)
recombinant tPA therapy in combination with Intracerebral haemorrhage. Lancet 373:1632–1644
Stroke 271
3. Danton GH, Dietrich WD (2003) Inflammatory mech- 14. Lindsberg PJ, Roine RO (2004) Hyperglycemia in
anisms after ischemia and stroke. J Neuropathol Exp acute stroke. Stroke 35:363–364
Neurol 62:127–136 15. Orlowski P, Chappell M, Park CS, Grau V, Payne S
4. Hua Y, Keep RF, Hoff JT, Xi G (2007) Brain injury (2011) Modelling of pH dynamics in brain cells after
after intracerebral hemorrhage: the role of thrombin stroke. Interface Focus 6:408–416
and iron. Stroke 38:759–762 16. The National Institute of Neurological Disorders and
5. Zaremba J (2004) Hyperthermia in ischemic stroke. Stroke rt-PA Stroke Study Group (1995) Tissue plas-
Med Sci Monit 10:RA148–RA153 minogen activator for acute ischemic stroke. N Engl J
6. Karaszewski B, Wardlaw JM, Marshall I, Cvoro V, Med 333:1581–1587
Wartolowska K, Haga K, Armitage PA, Bastin ME, 17. Tenser MS, Amar AP, Mack WJ (2011) Mechanical
Dennis MS (2009) Early brain temperature elevation thrombectomy for acute ischemic stroke using the
and anaerobic metabolism in human acute ischaemic MERCI retriever and penumbra aspiration systems.
stroke. Brain 132:955–964 World Neurosurg 76:S16–S23
7. Valenza F, Aletti G, Fossali T, Chevallard G, Sacconi 18. Lapchak PA, Araujo DM (2007) Advances in hemor-
F, Irace M, Gattinoni L (2005) Lactate as a marker of rhagic stroke therapy: conventional and novel
energy failure in critically ill patients: hypothesis. Crit approaches. Expert Opin Emerg Drugs 12:389–406
Care 9:588–593 19. Visse R, Nagase H (2003) Matrix metalloprotein-
8. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, ases and tissue inhibitors of metalloproteinases:
Makita Z, Sasaki N, Tashiro K (2003) Glycation: a structure, function, and biochemistry. Circ Res 92:
sweet tempter for neuronal death. Brain Res Brain 827–839
Res Rev 4:306–323 20. Garg R, Chaudhuri A, Munschauer F, Dandona P
9. Oddo M, Levine JM, Frangos S, Maloney-Wilensky E, (2006) Hyperglycemia, insulin, and acute ischemic
Carrera E, Daniel RT, Levivier M, Magistretti PJ, stroke: a mechanistic justification for a trial of insulin
LeRoux PD (2012) Brain lactate metabolism in humans infusion therapy. Stroke 37:267–273
with subarachnoid hemorrhage. Stroke 43:1418–1421 21. Tan JR, Koo YX, Kaur P, Liu F, Armugam A, Wong
10. Farooqui AA, Farooqui T, Panza F, Frisardi V (2012) PT, Jeyaseelan K (2011) microRNAs in stroke patho-
Metabolic syndrome as a risk factor for neurological genesis. Curr Mol Med 11:76–92
disorders. Cell Mol Life Sci 69:741–762 22. Sepramaniam S, Armugam A, Lim KY, Karolina DS,
11. Melamed E (1976) Reactive hyperglycaemia in Swaminathan P, Tan JR, Jeyaseelan K (2010)
patients with acute stroke. J Neurol Sci 29:267–275 MicroRNA 320a functions as a novel endogenous
12. Anne M, Juha K, Timo M, Mikko T, Olli V, Kyösti S, modulator of aquaporins 1 and 4 as well as a potential
Heikki H, Vilho M (2007) Neurohormonal activation in therapeutic target in cerebral ischemia. J Biol Chem
ischemic stroke: effects of acute phase disturbances on 285:29223–29230
long-term mortality. Curr Neurovasc Res 4:170–175 23. Tan KS, Armugam A, Sepramaniam S, Lim KY,
13. Zafari AM, Wang SS, Song Q (2006) Genetics of met- Setyowati KD, Wang CW, Jeyaseelan K (2009)
abolic syndrome. Clin Rev pp. 51–61. www.turner- Expression profile of MicroRNAs in young stroke
white.com/pdf/hp_oct06_genetic.pdf patients. PLoS One 4:e7689
Varicose Veins
pro-matrix metalloproteinase-9 (pro-MMP9) and About 60–70 % of patients with varicose veins
L-selectin released from leukocytes have been have incompetent saphenofemoral junctions
demonstrated in blood samples from varicose (located at the inguinal region) with reflux in
compared to non-varicose veins after postural the long saphenous system. Therefore, surgical
blood stasis [19]. The imbalance of proteinases or endovenous treatments are tailored toward
and inhibitors (see also chapter “Osteoarthritis”) treating the reflux. Open surgery involves high
in favor of proteinases, as well as reduced con- tie or saphenofemoral ligation followed by the
tent and arrangement of elastin and increased removal of the varicose long saphenous vein.
in collagen type I and loss of collagen type III Sclerotherapy, i.e., injection of a sclerosant into
fibers, is likely to weaken the vein wall and cause the varicose veins to make them shrink, has been
dilatation. found to be particularly effective [23]. The two
most commonly used endovenous treatments
include radiofrequency ablation and endovenous
Metabolic Changes laser ablation. These treatments work by provid-
ing a method of delivering thermal energy to the
There are very few studies, which have demon- venous endothelium, subsequently sealing the
strated direct metabolic changes in the varicose incompetent veins, thus favoring flow to alterna-
vein wall. Importantly, characteristic distribution tive, more competent veins. Technical success
of lipid metabolites including phosphatidylcho- and recurrence rates are comparable to open sur-
line, lysophosphatidylcholine, and sphingomy- gery. The pertinent complications of surgical and
elin has been observed around damaged valvular endovenous treatments include bleeding, infec-
regions and in the dilated vein wall [20]. Further, tion, nerve damage, skin pigmentation, deep vein
a significantly reduced number of lymphatic ves- thrombosis, and recurrence.
sels around varicose veins may be responsible for
this lipid accumulation and subsequent vein wall
degeneration [20]. Pharmacological Treatments and
Nuclear magnetic resonance (NMR) spec- Their Influence on Metabolism
troscopy (a method of studying metabolic per-
turbation in tissues and body fluids) revealed Varicose vein recurrence rates following sur-
significantly higher levels of lactate, creatine, gical intervention range between 20 and 40 %
and myoinositol in the varicose vein wall com- [24]. Existing pharmacological treatment is
pared to control veins [21]. The different metab- mainly symptomatic focusing on edema, pain,
olites reflect the underlying metabolic changes and itchiness. The pharmacological interven-
in the varicose vein wall. Whereas creatine and tion of venous disease can be classified into
its metabolites correlate with SMC hypertrophy, venoactive or non-venoactive. The precise
high levels of lactate convey the hypoxic state mechanism of venoactive drugs is not fully
of the varicose vein wall. Myoinositol, a con- known; however, they are suspected to improve
stituent of second messengers, is involved in venous tone and target the microcirculatory
cell signaling, which eventually results in cell changes induced by chronic venous hyperten-
proliferation [21]. sion, such as leukocyte activation and inflam-
matory cytokine release, increased capillary
permeability, and proteolysis [25].
Treatment of Varicose Veins Micronized purified flavonoid fraction or fla-
vonoids containing 90 % diosmin and 10 % hes-
Compression hosiery is the first-line treatment peridin (two flavonoids mainly found in citrus
option. Treatment is noninvasive but patients fruits) are the most studied venoactive agents.
can find compression hosiery uncomfortable, Treatment has resulted in significant improve-
expensive, unsightly, and difficult to apply [22]. ments in health-related quality of life, objective
276 R. Mandavia et al.
4. Scott TE, LaMorte WW, Gorin DR, Menzoian JO 17. Gandhi RH, Irizarry E, Nackman GB, Halpern VJ,
(1995) Risk factors for chronic venous insufficiency: Mulcare RJ, Tilson MD (1993) Analysis of the con-
a dual case-control study. J Vasc Surg 22:622–628 nective tissue matrix and proteolytic activity of pri-
5. Meissner MH, Gloviczki P, Bergan J, Kistner RL, mary varicose veins. J Vasc Surg 18:814–820
Morrison N, Pannier F, Pappas PJ, Rabe E, Raju S, 18. Lim CS, Shalhoub J, Gohel MS, Shepherd AC,
Villavicencio JL (2007) Primary chronic venous dis- Davies AH (2010) Matrix metalloproteinases in vas-
orders. J Vasc Surg 46:54S–67S cular disease – a potential therapeutic target? Curr
6. Brake M, Lim CS, Shepherd AC, Shalhoub J, Davies Vasc Pharmacol 8:75–85
AH (2013) Pathogenesis and etiology of recurrent 19. Jacob MP, Cazaubon M, Scemama A, Prié D,
varicose veins. J Vasc Surg 57:860–868 Blanchet F, Guillin MC, Michel JB (2002) Plasma
7. Anwar MA, Shalhoub J, Lim CS, Gohel MS, Davies matrix metalloproteinase-9 as a marker of blood stasis
AH (2012) The effect of pressure-induced mechanical in varicose veins. Circulation 106:535–538
stretch on vascular wall differential gene expression. 20. Tanaka H, Zaima N, Sasaki T, Yamamoto N, Sano M,
J Vasc Res 49:463–478 Konno H, Setou M, Unno N (2012) Loss of lymphatic
8. Somers P, Knaapen M (2006) The histopathology of vessels and regional lipid accumulation is associated
varicose vein disease. Angiology 57:546–555 with great saphenous vein incompetence. J Vasc Surg
9. Kakkos SK, Zolota VG, Peristeropoulou P, 55:1440–1448
Apostolopoulou A, Geroukalos G, Tsolakis IA 21. Anwar MA, Shalhoub J, Vorkas PA, Lim CS, Want EJ,
(2003) Increased mast cell infiltration in familial Nicholson JK, Holmes E, Davies AH (2012) In-vitro
varicose veins: pathogenetic implications? Int Angiol identification of distinctive metabolic signatures of
22:43–49 intact varicose vein tissue via magic angle spinning
10. Yamada T, Tomita S, Mori M, Sasatomi E, Suenaga E, nuclear magnetic resonance spectroscopy. Eur J Vasc
Itoh T (1996) Increased mast cell infiltration in vari- Endovasc Surg 44:442–450
cose veins of the lower limbs: a possible role in the 22. Hamdan A (2012) Management of varicose veins and
development of varices. Surgery 119:494–497 venous insufficiency. JAMA 308:2612–2621
11. Jacob T, Hingorani A, Ascher E (2005) Overexpression 23. Rasmussen LH, Lawaetz M, Bjoern L, Vennits B,
of transforming growth factor-beta1 correlates with Blemings A, Eklof B (2011) Randomized clinical
increased synthesis of nitric oxide synthase in vari- trial comparing endovenous laser ablation, radio-
cose veins. J Vasc Surg 41:523–530 frequency ablation, foam sclerotherapy and surgical
12. Cario-Toumaniantz C, Boularan C, Schurgers LJ, stripping for great saphenous varicose veins. Br J Surg
Heymann MF, Le Cunff M, Léger J, Loirand G, 98:1079–1087
Pacaud P (2007) Identification of differentially 24. Tsang FJ, Davis M, Davies AM, Davies AH (2005)
expressed genes in human varicose veins: involve- Incomplete saphenopopliteal ligation after short
ment of matrix gla protein in extracellular matrix saphenous vein surgery: a summation analysis.
remodeling. J Vasc Res 44:444–459 Phlebology 20:106–109
13. Wali MA, Eid RA (2001) Smooth muscle changes 25. Smith PD (2000) Micronized purified flavonoid frac-
in varicose veins: an ultrastructural study. J Smooth tion and the treatment of chronic venous insufficiency:
Muscle Res 37:123–135 microcirculatory mechanisms. Microcirculation 7:35–40
14. Ascher E, Jacob T, Hingorani A, Tsemekhin B, 26. Gohel MS, Davies AH (2010) Pharmacological treat-
Gunduz Y (2001) Expression of molecular media- ment in patients with C4, C5 and C6 venous disease.
tors of apoptosis and their role in the pathogen- Phlebology 25:35–41
esis of lower-extremity varicose veins. J Vasc Surg 27. Pittler MH, Ernst E (2012) Horse chestnut seed extract
33:1080–1086 for chronic venous insufficiency. Cochrane Database
15. Lim CS, Gohel MS, Shepherd AC, Paleolog E, Davies Syst Rev (11):CD003230
AH (2010) Venous hypoxia: a poorly studied etiologi- 28. Canali R, Comitato R, Schonlau F, Virgili F (2009)
cal factor of varicose veins. J Vasc Res 48:185–194 The anti-inflammatory pharmacology of Pycnogenol
16. Lim CS, Kiriakidis S, Paleolog EM, Davies AH (2012) ((R)) in humans involves COX-2 and 5-LOX mRNA
Increased activation of the hypoxia-inducible factor expression in leukocytes. Int Immunopharmacol
pathway in varicose veins. J Vasc Surg 55:1427–1439 9:1145–1149
Part XII
Blood
Overview
Anatomy and Physiology of Blood under part “Liver”), or excretion, generally the
kidney (see chapter “Overview” under part
Blood is made up of cells suspended in plasma. “Kidney”). These processes are essential for the
The plasma is composed of electrolytes, proteins, metabolic processes that sustain life.
glucose, and lipids dissolved or suspended in Due to the function of blood as the major
water. The cellular compartment comprises red transport system of the body, changes in blood
blood cells (erythrocytes, RBCs), platelets constituents influence all organs and tissues. In
(thrombocytes), and white blood cells (leuko- turn, many diseases can be diagnosed from bio-
cytes), which are all produced in the bone mar- markers in the blood.
row (Fig. 1). In this chapter, we shall describe the constitu-
Blood is the major transport and delivery sys- ents and metabolic activities of blood and high-
tem in the body. It transports the end product of light diseases resulting from aberrations in these
internal respiration, carbon dioxide (CO2), via the pathways.
vena cavae and the right side of the heart (see
chapter “Overview” under part “Heart”) to the
lungs for expiration (see chapter “Overview” Blood-Specific Metabolic/Molecular
under part “Lung”). It delivers oxygenated blood Pathways and Processes
from the lungs to the tissues, via the left side of
the heart and the arteries (see chapter “Overview” The constituents of blood are required for its own
under part “Blood vessels”). Blood also transports homeostasis and that of other bodily systems and
nutrients from the gut to the tissues (see chapter have many functions. The salient blood-specific
“Overview” under part “Gastrointestinal tract”). metabolic processes are outlined below.
The waste products of tissue metabolism are Many diseases are caused by or involve dereg-
transported via the blood to the site of detoxifica- ulated plasma proteins that are involved in a
tion, generally the liver (see chapter “Overview” plethora of metabolic pathways. Some of these
diseases are mentioned below.
D. Iskander (*)
Department of Haematology,
Imperial College London, Oxygen Transport
Hammersmith Campus, London W12 0NN, UK
e-mail: d.iskander@imperial.ac.uk
Oxygen (O2) transport depends upon RBCs and
B.J. Bain
hemoglobin, which are specially adapted for gas
Department of Haematology, Imperial College London,
St Mary’s Hospital Campus, London W2 1NY, UK transport. The affinity of hemoglobin for oxygen
e-mail: b.bain@imperial.ac.uk at different partial pressures is represented by a
Oxygen transport
100 %
X Xa X
RBC V Va
Platelet
AP
Ca2+
Prothrombin Thrombin
Plasma
Lymphocyte Fibrinogen Fibrin
Neutrophil
XIIIa XIII
Protects against Albumin and other Innate and adaptive Crosslinked fibrin
infections, generates transport proteins immunity
oxidants Hormones
Buffers and salts
Lipoproteins, Nutrients
Fig. 1 Important components of the blood and their phys- clotting is regulated by a complex, sequential, cascade-
iological function. Erythrocytes (red blood cells, RBCs) like activation of proteases resulting in cross-linked fibrin
are the major cellular component of the blood. RBCs to seal an injury. Lymphocytes, components of the
transport oxygen to the tissues via hemoglobin (Hb). immune system, are also transported by the blood.
Oxygen binding is mainly regulated by partial pressure of Similarly, neutrophils aid in host defense. Additionally,
O2 in the surrounding tissues. The major metabolic path- the blood plasma transports various proteins, hormones,
ways in RBCs are glycolysis and pentose phosphate path- ions, and buffers. AP activated platelets, HbF fetal hemo-
way (PPP). Platelets are small anucleate cell fragments in globin, HbA adult hemoglobin, HbS sickle-cell
the blood that play a major role in blood clotting. Blood hemoglobin
sigmoid-shaped oxygen dissociation curve (H+) decrease oxygen affinity (known as the
(Fig. 1). Oxygen binding depends on the struc- “Bohr effect” [2]) as does 2,3-diphosphoglycerate
ture of hemoglobin in terms of its subunits and on (2,3-DPG), a side product of glycolysis, so that
external factors such as acidity, temperature, and O2 is more easily released in metabolically active
partial pressure of oxygen. Hemoglobin is a tetra- tissues.
meric protein consisting of two α chains com-
bined with combined with, in adult Hb, 2 alpha
chains (HbA) or two delta chains (HbA2) and in Carbon Dioxide (CO2) Transport
fetal Hb, 2 y chains (HbF) [1]. In sickle-cell ane-
mia (see chapter “Sickle cell disease”), a variant This occurs by three mechanisms: CO2 dissolved
called HbS replaces HbA. This has reduced oxy- in plasma (5–10 %), CO2 bound to proteins such
gen affinity compared with HbA, partially as hemoglobin as a carbamate (5–10 %), and,
explaining the lower hemoglobin concentration principally, CO2 combined with water to form
observed in patients [1]. carbonic acid (H2CO3, 70–80 %). The latter reac-
Oxygen is transported by binding to the Fe2+ tion is catalyzed by carbonic anhydrase in the
present in the heme component of hemoglobin. If RBC. In an equilibrium reaction, carbonic acid
the iron is oxidized to Fe3+, oxygen does not bind. then dissociates to form bicarbonate ions (HCO3−)
Binding of oxygen to one heme molecule and H+. This not only allows transport of CO2 but
increases the oxygen affinity of other hemes by a also favors the release of O2 from hemoglobin at
mechanism called cooperativity. CO2 and protons the site of high aerobic demand [3].
Overview 283
Leukocytes
Iron Transport
Leukocytes, namely, neutrophils, eosinophils,
This occurs by iron binding to the plasma protein basophils, lymphocytes, and monocytes, are an
transferrin, although <0.5 % total body iron is important component of blood as they form part
present in the plasma. On average, two thirds of of the body’s defense mechanism against infec-
total body iron is incorporated into hemoglobin, tion (see chapter “Overview” under part “Immune
and the remainder is mainly stored in the liver, system”).
bound to ferritin, or in body macrophages, as
hemosiderin. Iron-deficiency anemia is preceded
by a depletion of body iron stores and a fall in Hormonal Transport for Regulation
serum ferritin concentration [4]. of Whole Body Metabolism
Ca2+, Pi TGs
Bilirubin
Liver
Intrinsic factor
Gastrin
O2
– +
HCO3 +H
CO2
RBC
O2
Stomach
HCO3–+H +
CO2
H 2O
Lung
Fig. 2 Interactions of blood with other organs. As the ketone bodies during prolonged fasting. Ions transported in
major transport system in the body, the blood interacts with the blood are critical for bone stability (mainly calcium)
virtually all organs and tissues. Nutrients absorbed from the and erythropoiesis (mainly iron). Hormones, such as eryth-
small intestine are transported to the liver and further to the ropoietin (EPO) from the kidney, are secreted into the
whole body (e.g., to skeletal muscle). Recycling and redis- blood by a large variety of endocrine organs. “Cleaning” of
tribution of nutrients and their products (e.g., from skeletal the blood occurs in the kidney, where unwanted contents
muscle and adipocytes) also occur via the blood. The liver such as nitrogenous waste can be excreted and pH changes
contributes a multitude of metabolic products to the blood can be regulated. Red blood cells (RBCs) transport O2 and
stream to be transported to the target tissues. This includes aid in CO2 transport from and to the lungs, respectively.
glucose from gluconeogenesis or glycogen stores and tri- Hemoglobin degradation products released from “dying”
glycerides (also called triacylglycerols, TGs) and choles- erythrocytes are generally removed via the liver. Pi inor-
terol being transported in lipoproteins, amino acids, and ganic phosphate (PO43−), Vit B12 vitamin B12
286 D. Iskander and B.J. Bain
then bilirubin glucuronide, which is excreted in insufficiency, and hypothyroidism all lead to
the bile. Iron is recycled. Within the intestine, anemia. Erythropoiesis likewise requires normal
bacteria convert bilirubin to urobilinogen, which renal function, including production of erythro-
either is reabsorbed and excreted in the urine or poietin (see chapter “Overview” under part
passes further down the intestinal tract forming “Kidney”). In renal failure (see chapter “Chronic
stercobilinogen [2]. Both products contribute to kidney disease”), there is reduced synthesis of
the color of the excretions. erythropoietin and thus anemia. In addition,
If the rate of hemolysis exceeds the plasma sup- nitrogenous waste products, including urea,
ply of haptoglobin, free hemoglobin is excreted in accumulate in the blood, suppressing erythropoi-
the urine with some being reabsorbed and the iron esis and leading to platelet dysfunction and hem-
incorporated into to ferritin and then hemosiderin orrhage. Acid/base disturbance can also impact
in the renal tubules. Initial hemoglobinuria is thus upon the oxygen dissociation curve.
followed by hemosiderinuria, as renal tubule cells In liver disease, abnormal metabolism can
(containing the hemosiderin) are lost in the urine. lead to specific forms of hemolytic anemia.
Acute intravascular hemolysis can cause renal fail- Zieve’s syndrome is characterized by acute
ure (see chapter “Chronic kidney disease”). Cell- hemolysis, irregularly contracted red cells, and
free plasma hemoglobin also acts as a nitric oxide hyperlipidemia associated with alcoholic fatty
scavenger, which can lead to adverse effects on liver. Spur cell hemolytic anemia shows marked
blood vessels (e.g., vasoconstriction, see chapter acanthocytosis (RBCs with a spiked, thorny cell
“Overview” under part “Blood vessels”). The membrane) occurring in liver failure of any etiol-
accumulation of bilirubin in the circulation also ogy. Acute oxidant-induced Heinz body hemo-
leads to a yellow discoloration of the skin, that is, lytic anemia can occur in advanced Wilson’s
jaundice. Chronic hemolysis leads to the forma- disease as a result of the oxidant effect of copper
tion of pigment gallstones [2]. released from damaged or dying liver cells. Liver
disease also leads to impaired synthesis of coagu-
lation factors and thus hemorrhage [6].
Outside-In: Metabolites of Other Acute infection can cause anemia, neutro-
Tissues Affecting the Blood philia, platelet consumption, and activation of
coagulation. Infection generates oxidant sub-
Impaired function of many organs, including the stances and can lead to hemolysis in G6PD-
lungs and kidneys, involved in the regulation of deficient subjects (see above). Chronic infections
blood oxygen levels, pH, and/or temperature can and inflammatory states lead to generation of
affect blood metabolism by shifting the oxygen cytokines, causing anemia of chronic disease, in
dissociation curve (Fig. 1). which iron is not mobilized from macrophages.
Normal hematopoiesis requires a supply of
nutrients, including iron, vitamin B12, and folic
acid. Their availability is dependent on normal Final Remarks
intestinal absorption. Vitamin B12 absorption
additionally requires that the stomach secretes The blood is the major transport system in the
intrinsic factor, which combines with B12, permit- body, delivering oxygen and nutrients to the tis-
ting its absorption by the small intestine (see sues for metabolic processes and removing the
chapter “Overview” under part “Gastrointestinal waste products of metabolic reactions.
tract” and Fig. 2). Thus, celiac disease and auto- Measurement of the levels of blood constituents
immune gastric atrophy can lead indirectly to can therefore assist the diagnosis and monitoring
anemia. Erythropoiesis requires normal levels of many diseases. Diseases of many organs and
of growth hormone and adrenal and thyroid tissues can adversely influence hematopoiesis and
hormones, so that hypopituitarism, adrenal impair the homeostatic mechanisms of the blood.
Overview 287
Introduction to Sickle Cell Disease cell trait and, with rare exceptions, are well [2].
HbS homozygotes show the most severe symp-
A mutation in the β-hemoglobin gene that codes toms and a great deal of phenotypic heterogene-
for a variant hemoglobin, sickle hemoglobin ity, likely as a result of many interacting genes or
(HbS), in which the glutamate at position 6 of the proteins. Chief among the genetic abnormalities
protein is exchanged for valine (HBB glu6val), is that modulate the phenotype of SCD is
the genetic basis of sickle cell disease (SCD). α-thalassemia, which reduces RBC density and
SCD is found in about 1 in 300 African Americans HbS concentration, reducing hemolysis, and
at birth, but its incidence can be much higher in mutations in various regulators of fetal hemoglo-
parts of Africa, the Middle East, and India, bin (HbF) gene expression. HbF can thwart the
regions where the HbS mutation first arose. When polymerization of HbS [3, 4]. Many other genes
deoxygenated, HbS polymerizes resulting in are likely to modulate the phenotype of SCD.
erythrocyte (RBC) deformation (known as “sick-
ling”) and cellular damage, provoking the clini-
cal and laboratory features characteristic of SCD. Pathophysiology of Sickle Cell
These include vasoocclusion, hemolytic anemia, Disease and Metabolic Alterations
widespread acute and chronic organ damage, and
reduced lifespan [1]. Patients with SCD can be HbS and its polymer damage the RBC mem-
homozygous for the HbS mutation, compound brane (Fig. 1), resulting in cation channel activa-
heterozygotes for the HbS mutation, and another tion (see below) leading to cellular dehydration
variant that “interacts” with HbS, compound het- and rigidity; abnormal adhesive interactions
erozygotes for HbS and a β-thalassemia muta- among RBCs, leukocytes, and endothelial cells
tion. Simple heterozygotes are said to have sickle mediated by a variety of adhesion molecules
and their ligands; and an inflammatory response
secondary to endothelial activation and dam-
D.A. Dworkis
age [5, 6]. Activation of the Gardos channel (a
Boston University School of Medicine,
15 Bigelow St, Apt#3, Cambridge, MA 02139, USA Ca2+-activated K+ channel) and K+:Cl− cotrans-
e-mail: ddworkis@bu.edu port channel and perhaps other ion transport
M.H. Steinberg (*) channels like PIEZO1 (a mechanosensitive ion
Department of Medicine, channel), by deoxygenation, acidification, cell
Boston University School of Medicine, swelling, Ca2+ influx, and cell sickling lead to
Center of Excellence in Sickle Cell Disease,
dense, dehydrated sickle RBCs in which the
72 East Concord St., Room E248, Boston,
MA 02118, USA polymerization tendency of HbS is increased.
e-mail: mhsteinb@bu.edu Perturbed endothelial cells display adhesion
Mutation
at ß6 Vasoocclusion
HbA HbS
GAG GTG
Glu Val
Ornithine
[NO-synthase]
Hemolysis
Scavenges
Hb NO Citrulline
Decrease cation transport:
Gardos channel, Vasoconstriction
K:Cl cotransport inhibitors
HbS solution
Oxygenated Increase NO bioavailability:
PDE5 inhibitors, NO donors,
Arginine
Fig. 1 Pathophysiology of sickle cell disease and patho- left), can reduce the polymerization tendency of HbS. Cell
physiological-based treatment approaches. DeoxyHbS density (and thus hemolysis) could be reduced by inhibit-
(sickle cell hemoglobin) polymerizes deforming and ing cation transport channels (bottom center), adhesive
injuring the sickle RBC (red blood cell), leading to vaso- interactions with the endothelium could be interrupted by
occlusion and hemolytic anemia. Intravascular hemolysis blocking receptor-ligand docking (upper right), and
of sickle cells releases heme into the blood that scavenges finally, availability and effects of NO could be increased
nitric oxide (NO), and the liberated arginase destroys argi- (bottom right). Current standard treatment options com-
nine, the substrate of the NO synthases. Each facet of the prise only HU. HDAC histone deacetylase, HbA adult
pathophysiology of disease could be targeted to interfere hemoglobin, Glu glutamate, Val valine, EC endothelial
with its adverse effects. Agents that induce HbF (fetal cell, ISC irreversible sickled cell, Hb Hemoglobin, ET-1
hemoglobin) expression, such as hydroxyurea (HU, upper endothelin-1, PDE phosphodiesterase
molecules like integrins, selectins, and VCAM, clusion. Hemolysis, or premature destruction of
produce cytokines and inflammatory mediators, RBCs, is a result of membrane damage to the
and develop a procoagulant phenotype, thereby sickle erythrocyte due to HbS polymer, oxidant
attracting adhesive erythrocytes, leukocytes, and radical generation, and the exposure of epitopes
platelets. Together, intrinsic features in the sickle that facilitate the interaction of sickle cells with
RBC, like polymer content, and extrinsic factors endothelium and macrophages. Intravascular
from their environment, like endothelial injury, hemolysis, which makes up 33 % percent of
may result in decreased blood flow and vasooc- all hemolysis, is accompanied by the liberation
Sickle Cell Disease 291
of free hemoglobin that scavenges nitric oxide altering the basic pathophysiology of the disease
(NO) promoting vasoconstriction and inflam- [10]. The sole available pathophysiological-
mation. Certain complications of disease are based treatment is hydroxyurea (HU, also known
strongly correlated with the intensity of intravas- as hydroxycarbamide), which increases HbF
cular hemolysis, NO depletion, and proliferative concentration [11–23]. Mechanistically, HU is
vasculopathy [7, 8]. Complications associated cytotoxic, causing erythroid regeneration and
with intravascular hemolysis include pulmonary selection of erythroid progenitors that synthe-
hypertension (due to vasoconstriction secondary size HbF; it may also lead to augmented γ-globin
to loss of NO), which affects up to 10 % of adults gene expression via a NO-mediated increase in
and is a leading cause of SCD mortality; skin cGMP [24], thus increasing HbF synthesis. Since
ulceration, usually around the ankles; priapism, HbF interferes with HbS polymerization, induc-
a prolonged undesirable painful erection (e.g., ing sufficiently high levels in most or all sickle
due to venous outflow occlusion in the penis RBCs should “cure” SCD; unfortunately, this is
because of reduced NO bioavailability), seen in not yet possible clinically [25]. HU is effective
40 % of men; and renal failure (due to kidney in reducing many of the complications of SCD
overload with degradation products). and prolongs life in SCD patients. It should be
Vasoocclusion and hemolysis provoke the given to nearly all patients homozygous for the
majority of clinical complications of SCD [9]. HbS gene starting very early in life. Although
“Sickle crises,” episodes of excruciating pain that its adverse effects in adults are minor, the long-
is likely to be initiated by sickle vasoocclusion term consequences of decades of use in children
and lasts hours to days, occur in most patients started on therapy in the first years of life have
with varying frequencies. Exactly why these yet to be assessed.
attacks occur is not known, but they are presumed An additional therapeutic approach is chronic
to originate from sickle vasoocclusion with sub- blood transfusion, which is tedious and includes
sequent inflammation. The acute chest syndrome, risks such as iron overload, alloimmunization (an
a vasooclusive episode of the lung of sickle cell immune reaction against the “foreign” blood),
disease patients often precipitated by necrotic and viral infection [26, 27]. Finally, hematopoi-
bone marrow emboli and infection among other etic stem-cell transplantation in children (and to
causes, is characterized by fever, chest pain, some extent in adults) can cure SCD [28]. Its
wheezing, cough, hypoxia, lung infiltrate, and a major difficulties lie in the lack of suitable bone
mortality rate of about 5 %. Osteonecrosis of the marrow donors (<10 %) and a 5–10 % mortality
hip and shoulder joints affects about half of all [28, 29].
patients and can progress to loss of joint func-
tionality. Osteonecrosis and bone marrow emboli
are likely caused by microvascular occlusion. Perspectives
Another major complication of sickle cell anemia
is stroke, caused by stenosis and vessel occlusion Although HU is generally successful, its effects
in children; hemorrhagic stroke is more common are inconsistent. Thus, new agents that induce
in adults. higher levels of HbF more consistently by remod-
eling chromosomal structure, like short-chain
fatty acids and their derivatives, or affect hypo-
Introduction to Treatment, methylation of the HbF gene promoters, like
Influence on Metabolism, decitabine, are currently undergoing clinical tri-
and Consequences for Patients als [30].
Drugs that target other aspects of sickle cell
Most treatments for SCD, such as fluid replace- pathophysiology like RBC dehydration, NO dys-
ment and opioid analgesics for acute and some- regulation, and inflammation might provide suc-
times chronic pain, only relieve symptoms without cessful adjunct therapy in the future.
292 D.A. Dworkis and M.H. Steinberg
Reducing the leak of potassium and water from hemoglobin S at physiologic ligand saturations. Proc
Natl Acad Sci U S A 90:5039–5043
the RBC (by using Gardos or K:Cl channel block-
5. Joiner CH, Gallagher PG (2009) The erythrocyte
ers, Fig. 1) may prevent dehydration and retard membrane. In: Steinberg MH, Forget BG, Higgs DR,
polymer formation by reducing HcblbS concen- Nagel RL (eds) Disorders of hemoglobin: genetics,
tration. However, as this approach is accompanied pathophysiology, and clinical management. Cambridge
University Press, Cambridge
by a reduction in hemolysis, it must be coupled
6. Conran N, Costa FF (2009) Hemoglobin disorders
with a concomitant increase in HbF to prevent and endothelial cell interactions. Clin Biochem 42:
viscosity-associated complications. Agents that 1824–1838
improve the bioavailability of NO, like arginine, 7. Reiter CD, Wang X, Tanus-Santos JE, Tanus-Santos
JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin
nitrite, and sildenafil (a phosphodiesterase-5
MT (2002) Cell-free hemoglobin limits nitric oxide
inhibitor, increasing the available cGMP and thus bioavailability in sickle-cell disease. Nat Med
the downstream effects of NO), may also be useful 8:1383–1389
[31]. Drugs that have anti-inflammatory properties 8. Kato GJ, Gladwin MT, Steinberg MH (2007)
Deconstructing sickle cell disease: reappraisal of the
may reduce the endothelial damage and SCD vas-
role of hemolysis in the development of clinical sub-
culopathy (Fig. 1) [32]. phenotypes. Blood Rev 21:37–47
Ultimately, gene therapy is a chief hope for 9. Steinberg MH (2011) In the clinic. Sickle cell disease.
treating SCD. Recent studies using lentiviral vec- Ann Intern Med 155:ITC31–15
10. Bartolucci P, Galacteros F (2012) Clinical manage-
tors for transducing erythroid progenitors with a
ment of adult sickle-cell disease. Curr Opin Hematol
“therapeutic” gene have brought this objective 19:149–155
closer to realization, but additional study is 11. Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B,
required [33, 34]. Nathan DG (1984) Hydroxyurea enhances fetal
hemoglobin production in sickle cell anemia. J Clin
When last carefully studied in the 1990s, the
Invest 74:652–656
median survival of SCD patients in the United 12. Dover GJ, Humphries RK, Moore JG, Ley TJ, Young
States was between 40 and 60 years, depending NS, Charache S, Nienhuis AW (1986) Hydroxyurea
on the genotype of disease. Nowadays, when induction of hemoglobin F production in sickle cell
disease: relationship between cytotoxicity and F cell
well managed, nearly all children survive to age
production. Blood 67:735–738
20 years. The impact of new treatment cannot be 13. Steinberg MH, Lu ZH, Barton FB, Terrin ML,
assessed, but earlier and more widespread use of Charache S, Dover GJ (1997) Fetal hemoglobin in
HU and better adherence to this treatment, along sickle cell anemia: determinants of response to
hydroxyurea. Multicenter Study of Hydroxyurea.
with continued improvement in supportive care,
Blood 89:1078–1088
might be expected to further improve the 14. Bridges KR, Barabino GD, Brugnara C, Cho MR,
outlook. Christoph GW, Dover G, Ewenstein BM, Golan DE,
Guttmann CR, Hofrichter J, Mulkern RV, Zhang B,
Eaton WA (1996) A multiparameter analysis of sickle
erythrocytes in patients undergoing hydroxyurea ther-
References apy. Blood 88:4701–4710
15. Cokic VP, Andric SA, Stojilkovic SS, Noguchi CT,
1. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ Schechter AN (2008) Hydroxyurea nitrosylates and
(2009) Disorders of hemoglobin: genetics, pathophys- activates soluble guanylyl cyclase in human erythroid
iology, clinical management, 2nd edn. Cambridge cells. Blood 111:1117–1123
University Press, Cambridge 16. Cokic VP, Beleslin-Cokic BB, Tomic M, Stojilkovic
2. Goldsmith JC, Bonham VL, Joiner CH, Kato GJ, SS, Noguchi CT, Schechter AN (2006) Hydroxyurea
Noonan AS, Steinberg MH (2012) Framing the induces the eNOS-cGMP pathway in endothelial
research agenda for sickle cell trait: building on the cells. Blood 108:184–191
current understanding of clinical events and their 17. Lanaro C, Franco-Penteado CF, Albuqueque DM,
potential implications. Am J Hematol 87:340–346 Saad ST, Conran N, Costa FF (2009) Altered levels of
3. Steinberg MH, Sebastiani P (2012) Genetic modifiers cytokines and inflammatory mediators in plasma and
of sickle cell disease. Am J Hematol 87:824–826 leukocytes of sickle cell anemia patients and effects of
4. Poillon WN, Kim BC, Rodgers GP, Noguchi CT, hydroxyurea therapy. J Leukoc Biol 85:235–242
Schechter AN (1993) Sparing effect of hemoglobin F 18. Charache S, Terrin ML, Moore RD, Dover GJ, Barton
and hemoglobin A 2 on the polymerization of FB, Eckert SV, McMahon RP, Bonds DR (1995)
Sickle Cell Disease 293
Effect of hydroxyurea on the frequency of painful cri- 26. Wayne AS, Kevy SV, Nathan DG (1993) Transfusion
ses in sickle cell anemia. N Engl J Med 332: management of sickle cell disease. Blood
1317–1322 81:1109–1123
19. Steinberg MH, Barton F, Castro O et al (2003) Effect 27. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F (2012)
of hydroxyurea on mortality and morbidity in adult Red blood cell alloimmunization in sickle cell dis-
sickle cell anemia: risks and benefits up to 9 years of ease: pathophysiology, risk factors, and transfusion
treatment. JAMA 289:1645–1651 management. Blood 120:528–537
20. Steinberg MH, McCarthy WF, Castro O, Pegelow 28. Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan
CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, CD, Kurlander R, Childs RW, Rodgers GP, Powell JD,
Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Tisdale JF (2009) Allogeneic hematopoietic stem-cell
Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, transplantation for sickle cell disease. N Engl J Med
Saunthararajah Y, Telfer M, Vichinsky E, Claster S, 361:2309–2317
Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin 29. Atkins RC, Walters MC (2003) Haematopoietic cell
M (2010) The safety and effectiveness of hydroxyurea transplantation in the treatment of sickle cell disease.
in sickle cell anemia: a 17.5 year follow-up. Am J Expert Opin Biol Ther 3:1215–1224
Hematol 85:403–408 30. Wilber A, Nienhuis AW, Persons DA (2011)
21. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Transcriptional regulation of fetal to adult hemoglo-
Minniti CP, Rana S, Thornburg CD, Rogers ZR, bin switching: new therapeutic opportunities. Blood
Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, 117:3945–3953
Howard TH, Wynn LW, Kutlar A, Armstrong FD, 31. Canalli AA, Franco-Penteado CF, Saad ST, Conran N,
Files BA, Goldsmith JC, Waclawiw MA, Huang X, Costa FF (2008) Increased adhesive properties of neu-
Thompson BW (2011) Hydroxycarbamide in very trophils in sickle cell disease may be reversed by
young children with sickle-cell anaemia: a multicen- pharmacological nitric oxide donation. Haematologica
tre, randomised, controlled trial (BABY HUG). 93:605–609
Lancet 377:1663–1672 32. Kotiah SD, Ballas SK (2009) Investigational drugs in
22. Voskaridou E, Christoulas D, Bilalis A, Plata E, sickle cell anemia. Expert Opin Investig Drugs
Varvagiannis K, Stamatopoulos G, Sinopoulou K, 18:1817–1828
Balassopoulou A, Loukopoulos D, Terpos E (2009) 33. Pawliuk R, Westerman KA, Fabry ME, Payen E,
The effect of prolonged administration of hydroxy- Tighe R, Bouhassira EE, Acharya SA, Ellis J, London
urea on morbidity and mortality in adult patients with IM, Eaves CJ, Humphries RK, Beuzard Y, Nagel RL,
sickle-cell syndromes: results of a 17-year, single cen- Leboulch P (2001) Correction of sickle cell disease in
ter trial (LaSHS). Blood 115:2354–2363 transgenic mouse models by gene therapy. Science
23. Thornburg CD, Files BA, Luo Z, Miller ST, Kalpatthi 294:2368–2371
R, Iyer R, Seaman P, Lebensburger J, Alvarez O, 34. Cavazzana-Calvo M, Payen E, Negre O, Wang
Thompson B, Ware RE, Wang WC (2012) Impact of G, Hehir K, Fusil F, Down J, Denaro M, Brady
hydroxyurea on clinical events in the BABY HUG T, Westerman K, Cavallesco R, Gillet-Legrand
trial. Blood 120:4304–4310 B, Caccavelli L, Sgarra R, Maouche-Chrétien
24. Almeida CB, Scheiermann C, Jang JE, Prophete C, L, Bernaudin F, Girot R, Dorazio R, Mulder GJ,
Costa FF, Conran N, Frenette PS (2012) Hydroxyurea Polack A, Bank A, Soulier J, Larghero J, Kabbara
and a cGMP-amplifying agent have immediate bene- N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier
fits on acute vaso-occlusive events in sickle cell dis- N, Aubourg P, Fischer A, Cornetta K, Galacteros F,
ease mice. Blood 120:2879–2888 Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-
25. Sankaran VG (2011) Targeted therapeutic strategies Abina S, Leboulch P (2010) Transfusion indepen-
for fetal hemoglobin induction. Hematology Am Soc dence and HMGA2 activation after gene therapy of
Hematol Educ Program 2011:459–465 human beta-thalassaemia. Nature 467:318–322
Hyperlipidemia
(13 ) Food
Nascent (1)
HDL
[LCAT]
(12)
Fig. 1 An outline of lipoprotein metabolism. (1) Food in target tissues to deliver cholesterol to sites of need. This
containing lipids (including fatty acids and cholesterol) as requires apoB100. (8) LDLs can be transported back to the
energy source and structural components of the body are liver and are taken up via similar receptors, using apoB100.
ingested and absorbed. (2) Triglycerides (TGs), choles- (9) Excess free cholesterol (FC) is transported from the
terol, phospholipids, and apolipoproteins B48 (apoB48) tissues to the liver via high-density lipoprotein (HDL).
and A1 are released from enterocytes as chylomicrons in Lecithin-cholesterol acyltransferase [LCAT] is required to
the lymphatic flow. Blue arrows indicate flow of TGs, integrate cholesterol and enlarge HDLs. (10) HDLs origi-
black arrows indicate flow of cholesterol or its derivatives, nally are created from the liver and contain apoA1 from
and green arrows indicate flow of apos. (3) In the capil- the liver or small intestine and FC from the liver. FCs were
lary endothelium of various tissues, lipoprotein lipase exported using the ATP-binding cassette transporter
(LPL) releases TGs from chylomicrons and generates free (ABCA) 1, also known as cholesterol efflux regulating
fatty acids (FA) and glycerol. Continuation of this process protein. (11) HDL transfers cholesterol to VLDL and chy-
yields remnants consisting primarily of cholesterol. (4) lomicrons as cholesteryl esters (CE) with the help of cho-
The remnants are taken up by the liver via low-density lesteryl ester transfer protein (CETP). (12) CE are cleared
lipoprotein (LDL) receptors (using apoE) or the heparan from HDLs in the liver via scavenger receptors. (13)
sulfate-LRP receptor. (5) The liver synthesizes very-low- Finally, cholesterol can be converted to bile acids in the
density lipoproteins (VLDL) to carry TGs to target tissues. liver to remove cholesterol from the body. Bile is excreted
VLDLs also contain apoB100. (6) Removal of TGs from into the small intestine where it also aids in the uptake of
VLDL or uptake of cholesteryl esters (see below) creates lipids, closing the circle. LRP low-density lipoprotein
LDLs, rich in cholesterol. (7) LDLs are taken up by cells receptor-related protein
Hyperlipidemia 297
remnants. These remnants carry cholesterol an atheroma develops with a fibrous cap overly-
absorbed from the gut and transferred from ing a cholesterol lake formed by necrosis and
smaller lipoproteins by cholesteryl ester transfer apoptosis of foam cells. Foam cells can also pro-
protein (CETP, see below). They are removed duce collagenase, which contributes to the likeli-
from the circulation via the liver [2, 3]. This hood of atheromatous lesions rupturing in regions
receptor-mediated clearance depends on apoE on where foam cells are active. Thrombosis on the
the remnants, which is acquired from HDLs ruptured surface of atheroma is a major cause of
(Fig. 1). In health, the whole process occurs acute cardiovascular events, such as acute coro-
within a few hours of ingesting food. nary syndrome and stroke.
LDL must, however, undergo atherogenic
modification such as oxidation, glycation, or gly-
Very-Low-Density Lipoprotein coxidation before its uptake by macrophage scav-
enger receptors is rapid enough for foam cell
VLDLs are triglyceride-rich lipoproteins secreted formation.
by the liver. The major role of VLDL is to trans-
port endogenously produced TGs to the target tis-
sues. Its TGs, like those of chylomicrons, are High-Density Lipoprotein
removed during circulation by LPL displayed on and Reverse Cholesterol Transport
the capillary endothelium of adipose tissue, skel-
etal and cardiac muscle, and lactating breast. High-density lipoprotein (HDL) is the principal
route for transporting cholesterol from tissues to
the liver. It is the smallest and most abundant
Low-Density Lipoprotein lipoprotein. HDL is rich in phospholipids and
cholesterol. It receives excess cholesterol from
Removal of TGs and/or uptake of cholesterol via peripheral tissues and free cholesterol exported
CETP convert VLDL to a cholesterol-rich smaller from the liver and protects LDL from chemical
lipoprotein termed low-density lipoprotein (LDL). modifications [2, 4]. Normally, free cholesterol is
LDL crosses the capillary endothelium and sup- esterified by LCAT in the outer layer of the HDL,
plies cholesterol to the tissues by endocytosis after allowing entrance to the hydrophobic particle
binding to cell-surface LDL receptors, which are core, permitting further uptake of free cholesterol
expressed when cholesterol is required for mem- into its surface. Without this process, HDL can-
brane growth, for repair, or for steroid synthesis. not enlarge sufficiently to escape filtration and
Thus, LDL delivers cholesterol to the tissues. loss through the kidneys [2]. Physiologically,
The liver also expresses LDL receptors and is cholesteryl ester can be cleared from HDL via
the major organ of LDL catabolism in adulthood. scavenger receptor B1 in the liver or transferred
Cholesterol entering liver by this route can be to larger lipoproteins, via CETP [2, 4].
eliminated as biliary cholesterol or bile salts.
LDL can also enter macrophages located in
the arterial wall contributing to atherosclerosis Apolipoproteins
(see chapter “Atherosclerotic heart disease”).
These macrophages are derived from blood The apoB proteins are essential for the assembly
monocytes crossing the vascular endothelium. In and release of chylomicrons and VLDL by gut and
the arterial subintima these macrophage- liver, respectively. More specifically, apoB48 is pro-
monocytes take up LDL to become foam cells duced by the small intestine and is present in chylo-
initiating fatty streak formation [2]. Subsequently, microns, where it is important for efficient lipid
298 P. Durrington and H. Soran
absorption, chylomicron formation, and metabo- Increased LDL cholesterol (LDLc, ≥2 mmol/l)
lism. ApoB100 produced by the liver is present on presents a major risk factor for cardiovascular
VLDL and LDL and mediates binding to the LDL disease (CVD) in western societies, where even
receptor on hepatocytes leading to LDL clearance. the mean values are unhealthy (common hyper-
As apoE also binds to the LDL receptor, chylo- cholesterolemia, see Table 1). This does not
micron remnants can, despite their lack of cause immediate clinical features but can result
apoB100, be cleared by LDL receptor as well as in corneal arcus, a peripheral corneal opacity.
by a multiligand receptor (heparan sulfate-low Hypertriglyceridemia (increase in serum TGs,
density lipoprotein receptor-related protein, see HTG, ≥1.7 mmol/l) occurs independently or
Fig. 1). ApoA1 is the main apolipoprotein in HDL combined with raised LDLc.
and is secreted by hepatocytes and intestinal
enterocytes. ApoA1 is important for the structural
integrity and function of HDL, including the Polygenic Hyperlipidemias
receptor-mediated release of cholesteryl ester to
hepatocytes during its passage through the liver. The great majority of hyperlipidemia patients
harbor polymorphisms predisposing them to
raised LDLc, which only manifests when com-
Various Hyperlipidemias, Molecular bined with nutritional excess [2–8]. Both, obesity
Origin, and Changes in Metabolism and high-fat/cholesterol intake increase the like-
lihood of raised LDLc.
Several disorders are grouped under the term When HTG occurs on its own and in
“hyperlipidemia” (Table 1) [1, 2, 5, 6]. combination with hypercholesterolemia within
to carbohydrates (e.g., fructose), which may induce levels and future risk of atherosclerotic CVD
HTG and may also raise serum urate levels. events [10, 12, 13]. In patients with established
Hypothyroidism can cause both hypercholes- atherosclerotic CVD, diabetes mellitus, mono-
terolemia because of decreased receptor- genic hyperlipidemia, and severe HTG, drug
mediated LDL catabolism and HTG because of treatment is indicated without multifactorial risk
decreased TGs clearance, probably mediated via evaluation. Lipid modification therapies are con-
decreased LPL activity. Nephrotic syndrome traindicated during pregnancy and breastfeeding.
raises LDLc. Obstructive liver disease is also
associated with high cholesterol, but this is
because of an abnormal, pathological lipoprotein Molecular Mechanism and Influence
(called LpX), which interferes with the uptake of on Metabolism of the Most
chylomicron remnants. LpX occurs when there is Common Lipid-Lowering Drugs
reflux of biliary phospholipids into the circula-
tion as a result of obstruction. Statins
Other inherited disturbances of lipoprotein
metabolism include LCAT deficiency, a cause of Statins inhibit 3-hydroxy-methyl-glutaryl-CoA
low HDL, corneal opacity, and proteinuria and anal- reductase mostly in the liver. This is the rate-
phalipoproteinemia, in which a mutation of ABCA1 limiting enzyme for cholesterol biosynthesis.
(also known as “cholesterol efflux regulating pro- The resulting decrease in intrahepatic cholesterol
tein”) prevents the egress of free cholesterol from leads to enhanced hepatic LDL receptor expres-
the liver leading to almost absent HDL, splenomeg- sion and thus a decrease in circulating LDLc
aly, and occasionally orange-yellow cholesterol [14]. They decrease CVD risk by about one fifth
deposits in the tonsils and rectal mucosa. In con- for every 1 mmol/l decrease in LDL cholesterol,
trast, in familial CETP deficiency, HDLc levels are irrespective of LDL cholesterol levels, making
high, and the HDL particles enlarged. them the most effective means of preventing
CVD [15]. Myositis (muscle inflammation) can
occasionally be a side effect, as can muscle ach-
Treatment of Hyperlipidemias ing and elevations of creatine kinase, which may
affect patient compliance. Co-treatment with
Treatment generally aims at a reduction of LDL agents, such as macrolide antibiotics, which
cholesterol (below 2 mmol/l, or even further in compete for the same degrading enzymes as
high-risk patients to avoid CVD) [9, 10, 12, 13]. statins, should be avoided. Grapefruit juice
Lowering TGs serum levels below 10 mmol/l is should be avoided for the same reason. Statins
important to avoid acute pancreatitis. are also prescribed for patients with HTG and/or
low HDLc as they decrease CVD even when
LDLc is not the principal disorder.
Dietary Treatment
13. Catapano AL, Reiner Z, De Backer G, Graham I, 14. Charlton-Menys V, Durrington PN (2008) Human
Taskinen MR, Wiklund O, Agewall S, Alegria E, cholesterol metabolism and therapeutic molecules.
Chapman M, Durrington P, Erdine S, Halcox J, Hobbs Exp Physiol 93:27–42
R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, 15. Cholesterol Treatment Trialists’ (CTT) Collaborators
Wood D (2011) ESC/EAS guidelines for the manage- (2012) The effects of lowering LDL cholesterol with
ment of dyslipidaemias The Task Force for the man- statin therapy in people at low risk of vascular disease:
agement of dyslipidaemias of the European Society of meta-analysis of individual data from 27 randomised
Cardiology (ESC) and the European Atherosclerosis trials. Lancet 380:581–590
Society (EAS). Eur Heart J 32:1769–1818
Part XIII
Immune System
Overview
Christian Münz
Afferent lymph
Lymph vessel
Naive B-cells and naive T-cells
Affected tissue
Circulating
Naive Circulating
B-cell
Memory B-cells
and plasma cells
T-cell zone
High endothelial
venule B-cell follicle
Fig. 1 Schematic section through a lymph node, a sec- antigen-stimulated B cells affinity mature their B-cell
ondary lymphoid organ. Information on the health of receptor, which will serve as blueprint for the antibody
peripheral tissues is continuously reported to the lymph that will be later secreted by this B cell. The somatically
nodes in the form of the degree and quality of dendritic mutated B-cell receptor has to still recognize the unpro-
cell (DC) activation. Processed peptide antigens are pre- cessed, original antigen, bound on the surface of follicular
sented on the major histocompatibility complex (MHC) DCs via complement or Fc receptors. The B cells still
molecules of DCs. Naive and memory T cells circulate require T cell help (not shown). Only if these two check-
through these organs via extravasation at high endothelial points are passed, the activated B cell will go on to develop
venules and exit through efferent lymph vessels. T cells into a memory cell or an antibody producing plasma cell.
get activated when their T-cell receptors bind to antigens These can also leave the lymph node via efferent lymph,
on activated DCs. T cells get primed (see text), proliferate, and plasma cells often home to the bone marrow or muco-
and differentiate into effector or memory T cells. Effector sal surfaces. Note that the cells are displayed in higher
T cells then home back to the diseased tissue to fight the magnification compared to the lymph node
infection or assist B cells in the germinal center. There,
and the B cell receives signals (“help”) from a T T and B cells emigrate from secondary lym-
cell (that in most cases has to recognize the same phoid tissues via the efferent lymphatics to the
antigen but in a processed form preferential on sites of the harmful insult guided by chemokine
MHC molecules, signal 2), the B cell survives gradients, like the chemokine (C-X-C motif)
this germinal center reaction and can go on to ligand (CXCL) 9 and CXCL10 (Fig. 1). This pro-
develop into a memory B cell or an antibody- cess of immune response initiation is called
secreting plasma cell. priming.
308 C. Münz
Antimicrobial
peptides
Antimicrobial
Virus particle state Cell death
Stromal cells
DAMPs PAMPs
(e.g. ureate crystals, ATP) (e.g. viral fragments)
Interferon-γ IL-22
Perforin/granzyme,
cell death
receptor ligands
MHC
Co-stimulatory
molecules
and cytokines
Fig. 2 Schematic pathway of dendritic cell and T-cell tertiary lymphoid tissues. The T cells then home to the
activation and subsequent cellular changes. The immune tissue to change its intracellular milieu and its secretome
system receives cues from all organs. Stromal cells in an via interferon (IFN) and interleukin (IL) secretion, e.g.,
inflamed or infected tissue can activate dendritic cells IL-22 and IFNγ. Primed T cells also influence the survival
through the release of danger- (DAMPs) and, if infected, of the cells within an inflamed tissue via cell-contact-
pathogen-associated molecular patterns (PAMPs), which dependent cytotoxicity, e.g., via perforin/granzyme or
are, e.g., contained in necrotic cellular debris. Once acti- apoptosis-inducing ligands
vated, dendritic cells can prime T cells in secondary or
secretion of cytokines, acting on the infected of glycolysis and lactate production. Importantly,
or transformed tissue, e.g., IFNγ to inhibit viral glucose is strictly required for T-cell prolifera-
replication, and the expression of cytotoxic tion and cytokine production, even when other
molecules, e.g., perforin-1, to directly destroy metabolic substrates such as glutamine or fatty
the diseased cells. acids are present, likely due to the ability of glu-
Distinct metabolic pathways, such as cose metabolism to consistently generate ATP
macroautophagy [14], are required for T-cell and NADPH and stabilize antiapoptotic proteins
proliferation [15], which also occurs locally in [16]. Moreover, aerobic glycolysis is necessary
infected tissues, presumably to further amplify for T-cell effector function, in particular for
the T-cell response. Oxidative phosphorylation IFNγ production [17]. Finally, whereas most T
generates most ATP in resting T cells. However, cells rely on glycolysis, a subset of T cells (such
activated T cells dramatically increase their rates as regulatory T cells, also called Treg, or CD8+
310 C. Münz
memory T cells) requires fatty acid oxidation, longer recognized as self by the immune system.
showing that energy metabolism influences This is in part explained by the circumstance that
immune responses [16]. the lymphocytes were educated toward a different
steady state. Sometimes the resulting autoimmune
responses are transient, just causing immunopa-
Inside-Out: Communication thology during the infectious or traumatic insult.
of Immune Cells with Stromal Cells However, sometimes, but fortunately rarely, they
result in self-perpetuating autoimmune disease
The effector molecules from polarized T cells are [22], depending in part on the genetic variation
then able to change tissue homeostasis in the of the affected individuals (see, e.g., chapters
inflamed and/or infected organs, from which the “Rheumatoid arthritis” and “Diabetes mellitus”).
DCs carried the antigens to the secondary lym-
phoid organs. A wide variety of responses can be
elicited, ranging from metabolic changes in tar- Final Remarks
get cells to release of antimicrobial peptides, or
to induction of apoptosis. Metabolic changes aim The key physiological function of the immune
to make cells less hospitable for infectious agents system is to defend multicellular organisms
and reduce pathogen replication. For example, against harmful “nonself” by transporting infor-
IFNs can induce an antiviral state in part by mation from organs to secondary lymphoid tis-
inhibiting anabolic pathways required for virus sues and mounting immune responses when this
production [18]. Secretion of antimicrobial pep- information indicates infection or tissue damage.
tides by epithelial cells at mucosal surfaces is Both overshooting (see chapter “Rheumatoid
stimulated by IL-22, which is either secreted by arthritis”) and too cautious immune reactions
innate lymphoid cells or Th17 polarized CD4+ T (see chapter “Community-acquired pneumonia”)
cells [19]. Cell death can be triggered by cyto- lead to disease and are caused by the combination
toxic CD8+ T cells via perforin-mediated gran- of the individual’s genetic predisposition and the
zyme injection into an infected target cell. During environmental conditions.
this process, at least one of the cell death initiat-
ing proteases of the granzyme family enters the
target cell through pores that are formed by per- References
forin. Alternatively, a cytotoxic T cell kills an
infected or transformed cell by activation of its 1. Waterston RH, Lindblad-Toh K, Birney E, Rogers J,
cell death receptors (Fig. 2) [20]. Thus, immune Abril JF, Agarwal P et al (2002) Initial sequencing
and comparative analysis of the mouse genome.
cells can dramatically change cellular physiology Nature 420:520–562
within an inflamed organ. 2. Seok J, Warren HS, Cuenca AG, Mindrinos MN,
Baker HV, Xu W, Richards DR, McDonald-Smith GP,
Gao H, Hennessy L, Finnerty CC, López CM,
Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE,
Miscommunication in the Immune Johnson JL, Sperry J, Nathens AB, Billiar TR, West
System as the Basis of Disease MA, Jeschke MG, Klein MB, Gamelli RL, Gibran
NS, Brownstein BH, Miller-Graziano C, Calvano SE,
The borderline between hyporesponsiveness of Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier
RV, Moldawer LL, Herndon DN, Davis RW, Xiao W,
the immune system resulting in susceptibility to Tompkins RG (2013) Genomic responses in mouse
disease [21] and hyperresponsiveness leading to models poorly mimic human inflammatory diseases.
immunopathology and autoimmunity [22] is not Proc Natl Acad Sci U S A 110:3507–3512
easily defended by the immune system and drawn 3. Kyewski B, Klein L (2006) A central role for central
tolerance. Annu Rev Immunol 24:571–606
by the genetic makeup of the individual. Any sig- 4. Jankovic M, Casellas R, Yannoutsos N, Wardemann
nificant insult that releases DAMPs can change the H, Nussenzweig MC (2004) RAGs and regulation of
organ environment and metabolism so that it is no autoantibodies. Annu Rev Immunol 22:485–501
Overview 311
5. Cyster JG (2005) Chemokines, sphingosine-1-phosphate, 16. Wahl DR, Byersdorfer CA, Ferrara JL, Opipari AW
and cell migration in secondary lymphoid organs. Annu Jr, Glick GD (2012) Distinct metabolic programs in
Rev Immunol 23:127–159 activated T cells: opportunities for selective immuno-
6. Victora GD, Nussenzweig MC (2012) Germinal cen- modulation. Immunol Rev 249:104
ters. Annu Rev Immunol 30:429–457 17. Chang CH, Curtis JD, Maggi LB Jr, Faubert B,
7. van de Pavert SA, Mebius RE (2010) New insights Villarino AV, O’Sullivan D, Huang SC, van der Windt
into the development of lymphoid tissues. Nat Rev GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones
Immunol 10:664–674 RG, Pearce EL (2013) Posttranscriptional control of
8. Martinon F, Mayor A, Tschopp J (2009) The inflam- T cell effector function by aerobic glycolysis. Cell
masomes: guardians of the body. Annu Rev Immunol 153:1239–1251
27:229–265 18. MacMicking JD (2012) Interferon-inducible effector
9. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ mechanisms in cell-autonomous immunity. Nat Rev
(2010) HMGB1 and RAGE in inflammation and can- Immunol 12:367–382
cer. Annu Rev Immunol 28:367–388 19. Sonnenberg GF, Fouser LA, Artis D (2011) Border
10. Trombetta ES, Mellman I (2005) Cell biology of anti- patrol: regulation of immunity, inflammation and tis-
gen processing in vitro and in vivo. Annu Rev sue homeostasis at barrier surfaces by IL-22. Nat
Immunol 23:975–1028 Immunol 12:383–390
11. Steinman RM, Hawiger D, Nussenzweig MC (2003) 20. Lopez JA, Brennan AJ, Whisstock JC, Voskoboinik
Tolerogenic dendritic cells. Annu Rev Immunol I, Trapani JA (2012) Protecting a serial killer: path-
21:685–711 ways for perforin trafficking and self-defence ensure
12. Steinman RM (2012) Decisions about dendritic cells: sequential target cell death. Trends Immunol 33:
past, present, and future. Annu Rev Immunol 30:1–22 406–412
13. Sallusto F, Mackay CR, Lanzavecchia A (2000) The role 21. Casanova JL, Abel L, Quintana-Murci L (2011)
of chemokine receptors in primary, effector, and memory Human TLRs and IL-1Rs in host defense: natural
immune responses. Annu Rev Immunol 18:593–620 insights from evolutionary, epidemiological, and clin-
14. Münz C (2009) Enhancing immunity through autoph- ical genetics. Annu Rev Immunol 29:447–491
agy. Annu Rev Immunol 27:423–429 22. Münz C, Lunemann JD, Getts MT, Miller SD (2009)
15. Gerriets VA, Rathmell JC (2012) Metabolic path- Antiviral immune responses: triggers of or triggered
ways in T cell fate and function. Trends Immunol by autoimmunity? Nat Rev Immunol 9:246–258
33:168–173
Fever
Endogenous Exogenous
Pyrogens
IL-1β
LPS
IL-6
TNFα
Arachidonic acid
Aspirin
[COX]
NSAIDs
Blood vessels
PGE2
Hypothalamus
POA
PGE2 Muscle
(shivering)
EP3 BAT Heat
(heat production) (rise in CBT)
Vasculature
Neuron (heat dissipation )
Fig. 1 Schematic representation of the mechanisms Importantly, antipyretic drugs including aspirin and other
involved in fever. Endogenous pyrogens, such as the pro- nonsteroidal anti-inflammatory drugs (NSAIDs) act by
inflammatory cytokines interleukin 1β (IL-1β), IL-6, and inhibiting COX activity. Released PGE2 then acts on neu-
tumor necrosis factor α (TNFα) or exogenous pyrogens rons in the hypothalamic preoptic area (POA) carrying the
such as the bacterial cell wall component lipopolysaccha- prostaglandin E receptor 3 (EP3). These neurons activate
ride (LPS), respectively, stimulate the cellular synthesis of production of heat primarily by activating a shivering
the prostaglandin E2 (PGE2). This involves biochemical reaction in skeletal muscles, heat production in the brown
pathways in the brain vasculature or the periphery caus- adipose tissue (BAT), and affecting heat dissipation by
ing the peroxidation of arachidonic acid causing the per- vasoconstriction in the periphery
oxidation of arachidonic acid by cyclooxygenase (COX).
Fever 315
a major contributor to treatment failure and mor- It is important to note that COXs do not partic-
tality [7–9]. Several endogenous pyrogens con- ipate uniquely in the synthesis of PGE2, but also
tribute to cachexia, including TNFα [10]. of other prostaglandins and inflammatory media-
On an exactly opposite side, it is interesting tors as well. At least two isoforms of cyclooxy-
to notice that recently the strategy to increase genases exist, termed COX-1 and COX-2, which
energy dissipation in the form of heat is being are constitutively or inducibly expressed, respec-
regarded as an attractive approach to treat obe- tively, and present in different cells and tissues.
sity and the metabolic syndrome (see chap- These differences are important when consider-
ter “Metabolic syndrome”). This was recently ing the side effects of distinct COX inhibitors
spurred by the confirmation that adult humans and explain the ongoing search for further anti-
retain active brown adipose tissue previously pyretics. For instance, aspirin irreversibly inhib-
believed to be significant only in infants. This its COX-1 by covalently linking to it, yet it also
mitochondria-rich tissue specializes in thermo- modifies the enzymatic activity of COX-2 [13].
genesis by uncoupling of the mitochondria elec- Since inhibition of COX-1 also reduces the
tron transport chain required for the production PGE2-dependent buffering activity that carbon-
of ATP, via the activation of uncoupling pro- ate has on gastric acidity, prolonged inhibition
tein 1 (UCP1). Several laboratories around the of this enzyme can have gastric side effects lead-
world are actively investigating the possibility of ing to bleeding ulcers (see chapter “Peptic ulcer
increasing the amount of brown adipose tissue or disease”). The most often used antipyretic drug
its activation for therapeutic purposes [11, 12]. today is ibuprofen, a nonselective COX inhibitor
(that also belongs to the NSAIDs) that inhibits
both COX-1 and COX-2. It is efficacious and
Introduction to Treatment safe, except for similar gastric side effects (as
and Influence on Metabolism mentioned above). Selective COX-2 inhibitors
(such as Vioxx, Celebrex, Bextra) without gas-
Adults with healthy cardiovascular and respira- tric side effects have been developed as arthritis
tory systems, who experience fever as a result of drugs (see chapter “Osteoarthritis”), although
a bacterial infection (usually for a few days), can they are also efficacious antipyretics. However,
withstand it safely without antipyretic drugs. But their use has been discouraged by adverse
even for these patients, the highly efficacious, effects on the cardiovascular system, leading to
over-the-counter available, cheap drugs have myocardial infarctions. Finally, acetaminophen
become routine use. Infants and small children, (paracetamol) is often used when aspirin and ibu-
who can run very high fever, are almost always profen are ineffective.
given antipyretics. Similarly, aged people are COX inhibitors have also been tested in treat-
invariantly treated because of suspected or mani- ing cachexia. It should, however, be mentioned
fest cardiovascular and respiratory weaknesses. that although fever is an important component
Antipyretic (fever-lowering) drugs have of this wasting syndrome, other factors also con-
been available and used long before the mecha- tribute to it. With respect to this, an important
nisms of fever and those of antipyretic drugs approach is the attempt to normalize the levels of
were understood. The most famous member of TNFα, which contribute to elevated temperature
the class, which is also called nonsteroidal anti- but can also damage tissues directly.
inflammatory drugs (NSAIDs), is acetylsalicylic It should also be noted that hyperthermia does
acid (aspirin), an inhibitor of cyclooxygenases not respond to antipyretic drugs that act by reset-
(COXs, see below). Synthesis of PGE2 requires ting the thermostat. In fact, hyperthermia is com-
the enzymatic peroxidation of arachidonic acid, monly treated by direct cooling with cold water
a reaction catalyzed by COXs, and, as fever is or ice to prevent excess heat from causing a cir-
ultimately mediated by PGE2, lowering their culatory collapse. Drug-induced hyperthermia is
level represents an effective antipyretic strategy. now treated with the muscle relaxant dantrolene.
Fever 317
Release of
endogenous Release of
catecholamines cortisol and IGF-1
Endogenous glucose
production
During sepsis, inflammatory mediators substrate in the muscle. However, the composi-
(including cytokines such as TNFα and IL-1, tion and amount of nutrition provided can largely
released by activated immune cells to counter- influence the size of the fat compartment, when
act the infection) and adipokines (such as leptin de novo lipogenesis occurs in case of excessive
and resistin released from adipose tissue) induce caloric intake.
and perpetuate insulin resistance and thus trig-
ger hyperglycemia [3]. They act by reducing
insulin receptor expression in peripheral tissues. Influence of Treatment on
Additionally, counter-regulatory hormones (cor- Metabolism and Consequences
tisol, glucagon, and growth hormones), which for Patients
are massively released during the early phase of
sepsis, and increased sympathetic drive also con- The first aim is to remove the causative agent
tribute to hyperglycemia. activating the stress response and causing sepsis.
In addition to hyperglycemia, the conse- Generally, sepsis treatment includes early and
quences of insulin resistance include decreased appropriate antimicrobial agents and the eradica-
uptake of glucose in insulin-dependent tissues tion of abscesses or septic foci, e.g., via surgical
(fat and muscle); increased glycogen breakdown measures.
and endogenous glucose production (gluconeo- As regards metabolism, there is no single spe-
genesis) from lactate, glycerol, and alanine; cific treatment for the metabolic changes induced
increased lipolysis; and protein breakdown. by sepsis. To avoid severe hyperglycemia, intra-
Insulin resistance increases and prolongs the sup- venous insulin is recommended, based on the
ply of glucose to tissues and cells essential for deleterious long-term effects of elevated glucose
survival (such as brain, heart, immune cells, and concentrations on several cell types, including
erythrocytes), as these do not depend on insulin. the immune cells [4]. A physiological level of
For example, glucose is the only useable source blood glucose is recommended, and insulin is
of energy for red and white blood cells, including titrated to avoid hyperglycemia, hypoglycemia,
immune and inflammatory cells; the uptake of and high glycemic variability [4]. On the other
glucose in these cells is proportional to the sur- hand, prolonged resistance to insulin is probably
rounding glucose concentration. Thus, some detrimental, as it will result in muscle wasting.
degree of insulin resistance and hyperglycemia is Hence, the use of therapies that increase the
adequate and beneficial. resistance to insulin, such as catecholamines and
Since adipocytes release glycerol, and skeletal steroids, should be limited in duration and dose
muscle releases glucogenic amino acids, the liver [5, 6]. Finally, some non-glycemic effects of
can use these substrates to produce more glucose insulin could also play a role in the improvement
via gluconeogenesis. of outcome of patients with sepsis [7].
Glucose is used as the primary fuel by the Nutritional support should provide an ade-
insulin-independent tissues during the first acute quate, but not excessive, amount of calories and
phase of sepsis. proteins, enteral if possible (to be more physio-
logic), but parenteral if necessary [8].
Physiological activity limits muscle wasting
Changes in Body Composition and long-term consequences of the metabolic
alterations of sepsis, such as intensive care unit-
Following these metabolic adaptations is a change acquired weakness [9]. The use of anabolic drugs
in body composition. The fat compartment may potentially limit the devastating conse-
decreases when sepsis is prolonged, reflecting the quences of prolonged catabolism, but risks asso-
consumption of glycerol as a gluconeogenic sub- ciated with these drugs, such as increased insulin
strate and of fatty acids as an alternative energy resistance, limit their usefulness.
322 J.-C. Preiser and J.-L. Vincent
Introduction to Allergies in the long term. The risk factors include family
history of allergy/genetic factors and environ-
During an allergic reaction, the immune system mental factors such as exposures to allergens and
reacts to normally harmless foreign substances microbes. However, a number of studies show
such as pollen, medications, food, or animal dan- conflicting data for the latter, suggesting that the
der. Although allergic reactions can principally interaction of certain allergens and infectious
take place in all organs, the primary target organs agents with the immune system is complicated.
are the skin, respiratory system, gastrointestinal Nonetheless, a dramatic increase in allergic dis-
tract, and eyes. Depending on the organs involved, eases in industrialized countries over the last sev-
symptoms of allergic reactions include nasal con- eral decades implicates environmental factors as
gestion, eczema, pruritus, cough, chest tightness, a major contributor. Allergic diseases affect up to
wheezing, dyspnea, and vomiting. In case of ana- 30 % of the population in these countries, result-
phylaxis, a potentially fatal severe allergic reaction, ing in high economical burden of the diseases.
cardiovascular changes resulting in hypotension
and tachycardia can additionally occur. Allergic
diseases are characterized by immune responses Pathophysiology of Allergies
predominantly driven by T-helper-2 (Th2) cells, and Metabolic Alterations
which activate many immune cells to produce
and release different inflammatory mediators dur- The immune mechanisms underlying allergic dis-
ing an allergic reaction (see chapter “Overview” eases could be summarized into two main phases,
under the part “Immune system”). Apart from the sensitization phase and the effector phase
allergen avoidance, the treatment principles are (Fig. 1). The sensitization phase takes place when
neutralization of these mediators particularly in an individual is exposed to the allergen for the
the short term and restoration of immune balance first time. Protein antigens are first processed into
between Th2 cells and other lymphocyte subsets peptides for presentation on major histocompat-
like T-helper-1 (Th1) or regulatory T (Treg) cells ibility complex (MHC) molecules on the surface
of antigen-presenting cells, most importantly
dendritic cells (DCs), to induce an immune or
N. Meyer (*) • J. Yun allergic response (see chapter “Overview” under
Division of Allergology, the part “Immune system”). DCs are present in an
Clinic for Rheumatology and Clinical Immunology/ epithelial cell layer, e.g., in the skin or lung [1].
Allergology, University of Bern,
When allergens enter the body, they have to
Bern CH-3010, Switzerland
e-mail: norbert.meyer@insel.ch; cross the epithelial cell layer. During this step,
james.j.yun@gmail.com they can activate receptors of the innate immune
Late phase
Allergen
DC
Epithelial barrier
Th17
Th2 Th1
Lymph node
B-cell Activation
Isotype switch Eosinophil Mast Basophil
cell
FcεR1
Mast + IgE
Plasma cell Basophil
cell
Fig. 1 Overview of a typical allergic reaction. The sen- prostaglandins, and leukotrienes initiating the early
sitization phase (left) leads to the generation of allergen- reactions of the effector phase. After a few hours, during
specific Th2 cells, which induce the production of the late-phase reaction, T helper cells, such as Th2-,
allergen-specific immunoglobulin E (IgE) by B cells. Th1-, and Th17 cells, recruited from the circulation,
Reexposure to the allergen initiates the effector phase enhance the local tissue inflammation causing contin-
(right) and causes cross-linking of the IgE-FcεRI com- ued inflammation, epithelial apoptosis, and vasoperme-
plexes on sensitized basophils and mast cells, which ability. DC dendritic cell, IL interleukin, IFN interferon.
activates them. This activation causes release of various Note that the cells are displayed in higher magnification
pro-inflammatory cytokines and chemokines, most compared to the lymph node
notably histamine, tumor necrosis factor α (TNFα),
system, such as Toll-like receptors, on epithelial peptides (see chapter “Overview” under the part
cells, which subsequently release several cyto- “Immune system”). Naive T cells did not have
kines affecting DCs [2]. For example, epithelial any contact with antigens before. In the lymph
cells secrete thymic stromal lymphopoietin or nodes, DCs secrete cytokines like IL-4, which
interleukin-25 (IL-25), which activates DCs to induce differentiation from naive T cells into Th2
secrete cytokines that induce and enhance Th2 cells. This is followed by the selective expansion
responses. After the allergen is taken up, pro- of allergen-specific Th2 cells that secrete mainly
cessed, and presented by DCs, these move to the IL-4, IL-5, IL-9, IL-13, and granulocyte macro-
regional lymph nodes, where naive CD4-positive phage colony-stimulating factor (GM-CSF), in
(CD4+) T lymphocytes recognize the presented order to increase the activity of several immune
Allergies 325
cells (e.g., mast cells, basophils, B cells) during receptor 1 and 2, the first of which has important
the allergic inflammation. Th2 cells then travel to functions during the induction of allergic inflam-
the initial site of allergen exposure. In the periph- mation in the lung or skin.
ery, a wide range of antigen-specific B cells is During the early effector phase, adhesion
normally present and produces immunoglobulin molecules appear on the surface of endothelial
(Ig) M and D antibodies. When these B cells are cells to recruit inflammatory cells like lympho-
activated by IL-4 and IL-13 released by Th2 cells, cytes and eosinophils, which enhance the aller-
they undergo “isotype switching” to produce gic reaction after 4–12 h (late effector phase).
mainly allergen-specific immunoglobulin E (IgE) Th2 cells are still present during the effector
rather than other immunoglobulin isotypes [3]. phase and release cytokines to enhance the func-
The secreted allergen-specific IgEs then bind to tion of immune cells implicated in the effector
the high-affinity IgE receptor (FcεRI) expressed phase. For example, IL-9 and IL-13 increase
on the surface of mast cells and basophils, lead- mast cell growth, and IL-3 and GM-CSF
ing to sensitization. enhance eosinophil maturation and survival and
Reexposure with the allergen triggers the basophil recruitment [3]. In addition, Th2 cyto-
effector phase of allergy, which could be divided kines also play a key role in mucus production
into an early and late phase. Re-exposure causes and smooth muscle contraction in the airways
cross-linking of the IgE-FcεRI complexes on during allergic asthma (see chapter “Asthma”).
sensitized basophils and mast cells and triggers Continuous presence of allergens results in
their activation and subsequent rapid release of chronic and more severe allergic inflammation
mediators like histamine, leukotrienes, prosta- (the late phase of allergies), which is character-
glandins, cytokines, chemokines, and growth ized by the activation of other effector T-cell
factors, a response also known as degranula- subsets like Th17- and Th1 cells, which further
tion. Histamine derived from the amino acid contribute to the allergic inflammation [5]. Th1
histidine through decarboxylation is one of the cells secrete interferon-γ which induces apop-
major inflammatory mediators during the effec- tosis of epithelial cells in the lung, nose, or
tor phase. After binding to histamine receptor, skin exacerbating the effector phase. Th17 cells
it activates phospholipase C and the phosphati- secrete IL-17, which enhances the secretion of
dylinositol pathway and causes vasodilatation, pro-inflammatory cytokines like IL-6 by epithe-
pruritus, bronchoconstriction, tachycardia, and lial cells. Basophils, mast cells, and eosinophils
flushing, symptoms characteristic of allergies. also play a role during the late-phase reaction.
While there are four types of histamine receptors, They secrete factors, which enhance local tissue
predominantly H1 receptors, and to lesser extent inflammation, vasopermeability, and attraction
H2 receptors, are responsible for these actions. of other inflammatory immune cells.
H1 receptors are abundantly expressed through- Upon allergen exposure, some individuals may
out the body, but receptor activation in smooth experience anaphylaxis due to sudden release of
muscle and vascular endothelial cells is mainly mediators from mast cells and basophils. A num-
responsible for these symptoms [4]. ber of mediators including histamine, tryptase,
Another class of inflammatory mediators, platelet-activating factor, and leukotrienes as
the leukotrienes, is derived from arachidonic well as complement and coagulation pathways
acid. There are two types of leukotrienes: the are involved. When these mediators are released
dihydroxy acid leukotrienes, predominantly in large quantity, they can cause sudden changes
produced by neutrophils, and the cysteinyl leu- in the cardiovascular and respiratory system
kotrienes, mainly secreted by activated eosino- resulting in hypotension, tachycardia, hypovole-
phils, mast cells, and basophils [3]. Cytokines mia due to increased vascular permeability, bron-
released by Th2 cells enhance eosinophil recruit- chospasm, and angioedema of upper airways.
ment to the tissues and trigger release of leukot- Anaphylaxis requires urgent attention and can be
rienes. Cysteinyl leukotrienes bind to leukotriene fatal if left untreated.
326 N. Meyer and J. Yun
a
Allergen-specific TGF-ß Th2
immunotherapy Treg IL-10
Isotype switch
IL-10 B-cell
IgE IgG4
Eosinophil
Basophil Mast
Mast cell stabilizers (e.g. Cromolyn sodium)
cell
Anti-IgE (e.g. Omalizumab)
Glucocorticoids
Th2
Fig. 2 Overview of the mode of action of allergic disease transforming growth factor β. (b) Several drugs exist to
treatments. (a) During allergen-specific immunotherapy, block the mediators released during allergic inflammation
Treg cells are induced by small, increasing amounts of the or for suppression of inflammatory cells. Glucocorticoids
allergen. Treg cells secrete interleukin-10 (IL-10), which show a broad spectrum of inhibitory potential (but also
shows a direct suppressive effect on Th2 cells, reduces most severe side effects). Antihistamines, mast cell stabi-
immunoglobulin E (IgE) secretion, induces IgG4 secre- lizers, anti-IgE antibodies, and leukotriene antagonists
tion in B cells (their most important effect), and inhibits inhibit specific mediators released or their signaling dur-
other inflammatory cells during allergic reaction. TGF-β ing allergic reactions but are also less effective
allergens for binding to the IgE on FcεRI of mast epinephrine auto-injector should be handed to
cells and basophils and thus acts as a blocking the patient with careful instruction on how and
antibody that decreases IgE-mediated degranula- when to use it.
tion of mast cells and basophils [9].
Finally, other strategies for the treatment of
allergic reactions include injection of humanized Perspectives
anti-IgE antibodies like omalizumab, which
binds to free IgE at the sites used to attach to One of the main tasks in the future is the develop-
FcεRI. As it cannot cross-link IgE bound to its ment of treatment strategies inhibiting specific
receptor, it only inhibits the binding of IgE to cytokines responsible for the allergic reaction.
FcεRI on mast cells and basophils (Fig. 2b) [10]. For example, blocking of Th2 cytokines could
In case of anaphylaxis, the most important provide an effective therapeutic option for allergic
treatment is epinephrine to immediately reverse diseases with fewer adverse effects compared to
vasodilatation and bronchospasm. As anaphy- glucocorticoids. Currently, antibodies antagoniz-
laxis is a potentially life-threatening condition, ing the action of Th2 cytokines are tested in clini-
its administration should not be delayed. When a cal trials but have not yet been approved as drugs
patient is considered at risk of anaphylaxis, an for allergic diseases. Finally, better understanding
328 N. Meyer and J. Yun
of the events involved in the sensitization of aller- B, Kogevinas M, Koppelman GH, Kowalski ML,
gens will be important in preventing the develop- Kull I, Kuna P, Larenas D, Lavi I, Le LT, Lieberman
P, Lipworth B, Mahboub B, Makela MJ, Martin F,
ment of allergic diseases in the first place. Martinez FD, Marshall GD, Mazon A, Melen E,
Meltzer EO, Mihaltan F, Mohammad Y, Mohammadi
A, Momas I, Morais-Almeida M, Mullol J, Muraro A,
Naclerio R, Nafti S, Namazova-Baranova L, Nawijn
References MC, Nyembue TD, Oddie S, O'Hehir RE, Okamoto
Y, Orru MP, Ozdemir C, Ouedraogo GS, Palkonen S,
1. Hammad H, Lambrecht BN (2008) Dendritic cells Panzner P, Passalacqua G, Pawankar R, Pigearias B,
and epithelial cells: linking innate and adaptive immu- Pin I, Pinart M, Pison C, Popov TA, Porta D, Postma
nity in asthma. Nat Rev Immunol 8:193–204 DS, Price D, Rabe KF, Ratomaharo J, Reitamo S,
2. Lambrecht BN, Hammad H (2012) The airway epi- Rezagui D, Ring J, Roberts R, Roca J, Rogala B,
thelium in asthma. Nat Med 18:684–692 Romano A, Rosado-Pinto J, Ryan D, Sanchez-Borges
3. Stone KD, Prussn C, Metcalfe DD (2010) IgE, mast M, Scadding GK, Sheikh A, Simons FE, Siroux V,
cells, basophils, and eosinophils. J Allergy Clin Schmid-Grendelmeier PD, Smit HA, Sooronbaev T,
Immunol 125:S73–S80 Stein RT, Sterk PJ, Sunyer J, Terreehorst I, Toskala
4. Ferstl R, Akdis CA, O’Mahony L (2012) Histamine E, Tremblay Y, Valenta R, Valeyre D, Vandenplas O,
regulation of innate and adaptive immunity. Front van Weel C, Vassilaki M, Varraso R, Viegi G, Wang
Biosci (Landmark Ed) 17:40–53 DY, Wickman M, Williams D, Wöhrl S, Wright J,
5. Bousquet J, Anto JM, Demoly P, Schünemann Yorgancioglu A, Yusuf OM, Zar HJ, Zernotti ME,
HJ, Togias A, Akdis M, Auffray C, Bachert C, Zidarn M, Zhong N, Zuberbier T (2012) Severe
Bieber T, Bousquet PJ, Carlsen KH, Casale TB, chronic allergic (and related) diseases: a uniform
Cruz AA, Keil T, Lodrup Carlsen KC, Maurer M, approach–a MeDALL–GA2LEN–ARIA position
Ohta K, Papadopoulos NG, Roman Rodriguez M, paper. Int Arch Allergy Immunol 158:216–231
Samolinski B, Agache I, Andrianarisoa A, Ang CS, 6. Coutinho AE, Chapman KE (2011) The anti-
Annesi-Maesano I, Ballester F, Baena-Cagnani CE, inflammatory and immunosuppressive effects of glu-
Basagaña X, Bateman ED, Bel EH, Bedbrook A, Beghé cocorticoids, recent developments and mechanistic
B, Beji M, Ben Kheder A, Benet M, Bennoor KS, insights. Mol Cell Endocrinol 335:2–13
Bergmann KC, Berrissoul F, Bindslev Jensen C, 7. Simons FE (2003) H1-Antihistamines: more relevant
Bleecker ER, Bonini S, Boner AL, Boulet LP, than ever in the treatment of allergic disorders.
Brightling CE, Brozek JL, Bush A, Busse WW, J Allergy Clin Immunol 112:S42–S52
Camargos PA, Canonica GW, Carr W, Cesario A, 8. Akdis CA (2012) Therapies for allergic inflammation:
Chen YZ, Chiriac AM, Costa DJ, Cox L, Custovic refining strategies to induce tolerance. Nat Med
A, Dahl R, Darsow U, Didi T, Dolen WK, Douagui 18:736–749
H, Dubakiene R, El-Meziane A, Fonseca JA, Fokkens 9. Flicker S, Valenta R (2003) Renaissance of the block-
WJ, Fthenou E, Gamkrelidze A, Garcia-Aymerich ing antibody concept in type I allergy. Int Arch
J, Gerth van Wijk R, Gimeno-Santos E, Guerra S, Allergy Immunol 132:13–24
Haahtela T, Haddad H, Hellings PW, Hellquist-Dahl 10. Beck LA, Marcotte GV, MacGlashan D, Togias A,
B, Hohmann C, Howarth P, Hourihane JO, Humbert Saini S (2004) Omalizumab-induced reductions in
M, Jacquemin B, Just J, Kalayci O, Kaliner MA, mast cell Fce psilon RI expression and function.
Kauffmann F, Kerkhof M, Khayat G, Koffi N'Goran J Allergy Clin Immunol 114:527–530
Part XIV
Kidney
Overview
Anatomy and Physiology of the are filtered based on their charge and molecular
Kidneys size (approx. <70 kDa) resulting in almost protein-
free primary urine. The normal glomerular filtra-
The two human kidneys are localized in the retro- tion rate (GFR) ranges from 130 to 180 l/day. The
peritoneal space of the abdomen. The adult size primary urine is then collected in Bowman’s cap-
is approximately 11 × 6 × 4 cm. Anatomically, the sule and further transported via the proximal tubule
kidney can be subdivided into three segments, the followed by the loop of Henle into the medulla
cortex, medulla, and pelvis (Fig. 1a). The latter where it makes a hairpin turn and ascends back into
gives rise to the ureter, which exits the kidney at the cortex before it enters the distal tubule and the
the hilum. connecting tubule into the collecting duct.
Each kidney harbors approx. one million neph- A prominent brush border at the apical, lumen-
rons, its functional units, which are composed of oriented plasma membrane of epithelial cells
glomeruli and tubules (Fig. 1b, c). The glomeruli characterizes the proximal tubule (Fig. 1b, c, e).
are located in the renal cortex and are perfused by The loop of Henle consists of a thin descending
4,000–5,000 l/day of blood. The glomerulus con- followed by a thin and subsequently thick ascend-
tains a capillary bed in which the primary urine is ing part (Fig. 1b, f). The distal convoluted tubule
filtered into the tubules. The three-layered filter shows a similar structure as the proximal tubule;
consists of the fenestrated vascular endothelial however, it lacks its prominent brush border. At
cells (see chapter “Overview” under the part the macula densa of the distal tubule (Fig. 1b, g),
“Blood vessels”), the glomerular basement mem- the nephron passes its own glomerulus at very
brane, and visceral epithelial cells, the podocytes, close proximity (Fig. 1b, c). Several connecting
located at the outer aspect of the capillary loops tubules finally enter one of the collecting ducts
(Fig. 1c, d). The latter form specific foot processes (Fig. 1b, h), which transport the urine through the
with a 40 nm gap in between neighboring foot pro- entire medulla and release it into the pelvis.
cesses bridged by a specialized cell-cell contact, Along the nephrons, the primary urine is concen-
the slit diaphragm [1]. Plasma and plasma proteins trated to 1–3 l/day of terminal urine.
The blood flow of the kidney is maintained via
the renal artery and renal vein. Continuous blood
M.M. Rinschen (*) • L.A. Völker • P.T. Brinkkötter
Department II of Internal Medicine and Center for supply is of utmost importance to maintain high-
Molecular Medicine Cologne (CMMC), University of capacity, energy-consuming transport processes
Cologne, Kerpener Str. 62, Cologne DE-50937, (Fig. 1e–h) and other biological functions of the
Germany
entire kidney epithelium. The renal artery enters
e-mail: markus.rinschen@uk-koeln.de;
linus.voelker@uk-koeln.de; the kidney at the hilum and divides into main
paul.brinkkoetter@uk-koeln.de segment arterial branches and subsequently into
Renal c
vein Proximal
tubule
Distal tubule
Renal
Ascending
artery
loop of Henle
K+ Vasopressin
Ca 2+
PTH
TRPV5
H 2O
AQP2
Type A
H+ intercalated cell
H -ATPase
+
Overview 333
Fig. 1 Anatomy and basic physiology of renal reabsorp- transporters (SGLT 1/2) and glucose transporter 2 (GLUT)
tion and secretion. (a) Cross section through a kidney are necessary (see chapter “Diabetes mellitus“). If bicar-
revealing renal artery and vein and the ureter emerging bonate resorption is necessary, it occurs via CO2, formed
from the renal hilum. Each kidney contains around one and disposed of by carbonic anhydrase (CA). Parathyroid
million nephrons each oriented with their glomeruli hormone (PTH; see chapter “Overview” under the part
toward the renal cortex and descending toward the “Teeth and bones”) is able to downregulate phosphate (Pi)
medulla. (b) The nephron is the functional unit of the kid- reuptake. (f) In the thick ascending limb of Henle, urine is
ney, consisting of glomerulus and tubular system (proxi- concentrated by massive resorption of ions. Mg2+ and Ca2+
mal tubule, descending and ascending loop of Henle, are absorbed mainly paracellularly. Na+ and K+ are reab-
distal tubule, and collecting duct). Blood vessels (not sorbed via the Na-K-Cl cotransporter (NKCC2), a trans-
shown) supply the glomerulus and also the parts closer to porter driven by the sodium gradient. (g) In the distal
the renal medulla (vasa recta). (c) Ultrastructure of the tubule, Na+ and K+ are further reabsorbed, and Ca2+ reab-
glomerulus. The kidney filtration barrier consists of endo- sorption can be upregulated by PTH. Angiotensin II (AT
thelial cells, the glomerular basement membrane, and slit II; see chapters “Hypertension” and “Chronic kidney dis-
diaphragms spanning between podocyte foot processes. ease”) can directly increase sodium reabsorption and sub-
The glomerulus is surrounded by Bowman’s capsule col- sequent water retention by activating the sodium-chloride
lecting the filtrate and directing it toward the proximal symporter, also known as Na+-Cl− cotransporter (NCCT).
tubules. The distal convoluted tubule, a part of the distal (h) The collecting duct consists of two major cell types,
tubules, sends feedback to the glomerulus. (d) The filtra- i.e. principal cells responsible for water and urea reab-
tion barrier consists of fenestrated endothelium, glomeru- sorption and intercalated cells responsible for acid-base
lar basement membrane, and foot processes of surrounding homeostasis. Sodium and water resorption can be upregu-
podocytes containing a slit diaphragm. (e–h) Detailed lated by aldosterone (see chapters “Hypertension” and
views of key transport processes in the nephron from the “Chronic kidney disease”) and vasopressin (see chapters
luminal side (yellow background) to the blood (white “Overview” under the part “Brain” and “Cirrhosis”),
background). (e) Transport processes in the proximal respectively. Names of transporters and channels not spe-
tubule include trans- and paracellular water uptake, bicar- cifically mentioned in the text or not regulated by signals
bonate reabsorption, and sugar and amino acid (AA) reab- mentioned in the book where omitted due to space con-
sorption. The latter are mostly driven by secondary straints. AQP aquaporin, TRPV5 transient receptor poten-
gradients of Na+ built up by basolateral Na+/K+-ATPase. tial cation channel subfamily V member 5, ENaC
For reabsorption of glucose, sodium-glucose linked epithelial Na+ channel
interlobular arteries and afferent arterioles to the ing mathematical algorithms, e.g. CKD-EPI
glomerulus as well as the vasa recta for the blood 2009/2012 formulas. The clearance refers to the
support of the inner medulla (Fig. 1a, c). plasma volume, which is cleared from these sub-
The kidney participates in the body homeosta- stances within a given time. Its calculation requires
sis to maintain a relatively constant extracellular the measurement of urine concentration of creati-
environment. Among its specific functions are (1) nine, serum concentration of creatinine, and urine
regulation of water and electrolyte metabolism, (2) volume within a given time (usually 24 h).
regulation of acid-base homeostasis, (3) detoxifi- The filtration fraction is strictly regulated by
cation and excretion of waste products, (4) reab- filtration pressure. This pressure depends on the
sorption of glucose and other essential metabolites, hydrostatic pressure, which is dependent on the
(5) endocrine function, and (6) synthesis of glu- resistance of the afferent and efferent arteriole,
cose under fasting conditions. and the oncotic pressure built up by the plasma
protein concentration.
The main task of the kidney is to control water
Kidney-Specific Metabolic and and electrolyte metabolism, to save and reabsorb
Molecular Pathways and Processes several essential metabolites from the primary
urine, and to excrete toxic metabolites. These pro-
The GFR equals the sum of the filtration rates of cesses occur in a segment-specific manner. The kid-
all nephrons and is defined as the freely filtered ney tubular function largely depends on the unique
plasma volume per time. It can be measured as distribution of transporters, channels, and pumps in
inulin or creatinine clearance or estimated apply- various leaky or tight subsegments. The entire
334 M.M. Rinschen et al.
kidney tubule has a polarized epithelium with In the thin descending limb of Henle, water is
unique distribution of transport proteins between mainly reabsorbed without the reabsorption of
the cell surfaces at the apical urinary space and the sodium resulting in a hyperosmolar urine, which
basolateral blood side. The Na+/K+-ATPase as a is further concentrated in the thick ascending
main pump sits on the basolateral side of the neph- loop of Henle (Fig. 1f). Here, the Na-K-Cl
ron and commonly serves as the driving force for cotransporter (NKCC2) on the basal cell surface
direct or indirect electrolyte transport processes [2]. is crucially involved in actively taking up all
The proximal tubule is the main segment for three mentioned ions [5]. Cells in the loop of
Na+, bicarbonate (HCO3−), and water reabsorp- Henle are therefore largely dependent on respira-
tion (Fig. 1e). Na+ is mainly reabsorbed via sev- tory mitochondrial ATP generation and are the
eral cotransporters. Importantly, under first cells to detrude during malperfusion of the
physiological conditions, the proximal tubule kidney (e.g., in acute kidney failure; compare
reabsorbs all of the filtered glucose (via the api- with chapter “Chronic kidney disease”). Since
cally localized sodium-glucose linked transport- the epithelium of the ascending loop of Henle is
ers SGLT1 and SGLT2) as well as all amino acids non-permeable to water, it releases a hypotonic
[3]. The capacity for glucose reabsorption by the urine. The large export of sodium from this seg-
proximal tubule is approximately 200 mg/dl. ment of the loop of Henle is responsible for the
Water is transported both transcellularly via accumulation of salt and urea in the kidney
the water channel aquaporin 1 (AQP 1) as well as medulla and generates a corticomedullary osmo-
paracellularly via leaky cell-cell contacts. larity gradient. The diffusion of K+ back into the
The brush border of the proximal tubule con- lumen generates a positive transluminal poten-
tains the enzyme carboanhydrase, which cata- tial. This facilitates paracellular Mg2+ and Ca2+
lyzes the conversion of carbonic acid (H2CO3) to reabsorption.
water (H2O) and carbon dioxide (CO2), which The regulation of salt and water excretion
can diffuse freely through the epithelial cell takes place in the principal cells of the collecting
membrane. CO2 is converted back to HCO3− by duct (Fig. 1h). Upon stimulation with aldoste-
carboanhydrase expressed in the proximal tubule rone, Na+ is reabsorbed in exchange to K+ [6].
cells. These processes facilitate the reabsorption Aldosterone increases both expression and activ-
of bicarbonate in the proximal tubule cells in ity of the apical sodium channel ENaC. Upon
order to compensate acidotic plasma conditions. stimulation with antidiuretic hormone (ADH or
In addition, several metabolites are secreted or vasopressin), water is reabsorbed passively due
reabsorbed via various cation and anion trans- to the corticomedullary osmolarity gradient. In
porters. The proximal tubule secretes exogenous addition, urea is passively reabsorbed via specific
metabolites such as penicillin and organic bases urea transporters. Urea is taken up by the vasa
such as choline and histamine [4]. Some of the recta and circulates between inner and outer
excreted substances end up in the terminal urine, medulla (recycling of urea) [7]. Urea diffusion is
which serves the detoxifying function of the kid- mediated via urea transporters UT-A1, UT-A2,
ney. Ammonia (NH3) is secreted to buffer lumi- and UT-A3, which are abundantly expressed in
nal protons. Urate, a metabolite accumulating in the medullary parts of collecting ducts, loop of
gout (see chapter “Gout and hyperuricemia”), is Henle, and vasa recta. Both water and urea trans-
reabsorbed in the proximal tubule. port are crucial for the final concentration of
Under fasting conditions, the epithelial cells urine and fine-tunes diuresis.
of the cortical tubular system are able to gener- Interspersed between the principal cells in the
ate glucose. This occurs to a lesser extent than collecting duct, intercalated cells regulate the
in the liver. The kidney uses lactate and gluta- acid-base metabolism (Fig. 1h) [8]. Type A inter-
mine as substrates for glucose formation via calated cells actively secrete H+ ions (via an api-
gluconeogenesis. cal H+/K+-ATPase), whereas type B intercalated
Overview 335
Blood pressure
Kidney
System System
inhibit PTH release as part of a negative feedback tubule and decreases phosphate reabsorption in
loop (see also chapter “Overview” under the part the proximal tubule via its G-protein-coupled
“Teeth and bones”). receptor (called PTH receptor, Fig. 1g) [10]. In
addition, it stimulates calcitriol production in the
proximal tubule, which is responsible for
Outside-In: Metabolites of Other increased Ca2+ and PO43− absorption from the gut.
Tissues Affecting the Kidney Renal failure is associated with increased PTH
levels already evident at early stages of chronic
Kidney function is under tight regulation by a kidney disease most likely due to decreased Ca2+
variety of stimuli and fine-tunes water and salt levels (see chapter “Chronic kidney disease”).
metabolism as well as blood pressure (Fig. 2). ATII, the final effector of the renin-
The atrial natriuretic factor (ANF), also known angiotensin-aldosterone system, causes efferent
as atrial natriuretic peptide (ANP), is a peptide arteriole constriction and thus an increase in
hormone secreted by the cardiac atria in response GFR. In general, it increases blood pressure via
to an increase in atrial pressure (see chapter its vasoconstrictive effect mediated by the AT1
“Overview” under the part “Heart”). It directly receptor. ATII directly acts on the distal part of
relaxes the afferent arteriole of the glomeruli, the nephron to increase Na+ and HCO3− reabsorp-
thereby increasing GFR, and it induces an tion. In addition, ATII triggers release of the ste-
increase in sodium excretion, mainly via direct roid hormone aldosterone from the adrenal
effects on the proximal tubule. glands, which increases Na+ reabsorption via
PTH is a key hormone of calcium metabolism. increased expression and apical localization of
It is secreted by the parathyroid glands in epithelial Na+ channels in the distal tubules and
response to decreased plasma calcium (Ca2+) increases K+ secretion via the renal outer medul-
levels. It leads to massive calcium and phosphate lary potassium channels [2]. It also leads to an
release from the skeletal system. In the kidney, increase in H+ secretion. Adrenal insufficiency,
PTH increases calcium reabsorption in the distal as in Addison’s disease, is associated with
Overview 337
decreased aldosterone levels, decreased Na+, and glucose and other essential metabolites, (5) endo-
increased K+ levels. crine function, and (6) synthesis of glucose under
Vasopressin is a polypeptide hormone that is fasting conditions. Perturbation of these func-
secreted by the posterior pituitary (see chapter tions is seen in a variety of pathophysiological
“Overview” under the part “Brain”) in response conditions.
to increased plasma osmolarity and decreased
blood volume. It binds to basolateral receptors on
principal cells of the collecting duct, i.e. the vaso- References
pressin-2 (V2) receptor, a G-protein-coupled
receptor signaling through increased levels of 1. Pavenstädt H, Kriz W, Kretzler M (2003) Cell biology
cAMP and subsequent activation of PKA. This of the glomerular podocyte. Physiol Rev
leads to increased translocation of the water 83(1):253–307
2. Greger R (2000) Physiology of renal sodium trans-
channel aquaporin-2 (AQP2) to the apical cell
port. Am J Med Sci 319(1):51–62
surface (Fig. 1h). Water is then reabsorbed trans- 3. Wright EM (2001) Renal Na(+)-glucose cotransport-
cellularly via apical AQP2 and basolateral AQP3 ers. Am J Physiol Renal Physiol 280(1):F10–F18
and AQP4 channels [11]. Thus, vasopressin 4. Pritchard JB, Miller DS (1993) Mechanisms mediat-
ing renal secretion of organic anions and cations.
increases passive water reabsorption. Failure of
Physiol Rev 73(4):765–796
this system leads to diabetes insipidus, a disease 5. Greger R, Schlatter E, Hebert SC (2001) Milestones
associated with urinary output of up to 20 l/day. in nephrology: presence of luminal K+, a prerequisite
Increased vasopressin secretion under patho- for active NaCl transport in the cortical thick ascend-
ing limb of Henle’s loop of rabbit kidney. J Am Soc
physiological conditions leads to dilutional hypo-
Nephrol 12(8):1788–1793
natremia. Besides its antidiuretic function, 6. Lang F, Rehwald W (1992) Potassium channels in
vasopressin directly increases blood pressure via renal epithelial transport regulation. Physiol Rev
arteriole constriction mediated by activation of 72(1):1–32
7. Knepper MA, Roch-Ramel F (1987) Pathways of urea
the V1a receptor on arteriolar smooth muscle
transport in the mammalian kidney. Kidney Int
cells (see chapter “Hypertension”). 31(2):629–633
8. Al-Awqati Q (2013) Cell biology of the intercalated
cell in the kidney. FEBS Lett 587(13):1911–1914
9. Schnermann J, Levine DZ (2003) Paracrine factors in
Final Remarks tubuloglomerular feedback: adenosine, ATP, and
nitric oxide. Annu Rev Physiol 65:501–529
The kidney serves important functions for body 10. Hernando N, Forster IC, Biber J, Murer H (2000)
homeostasis including (1) regulation of water Molecular characteristics of phosphate transporters
and their regulation. Exp Nephrol 8(6):366–375
and electrolyte metabolism, (2) regulation of
11. Nielsen S, Frøkiaer J, Marples D, Kwon T-H, Agre P,
acid-base homeostasis, (3) detoxification and Knepper MA (2002) Aquaporins in the kidney: from
excretion of waste products, (4) reabsorption of molecules to medicine. Physiol Rev 82(1):205–244
Hypertension
Weight gain
Baseline status indicates the variables before treatment. Hs-CRP C-reactive protein, n/a not available, CCB calcium channel blockers
RAAS blocker refers to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
Thiazide diuretics refer to hydrochlorothiazide, indapamide, and chlorthalidone
Vasodilating β-blockers refer to carvedilol and nebivolol
Vasodilators refer to hydralazine and minoxidil
Weight gain is in reference to increases of 1–2 kg from baseline; double arrows refer to 3–4 kg weight gain. A downward arrow indicates reduced weight gain
Note: The use of one agent that worsens a variable is not necessarily counteracted by one that improves that variable
341
342 C. Flynn and G.L. Bakris
Lastly, arterial vasodilators (e.g., hydralazine, Selective antagonists of the adrenergic α-1
minoxidil) are used in patients with resistant receptor can cause orthostatic hypotension.
hypertension or those who cannot tolerate one of RAAS blockers have demonstrated positive or
the other vasodilating classes [22]. These agents neutral effects on the development of metabolic
work by direct vasodilation of arteries (hydrala- conditions as they improve insulin sensitivity
zine) or by opening barium-sensitive K+ channels (secondary to reductions in ANG II, which lead
in the arteries leading to vasodilation. to vasodilation and enhanced insulin utilization
by the skeletal muscle related to improved blood
flow), increase adiponectin levels (see chapter
Influence of Treatment “Diabetes mellitus”), and do not cause weight
on Metabolism and Consequences gain [28].
for Patients
or refractory hypertension in the small subgroup 13. Hooper L, Abdelhamid A, Moore HJ, Douthwaite W,
Skeaff CM, Summerbell CD (2012) Effect of reduc-
that requires more than three medications and
ing total fat intake on body weight: systematic review
still has systolic BP levels above 160 mmHg. and meta-analysis of randomised controlled trials and
These procedures are not approved in the United cohort studies. BMJ 345:e7666
States, and only renal denervation is approved in 14. Gradman AH, Basile JN, Carter BL, Bakris GL
(2011) Combination therapy in hypertension. J Clin
Europe and Australia.
Hypertens (Greenwich) 13:146–154
15. Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B,
Jamerson K, Velazquez EJ, Staikos-Byrne L, Kelly
RY, Shi V, Chiang YT, Weber MA (2010) Renal out-
References comes with different fixed-dose combination thera-
pies in patients with hypertension at high risk for
1. Giles TD, Materson BJ, Cohn JN, Kostis JB (2009) cardiovascular events (ACCOMPLISH): a prespeci-
Definition and classification of hypertension: an fied secondary analysis of a randomised controlled
update. J Clin Hypertens (Greenwich) 11:611–614 trial. Lancet 375:1173–1181
2. Kannel WB, Garrison RJ, Dannenberg AL (1993) 16. Eriksson JW, Jansson PA, Carlberg B, Hägg A,
Secular blood pressure trends in normotensive persons: Kurland L, Svensson MK, Ahlström H, Ström C,
the Framingham Study. Am Heart J 125:1154–1158 Lönn L, Ojbrandt K, Johansson L, Lind L (2008)
3. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Hydrochlorothiazide, but not Candesartan, aggravates
Dietz WH (1999) The disease burden associated with insulin resistance and causes visceral and hepatic fat
overweight and obesity. JAMA 282:1523–1529 accumulation: the mechanisms for the diabetes pre-
4. Egan BM, Zhao Y, Axon RN (2010) US trends in venting effect of Candesartan (MEDICA) Study.
prevalence, awareness, treatment, and control of Hypertension 52:1030–1037
hypertension, 1988-2008. JAMA 303:2043–2050 17. Gainer JV, Morrow JD, Loveland A, King DJ, Brown
5. Chobanian AV, Bakris GL, Black HR, Cushman WC, NJ (1998) Effect of bradykinin-receptor blockade on
Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil the response to angiotensin-converting-enzyme inhib-
S, Wright JT Jr, Roccella EJ (2003) The seventh itor in normotensive and hypertensive subjects.
report of the Joint National Committee on Prevention, N Engl J Med 339:1285–1292
Detection, Evaluation, and Treatment of High Blood 18. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt
Pressure: the JNC 7 report. JAMA 289:2560–2572 BM (2007) Renin-angiotensin system and cardiovas-
6. Goodfriend TL, Calhoun DA (2004) Resistant hyper- cular risk. Lancet 369:1208–1219
tension, obesity, sleep apnea, and aldosterone: theory 19. Bakris GL (2011) Recognition, pathogenesis, and
and therapy. Hypertension 43:518–524 treatment of different stages of nephropathy in
7. Massiéra F, Bloch-Faure M, Ceiler D, Murakami K, patients with type 2 diabetes mellitus. Mayo Clin Proc
Fukamizu A, Gasc JM, Quignard-Boulange A, Negrel 86:444–456
R, Ailhaud G, Seydoux J, Meneton P, Teboul M 20. Fleckenstein A, Fleckenstein-Grün G (1988)
(2001) Adipose angiotensinogen is involved in adi- Mechanism of action of calcium antagonists in heart
pose tissue growth and blood pressure regulation. and vascular smooth muscle. Eur Heart J 9(Suppl
FASEB J 15:2727–2729 H):95–99
8. Sharma AM (2002) Adipose tissue: a mediator of car- 21. Sica DA, Carter B, Cushman W, Hamm L (2011)
diovascular risk. Int J Obes Relat Metab Disord Thiazide and loop diuretics. J Clin Hypertens
26(Suppl 4):S5–S7 (Greenwich) 13:639–643
9. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer 22. Ferdinand KC (2011) A compendium of antihy-
PJ, Sacks FM (2006) Dietary approaches to prevent pertensive therapy. J Clin Hypertens (Greenwich)
and treat hypertension: a scientific statement from the 13:636–638
American Heart Association. Hypertension 23. Frishman WH, Saunders E (2011) beta-Adrenergic
47:296–308 blockers. J Clin Hypertens (Greenwich) 13:649–653
10. Bray GA, Vollmer WM, Sacks FM, Obarzanek E, 24. Elliott WJ, Meyer PM (2007) Incident diabetes in
Svetkey LP, Appel LJ (2004) A further subgroup anal- clinical trials of antihypertensive drugs: a network
ysis of the effects of the DASH diet and three dietary meta-analysis. Lancet 369:201–207
sodium levels on blood pressure: results of the DASH- 25. Bakris G (2009) An in-depth analysis of vasodila-
Sodium Trial. Am J Cardiol 94:222–227 tion in the management of hypertension: focus on
11. He FJ, Markandu ND, MacGregor GA (2001) adrenergic blockade. J Cardiovasc Pharmacol 53:
Importance of the renin system for determining blood 379–387
pressure fall with acute salt restriction in hypertensive 26. Bakris GL, Fonseca V, Katholi RE, McGill JB,
and normotensive whites. Hypertension 38:321–325 Messerli FH, Phillips RA, Raskin P, Wright JT Jr,
12. Adrogué HJ, Madias NE (2007) Sodium and potas- Oakes R, Lukas MA, Anderson KM, Bell DS
sium in the pathogenesis of hypertension. N Engl J (2004) Metabolic effects of carvedilol vs meto-
Med 356:1966–1978 prolol in patients with type 2 diabetes mellitus and
344 C. Flynn and G.L. Bakris
hypertension: a randomized controlled trial. JAMA 29. Barzilay JI, Davis BR, Pressel SL, Cutler JA,
292:2227–2236 Einhorn PT, Black HR, Cushman WC, Ford CE,
27. Manrique C, Lastra G, Habibi J, Pulakat L, Margolis KL, Moloo J, Oparil S, Piller LB,
Schneider R, Durante W, Tilmon R, Rehmer J, Hayden Simmons DL, Sweeney ME, Whelton PK, Wong ND,
MR, Ferrario CM, Whaley-Connell A, Sowers JR Wright JT Jr (2012) Long-term effects of incident dia-
(2011) Nebivolol improves insulin sensitivity in the betes mellitus on cardiovascular outcomes in people
TGR(Ren2)27 rat. Metabolism 60:1757–1766 treated for hypertension: the ALLHAT Diabetes
28. Flynn C, Bakris GL (2011) Interaction between adi- Extension Study. Circ Cardiovasc Qual Outcomes
ponectin and aldosterone. Cardiorenal Med 1:96–101 5:153–162
Chronic Kidney Disease
Introduction to Chronic Kidney sified into five stages according to the GFR, and
Disease its clinical symptoms are presented in Table 1.
CKD is often diagnosed due to fatigue caused by
Chronic kidney disease (CKD) is a pathological anemia and azotemia, but these symptoms only
status characterized by decreased glomerular fil- appear late in the course of progression (usually
tration rate (GFR) due to various reasons and with stage IV or greater). This chapter will expand on
potentially fatal outcome. It affects more than metabolic issues associated with CKD and its
25 % of the population aged 60 years or older in the management.
United States. The most common causes of CKD
are diabetes (see chapter “Diabetes mellitus”)
and hypertension (see chapter “Hypertension”) Pathophysiology of Chronic Kidney
collectively being responsible for about 75 % of Disease and Metabolic Alterations
patients requiring renal replacement therapy.
There is a decline in renal function that occurs CKD results in pathological metabolic changes,
in the general population with advancing age, namely, increased risk of cardiovascular disease
with an approximate loss of GFR of 1 ml/min/ (see chapter “Atherosclerotic heart disease”), dis-
year of age after about 30 (starting at a GFR of turbances in mineral and electrolyte metabolism,
100–120 ml/min/1.73 m2). As expected, the loss anemia, and uremia, corresponding to the disease
is greater among subjects with underlying risk. stage.
Proteinuria is a marker renal injury and may con-
tribute to loss of renal function further injuring
the kidney directly. CKD is diagnosed and clas- Cardiovascular Disease
maintain fluid homeostasis. Hypertension can reduces the synthesis of calcitriol (the active
develop secondary to an increase in sympa- form of vitamin D3), and increases parathyroid
thetic neural activity with increased β-adrenergic hormone (PTH) secretion to maintain Pi homeo-
responsiveness as well as an increase in angioten- stasis (Fig 1). Intact (full-length) PTH monitor-
sin II activity (a part of the RAAS) and mineralo- ing should be done frequently and low and high
corticoid excess (see chapter “Hypertension”). levels treated.
Activation of the RAAS increases glomerular Renal osteodystrophy refers to abnormali-
pressures and flows, increasing single nephron ties of bone associated with CKD. This can be
GFR. This increase in pressure and flow may also manifested as osteitis fibrosa cystica (persis-
accelerate renal injury when kidney disease is tent secondary hyperparathyroidism resulting in
advanced. Decrease in the synthesis of a kidney- high-turnover bone disease), osteomalacia (low-
derived protein, renalase, may also contribute to turnover bone disease characterized by increased
hypertension. Additionally, aldosterone, by act- unmineralized osteoid secondary to vitamin D3
ing on kidney tubules, increases the reabsorp- deficiency and hypocalcemia), adynamic bone
tion of Na+ and water. Prolonged exposure to disease (low-turnover condition secondary to
aldosterone (in the setting of volume expansion functional hypoparathyroidism due to excess of
such as encountered in CKD) contributes to both vitamin D3 supplements and/or calcium loading).
chronic heart failure (see chapter “Heart failure”) Thus, close monitoring of Ca2+, Pi, vitamin D3,
and progressive renal injury. In CKD, increased and intact PTH is required in CKD patients.
blood volume due to reduced GFR, deregulation
of hormonal systems, and increased sympathetic
neural activity plays a role in the development of Acid-base and Electrolyte
secondary hypertension. Consequently, increased Disturbances
blood pressure is common in CKD.
With advanced kidney disease, hyperkalemia
develops due to reduced renal excretion of K+.
Mineral and Bone Disorders Hyperkalemia is especially common in diabetic
kidney disease, due to hyporeninemic hypoal-
CKD is associated with progressive changes in dosteronism, reducing the fractional excretion
mineral and bone metabolism affecting blood of K+ that usually occurs. In CKD, especially in
vessels and bone structure and strength. The term diabetes, renal tubular damage may cause inad-
“chronic kidney disease-mineral and bone disor- equate renin production and release. Adrenal
der” refers to a syndrome of bone abnormalities dysfunction may lead to inadequate aldosterone
and extraskeletal calcifications seen in patients production; and the principal cells of the cortical
with CKD. Phosphate (Pi) and Ca2+ levels are connecting tubule may not respond normally to
regulated in part by the kidneys (see chapters aldosterone. In true hyporeninemic hypoaldoste-
“Overview” under the part “Teeth and bones”and ronism, the juxtaglomerular apparatus atrophies.
“Overview” under the part “Kidney”) [2]. Low Hyperkalemia can impair neuromuscular con-
GFR (<50 ml/min/1.73 m2) is associated with duction, leading to muscle weakness and cardiac
phosphate retention playing a role in the release conduction abnormalities, including heart blocks
of fibroblast growth factor 23 by bone, which and fatal ventricular arrhythmias. Metabolic aci-
in turn increases urinary phosphate excretion, dosis develops in advanced CKD, mainly due to
Chronic Kidney Disease 347
Kidney GI tract
GFR Urinary Pi
Calcitriol Pi, Ca2+ absorption
excretion
Plasma Pi
Left ventricular
PTH
FGF23 hypertrophy
secretion
CVD
Fig. 1 Important mechanisms and molecules causing (PTH) secretion. FGF23 also increases Pi excretion in the
metabolic derangements during chronic kidney disease. urine and reduces synthesis of calcitriol by the kidney.
As glomerular filtration rate (GFR) declines, phosphate Subsequently, decreased levels of calcitriol cause a reduc-
(Pi) is retained in the kidney, leading to hyperphosphate- tion in gastrointestinal (GI) absorption of Pi and Ca2+ (see
mia. Increased Pi in the blood causes release of fibroblast also chapter “Overview” under the part “Teeth and
growth factor (FGF) 23 from bone. FGF23 acts on the bones”). Finally, as the GFR continues to decline, rising
parathyroid glands to increase parathyroid hormone FGF23 levels lead to cardiovascular disease (CVD)
reduced renal ammonium excretion. In addition, (late-stage) CKD. Erythropoietin (EPO) is syn-
there is reduced “titratable acidity” in urine, due thesized by the kidney, and loss of GFR is associ-
to reduced phosphate excretion (also resulting in ated with loss of functional renal mass. As GFR
hyperphosphatemia), the principal buffer pres- declines, EPO deficiency becomes apparent,
ent in urine. Hyperkalemia reduces the activity leading to anemia, as EPO is necessary for the
of glutaminase within the kidney, decreasing survival of erythroid progenitors and protection
ammonia production and worsening the meta- of new red cells from cytolysis. Hypoxic kidneys
bolic acidosis. produce hypoxia-inducible factor 1 stimulat-
ing EPO synthesis [3]. In patients with normal
kidney function, sustained anemia or hypoxemia
Anemia leads to rise in EPO levels. However, decreased
kidney function in the setting of CKD decreases
Anemia, which is a reduction of hemoglobin EPO production, leading to anemia. Anemia
concentration, is a common complication of leads to fatigue and decreased cognitive skills
348 G. Odabaei et al.
and sense of well-being and may be associated including albumin are thought to be more oxi-
with cardiovascular complications and left ven- dized in the uremic state. Lipoprotein structure
tricular hypertrophy. and function is disordered, with an increased
level of oxidized low-density lipoproteins and
decreased levels of high-density lipoproteins
Uremia occurring (see chapter “Hyperlipidemia”). The
HDL found in patients with advanced kidney
Uremia (literally “urine in the blood”) occurs disease is also structurally abnormal. This, com-
in end-stage kidney disease and is character- bined with the pro-inflammatory state afforded
ized by retained organic solutes (in the blood, by uremia, and increased insulin resistance,
see Table 2) [4] and often accompanies derange- likely puts patients at an increased risk of car-
ments in metabolism of inorganic compounds diovascular disease. The classic symptoms of
(such as Ca2+, Pi), hormonal imbalances (such as uremia include lethargy, anorexia, itching,
PTH), and disorders of extracellular volume. In and various neurologic manifestations includ-
general, three classes of uremic solutes exist (see ing sleep disturbances, seizures, restless legs
Table 2): (1) small water-soluble substances, (2) (potentially due to reduced membrane poten-
small lipid-soluble or protein-bound substances, tial), and, in advanced cases, coma. Azotemia is
and (3) larger so-called middle molecules. Urea, the early stage of uremia, in which a change in
belonging to the first class, is a by-product of markers can be measured, but no symptoms are
protein catabolism and the most abundant of the present (yet).
uremic solutes. It is used clinically for diagnosis
of uremia. However, studies have shown that it is
probably only a weak toxin per se. Introduction to Treatment
Interestingly, many of the uremic solutes arise and Influence on Metabolism
from protein or amino acid degradation and/or
are generated from bacterial metabolism in the Treatment of CKD focuses mainly on reducing
gut. They contribute to CKD, often by increasing the complications caused by CKD and on preven-
inflammatory reactions. tion of disease progression. Ultimately, CKD can
The uremic state also is thought to alter only be treated by replacement therapy, meaning
oxidative stress in the body. Several proteins dialysis or kidney transplantation.
Chronic Kidney Disease 349
to a hemoglobin level of 13 g/dl. The current bone and mineral metabolism abnormalities and
hemoglobin target is 10 g/dl, but even this target symptoms due to accumulation of organic solutes
may be reduced in the future. in the blood (uremia). While dialysis corrects
these abnormalities at least partially and offers
symptom relief from uremia, renal transplanta-
Uremia tion offers the best hope today for the patient with
end-stage kidney disease. Therefore, the focus
In the true sense of the word, “uremic” symptoms should be on prevention of CKD.
can be treated only with dialysis or by renal trans-
plantation, which removes the “urine components”
and promptly corrects most of the symptoms. References
Traditional hemodialysis is performed three
times a week, for an average of about 3.5 h per 1. Depner TA (2001) Uremic toxicity: urea and beyond.
session, in the United States. More intensive dial- Semin Dial 14:246–251
2. Schrier J, Schrier RW (2000) Manual of nephrology:
ysis such as increase in frequency or in duration diagnosis and therapy, 5th edn. Lippincott Williams &
has been shown to improve sense of well-being, Wilkins, Philadelphia
to restore better sleep quality, and also to reduce 3. Deng A, Arndt MA, Satriano J, Singh P, Rieg T,
left ventricular mass. Thomson S, Tang T, Blantz RC (2010) Renal protec-
tion in chronic kidney disease: hypoxia-inducible fac-
tor activation vs. angiotensin II blockade. Am J Physiol
Renal Physiol 299:F1365–F1373
Perspectives 4. Meyer TW, Hostetter TH (2007) Uremia. N Engl J
Med 357:1316–1325
5. American College of Physicians; August P (ed) (2010)
In summary, CKD produces an array of meta- MKSAP 15 medical knowledge self-assessment pro-
bolic complications in the patient, including ane- gram: nephrology. American College of Physicians,
mia, blood volume and electrolyte disorders, and Philadelphia
Gout
Introduction to Gout Gout starts with a first acute attack (flare) fol-
lowed by an intercritical phase without attacks.
Acute gout is the inflammatory reaction provoked Overtime, gout will become chronic (Fig. 1).
by monosodium urate (MSU) crystals when they Diagnosis is based on clinical symptoms and the
form within a joint. It affects mainly males, due presence of MSU crystals in the joints.
to their physiologically higher serum uric acid
(UA) levels, and there is epidemiological evi-
dence that the prevalence of gout and hyperurice- Pathophysiology of Gout
mia is on the increase in western and Asian and Metabolic Alterations
populations in both sexes and with aging. It is
estimated that the prevalence of gout increased UA in body fluid, at pH 7.4, exists in the urate
by 60 % in those aged over 65 and doubled in the form. It is generated by catabolism of purine
population over 75 years of age between 1990 nucleotides, which occurs mainly in the liver.
and 1999 [1]. The prevalence is estimated to be The last step consists of the conversion of xan-
1.4 % in the adult population in the UK, with a thine to UA, and it is catalyzed by the enzyme
peak of over 7 % in men aged over 75 years old xanthine oxidase. Humans, as opposed to other
[2]. In addition, a strong association between mammals, lack the ability to further degrade
hyperuricemia and the metabolic syndrome (see urate to allantoin because the enzyme uricase is
chapter “Metabolic syndrome”) was observed. nonfunctional due to gene mutation [3].
Potential explanations include lifestyle and Hyperuricemia is defined as the level of serum
dietary changes brought about by increasing urate that exceeds its plasma solubility. This
prosperity and increased life expectancy of the favors crystal formation and deposition in soft
population, not to mention the coexistence of tissues and around joints, leading to tophus
multiple medical comorbidities and their (aggregates of MSU crystals) formation and trig-
treatments (i.e., hypertensive agents) that favor gering an acute inflammatory reaction. In addi-
hyperuricemia in the elderly. tion, increased urinary concentrations of urate
can also lead to renal stone formation (see chapter
“Kidney stones”). Although these renal manifes-
tations are well documented in the literature, they
S. Nasi (*) • A. So are much less frequently encountered than gout,
Service de Rhumatologie, CHUV, the most common clinical presentation.
Avenue Pierre Decker, 5, Lausanne,
Hyperuricemia is either the result of excess for-
1011, Switzerland
e-mail: sonia.nasi@chuv.ch; mation of urate due to increased purine metabo-
alexanderkai-lik.so@chuv.ch lism or the consequence of insufficient renal
Xanthine
[XO]
Serum urate
Serum urate
> 6.8 mg/dl
Kidney
Asymptomatic MSU crystal formation
hyperuricemia Acute flare
Intercritical period
Reabsorption
to maintain
Chronic
3.3 − 6.8 mg/dl
tophaceous gout
Fig. 1 Mechanisms and progression of gout. Uric acid is stages. Initially, the condition is asymptomatic (and can
the end point of purine degradation, resulting from the con- remain so). Crystals can be released into the joint space,
version of xanthine by xanthine oxidase (XO), and is pres- triggering an interleukin (IL-)1-dependent inflammatory
ent in the blood as urate. Urate is filtered by the kidney and response, resulting in an acute flare, characterized by severe
is reabsorbed to maintain a serum concentration below pain and fever. An initial flare usually resolves in 3–14 days.
6.8 mg/dl under healthy conditions. Serum urate concentra- The periods between acute flares are termed intercritical
tions can be increased by dietary factors and genetic disor- periods, in which symptoms are absent, but urate crystals
ders (not shown). When serum urate levels exceed its are still present in previously involved joints, stimulating
solubility (6.8 mg/dl), monosodium urate (MSU) crystals low-grade inflammation. In untreated patients, continuing
may form. Gout progresses through clinically distinct urate accumulation leads to chronic tophus formation
elimination of urate to maintain normal physio- Data from family studies showed that gout
logical values, or a mixture of both (Fig. 1). and hyperuricemia are polygenic traits [7]. In the
In the majority of cases, hyperuricemia is kidney, urate undergoes glomerular filtration,
mainly explained by diet as well as idiopathic tubular reabsorption, and then reexcretion. Most
underexcretion of urate by the kidney. Studies con- of the genes associated with hyperuricemia are
firmed that increased consumption of certain foods, implicated in either the excretion or reabsorption
liquor, and sugar-sweetened soft drinks increased of urate in the renal tubule. The strongest associa-
the risk of developing gout [4–6]. Meat, seafood, tion found is with a urate transporter, solute car-
and beer are risky because of their high purine con- rier family 2, facilitated glucose transporter
tent; sugar-sweetened soft drinks increase risk due member 9 (SLC2A9) [8].
to their high fructose content. Excess fructose (in It is now well established that one of the major
the liver) and also alcohol deplete ATP levels and mechanisms of gouty inflammation is through
increase adenine degradation to UA. Other mecha- release of interleukin-1β (IL-1β) when MSU crys-
nisms to increase UA play a role as well. An addi- tals are in contact with monocytes and neutrophils.
tional contributory factor to hyperuricemia, In vitro, MSU crystals are capable of activating
particularly in the older population, is drug-induced the NOD-like receptor family, pyrin domain con-
underexcretion due to use of thiazide diuretics (see taining 3 (NLRP3) inflammasome in monocytes
chapter “Hypertension”) and low-dose aspirin, and dendritic cells to secrete large quantities of
which reduce the renal excretion of UA. IL-1β (see chapter “Overview” under the part
Gout 353
Caution anaphylaxis,
Xanthine hypersensitivity reaction
XO inhibitors
[XO]
Allopurinol*, Febuxostat
[Uricase]
Serum urate Allantoin
*Caution
hypersensitivity reaction
Serum urate
Caution >6.8 mg/dl
Renal calculi
Kidney
Uricosurics:
MSU crystal formation
Probenicid,
Benzbromarone
Acute flare
Reabsorption Excretion
Fig. 2 Location of the different targets of currently available excretion of urate by the kidney (uricosurics). Inflammation
treatments of acute gout and hyperuricemia. Urate-lowering inhibitors relieve the acute signs and symptoms of gout, usu-
therapies have three major mechanisms of action: inhibition ally arthritis. MSU monosodium urate, NSAIDs nonsteroidal
of xanthine oxidase (XO), addition of uricase, or increased anti-inflammatory drugs, IL interleukin
“Immune system”) [9]. The NLRP3 inflamma- Since the body cannot react to hyperuricemia
some is a cytoplasmic protein complex composed with a feedback mechanism or counter-regulation,
of NLRP3 (a protein of the NLRP family), an people with hyperuricemia will remain with high
adapter protein, as well as caspase-1. Caspase-1 urate levels for all their life, unless treated with
catalyzes the cleavage of pro-IL-1β and pro-IL-18 urate-lowering agents.
into their active forms (IL-1β and IL-18) leading
to their secretion. Recently, protein kinase R (an
RNA-dependent protein kinase) has been impli- Treatment of Gout
cated in MSU-stimulated IL-1β release, as genetic
deficiency in mice for this molecule blocked IL-1β Gout therapy is based on two principal strategies:
secretion. Indeed, it interacts physically with the the control of hyperuricemia that predisposes to
inflammasome to initiate caspase-1 activity [10]. formation of crystals (urate-lowering therapies)
In addition, MSU crystals can elicit inflamma- and the control of gouty inflammation to calm the
tion in an inflammasome-independent manner acute attack. All patients should be given dietary
triggering at least two different pathways: one advice and general counseling of the importance
through crystals interacting with the cell surface of long-term treatment adherence.
(dendritic cells and macrophages) to initiate an The aim of the first group of therapies is to
intracellular signaling cascade that involves reduce the serum urate level to below the solubil-
spleen tyrosine kinase (Syk), another via the ity threshold for crystal formation. Inhibition of
release of pro-IL-1β into the extracellular space xanthine oxidase (XO) is the most widely used
during cell activation or cell death, and its subse- approach to control hyperuricemia, and two
quent cleavage by serine proteases such as inhibitors are currently available, allopurinol and
cathepsin G, elastase, and proteinase 3 released febuxostat.
by neutrophils at site of inflammation [11]. The treatment of acute gout (Fig. 2) aims
Finally, novel studies have also shown a role of to relieve pain and inflammation rapidly.
IL-1α in the inflammatory process [12]. Traditional approaches include nonsteroidal
354 S. Nasi and A. So
anti-inflammatory drugs (NSAIDs), such as against flare for any patient who starts a urate-
diclofenac and indomethacin, colchicine (a drug lowering therapy.
that inhibits tubulin polymerization), and cortico-
steroids. In most cases, these drugs are rapidly
effective, but caution has to be exercised in some Allopurinol (An XO Inhibitor)
patients.
NSAIDs can cause side effects such as renal Allopurinol is a purine analogue that is metabo-
dysfunction and raise blood pressure. The serum lized to active oxypurinol, a potent inhibitor of XO
concentration of colchicine is influenced by cyto- (Fig. 2). The dose of allopurinol required to reduce
chrome P450 3A4 and P-glycoprotein (also serum urate levels below the limit of solubility can
called multidrug resistance protein 1) activities, vary. As the drug is eliminated by the kidney,
and both enzymes are affected by drug interac- attention has to be paid to renal function in deter-
tions (necessitating close observation of potential mining the effective as well as safe maximal dose.
co-treatments). The most severe side effect is the allopurinol
The discovery of the IL-1 axis of gouty inflam- hypersensitivity syndrome, a Stevens-Johnson’s
mation has led to studies that have evaluated the type reaction that is characterized by fever, skin
effectiveness of IL-1 inhibitors. They are effec- rashes, and desquamation, liver function abnor-
tive, either in the prevention or in the treatment of malities, and a fatal outcome in a significant pro-
an acute flare. The frequency of flares was halved portion of patients.
using a monoclonal antibody against IL-1β
(Canakinumab), and pain was significantly
reduced [13, 14]. Similarly, an inhibitor of both Febuxostat (Non-purine XO Inhibitor)
IL-1α and IL-1β (Rilonacept) reduced gout flares
by around 50 % [15]. Febuxostat is a non-purine selective inhibitor of
In uncontrolled studies, an IL-1 receptor antag- XO (Fig. 2). In vitro studies showed that febuxo-
onist called anakinra was effective in the treatment stat is a potent ligand for and inhibitor of both the
of acute gout in patients who had either intoler- oxidized and reduced forms of XO, and clinical
ance or contraindications to standard therapy [16]. studies have confirmed its efficacy in reducing
Currently, anakinra is mainly used to treat rheuma- serum urate levels [17]. Consequently, it raises
toid arthritis (see chapter “Rheumatoid arthritis”). serum xanthine levels, but this does not present a
Uricosurics are drugs that promote renal urate clinical problem. Febuxostat shows a dose-
excretion instead of lowering urate concentra- dependent effect. The side effect profile of febux-
tions and include benzbromarone and probene- ostat is comparable to that of allopurinol [18].
cid. Finally, it is possible to lower serum urate by The serious adverse events reported included
administration of exogenous uricase, the enzyme liver function abnormalities and cardiovascular
responsible for the oxidation of urate to allantoin, events. Rashes were observed in <2 % of
whose gene is no longer functional in man. febuxostat-treated patients, but a reaction that
resembles the allopurinol hypersensitivity syn-
drome is not observed.
Influence of Treatment on
Metabolism and Consequences
for Patients Uricosuric Drugs
All drugs that reduce serum urate can cause acute Uricosuric drugs interfere with tubular mecha-
flares when treatment is started. This is due to an nisms of urate reabsorption to enhance uricos-
alteration of the stability of MSU crystals when uria, such as the inhibition of the renal/liver
UA levels decrease suddenly. It is therefore transporters SLC2A9 and SLC22A2 (Fig. 2).
important to provide adequate prophylaxis These drugs should not be used in patients with
Gout 355
high urate excretion, as they can precipitate renal between metabolic syndrome (see chapter
stones or urate nephropathy. Benzbromarone is “Metabolic syndrome”) and hyperuricemia. In
the most powerful drug in terms of urate reduc- addition, new XO inhibitors and IL-1 inhibitors,
tion but shows serious hepatotoxic side effects which are currently studied, could become future
severely restricting its distribution. Currently, drugs for gout treatment.
probenecid is the most frequently prescribed
uricosuric.
As probenecid also increases urine calcium
excretion, it is contraindicated in patients with a
References
history of renal calculi. Probenecid can interfere 1. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann
with renal excretion of other drugs (penicillins, R (2004) Increasing prevalence of gout and hyperuri-
some antivirals), so a careful drug history is vital cemia over 10 years among older adults in a managed
before initiating treatment. care population. J Rheumatol 31:1582–1587
2. Mikuls TR, Farrar JT, Bilker WB, Fernandes S,
Schumacher HR Jr, Saag KG (2005) Gout epidemiol-
ogy: results from the UK General Practice Research
Uricase Database, 1990–1999. Ann Rheum Dis 64:267–272
3. Choi HK, Mount DB, Reginato AM, American
College of Physicians; American Physiological
This therapy uses exogenous uricase that is Society (2005) Pathogenesis of gout. Ann Intern Med
chemically linked to polyethylene glycol in order 143:499–516
to prolong its half-life. Uricase rapidly reduces 4. Choi HK, Atkinson K, Karlson EW, Willett W,
serum urate levels, can decrease tophus size, and Curhan G (2004) Purine-rich foods, dairy and protein
intake, and the risk of gout in men. N Engl J Med
can significantly reduce the urate levels (Fig. 2) 350:1093–1103
[19]. The resulting allantoin does not cause 5. Choi HK, Curhan G (2004) Beer, liquor, and wine
adverse effects, but long-term uricase therapy can consumption and serum uric acid level: the Third
cause drug sensitization and allergic reactions, National Health and Nutrition Examination Survey.
Arthritis Rheum 51:1023–1029
and this may be the major problem in chronic 6. Choi JW, Ford ES, Gao X, Choi HK (2008) Sugar-
therapy. sweetened soft drinks, diet soft drinks, and serum uric
acid level: the Third National Health and Nutrition
Examination Survey. Arthritis Rheum 59:109–116
7. Smyth CJ, Cotterman CW, Freyberg RH (1948) The
Perspectives genetics of gout and hyperuricaemia; an analysis of
19 families. J Clin Invest 27:749–759
Gout is a common medical condition that is well 8. So A, Thorens B (2010) Uric acid transport and dis-
understood in terms of physiology, but its treat- ease. J Clin Invest 120:1791–1799
9. Martinon F (2010) Mechanisms of uric acid
ment remains suboptimal in many countries. crystal-mediated autoinflammation. Immunol Rev
Besides treatment of the acute attack, urate- 233:218–232
lowering therapies are important to maintain a 10. Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundbäck
low serum urate level in order to prevent severe P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou
Y, Erlandsson-Harris H, Yang H, Ting JP, Wang H,
complications and frequent attacks. Currently, Andersson U, Antoine DJ, Chavan SS, Hotamisligil
the treatment of asymptomatic hyperuricemia is GS, Tracey KJ (2012) Novel role of PKR in inflam-
not recommended, but this recommendation may masome activation and HMGB1 release. Nature
be modified in the future, as there is strong evi- 488:670–674
11. Joosten LA, Netea MG, Fantuzzi G, Koenders MI,
dence linking hyperuricemia to cardiovascular Helsen MM, Sparrer H, Pham CT, van der Meer JW,
and renal morbidity. Dinarello CA, van den Berg WB (2009) Inflammatory
Current research topics will bring new under- arthritis in caspase 1 gene-deficient mice: contribution
standing of the genetics of gout and hyperurice- of proteinase 3 to caspase 1-independent production
of bioactive interleukin-1beta. Arthritis Rheum
mia as well as the mechanisms that regulate 60:3651–3662
gouty inflammation, the renal and liver urate 12. Narayan S, Pazar B, Ea HK, Kolly L, Bagnoud N,
transporters, and the biochemical interaction Chobaz V, Lioté F, Vogl T, Holzinger D, Kai-Lik So
356 S. Nasi and A. So
A, Busso N (2011) Octacalcium phosphate crystals confirmatory efficacy study. Arthritis Care Res
induce inflammation in vivo through interleukin-1 but (Hoboken) 64:1462–1470
independent of the NLRP3 inflammasome in mice. 16. So A, De Smedt T, Revaz S, Tschopp J (2007) A pilot
Arthritis Rheum 63:422–433 study of IL-1 inhibition by anakinra in acute gout.
13. Schlesinger N, Alten RE, Bardin T, Schumacher HR, Arthritis Res Ther 9:R28
Bloch M, Gimona A, Krammer G, Murphy V, Richard 17. Schumacher HR Jr, Becker MA, Wortmann RL,
D, So AK (2012) Canakinumab for acute gouty arthri- Macdonald PA, Hunt B, Streit J, Lademacher C,
tis in patients with limited treatment options: results Joseph-Ridge N (2008) Effects of febuxostat versus
from two randomised, multicentre, active-controlled, allopurinol and placebo in reducing serum urate in
double-blind trials and their initial extensions. Ann subjects with hyperuricemia and gout: a 28-week,
Rheum Dis 71:1839–1848 phase III, randomized, double-blind, parallel-group
14. Schlesinger N, Mysler E, Lin HY, De Meulemeester trial. Arthritis Rheum 59:1540–1548
M, Rovensky J, Arulmani U, Balfour A, Krammer G, 18. Becker MA, Schumacher HR, Espinoza LR, Wells
Sallstig P, So A (2011) Canakinumab reduces the risk AF, MacDonald P, Lloyd E, Lademacher C (2010)
of acute gouty arthritis flares during initiation of allo- The urate-lowering efficacy and safety of febuxostat
purinol treatment: results of a double-blind, ran- in the treatment of the hyperuricemia of gout: the
domised study. Ann Rheum Dis 70:1264–1271 CONFIRMS trial. Arthritis Res Ther 12:R63
15. Schumacher HR Jr, Evans RR, Saag KG, Clower J, 19. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield
Jennings W, Weinstein SP, Yancopoulos GD, Wang MS (2006) Control of hyperuricemia in subjects with
J, Terkeltaub R (2012) Rilonacept (interleukin-1 refractory gout, and induction of antibody against
trap) for prevention of gout flares during initiation poly(ethylene glycol) (PEG), in a phase I trial of sub-
of uric acid-lowering therapy: results from a phase cutaneous PEGylated urate oxidase. Arthritis Res
III randomized, double-blind, placebo-controlled, Ther 8:R12
Urinary Tract Infections
Septicemia, hypertension,
uremia, kidney failure
Kidney damage,
scarring
Pyelonephritis
Bladder Obesity
remodeling
Cystitis Diabetes
Pregnancy
Bladder
dysfunction
Fig. 1 The effects of metabolism and disease on urinary leading to hypertension, uremia, septicemia, and kidney
tract infection (UTI). The left side depicts the effects and failure. The right side displays how different metabolic
consequences of UTI on host metabolism. Cystitis in the states influence UTI susceptibility. Both obesity and dia-
lower urinary tract results from bacterial infection and the betes cause bladder remodeling. Diabetes also reduces the
associated inflammatory response. This inflammation can number of leukocytes (reducing bacterial clearance) and
induce damage to the bladder and urinary tract favoring facilitates bacterial infection (not shown). Pregnancy
remodeling processes, which in turn facilitate recurrent increases the risk of UTI via gestational diabetes and
infection. Pyelonephritis (kidney infection) is a more reduced bladder function. Bladder remodeling (indepen-
severe condition. Immune response causes local inflam- dent of its origin) leads to bladder dysfunction, which
mation that increases reactive oxygen species. This, in increases the likelihood of infection in the lower urinary
turn, can cause kidney damage and scarring, ultimately tract and kidney
metabolic state and can predispose the host to and diabetes (see chapter “Diabetes mellitus”),
recurrent UTI (Fig. 1). Remodeling is due in part lead to an increased susceptibility to UTIs (Fig. 1)
to the exfoliation of the bladder epithelial cells in [4]. The metabolic effects of diabetes and obesity
response to bacterial invasion, altering the tissue are associated with urological conditions such as
structure and epithelial metabolism due to sexual dysfunction, incontinence, and UTI.
attempts to replace the superficial cells. Diabetics have a fourfold higher incidence of
Though cystitis has not been shown to have UTI, are infected with a broader range of uro-
effects on overall host metabolism, many altera- pathogens, and more commonly develop serious
tions in the host metabolic state, such as obesity UTI sequela than nondiabetics [2].
Urinary Tract Infections 359
UPEC produces hair-like fibers called type 1 prevent severe sequelae [13]. Women with severe
pili that bind mannosylated uroplakin residues on recurrent UTIs are often treated with long-term pro-
the urothelium, allowing for bacterial colonization phylactic antibiotics. In addition to antibiotics,
and invasion into the bladder tissue [1]. Uroplakins patients may be prescribed analgesics to relieve
are glycosylated proteins that help to establish an pain. Severe cases that result in impaired kidney
impermeable barrier on the bladder surface. This function may require dialysis treatments.
interaction is strengthened on epithelial cells from
type 2 diabetes due to unknown reasons [7]. In
addition, leukocyte counts are lower in the bladders Influence of Treatment
of diabetics than nondiabetics, which may result in on Metabolism
reduced clearance of bacteria in diabetics [8].
Further, diabetic bladder disorder is characterized Removal of bacteria generally abrogates symp-
by decreased sensation, increased capacity, and toms such as pyuria and frequency quickly. Local
poor emptying. During diabetes, hyperglycemia- disturbances in the cellular environment that pre-
induced osmotic polyuria and the accumulation of dispose for recurring infection take longer to nor-
oxidative stress products are the main factors in malize, such as restoration of the bladder
bladder enlargement, urothelial thickening, muscle epithelium or repair of renal scarring.
hypertrophy, and altered urothelial cell composi- While a single course of antibiotics to clear an
tion, finally leading to decreased voiding and urine acute UTI has minimal impact, extended use of
retention [9]. This decreased flow rate and urine antibiotics, in the case of recurrent UTIs, has a
turnover provide a niche for bacterial colonization. dramatic effect on the composition of the gut
Compared to nonpregnant women, UTI and microbiota [14]. Disturbance of this bacterial
ASB are more prevalent in pregnant females, community directly influences nutrient uptake
probably due to gestational diabetes (see chapter and host metabolism by altering the microflora
“Diabetes mellitus”) [3, 10]. In conjunction, pro- responsible for macromolecule breakdown and
gesterone levels increase dramatically during absorption [15]. In addition, some antibiotics are
pregnancy which causes decreased bladder mus- associated with liver and kidney dysfunction
cle tone [11]. Less forceful voiding contractions disturbing normal host metabolic processes [16].
lead to decreased shear forces in the bladder, This is hypothesized to be due to tissue stress,
incomplete emptying, and increased reflux to the interruption of metabolite transport, and accumu-
kidneys resulting in a 25–40 % increased likeli- lation of toxic intermediates.
hood of kidney infection [11].
Perspectives
Treatment of Urinary Tract
Infections As the western lifestyle increasingly leads to obe-
sity and associated metabolic syndrome, the inci-
The standard treatment for lower UTI involves oral dence of UTI will continue to rise. Concurrently,
antibiotics (trimethoprim/sulfamethoxazole or cip- antibiotic resistance is proliferating among uro-
rofloxacin) to remove the infectious agent. pathogens including the emergence of multidrug-
Pyelonephritis is treated more aggressively with resistant UPEC [1]. To combat this rise of antibiotic
oral or intravenous antibiotics (cephalosporins) or a resistance, new therapies and preventative mea-
combinatorial therapy [12]. While diabetics receive sures are being developed such as the mannoside
similar treatment as nondiabetics, pregnant women class of anti-virulence compounds. These act as
with UTI are treated with antibiotics that carry a low high-affinity-binding antagonists to block type 1
risk of complications with the pregnancy (cepha- pilus-mediated UPEC attachment to the urothe-
lexin, nitrofurantoin) [13]. ASB is usually untreated. lium [17]. Similarly, small-molecule compounds,
However, in diabetics or pregnant women, antimi- which inhibit pilus biogenesis, are being examined
crobial treatment of ASB is recommended to as a possible anti-virulence UTI treatment.
360 M.S. Conover et al.
In addition, several vaccines are undergoing clini- symptomatic urinary tract infection in women with
diabetes. Diabetes Care 23:1737–1741
cal trials targeting bacterial virulence factors or
8. Geerlings SE (2008) Urinary tract infections in
whole uropathogens [17]. patients with diabetes mellitus: epidemiology, patho-
genesis and treatment. Int J Antimicrob Agents
31(Suppl 1):S54–S57
9. Cai H, Dikalov S, Griendling KK, Harrison DG (2007)
References Detection of reactive oxygen species and nitric oxide
in vascular cells and tissues: comparison of sensitivity
1. Hannan TJ, Totsika M, Mansfield KJ, Moore KH, and specificity. Methods Mol Med 139:293–311
Schembri MA, Hultgren SJ (2012) Host-pathogen 10. Lain KY, Catalano PM (2007) Metabolic changes in
checkpoints and population bottlenecks in persistent pregnancy. Clin Obstet Gynecol 50:938–948
and intracellular uropathogenic Escherichia coli blad- 11. Dielubanza EJ, Schaeffer AJ (2011) Urinary tract
der infection. FEMS Microbiol Rev 36:616–648 infections in women. Med Clin North Am 95:27–41
2. Boyko EJ, Fihn SD, Scholes D, Abraham L, Monsey 12. Naber KG, Wullt B, Wagenlehner FM (2011)
B (2005) Risk of urinary tract infection and asymp- Antibiotic treatment of uncomplicated urinary tract
tomatic bacteriuria among diabetic and nondiabetic infection in premenopausal women. Int J Antimicrob
postmenopausal women. Am J Epidemiol 161: Agents 38(Suppl):21–35
557–564 13. Guinto VT, De Guia B, Festin MR, Dowswell T
3. Delzell JE Jr, Lefevre ML (2000) Urinary tract infec- (2010) Different antibiotic regimens for treating
tions during pregnancy. Am Fam Physician 61: asymptomatic bacteriuria in pregnancy. Cochrane
713–721 Database Syst Rev (9):CD007855
4. Semins MJ, Shore AD, Makary MA, Weiner J, 14. Cotter PD, Stanton C, Ross RP, Hill C (2012) The
Matlaga BR (2012) The impact of obesity on urinary impact of antibiotics on the gut microbiota as revealed
tract infection risk. Urology 79:266–269 by high throughput DNA sequencing. Discov Med
5. Pohl HG, Sedberry-Ross S, Rushton G (2011) Urinary 13:193–199
tract infections. In: Palmer JS (ed) Pediatric urology. 15. Tremaroli V, Backhed F (2012) Functional interac-
Humana Press, New York, pp 37–69 tions between the gut microbiota and host metabo-
6. Svensson M, Yadav M, Holmqvist B, Lutay N, lism. Nature 489:242–249
Svanborg C, Godaly G (2011) Acute pyelonephritis 16. Wawruch M, Bozekova L, Krcmery S, Kriska M
and renal scarring are caused by dysfunctional innate (2002) Risks of antibiotic treatment. Bratisl Lek Listy
immunity in mCxcr2 heterozygous mice. Kidney Int 103:270–275
80:1064–1072 17. Barber AE, Norton JP, Spivak AM, Mulvey MA
7. Geerlings SE, Stolk RP, Camps MJ, Netten PM, (2013) Urinary tract infections: current and emerging
Collet TJ, Hoepelman AI (2000) Risk factors for management strategies. Clin Infect Dis 57:719–724
Kidney Stones
Promoters Inhibitors
Sodium intake Citrate
Dietary calcium Magnesium
High acid intake
Kidney stones
Calcium
Ca oxalate phosphate Uric acid Struvite Cystine
Metabolic
Ca supplements
Fig. 1 Factors influencing formation of different stone show different structures and, more importantly, chemical
types, their pathogenesis, and therapy. Risk factors for composition and are grouped into noninfectious, infec-
stone disease generally include lifestyle and genetic/epi- tious, and genetic stones. Causes and/or diagnostic mark-
genetic contributions. Formation of kidney stones is mod- ers for the important subgroups are shown, as well as the
ulated by promoting or inhibiting metabolic factors most common treatment. General promoters and inhibi-
(mainly concerning ion composition). Kidney stones can tors are mentioned
and high urinary Na+, sulfate, and phosphate complexes with Ca2+ ions, thus inhibiting Ca2+
(Pi), due to dietary intake. Metabolic risk factors stone formation.
include high urinary Ca2+ (idiopathic hypercalci- Critical care must be taken to the underlying
uria) [5], oxalate (hyperoxaluria), and uric acid mechanism, when evaluating high-risk patients
(hyperuricosuria), low urinary citrate (hypoci- including children, middle-aged white males
traturia), and abnormally high or low pH (as with a family history of stones, and patients with
in gouty diathesis). Decreased urinary volume chronic diarrheal or GI malabsorptive states,
and/or increase in ions that can participate in bone disease (see chapters “Overview” under
stone formation (Ca2+, oxalate, Na+, sulfate, Pi) the part “Teeth and bones” and “Osteoporosis”),
can cause supersaturation and crystallization. urinary tract infection (see chapter “Urinary
Citrate is a crystallization inhibitor and builds tract infections”), gout (see chapter “Gout and
Kidney Stones 363
disease, environmental or metabolic state of the Crohn’s disease need to avoid Ca2+ products
respective stone class. Specific treatments for the due to their intolerance to any calcium-
respective stone classes are discussed in the next containing products.
section.
Treatment of Calcium-Containing
Influence of Treatment on Stones due to Hypocitraturia
Metabolism and Consequences
for Patients By forming a more soluble calcium-citrate com-
plex, citrate decreases the effective concentration
Treatment of Calcium Stones due of free Ca2+ and thus urinary saturation of cal-
to Hypercalciuria cium oxalate. Hypocitraturia often coexists with
hypercalciuria or hyperuricosuria. Thus, potas-
Thiazide diuretics are the recommended medica- sium citrate is an efficient and safe treatment for
tions for hypercalciuria as they limit urinary Ca2+ hypocitraturia [11].
excretion, decreasing formation of Ca-containing
stones. Thiazides inhibit the Na+-Cl− symporter.
This decreases the Na+ levels in renal tubular Treatment of Uric Acid-Containing
cells, activating the basolateral Na+/Ca2+-ATPase Stones due to Hyperuricemia/Gouty
antiporter. The subsequent reduction of Ca2+ in Diathesis
the cell increases reabsorption from the tubule.
However, thiazides can cause (secondary) hypo- As the primary cause of uric acid stones is an
kalemia and hypocitraturia (via similar mecha- excessively increased uric acid level in the blood
nisms). Thus, potassium citrate is typically and (acid) urine (pH < 5.5), correction of both is
administered as adjunctive. aspired. The major goal is to decrease urinary
saturation of uric acid by raising the urine pH to
6.5–7.0, by increasing urine volume, and by pro-
Treatment of Oxalate Stones due viding alkali therapy. As the solubility for uric
to Hyperoxaluria or Enteric acid increases tenfold with a pH change from
Hyperoxaluria 5.0 to 7.0, urinary alkalization is by far the most
important factor. Therefore, citrate (or sodium
A general strategy to prevent formation of oxa- bicarbonate) is appropriate, as these salts will
late stones is dietary reduction of oxalate (see alkalize the urine. Moreover, allopurinol and a
above). Patients with intestinal malabsorption diet poor in purines are recommended to lower
of fat, as seen in patients with Crohn’s disease, total endogenous uric acid (see chapter “Gout
often present with increased levels of oxalate in and hyperuricemia”).
blood and urine after intestinal resection or
jejunoileal bypass (enteric hyperoxaluria). The
loss of fatty acids is combined with loss of Ca2+, Treatment of Distal Renal Tubular
which disturbs the normal complex formation Acidosis
between oxalate and calcium in the bowel,
thereby increasing oxalate absorption. Oral The metabolic acidosis and hypokalemia found
administration of Ca2+ supplements [9] has in patients with distal renal tubular acidosis can
been recommended, to enable calcium oxalate be corrected with potassium citrate, as citrate is
complexation in the intestine. Pyridoxine (vita- (in part) metabolized to bicarbonate. Normal
min B6) can also be used to reduce the urine urine citrate concentrations can be achieved.
oxalate by reducing the primary oxalate synthe- Correction of the acidosis should lead to a decline
sis in the liver [10], as many patients with in the urinary Ca2+ excretion [12].
Kidney Stones 365
The gonads are the end organs of reproduction, Steroids are produced by several tissues, includ-
represented by the ovary in women and the testis ing the adrenal cortex, the gonads, the placenta,
in men (Fig. 1). They produce and release germ and the peripheral tissues such as the adipose tis-
cells, central to the survival of the species. sue and the brain. All steroid hormones are deriv-
Ovaries contain all the oocytes they will ever atives of cholesterol, and production of sex
have at birth, although they will not begin to be steroids requires the expression of enzymes
released until puberty. The testis can produce within the steroidogenic pathway (Fig. 1) [1].
sperm from the age of puberty until death. The testis mainly produces androgens, such as
Besides the formation of germ cells, testes and androstenediol, androstenedione, testosterone,
ovaries produce sex hormones that affect the dihydrotestosterone, and small amounts of dehy-
physiology of many, if not all nonreproductive droepiandrosterone (DHEA), released from the
organs. The steroid hormone-producing cells of Leydig cells, whereas the Sertoli cells in the testis
the ovary are the theca and granulosa cells of the convert testosterone to small amounts of estro-
ovarian follicle; those of the testis are the Sertoli gen, such as estradiol (E2), required for sper-
and Leydig cells. The function of the gonads is matogenesis. Estrogens in men are produced at a
mainly regulated by the hypothalamus-pituitary much lower rate than in women.
axis (Fig. 1). The human breast is a secondary The ovaries produce estrogens, such as estrone
reproductive organ that serves to feed the infant (E1) and E2; progesterones, i.e., progesterone
in the first period of life. (P4) and 17α-hydroxy-progesterone; and andro-
gens (similar to the testis, except for dihydrotes-
tosterone). Androgen production in women is
D.J. Schust (*) much lower than in men. For example, levels of
Department of Obstetrics, Gynecology and Women’s
circulating testosterone in women are about 1/8th
Health, University of Missouri School of Medicine,
500 North Keene Street, Suite 203, Columbia, that of men. DHEA is found in fairly high con-
MO 65201, USA centrations in the circulation of women, mostly
e-mail: schustd@health.missouri.edu in its sulfated form: DHEA-S. Sulfation of DHEA
D.R. Gullicks occurs in the adrenals, the liver, and the intestine.
Department of Obstetrics, Gynecology and Women’s The major function of DHEA is that of a precur-
Health, University of Missouri School of Medicine,
sor to other androgens and estrogens (Fig. 1). The
402 North Keene Street, Third floor,
Columbia, MO 65212, USA weak estrogen, estriol (E3), is produced only dur-
e-mail: gullicksr@health.missouri.edu ing pregnancy, by the placenta.
Hypothalamus
GnRH neurons
Progesterone
GnRH
Inhibin Inhibin
Anterior
pituitary
Testosterone Estradiol
FSH LH
Androgens,
Estrogens,
Progesterone Ovary
Testis
Cholesterol
Fig. 1 Production pathways of sex steroids and the hypo- showing important intermediates and enzymes. Gray
thalamic-pituitary-gonadal axis. Upper part: regulation of boxes indicate enzymes. [1] 3β-OH dehydrogenase:
sex steroid production by the hypothalamus-pituitary axis Δ5Δ4 isomerase, [2] aromatase, [3] 5α-reductase.
and feedback mechanisms. GnRH gonadotropin-releasing Further, enzymes and molecules in Light gray are not
hormone, FSH follicle-stimulating hormone, LH luteiniz- mentioned in the text but included for completeness.
ing hormone. Lower part: steroid hormone biosynthesis DHEA dehydroepiandrosterone
Overview 371
The adrenal gland generally produces sex ste- composed of three parts: the anterior lobe, the
roids as byproducts of gluco- and mineralocorti- posterior lobe, and the pars intermedia (Fig. 1)
coids and therefore in fairly small amounts when [2]. Three specific cell types within the anterior
compared to the gonads. One important physio- pituitary play a central role in reproduction (see
logic exception is that approximately half of the below).
circulating androgens in women are of adrenal The hypothalamus is divided into nuclei,
origin. which generate neural signals and have neuroen-
docrine capabilities. Most centrally involved in
gonad regulation are those nuclei that integrate
Inside-In: Signals in the olfactory, visual, emotional, and other signals
Reproductive Organs [3]. The neuroendocrine signals consist of a set
of peptide hormones that either are stored in the
Development and release of each type of germ posterior pituitary and then released into the
cell require delicately balanced interactions blood or target the anterior lobe of the pituitary
between several gonad-specific cell types (testic- (Fig. 1). The latter substances stimulate or inhibit
ular Sertoli and Leydig cells in men and ovarian the production of tropic hormones. These hor-
granulosa and theca cells in women) and the sex mones are commonly named according to their
steroids produced by these cells. function as “releasing” and “stimulating” hor-
Theca cells surrounding the ovarian follicle mones, respectively.
produce androgens, which are converted to estro-
gens by the granulosa cells of the ovarian follicle.
Ovarian E2 and its feedback interactions with the Signals from the Hypothalamus
hypothalamus and pituitary gland direct the
development of the ovarian follicle. Peptide hor- Oxytocin and vasopressin (also known as antidi-
mones produced by the ovary (e.g., inhibin, uretic hormone, ADH) are synthesized by the
activin, and follistatin) also participate in positive hypothalamus and stored in the posterior pitu-
and negative regulation of the hypothalamic- itary. Oxytocin acts on uterine smooth muscle
pituitary-gonadal axis and function in controlling resulting in contractions and affects specialized
menstrual cyclicity. myoepithelial cells in the breast allowing for
Testicular androgens are mostly produced by milk letdown.
the Leydig cells under the influence of pituitary Gonadotropin-releasing hormone (GnRH) is
luteinizing hormone (LH). The Sertoli cells of released in a pulsatile fashion from the hypothal-
the testis support sperm proliferation and matura- amus and stimulates gonadotropic cells in the
tion and can convert androgens to estrogens via anterior pituitary to produce follicle-stimulating
aromatase or to dihydrotestosterone via hormone (FSH) and LH. These gonadotropins
5α-reductase (Fig. 1). They also secrete inhibin are secreted by the same cell type, and their
to regulate LH release (Fig. 1 and below). Most secretion is modulated by the frequency of the
dihydrotestosterone, however, is synthesized GnRH pulse, with higher frequency favoring LH
locally in androgen-responsive tissues (such as over FSH and a lower frequency favoring FSH
hair follicle cells). over LH.
Dopamine from the hypothalamus, also called
prolactin inhibitory factor, suppresses prolactin
Outside-In: Hypothalamus/ production by lactotrope cells in the pituitary.
Pituitary/Reproductive Organ Axis Pituitary lactotropes are also regulated by a num-
ber of other factors (see below).
The major organ controlling the gonads is the The third pituitary cell type involved in
pituitary gland, which itself is (primarily) con- gonad regulation, the thyrotropes, produces
trolled by the hypothalamus. The pituitary is thyroid-stimulating hormone (TSH), triggered by
372 D.J. Schust and D.R. Gullicks
thyrotropin-releasing hormone from the and IGF receptors of the somatotropic axis
hypothalamus. enhance ovarian steroidogenesis.
Bronchial
P4 constriction
Respiratory function/
characteristics
Lung
Pregnancy
Short-term increase in circulating
estrogens and P4 P4 Cell-mediated
immunity
Immune Fetal tolerance
system
Ovarian P4,
Delayed gastric
estrogens
P4, estrone, E2 emptying
Bowel motility
GI tract
Circulating hormone
Estrogens binding proteins
Placenta
Angiotensinogen
P4, estriol Clotting factors
Liver
Cardiac output
Systemic vascular
P4 resistance
Blood volume
Cardiovascular disease
Cardiovascular system
Androgen
Estrogen
Menopause
Long-term decrease in ovarian Hair loss
production of estrogens and Hair follicle Acne
P4 due to follicular depletion Hirsutism
E2
Osteoporosis
Bone
Ovary
Hypothalamus
Fig. 2 Effects of female steroid hormones (exemplified by changes in these hormones during pregnancy and meno-
pause) P4 progesterone, E2 estradiol
374 D.J. Schust and D.R. Gullicks
pregnancy dominate the systemic steroid effec- often note an exacerbation of symptoms, while
tors in maternal blood. Estrogens and P4 increase those with T-cell-based inflammatory conditions
maternal blood volume and cardiac output to sup- may experience improvement [7]. Interestingly,
ply the developing fetus with blood while main- immune effects of P4 in pregnancy are thought to
taining or lowering maternal blood pressure. E1, be mediated through the glucocorticoid receptor
E2, and E3 can all exert these effects via estrogen or through nonclassical P4 receptors (as classical
receptor binding; however, E3 comprises approx- are not expressed on most immune cells) [8].
imately 80 % of circulating maternal estrogens
during pregnancy and therefore may exert the
most significant effects. Elevated placental estro- Menopause
gens increase the production of angiotensinogen
(by the liver), and estrogens and P4 increase At menopause, there is a cessation of ovarian fol-
renin (from the kidney), thus increasing the level licular development with resultant marked
of angiotensin and subsequently aldosterone, decreases in circulating estrogen, inhibin, and P4
which, in turn, promotes sodium and water reten- levels. Ovarian androgen production remains
tion (see chapter “Overview” under the part relatively intact. This relative hormone deficiency
“Kidney”). Although the maintenance of mater- has several physiologic effects. Decreased estro-
nal blood pressure in the face of increased blood gen and inhibin release the negative feedback on
volume is largely the result of the lower maternal the hypothalamus and pituitary gland (Fig. 1),
responsivity to angiotensin II during pregnancy, and consequently FSH levels rise. Alterations in
the elevated levels of circulating P4 accentuate these hormones have been linked to the hot
this adaptation by mediating smooth muscle flashes, insomnia, and depressed mood that are
relaxation throughout the mother’s body. This commonly found in peri- and early postmeno-
latter effect of P4 also results in delayed gastric pausal women. Estrogen deficiency leads to tis-
and gallbladder emptying, reduced bowel motil- sue atrophy and loss of elasticity in the breast,
ity, and relaxation of the lower esophageal vagina, and skin. As estrogen antagonizes the
sphincter in the pregnant women, often experi- effects of parathyroid hormone on Ca2+ mobiliza-
enced by the mother as reflux, nausea, vomiting, tion in bone (see chapter “Overview” under the
and/or constipation. part “Teeth and bones”), and since estrogen defi-
P4-related bronchial and tracheal smooth ciency increases osteoclast activity, postmeno-
muscle relaxation may improve asthma symp- pausal women are at increased risk for
toms (see chapter “Asthma”) in pregnancy. Other osteoporosis (see chapter “Osteoporosis”).
respiratory effects of elevated maternal P4 Estrogen increases circulating high-density
include an increase in tidal volume (lung vol- lipoproteins and decreases low-density lipopro-
ume), minute ventilation (the volume of gas teins (see chapter “Hyperlipidemia”). Moreover,
inhaled or exhaled per minute), and respiratory it decreases endothelial production of endothelin-
rate (breathing frequency), resulting in an overall 1, a potent vasoconstrictor (see chapter
decrease in arterial CO2 gas tension via central “Overview” under the part “Blood vessels”).
nervous system changes that increase sensitivity These two protective cardiovascular effects of
to CO2 [6]. estrogens may help to explain the lower rates of
Estrogens upregulate hepatic synthesis of cardiovascular disease (see chapter
hormone-binding proteins and several clotting “Atherosclerotic heart disease”) seen in women
factors promoting hypercoagulability and an compared to men. Reduced estrogens, in combi-
increase in total circulating thyroid hormones. P4 nation with a relatively intact androgen produc-
and estrogens exert effects on maternal immune tion, cause a gradual loss of this protection after
function causing susceptibility to certain viral menopause. Interestingly, androgens are con-
infections (e.g., varicella) but allowing tolerance verted to dihydrotestosterone in hair follicles (see
against the semi-allogenic fetus. Pregnant women above), and continued production of this potent
with antibody-mediated autoimmune diseases androgen often results in hirsutism and some
Overview 375
degree of hair loss on the scalp of postmeno- Additionally, as aging males tend to be over-
pausal women. Adipose tissue is an important weight, circulating E2 levels are often increased.
source of the enzyme aromatase that converts Estrogen-stimulated increases in hepatic sex hor-
androgens to estrogen. Obesity can therefore mone-binding globulin production effectively
increase levels of circulating estrogens in post- decrease levels of circulating free testosterone in
menopausal women, somewhat protecting these the aging male.
women from the effects of decreased ovarian
estrogens.
Male reproductive hormones have equally Anatomy and Physiology
dramatic effects on the vast array of tissues that of the Human Breast
express androgen receptors. For example, andro-
gen receptors are expressed in skeletal muscle, The human breast is comprised of glandular and
and their activation stimulates the myogenesis ductal tissues embedded in adipose tissue.
responsible for the increased muscle mass noted Alveolar glandular tissues in the 15–20 lobes of
in the postpubertal men compared to women [9]. the adult breast dump secretions into a converg-
The elevated levels of circulating androgens in ing series of excretory and lactiferous ducts that
men combine with genetic predisposition to terminate in approximately 15 distinct orifices on
make baldness much more common in men than the nipple surface [12]. These ducts are lined by
in women (see above). Androgens increase bone stratified squamous epithelium.
mass through receptor-mediated direct and indi-
rect effects on osteoclasts. Their effects on car-
diovascular disease are complex, but androgens Tissue-Specific Metabolic Pathways
certainly promote less favorable lipid profiles by of the Breast
increasing LDL and triglyceride levels and
decreasing HDL levels (see chapter The breast is the only tissue that can secrete a fully
“Hyperlipidemia”) [10]. The prostate gland is life-sustaining product. Human milk is a fat emul-
unique among the male internal reproductive sion in liquid phase that contains over 100 distinct
tract constituents in that dihydrotestosterone, substances. The main constituents are lactose
rather than testosterone, is required for its devel- (7 %), fat (3–5 %), proteins (casein, α-lactalbumin,
opment, growth, and maintenance. The nuclear lactoferrin, immunoglobulin A, lysozyme, and
androgen receptors in the prostate have a higher albumin; 1%” to be consistent with the inclusion
affinity for dihydrotestosterone, so adequate of percentages of the other constituents), and min-
5α-reductase activities are essential for prostate erals (0.2 %) [13].
growth. Men lacking this enzyme have a poorly
developed prostate gland and essentially no risk
for subsequent prostate hypertrophy or prostate Outside-In: Signaling of the Breast
cancer (see chapter “Prostate cancer”). Like
women, men experience reproductive aging, At birth, the breast consists mainly of primitive
termed andropause, although its onset and pro- ductal tissues, which remain mostly quiescent
gression is less predictable and more gradual. until the onset of puberty. In females, pubertal
Circulating testosterone levels decrease, thus elevations in circulating ovarian estrogens
causing osteopenia and osteoporosis (see chapter (mainly E2 and P4) stimulate the resumption of
“Osteoporosis”), decreased muscle mass, erectile growth and differentiation of the rudimentary
dysfunction, and impaired sperm parameters ducts. The elevations in serum P4 that accom-
[11]. Testicular Leydig cells also become less pany maturation of the hypothalamic-pituitary-
responsive to LH with aging. In response, LH ovarian axis to allow ovarian cyclicity also
levels increase to maintain androgen produc- maintain ductal and initiate glandular growth and
tion (see above) but also increase the ratio of differentiation in the breast. Mammary develop-
testicular estrogen to androgen secretion. ment continues for several years after menarche
376 D.J. Schust and D.R. Gullicks
but will not be fully complete until late in the first cancer”) and prostate cancer (see chapter
trimester of a woman’s initial pregnancy. All “Prostate cancer”). With regard to metabolism,
aspects of mammary growth are supported by the gonads are major producers of androgens and
GH and adrenal steroids. estrogens, steroid hormones that act on multiple
The initiation of milk production is largely targets throughout the body, mainly at the level of
controlled by pituitary prolactin [14]. Serum lev- gene transcription. In addition to reproduction,
els of prolactin are elevated during the last tri- they influence muscle strength, bone stability,
mester of pregnancy, but milk production is hair growth, lipoprotein profiles, and many other
inhibited until after delivery by simultaneous physiologic functions.
elevations in serum estrogen. Oxytocin drives
milk ejection. Suckling and the stimulation of
additional sensorineural pathways control pitu-
References
itary oxytocin secretion. Although basal serum
prolactin levels return to prepregnancy levels and 1. Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA
suckling-related spikes in prolactin secretion (2001) Luteinizing hormone receptor, steroidogenesis
abate by approximately 2 months post-delivery, acute regulatory protein, and steroidogenic enzyme
the breast-feeding mother may still be producing messenger ribonucleic acids are overexpressed in the-
cal and granulosa cells from polycystic ovaries. J Clin
large amounts of breast milk, since milk delivery Endocrinol Metab 86:1318–1323
can be maintained by nipple stimulation and oxy- 2. Braak H, Braak E (1992) Anatomy of the human
tocin alone. This can continue indefinitely. hypothalamus (chiasmatic and tuberal region). Prog
Brain Res 93:3–14; discussion 14–16
3. Clifton DK, Steiner RA (2009) Neuroendocrinology
of reproduction. In: Straus JF, Barbieri RL (eds) Yen
Inside-Out: Signaling of the Breast and Jaffe’s reproductive endocrinology, 6th edn.
Elsevier Saunders, Philadelphia, pp 3–75
The suckling reflex describes the series of sensory 4. Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall
JE (2010) Estrogen negative feedback on gonadotro-
impulses that travel from the nipple to the brain pin secretion: evidence for a direct pituitary effect in
with breast-feeding. These impulses cause the women. J Clin Endocrinol Metab 95:1955–1961
release of prolactin to aid in continued milk pro- 5. Lejeune H, Sanchez P, Chuzel F, Langlois D, Saez JM
duction. Prolactin inhibits the secretion of FSH (1998) Time-course effects of human recombinant
leuteinizing hormone on porcine Leydig cell spe-
from the pituitary directly, but also indirectly cific differentiated functions. Mol Cell Endocrinol
through inhibition of the GnRH pulse generator 144(1–2):59–69
and appropriate pulsatile secretion of GnRH. This 6. Weinberger SE, Weiss ST, Cohen WR, Weiss JW,
typically prevents ovulation in the first months Johnson TS (1980) Pregnancy and the lung. Am Rev
Respir Dis 121(3):559–581
after delivery and can be a contraceptive in fre- 7. Jackson DL, Schust DJ (2011) The role of the pla-
quent and exclusive breast-feeders [15]. centa in autoimmune disease and early pregnancy
loss. In: Kay H, Nelson DM, Wang Y (eds) The pla-
centa: from development to disease. Wiley-Blackwell
Publishing, Inc, Chichester, pp 215–221
Final Remarks 8. Schust DJ, Anderson DJ, Hill JA (1996) Progesterone-
induced immunosuppression is not mediated through
The gonads are responsible for the production of the progesterone receptor. Hum Reprod 11(5):
germ cells, and the female reproductive organs 980–985
9. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF,
support embryonic and early postnatal develop- Zheng W, Bhasin S (2004) Androgen receptor in
ment. As the cells within the reproductive tissues human skeletal muscle and cultured muscle satellite
are highly proliferative or available for remodel- cells: up-regulation by androgen treatment. J Clin
ing, cancers of these tissues are common dis- Endocrinol Metab 89(10):5245–5255
10. Pederson L, Kremer M, Judd J, Pascoe D, Spelsberg
eases, and the underlying hormonal signaling TC, Riggs BL, Oursler MJ (1999) Androgens regulate
pathways are of critical importance for the devel- bone resorption activity of isolated osteoclasts in
opment of both breast cancer (see chapter “Breast vitro. Proc Natl Acad Sci U S A 96:505–510
Overview 377
11. Crosnoe LE, Kim ED (2013) Impact of aging on male 14. Motil KJ, Thotathuchery M, Montandon CM, Hachey
fertility. Curr Opin Obstet Gynecol 25(3):181–185 DL, Boutton TW, Klein PD, Garza C (1994) Insulin,
12. Rusby JE, Brachtel EF, Michaelson JS, Koerner FC, cortisol and thyroid hormones modulate maternal pro-
Smith BL (2007) Breast duct anatomy in the human tein status and milk production and composition in
nipple: three-dimensional patterns and clinical impli- humans. J Nutr 124:1248–1257
cations. Breast Cancer Res Treat 106:171–179 15. Konner M (1978) Nursing frequency and birth spac-
13. Jenness R (1979) The composition of human milk. ing in Kung hunter-gatherers. IPPF Med Bull 15:1–3
Semin Perinatol 3:225–239
Breast Cancer
Introduction to Breast Cancer therapies (see below). Risk factors for BC are
manifold and include genetics, high age at first
Breast cancer (BC) is a type of cancer origi- birth, short time of breast-feeding, obesity,
nating from the epithelium of the mammary early menarche, late menopause, and hormonal
gland. As most cancers, it can be invasive or treatment.
noninvasive. Carcinomas can originate from BC diagnosis includes mammography and
ducts (70 %) or from lobules (10 %). Rare sub- sonography and, in case of suspicion, magnetic
types (mucinous, tubular, medullar, cribriform, resonance imaging. Whenever any abnormality
and adenoid cystic cancers) make up the rest. is seen, a biopsy is necessary. In general, pri-
Besides histology, BC is classified accord- mary and recurrent BC is considered a curable
ing to the expression of the estrogen receptor disease, while metastatic disease is not curable.
(ER), with 70 % being positive (ER+) and 30 % Nevertheless in approximately 10–15 % of meta-
being negative (ER-), or the expression of the static cases, survival of at least 15 years has been
oncogene HER2 encoding the human epidermal observed with appropriate treatment.
growth factor receptor 2 (HER2), with 20–25 %
Her2+ BCs and 75–80 % Her2− BCs. Today, a
classification by a combination of gene expres- Anatomy and Development
sion profiling and classical pathology into four of the Mammary Gland
subtypes, luminal A, luminal B, Her2 overex-
pression, and basal-like BC, is commonly used The mammary ducts and alveoli of the adult
(Table 1, adapted from [1]). human breast are lined by an inner layer of
BC is the most frequent female cancer world- secretory luminal epithelial cells that produce
wide with about 1.4 million newly diagnosed milk during lactation and are surrounded by
cases and approximately 460,000 deaths per basement membrane and contractile myo-
year [2]. Whereas incidence is rising, mortality epithelial cells for milk ejection. During the
has dropped, likely resulting from improved pregnancy and lactation cycle, the mammary
screening programs and better systemic adjuvant gland matures into a functional milk-secreting
organ [3]. After pregnancy, these developments
regress. This continuous remodeling is protec-
T. Fehm (*) • E. Ruckhäberle tive against breast cancer [4], particularly when
Department of Obstetrics and Gynecology, it occurs before the age of 30 and with an inter-
Heinrich Heine University Düsseldorf,
val of less than 14 years between menarche and
Moorenstrasse 5, Düsseldorf, 40225 Germany
e-mail: tanja.fehm@med.uni-duesseldorf.de; the first pregnancy. Multiparity confers slightly
eugen.ruckhaeberle@med.uni-duesseldorf.de more protection [5].
can also be activated by complexing with other cell division [15], a prerequisite for tumor for-
transmembrane receptors such as insulin-like mation, and high glucose concentrations may
growth factor-1 receptor (IGF-1R) [13]. Adding favor tumor cell proliferation and selection of
another level of interaction, HER2 and IGF-1 malignant cells over nonmalignant ones [16].
signaling can activate ER (in what is called Insulin also increases the level of sex hormone-
ligand-independent activation), e.g., via MAPK, binding globulin and thus bioavailability of
PI3K/Akt, or p38 signaling. estrogens. Second, synthesis and bioavailabil-
Obesity is linked to BC risk via various ity of sex steroids, most importantly estradiol,
mechanisms [14]. First, the insulin-cancer are increased, due to the expression of aroma-
hypothesis attributes an important role to tase by adipose tissue (see chapter “Overview”
insulin resistance, which causes high insu- under the part “Reproductive system” and
lin and glucose levels (see chapter “Diabetes below) [17]. Finally, obesity is characterized
mellitus”). Increased activation of the insulin by a state of chronic low-grade inflammation
receptor on breast epithelial cells stimulates due to increased levels of pro-inflammatory
EGF IGFs
E2 MMPs E2
HER1 HER2 IGFR
*
Caveolae
Lapatinib
ER Src Neratinib Afatinib PI3K * GPER
Ras
Akt *
Saracatinib
Dasatinib Raf
mTOR Everolimus
(Temsirolimus)
MAPK *
Ligand binding Dimerization
domain (I) domain (II)
ERE
Growth Apoptosis
Angiogenesis IV Pertuzumab
Proliferation Trastuzumab
HER2
Receptor tyrosine
Nucleus kinase
Fig. 1 Important signaling pathways and treatment strat- signaling pathways utilized by HER and IGFR, namely,
egies in breast cancer. Important signaling pathways in signaling via Ras, Raf, and mitogen-activated protein
breast cancer include estrogen receptor (ER), HER recep- kinase (MAPK), as well as phosphatidyl-inositol-3-kinase
tor and insulin-like growth factor receptor (IGFR or (PI3K) and Akt signaling activating mammalian target of
IGF-1R) signaling. Estrogen (E2) can activate intracellu- rapamycin (mTOR). Ultimately these signals also promote
lar ER and G-protein-coupled ER (GPER) in caveolae cancer progression by increasing growth, proliferation,
leading to genomic and non-genomic alterations. The for- and angiogenesis and by inhibiting apoptosis. Major
mer involves binding of the ER to estrogen response ele- breast cancer treatments target these signaling pathways
ments (ERE) to activate target genes involved in growth, by blocking Src or mTOR or by interacting with multiple
proliferation, and transformation. The latter involves acti- sites on the HER receptors. A great variety of drugs
vation of Src kinase and release of matrix metalloprotein- against novel targets is currently under development, as
ases (MMPs). ER signaling also feeds into intracellular indicated by asterisks. EGF epidermal growth factor
382 T. Fehm and E. Ruckhäberle
adipokines, such as tumor necrosis factor-α Estrogen synthesis inhibitors are often aro-
(TNFα), and the interleukins IL-1, IL-6, IL-8, matase inhibitors and decrease estrogen levels,
and IL-10, which link to cancer [18]. because estrogens are produced from androstene-
dione and testosterone via aromatase (see chapter
“Overview under the part “Reproductive sys-
Treatment of Breast Cancer tem”). This effect is most relevant in postmeno-
pausal women, in whom estrogen production
Standard treatment of BC includes operative, occurs primarily by aromatization in peripheral
systemic, and radiation treatment. Surgical treat- tissues such as adipose tissue. Steroidal aroma-
ment is still a mainstay; it is followed by local tase inhibitors (e.g., exemestane) bind irrevers-
or systemic adjuvant therapy, meaning a support- ibly, and nonsteroidal aromatase inhibitors (e.g.,
ive therapy to save and intensify the success of anastrozole) bind reversibly to inhibit aromatase
surgical BC treatment. Neoadjuvant therapy, a activity.
more recent treatment, uses the same substances Finally, selective ER downregulators (SERDs)
and regimens like adjuvant treatment but is induce receptor polyubiquitination and subse-
given before surgery. Advantages of this concept quent degradation via the proteasome. The SERD
include shrinkage of the tumor and a reduced fulvestrant is a pure antagonist with no agonistic
number of breast amputations. effect, in contrast to tamoxifen.
Since circulating tumor cells are detectable Side effects of antihormonal therapy include
in many patients at the time of breast surgery, hot flashes, sleeping disturbances, huffi-
systemic recurrence often occurs under local ness, a decrease in bone density (see chapter
therapy, thus arguing for systemic adjuvant treat- “Osteoporosis”), weight gain, and an increase
ment. Three different systemic adjuvant therapies in cholesterol. Unfortunately, up to 50 % of
exist: (1) targeted therapy such as endocrine ther- patients on endocrine therapy exhibit a primary
apy or treatment blocking the HER2 pathway, (2) (de novo) or acquired resistance [19]. Potential
systemic chemotherapy, and (3) immunotherapy escape mechanisms include loss or modifica-
after primary surgery. tion of ER expression, cross talk between path-
Targeted therapy depends on the BC subtype. ways, an alteration in the expression of specific
Endocrine therapy, an antihormonal treatment, micro-RNA, and alterations in drug metabolism
was the first and still is the most common adju- [20, 21].
vant and neoadjuvant treatment. It aims to either Treatments against HER2 include monoclo-
reduce estrogen levels or to block ER signaling. nal antibodies and tyrosine kinase inhibitors.
Traditionally, this was achieved via ovarian abla- The first approved agent was trastuzumab, a
tion. However, today, drugs that target ER directly monoclonal antibody (thus the ending –mab). It
or indirectly are used. Three classes of antihor- substantially improves outcomes in early-stage
monal endocrine agents are used: selective estro- and metastatic BC and likely induces internal-
gen receptor modulators (e.g., tamoxifen) that ization and degradation of HER2, disrupting
block the activity of ER, estrogen synthesis inhibi- signaling and by this resulting in apoptosis
tors (e.g., aromatase inhibitors such as anastrozole, (Fig. 1). Side effects are rare as trastuzumab
letrozole, and exemestane), and selective estrogen is specific for HER2. However, de novo and
receptor downregulators (e.g., fulvestrant) that acquired resistance occur. Escape mecha-
induce destabilization and degradation of ER. nisms may include signaling through alterna-
Selective ER modulators (SERMs), e.g., tive receptors (e.g., IGF-1R), upregulation
tamoxifen and raloxifene, competitively inhibit of downstream signaling pathways, and fail-
binding of estrogen to ERα, blocking both its ure to elicit an appropriate immune response
genomic and non-genomic activity. Tamoxifen against the trastuzumab-bound BC cells [22,
hampers interactions with activators and blocks 23]. Thus, new treatment concepts also tar-
transcription of ER target genes. get escape mechanisms [24]. For example,
Breast Cancer 383
7. Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER Dowsett M, Ingle J, Peto R (2011) Relevance of breast
(2002) ERs associate with and regulate the produc- cancer hormone receptors and other factors to the
tion of caveolin: implications for signaling and cel- efficacy of adjuvant tamoxifen: patient-level meta-
lular actions. Mol Endocrinol 16:100–115 analysis of randomised trials. Lancet 378:771–784
8. Migliaccio A, Piccolo D, Castoria G, Di Domenico 20. Fedele P, Calvani N, Marino A, Orlando L, Schiavone
M, Bilancio A, Lombardi M, Gong W, Beato M, P, Quaranta A, Cinieri S (2012) Targeted agents to
Auricchio F (1998) Activation of the Src/p21ras/Erk reverse resistance to endocrine therapy in metastatic
pathway by progesterone receptor via cross-talk with breast cancer: where are we now and where are we
estrogen receptor. EMBO J 17:2008–2018 going? Crit Rev Oncol Hematol 84:243–251
9. Schiff R, Massarweh SA, Shou J, Bharwani L, 21. Bianco S, Gévry N (2012) Endocrine resistance in
Mohsin SK, Osborne CK (2004) Cross-talk between breast cancer: from cellular signaling pathways to
estrogen receptor and growth factor pathways as a epigenetic mechanisms. Transcription 3:165–170
molecular target for overcoming endocrine resistance. 22. Hubalek M, Brunner C, Matthä K, Marth C (2010)
Clin Cancer Res 10:S331–S336 Resistance to HER2-targeted therapy: mechanisms
10. Deroo BJ, Korach KS (2006) Estrogen receptors and of trastuzumab resistance and possible strategies to
human disease. J Clin Invest 116:561–570 overcome unresponsiveness to treatment. Wien Med
11. Hadler-Olsen E, Winberg JO, Uhlin-Hansen L (2013) Wochenschr 160:506–512
Matrix metalloproteinases in cancer: their value as 23. Pohlmann PR, Mayer IA, Mernaugh R (2009)
diagnostic and prognostic markers and therapeutic Resistance to trastuzumab in breast cancer. Clin
targets. Tumour Biol 34:2041–2051 Cancer Res 15:7479–7491
12. Köhrmann A, Kammerer U, Kapp M, Dietl J, Anacker 24. Tsang RY, Finn RS (2012) Beyond trastuzumab:
J (2009) Expression of matrix metalloproteinases novel therapeutic strategies in HER2-positive meta-
(MMPs) in primary human breast cancer and breast static breast cancer. Br J Cancer 106(1):6–13
cancer cell lines: new findings and review of the lit- 25. Mendelsohn J, Baselga J (2003) Status of epidermal
erature. BMC Cancer 9:188 growth factor receptor antagonists in the biology and
13. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ treatment of cancer. J Clin Oncol 21:2787–2799
(2005) Insulin-like growth factor-I receptor/human 26. Gallagher EJ, LeRoith D (2011) Diabetes, cancer, and
epidermal growth factor receptor 2 heterodimeriza- metformin: connections of metabolism and cell pro-
tion contributes to trastuzumab resistance of breast liferation. Ann N Y Acad Sci 1243:54–68
cancer cells. Cancer Res 65:11118–11128 27. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier
14. Patterson RE, Rock CL, Kerr J, Natarajan L, Marshall CR (2010) Long-term metformin use is associated
SJ, Pakiz B, Cadmus-Bertram LA (2013) Metabolism with decreased risk of breast cancer. Diabetes Care
and breast cancer risk: frontiers in research and prac- 33(6):1304–1308
tice. J Acad Nutr Diet 113(2):288–296 28. Shaw RJ, Lamia KA, Vasquez D, Koo SH,
15. Faulds MH, Dahlman-Wright K (2012) Metabolic Bardeesy N, Depinho RA, Montminy M, Cantley LC
diseases and cancer risk. Curr Opin Oncol 24:58–61 (2005) The kinase LKB1 mediates glucose homeo-
16. Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, stasis in liver and therapeutic effects of metformin.
Schünemann HJ, Ram M, Freudenheim JL, Sieri S, Science 310(5754):1642–1646
Trevisan M, Berrino F (2002) Fasting glucose is a risk 29. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T,
factor for breast cancer: a prospective study. Cancer Lind SE, Thor AD (2009) Metformin inhibits breast
Epidemiol Biomarkers Prev 11:1361–1368 cancer cell growth, colony formation and induces cell
17. Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity cycle arrest in vitro. Cell Cycle 8(6):909–915
and cancer risk: the role of the insulin-IGF axis. 30. Jungbauer A, Medjakovic S (2012) Anti-inflammatory
Trends Endocrinol Metab 17(8):328–336 properties of culinary herbs and spices that amelio-
18. Heikkila K, Ebrahim S, Lawlor DA (2007) A sys- rate the effects of metabolic syndrome. Maturitas
tematic review of the association between circulat- 71(3):227–239
ing concentrations of C reactive protein and cancer. J 31. Baliga MS, Haniadka R, Pereira MM, D’Souza JJ,
Epidemiol Community Health 61:824–833 Pallaty PL, Bhat HP, Popuri S (2011) Update on the
19. Davies C, Godwin J, Gray R, Clarke M, Cutter D, chemopreventive effects of ginger and its phytochem-
Darby S, McGale P, Pan HC, Taylor C, Wang YC, icals. Crit Rev Food Sci Nutr 51(6):499–523
Prostate Cancer
ADT
Brain
Gynecomastia
Liver
Dyslipidemia
Insulin sensitivity Fat tissue
Vessel
Bone density
Fractures
Penis
Erectile dysfunction
Fig. 1 Metabolic toxicities associated with androgen deprivation therapy. Gynecomastia is a significant breast enlarge-
ment in men. ADT androgen deprivation therapy
levels to zero, and the androgens that remain can this has led to two key insights: (i) tumors often
stimulate PC growth in this setting. PC that has remain dependent on AR signaling in CRPC, and
progressed on primary ADT (as described above) (ii) further manipulations to inhibit the androgen
was formerly thought to be “hormone refractory” signaling axis have significant therapeutic poten-
or “castrate resistant” (CRPC) and independent tial in this setting.
of signaling through the androgen receptor. In Key adaptations which allow disease pro-
addition, it was observed that discontinuing first- gression on first-generation ADT include (1)
generation AR antagonist treatment at the time of increased expression of AR [14]; (2) AR muta-
disease progression can lead to declines in serum tions, which increase promiscuity of ligand-
prostate-specific antigen, a clinical marker of PC mediated activation, e.g., allowing estradiol or
progression, and regression of tumors (termed progesterone to bind [15]; (3) upregulation of
antiandrogen withdrawal response) in a subset of intra-tumoral androgen synthesis [16]; and (4)
patients [13]. As first-generation AR antagonists ligand-independent activation of the AR poten-
show small residual agonistic activity, thus acti- tially via constitutively active AR splice vari-
vating AR signaling even under ADT treatment, ants (Fig. 2) [17]. Secondary hormonal therapies
388 R. Aggarwal and E. Small
Early-stage PC CRPC
T FSH
Pituitary
T
FSH Testis
Androgen
Testis
synthesis
inhibition
Orchiectomy
Adrenal gland Adrenal gland
T T
T T
Androgen
AR
synthesis T
AR mutation
Proliferation
Proliferation
PC cell PC cell
Fig. 2 Molecular mechanism and treatment approaches in the prostate cancer (PC) cell on the right. GnRH gonado-
early-stage and castrate-resistant prostate cancer. Cellular tropin-releasing hormone, FSH follicular-stimulating hor-
adaptations that promote continued androgen signaling in mone, T testosterone, AR androgen receptor
castration-resistant prostate cancer (CRPC) are shown in
targeting these adaptations have been developed, inhibitors such as abiraterone acetate have been
which have significant activity against PCs in this developed to more selectively and potently target
setting. the cytochrome P450 17 enzyme, which shunts
pregnenolone and progesterone precursors down
the androgenic pathway [18]. One of the meta-
Androgen Synthesis Inhibition bolic side effects of selective cytochrome P450 17
inhibition is elevation of mineralocorticoids (see
Blockade of androgen synthesis from the adrenal chapter “Overview” under the part “Reproductive
gland and the PC cells itself has been developed system”), including corticosterone and 11-deoxy-
as an effective treatment strategy. Ketoconazole is cortisol, which can cause hypertension, hypokale-
a nonspecific inhibitor of multiple enzymatic mia, and peripheral edema. These effects can be
steps within the adrenal androgen hormone syn- partially abrogated with the concomitant adminis-
thesis pathway (see chapter “Overview” under the tration of low-dose corticosteroids, which block
part “Reproductive system”), with demonstrated adrenal mineralocorticoid synthesis via feedback
clinical activity in PC. Novel androgen synthesis inhibition of the pituitary gland.
Prostate Cancer 389
Second-Generation AR Antagonists 3. MacInnis RJ, English DR (2006) Body size and com-
position and prostate cancer risk: systematic review
and meta-regression analysis. Cancer Causes Control
Novel, second-generation AR antagonists 17(8):989–1003
(enzalutamide, ARN-509) were developed using 4. Sharma NL, Massie CE, Ramos-Montoya A, Zecchini
prostate cancer models with AR overexpres- V, Scott HE, Lamb AD, MacArthur S, Stark R,
Warren AY, Mills IG, Neal DE (2013) The androgen
sion, simulating the molecular characteristics
receptor induces a distinct transcriptional program in
commonly observed with CRPC tumors [19]. castration-resistant prostate cancer in man. Cancer
Second-generation AR antagonists are ten times Cell 23(1):35–47
more potent than first-generation drugs and lack 5. Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X,
Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H,
any agonistic activity. Use of these agents in
Laxman B, Vellaichamy A, Shankar S, Li Y,
CRPC has significant clinical benefit [20]. The Dhanasekaran SM, Morey R, Barrette T, Lonigro
long-term metabolic consequences of potent AR RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan
blockade remain to be elucidated in follow-up AM (2010) An integrated network of androgen
receptor, polycomb, and TMPRSS2-ERG gene
studies.
fusions in prostate cancer progression. Cancer Cell
17(5):443–454
6. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS
Perspectives (2005) Risk of fracture after androgen deprivation for
prostate cancer. N Engl J Med 352:154–164
7. Keating NL, O’Malley J, Smith MR (2006) Diabetes
As potent androgen axis inhibitors have demon- and cardiovascular disease during androgen depri-
strated clinical benefit in advanced CRPC, the vation therapy for prostate cancer. J Clin Oncol
role of these agents in improving the efficacy and 24:4448–4456
8. Aggarwal R, Ryan CJ, Chan J (2013) Insulin-like
mitigating the toxicity of standard ADT in earlier
growth factor pathway: a link between androgen
disease settings is being explored. The availabil- deprivation therapy (ADT), insulin resistance, and
ity of potent AR antagonists offers the possibility disease progression in patients with prostate cancer?
to deliver non-castrating yet highly potent ther- Urol Oncol 31:522–530
9. Yu EY, Kuo KF, Gulati R, Chen S, Gambol TE, Hall
apy to control PC and minimize the development
SP, Jiang PY, Pitzel P, Higano CS (2012) Long-term
of metabolic derangements by avoiding estrogen dynamics of bone mineral density during intermittent
depletion. Clinical trials are underway to test this androgen deprivation for men with nonmetastatic,
hypothesis. Ultimately, rather than uniformly hormone-sensitive prostate cancer. J Clin Oncol
30(15):1864–1870
applying ADT to all patients with PC, future ther-
10. Crook JM, O’Callaghan CJ, Duncan G,
apy might be delivered on a risk-adapted basis, Dearnaley DP, Higano CS, Horwitz EM, Frymire E,
with non-castrating peripheral AR blockade as Malone S, Chin J, Nabid A, Warde P, Corbett T,
monotherapy for patients with standard-risk dis- Angyalfi S, Goldenberg SL, Gospodarowicz MK,
Saad F, Logue JP, Hall E, Schellhammer PF, Ding K,
ease, and combination therapy with GnRH ana-
Klotz L (2012) Intermittent androgen suppression
logues in those predicted to have a short duration for rising PSA level after radiotherapy. N Engl J Med
of response to primary ADT. Such an approach 367:895–903
may offer a more favorable risk-benefit ratio of 11. Hussain M, Tangen CM, Berry DL, Higano CS,
Crawford ED, Liu G, Wilding G, Prescott S,
therapy and partially mitigate the long-term met-
Kanaga Sundaram S, Small EJ, Dawson NA,
abolic toxicities of ADT given the chronic nature Donnelly BJ, Venner PM, Vaishampayan UN,
of advanced PC treatment. Schellhammer PF, Quinn DI, Raghavan D, Ely B,
Moinpour CM, Vogelzang NJ, Thompson IM Jr (2013)
Intermittent versus continuous androgen deprivation
in prostate cancer. N Engl J Med 368(14):1314–1325
References 12. Smith MR, Goode M, Zietman AL, McGovern FJ,
Lee H, Finkelstein JS (2004) Bicalutamide monother-
1. Siegel R, Naishadham D, Jemal A (2013) Cancer sta- apy versus leuprolide monotherapy for prostate can-
tistics, 2013. CA Cancer J Clin 63:11–30 cer: effects on bone mineral density and body
2. Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh composition. J Clin Oncol 22:2546–2553
PC (1990) Family history and the risk of prostate can- 13. Small EJ, Halabi S, Dawson NA, Stadler WM,
cer. Prostate 17(4):337–347 Rini BI, Picus J, Gable P, Torti FM, Kaplan E,
390 R. Aggarwal and E. Small
Vogelzang NJ (2004) Antiandrogen withdrawal alone Brodie AM, Edwards J, Qiu Y (2009) A novel andro-
or in combination with ketoconazole in androgen- gen receptor splice variant is up-regulated during
independent prostate cancer patients: a phase III trial prostate cancer progression and promotes androgen
(CALGB 9583). J Clin Oncol 22:1025–1033 depletion-resistant growth. Cancer Res 69:2305–2313
14. Taylor BS, Schultz N, Hieronymus H, Gopalan A, 18. Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff
Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, P, Raynaud F, Martins V, Lee G, Kheoh T, Kim J,
Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev Molina A, Small EJ (2010) Phase I clinical trial of the
I, Major JE, Wilson M, Socci ND, Lash AE, Heguy CYP17 inhibitor abiraterone acetate demonstrating
A, Eastham JA, Scher HI, Reuter VE, Scardino PT, clinical activity in patients with castration-resistant
Sander C, Sawyers CL (2010) Integrative genomic prostate cancer who received prior ketoconazole ther-
profiling of human prostate cancer. Cancer Cell apy. J Clin Oncol 28:1481–1488
18:11–22 19. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora
15. Taplin ME, Rajeshkumar B, Halabi S, Werner CP, V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A,
Woda BA, Picus J, Stadler W, Hayes DF, Kantoff PW, Wasielewska T, Welsbie D, Chen CD, Higano CS,
Vogelzang NJ, Small EJ (2003) Androgen receptor Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL
mutations in androgen-independent prostate cancer: (2009) Development of a second-generation antian-
Cancer and Leukemia Group B Study 9663. J Clin drogen for treatment of advanced prostate cancer.
Oncol 21:2673–2678 Science 324:787–790
16. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, 20. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN,
Kalhorn TF, Higano CS, True LD, Nelson PS (2008) Miller K, de Wit R, Mulders P, Chi KN, Shore ND,
Maintenance of intratumoral androgens in metastatic Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P,
prostate cancer: a mechanism for castration-resistant Fleming M, Hainsworth JD, Hirmand M, Selby B,
tumor growth. Cancer Res 68:4447–4454 Seely L, de Bono JS (2012) Increased survival with
17. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, enzalutamide in prostate cancer after chemotherapy.
Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, N Engl J Med 367:1187–1197
Part XVI
Cancer
Overview
reported by Otto Warburg back in the 1920s. fact, mitochondria are functional in many cancers
Many, but not all, cancers exhibit aerobic gly- [7]. The TCA cycle provides precursors for cel-
colysis [2]. While aerobic glycolysis produces lular building blocks (Fig. 1). It provides citrate
much fewer ATP per molecule of glucose than for fatty acid synthesis, malate, which can be
oxidative glucose catabolism, it allows glucose used for the production of NADPH through con-
to contribute to alternative biosynthetic path- version to pyruvate, or oxaloacetate for synthesis
ways that begin with glycolytic intermediates, of aspartate, which in turn is used to synthesize
while the cells utilize other sources of energy for nucleotides or other amino acids (Fig. 1).
ATP production. Thus, aerobic glycolysis shunts However, since little glucose enters the TCA
glucose carbons for biosynthesis and catabolizes cycle due to the Warburg effect, many cancer
glucose to lactate for rapid ATP production [3]. cells fuel the TCA cycle with glutamine (Gln)
The avid uptake of glucose by cancer cells is [8], and in culture, many cancer cells fail to grow
even used to identify tumors. Using a labeled when deprived of Gln. To enter the TCA cycle,
glucose derivative, 18F-deoxyglucose, positron- Gln is first converted to glutamate by glutamin-
emission tomography (PET) allows localization ase and then to the TCA cycle intermediate
and imaging of tumors in patients. α-ketoglutarate by glutamate dehydrogenase
Glycolysis shares common intermediates with (GLUD) or aminotransferases. Importantly,
other anabolic pathways. For example, the pen- using this mechanism, Gln can fuel the TCA
tose phosphate pathway (PPP, see also chapter cycle even in hypoxic conditions, allowing cells
“Sickle cell disease”) shares glucose 6-phosphate to obtain the required building block and survive
as a starting molecule with glycolysis (Fig. 1) [4]. in the poorly vascularized hypoxic tumor envi-
In the PPP, glucose 6-phosphate is converted to ronment [9]. Additionally, Gln plays a central
ribose by a multiple-step pathway, the 5-carbon role in the formation of the antioxidant tripeptide
sugar required for nucleotide synthesis. glutathione through its role in glutamate produc-
Additionally, the PPP is a major source of NADPH tion and cysteine import, which is critical for
(nicotinamide adenine dinucleotide phosphate), a controlling reactive oxygen species [10].
reducing agent required for nucleic acid synthe- Proliferating cells need to generate sufficient lip-
sis, fatty acid synthesis, and detoxification of ids (in form of triglycerides and phospholipids) to
reactive oxygen species. Therefore, the PPP pro- make cell membrane for growth and cell division and
vides much of the reducing power and ribose that for storage of energy [11]. While some lipids may be
cancer cells require for nucleotide biosynthesis. obtained exogenously, many cancers synthesize lip-
In proliferating cells, glucose is critically ids de novo. Fatty acid synthesis occurs in the cyto-
required as a donor of methyl groups. To this end, plasm. Its educt acetyl-CoA is generated from citrate,
glucose, or rather the glycolytic intermediate, as the latter can be exported from the mitochondrion,
3-phosphoglycerate, is first converted to serine whereas acetyl-CoA itself cannot (Fig. 1). Citrate can
[5], which is then converted to glycine (or used be derived from either glutamine through transfor-
for protein synthesis) (Fig. 1). Glycine is an mation to α-ketoglutarate and reductive carboxyl-
important carbon donor [6] and source of CHO- ation or glucose through its mitochondrial production
groups or CH2-tetrahydrofolate, which are both of acetyl-CoA through pyruvate dehydrogenase
used for nucleotide and methionine synthesis. (Fig. 1). This initially removes a molecule of oxalo-
Indeed, many rapidly proliferating cancer cells acetate from the TCA cycle, which is regenerated
are dependent on increased serine and glycine from citrate in the cytoplasm and the oxaloacetate is
uptake and synthesis [5, 6]. Diversion of glucose returned to the mitochondrion in the form of malate
into the serine/glycine synthesis pathways allows (Fig. 1). Additionally, glucose also contributes to
cancer cells to create building blocks for growth. triglyceride production through the production of
Warburg mistakenly believed that glucose is glycerol-3-phosphate from the glycolytic intermedi-
robustly converted to lactate due to a lack of ate dihydroxyacetone phosphate. However, some
functioning mitochondria in all cancer cells. In cancer cells do not produce lipids, but β-oxidize fatty
Overview 395
Glucose
NADP+ NADPH
Glucose 6-P Ribose Nucleotide synthesis Lipid synthesis
PPP
2 ADP
Glycolysis Serine Glycine THF
Acetyl-CoA
2 ATP THF
Pyruvate Acetyl-CoA
Reductive carboxylation
[IDH]
Fumarate TCA Cycle Isocitrate
[GLUD]
[GLS]
[GLUD]
Mitochondrium
Cytoplasm
Fig. 1 Cancer cells reprogram metabolism to promote bio- enters the TCA cycle following its conversion to
synthesis. Glucose and glutamine (Gln) play a central role in α-ketoglutarate (α-KG). Citrate, a precursor for lipid syn-
cancer metabolism. Cancer cells show enhanced shunting of thesis, can be derived from either glucose or Gln. Please
glucose to lactate and biosynthetic pathways. The pentose note that transporters shown only mediate transport across
phosphate pathway (PPP) provides ribose for nucleotides the inner mitochondrial membrane, as the outer membrane
and NADPH for biosyntheses. The serine/glycine synthesis is more penetrable. Space constraints do not permit accurate
pathway provides carbon donors for nucleotide synthesis. depiction. THF tetrahydrofolate, Glu glutamate, GLS gluta-
Cancer cells depend on Gln to fuel the tricarboxylic acid minase, GLUD glutamate dehydrogenase, IDH isocitrate
(TCA) cycle for energy and biosynthetic precursors. Gln dehydrogenase, suc-CoA succinyl-CoA, OAA oxaloacetate
acids to obtain energy by catabolizing them to pro- Activating mutations in oncogenes such as
duce acetyl-CoA that then enters the TCA cycle [11]. growth factor receptors lead to continuous induc-
These cells likely depend on exogenous lipids for tion of cell division irrespective of external sig-
membrane formation. nals. For example, “constitutively active”
phosphatidylinositol-3-kinase (PI3K) or Akt
(also called protein kinase B) signaling pathways
Common Mutations Affecting are observed in numerous cancer types, leading
Metabolism to activation of the mammalian target of rapamy-
cin complex 1 (mTORC1) and increased aerobic
Many oncogenes have been shown to reprogram glycolysis. mTORC1 is a master regulator of cell
cellular metabolism in cancer (Fig. 2) [1]. metabolism, growth, mitochondrial biogenesis,
396 Z.E. Stine and C.V. Dang
lipogenesis, and protein synthesis [12]. Enhanced Mutations in some metabolic enzymes can cause
glycolysis is also partly due to non-hypoxic the buildup of metabolites, termed oncometabolites,
increase in hypoxia-inducible factor 1α (HIF-1α) which are proposed to play a role in tumor progres-
downstream of mTORC1. sion. Mutated isocitrate dehydrogenase, a TCA
Constitutively active PI3K signaling can also cycle enzyme, creates an oncometabolite (2-hydrox-
occur through loss-of-function mutations in phos- yglutarate), which interferes with differentiation by
phatase and tensin homolog (PTEN), a PI3K causing epigenetic changes through the inhibition
inhibitor and major tumor suppressor, or direct of α-ketoglutarate-dependent regulation of chroma-
activating mutations in PI3K. Mutations in PI3K tin modifications and DNA methylation [21].
pathway signaling components seem to be present Frequent mutations in the TCA cycle enzyme fuma-
in ~70 % of breast cancers (see chapter “Breast rate hydratase (also called fumarase) cause the
cancer”) and 50 % of colorectal cancers (see chap- accumulation of fumarate, proposed to disrupt
ter “Colorectal cancer”), which is likely to lead to metabolism and stabilize HIF-1α [22]. However,
mTORC1-driven cell growth [13, 14]. mTORC1 much more remains to be understood about how the
can also be constitutively activated through acti- accumulation of oncometabolites in a cell can con-
vating mutations of Kirsten rat sarcoma viral tribute to cancer development.
oncogene homolog (KRAS) or rapidly accelerated
fibrosarcoma (B-RAF) mutations or loss of the
mTORC1 inhibitors liver kinase B1 (LKB1) or Treatment of Cancer
tuberous sclerosis complex (TSC) 1/2 (Fig. 2).
Transcription factors that play a central role in Cancer treatment often focuses on the use of DNA-
cancer can also control metabolism. c-Myc, one damaging radiation or cytotoxic chemotherapy
of the most commonly overexpressed genes in agents (see chapter “Breast cancer”) that damage
cancer, has been shown to enhance the Warburg rapidly dividing cells by inhibiting DNA synthesis,
effect and increase glutamine dependence of cells transcription, and cell division. As metabolism
[15]. In addition to promoting mitochondrial bio- plays a key role in DNA synthesis, antimetabolic
genesis, c-Myc promotes the expression of gluta- therapies may sensitize cancer cells to cytotoxic
minase, the first gene in glutamine metabolism, chemotherapies. In turn, cytotoxic agents likely
and glutamine transporters to promote the uptake cause disruption of cancer metabolism.
of glutamine [8, 15]. c-Myc promotes expression The ideal cancer therapies target and kill cancer
of many of the genes involved in glycolysis, as cells while sparing the noncancerous tissues around
well as many of the transporters and enzymes them. Classical therapies aim to target the deregu-
involved in glucose uptake [15]. p53 is one of the lated signaling pathways leading to malignant
most frequently mutated genes in cancer, acting growth and proliferation. For example, the ATP
as a tumor suppressor through its role in cell analogue sunitinib blocks several important recep-
cycle arrest or apoptosis in response to DNA tor tyrosine kinases, which favor proliferation.
damage or other stress. p53 mutations have also Similarly, vemurafenib, a Raf inhibitor, targets the
been shown to alter metabolism controlling mitogen-activated protein kinase pathway to induce
glycolysis, the PPP, oxidative respiration, and cancer cell death. As cancer cells exhibit altered
serine metabolism [16–19]. Due to rapid growth metabolism compared to quiescent cells, cancer
and poor tumor vascularization, many cancer metabolism has generated interest as a potential
cells have limited oxygen availability and thus therapeutic target [23], e.g., inhibiting aerobic gly-
activate the transcription factor HIF-1α [20]. colysis or glutamine metabolism may slow cancer
HIF-1α controls transcription of key metabolic growth [8]. A glucose analogue, 2-deoyxglucose,
genes including glucose transporters and glyco- is used to inhibit glycolysis and thus hampers cell
lytic enzymes to enhance the Warburg effect, growth. Cancer metabolism-based therapy seeks to
optimizing tumor metabolism for the tumor disrupt one or more of the numerous metabolic
microenvironment. changes that occur in cancer to slow cancer cell
Overview 397
Growth
factor Sunitinib
RTK
Vemurafenib
Cellular
energy
[RAF] [Akt] status
2-deoxyglucose
Rapamycin
Lipogenesis
HIF-1 expression Glycolysis
mTORC1 Protein synthesis
Mitochondrial biogenesis
Cell growth Gemcitabine
Nucleotide synthesis
Methotrexate
Fig. 2 Cancer therapies target cancer metabolism and the kinase B1 (LKB1) in cancer lead to mammalian target of
pathways that control them. Commonly found activating rapamycin complex 1 (mTORC1) activation and down-
mutations of many oncogenes such as receptor tyrosine stream metabolic changes. Consequently, these represent
kinases (RTK) and their downstream signaling factors targets of anticancer drugs. Activation of mTORC1 is tar-
phosphatidylinositol-3-kinase (PI3K), Kirsten rat sarcoma geted at the level of RTK inhibition (e.g., sunitinib), RAF
viral oncogene homolog (KRAS), protein kinase B (Akt), inhibition (vemurafenib), or direct inhibition of mTORC1
rapidly accelerated fibrosarcoma (RAF), mitogen-activated (rapamycin). Additionally, drugs target mTORC1-regu-
protein kinase (MAPK), or inactivating mutations of tumor lated pathways such as glycolysis (2-deoxyglucose) and
suppressors such as phosphatase and tensin homolog nucleotide synthesis (gemcitabine). AMPK AMP-activated
(PTEN), tuberous sclerosis complex (TSC) 1/2, or liver protein kinase, HIF-1 α hypoxia-inducible factor 1α
growth, induce cancer cell death, or enhance sensi- e.g., the anti-diabetes drug metformin (see chap-
tivity to other treatments. However, metabolic can- ter “Diabetes mellitus”), which inhibits mito-
cer therapies are complicated by the metabolic chondrial function and indirectly activates the
flexibility of cancer cells, the feedback loops, and cellular energetic sensing AMP-dependent pro-
the metabolic similarities between cancer cells and tein kinase, has anticancer effects. The first
some proliferating cells. The first drugs to target mTORC inhibitors (e.g., rapamycin itself) are
cancer metabolism were antifolate drugs in the now approved by the FDA [12] as anticancer
1940s [24], giving rise to the commonly used anti- drugs, with others moving toward the clinic.
folate drug methotrexate. Folate is an important
donor of methyl groups during nucleotide synthe-
sis. Other treatments, like the nucleoside analogue Influence of Treatment on
gemcitabine, also inhibit nucleotide synthesis. As Metabolism
glycolytic intermediate-derived glycine is a critical
source of folate, anti-glycolytic therapy may sensi- Cytotoxic chemotherapeutic agents can have a
tize cancer cells to antifolate drugs. wide array of side effects due to their effects on
Other therapies propose to target master regu- noncancerous cells, including organ damage,
lators of metabolism or mitochondrial function, immune problems, gastrointestinal defects, hair
398 Z.E. Stine and C.V. Dang
loss, fatigue, and cognitive alterations. Anticancer 5. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim
D, Birsoy K et al (2011) Functional genomics reveal
therapies have global metabolic effects in patients
that the serine synthesis pathway is essential in breast
that are poorly understood. Many patients under- cancer. Nature 476(7360):346–350, Epub 2011/07/16
going chemotherapy experience changes in 6. Jain M, Nilsson R, Sharma S, Madhusudhan N,
weight and fat accumulation. While nausea and Kitami T, Souza AL et al (2012) Metabolite profiling
identifies a key role for glycine in rapid cancer cell
other side effects can cause weight loss in many
proliferation. Science 336(6084):1040–1044, Epub
cancers, women receiving adjuvant therapy (see 2012/05/26
chapter “Breast cancer”) often experience weight 7. Wallace DC (2012) Mitochondria and cancer. Nat Rev
gain. Cancer 12(10):685–698, Epub 2012/09/25
8. Wise DR, Thompson CB (2010) Glutamine addiction:
a new therapeutic target in cancer. Trends Biochem
Sci 35(8):427–433, Epub 2010/06/24
Perspectives 9. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi
J et al (2012) Glucose-independent glutamine metabo-
lism via TCA cycling for proliferation and survival in
Cancer cells undergo profound metabolic
B cells. Cell Metab 15(1):110–121, Epub 2012/01/10
changes, allowing for rapid proliferation and cell 10. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio
maintenance in a hostile tumor microenviron- M et al (2013) Glutamine supports pancreatic cancer
ment. While aerobic glycolysis can fuel biosyn- growth through a KRAS-regulated metabolic path-
way. Nature 496(7443):101–105, Epub 2013/03/29
thetic pathways, glutamine can fuel the TCA
11. Santos CR, Schulze A (2012) Lipid metabolism in
cycle to provide energy and other cellular build- cancer. FEBS J 279(15):2610–2623, Epub 2012/05/25
ing blocks. Hence, enhanced understanding of 12. Laplante M, Sabatini DM (2012) mTOR signaling in
changes in cancer metabolism and the mutations growth control and disease. Cell 149(2):274–293,
Epub 2012/04/17
that cause them should provide a potential thera-
13. Cancer Genome Atlas Network (2012) Comprehensive
peutic avenue for treating cancer, and multiple molecular characterization of human colon and rectal
antimetabolic drugs are in clinical trials. Novel cancer. Nature 487(7407):330–337, Epub 2012/07/20
approaches include inhibitors against oncogenic 14. Cancer Genome Atlas Network (2012) Comprehensive
molecular portraits of human breast tumours. Nature
isocitrate dehydrogenase mutations [25, 26], gly-
490(7418):61–70, Epub 2012/09/25
colysis, and glutaminase. By linking recurrent 15. Dang CV (2012) MYC on the path to cancer. Cell
genetic changes with alterations in metabolism, 149(1):22–35, Epub 2012/04/03
antimetabolic cancer drugs may even be tailored 16. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano
K, Bartrons R et al (2006) TIGAR, a p53-inducible
for personalized therapy.
regulator of glycolysis and apoptosis. Cell
126(1):107–120, Epub 2006/07/15
17. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z
(2010) Glutaminase 2, a novel p53 target gene regu-
References lating energy metabolism and antioxidant function.
Proc Natl Acad Sci U S A 107(16):7455–7460, Epub
1. Ward PS, Thompson CB (2012) Metabolic repro- 2010/04/10
gramming: a cancer hallmark even warburg did not 18. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M
anticipate. Cancer Cell 21(3):297–308, Epub et al (2011) p53 regulates biosynthesis through direct
2012/03/24 inactivation of glucose-6-phosphate dehydrogenase.
2. Koppenol WH, Bounds PL, Dang CV (2011) Otto Nat Cell Biol 13(3):310–316, Epub 2011/02/22
Warburg’s contributions to current concepts of cancer 19. Maddocks OD, Berkers CR, Mason SM, Zheng L,
metabolism. Nat Rev Cancer 11(5):325–337, Epub Blyth K, Gottlieb E et al (2013) Serine starvation
2011/04/22 induces stress and p53-dependent metabolic remodel-
3. Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel ling in cancer cells. Nature 493(7433):542–546, Epub
BA, Cheng EY et al (2005) Progress and promise of 2012/12/18
FDG-PET imaging for cancer patient management 20. Semenza GL (2010) HIF-1: upstream and down-
and oncologic drug development. Clin Cancer Res stream of cancer metabolism. Curr Opin Genet Dev
11(8):2785–2808, Epub 2005/04/20 20(1):51–56, Epub 2009/11/28
4. Riganti C, Gazzano E, Polimeni M, Aldieri E, Ghigo 21. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-
D (2012) The pentose phosphate pathway: an antioxi- Wahab O et al (2012) IDH mutation impairs histone
dant defense and a crossroad in tumor cell fate. Free demethylation and results in a block to cell differentia-
Radic Biol Med 53(3):421–436, Epub 2012/05/15 tion. Nature 483(7390):474–478, Epub 2012/02/22
Overview 399
22. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, antagonist, 4-aminopteroyl-glutamic acid. N Engl J
Chung YL et al (2005) HIF overexpression correlates Med 238(23):787–793, Epub 1948/06/03
with biallelic loss of fumarate hydratase in renal can- 25. Rohle D, Popovici-Muller J, Palaskas N, Turcan S,
cer: novel role of fumarate in regulation of HIF stabil- Grommes C, Campos C et al (2013) An inhibitor of
ity. Cancer Cell 8(2):143–153, Epub 2005/08/16 mutant IDH1 delays growth and promotes differentia-
23. Tennant DA, Duran RV, Gottlieb E (2010) Targeting tion of glioma cells. Science 340:626–630
metabolic transformation for cancer therapy. Nat Rev 26. Wang F, Travins J, Delabarre B, Penard-Lacronique
Cancer 10(4):267–277, Epub 2010/03/20 V, Schalm S, Hansen E et al (2013) Targeted inhibi-
24. Farber S, Diamond LK (1948) Temporary remissions tion of mutant IDH2 in leukemia cells induces cellular
in acute leukemia in children produced by folic acid differentiation. Science 340:622–626
Index
Colon, 123–128, 137, 143–145, 149–153, 160, 349 De Ley-Doudoroff pathway, 143
Colon cancer, 149, 150 Dementia, 31, 35, 39, 54
Colonic microbiota, 150, 151 Demineralisation, 90
Colorectal cancer (CRC), 149–154 Demyelination, 47–50
cancer screening and chemoprevention, 152–153 Dendritic cell, 208, 216, 217, 222, 244, 306–309
dietary modifications for minimizing risk of Dendritic spine pathology, 55
colorectal cancer, 152 Dense capillary network, 208, 209
introduction to CRC, 149 Dental caries, 87–92
pathophysiologic role of the colonic influence of treatment on metabolism, 90–91
microbiota, 150–152 introduction to dental caries, 87
pathophysiology of CRC, 149–150 pathophysiology of dental caries and metabolic
perspectives, 153 alterations, 87–90
prevention, 152 perspectives, 91
treatment and influence on metabolism, 152 treatment and implications for patients, 90
treatment of CRC, 153 Dentin, 81–84, 87, 89
Community-acquired pneumonia (CAP), 227–231 2-Deoxyglucose, 36, 394, 397
influence of treatment on metabolism and Depolarization, 6, 7, 61, 158, 159, 213, 236, 237, 255
consequences for patients, 229–230 Depression, 11–16
introduction to CAP, 227–228 Detoxification, 176, 281, 333, 337, 394
pathophysiology of CAP, 228 Dexamethasone, 45
perspectives, 230–231 Diabetes mellitus, 163–169
treatment, 229 complications, 166
Complement system, 67, 68, 71, 305 diabetes treatment and its influence
Compression hosiery, 275 on metabolism, 166–168
Compulsive eating, 31 introduction to diabetes mellitus, 163
Computer tomography (CT), 35, 363 pathophysiology of diabetes mellitus and
Conduit and resistance vessels, 265 metabolic alterations, 164
Contractile phenotype, 274 perspectives, 168
Core body temperature (CBT), 313 type 1 diabetes, 164
Coronary artery disease (CAD), 243, 246–248 type 2 diabetes, 164–166
Corticosteroids, 13, 14, 45, 51, 93, 108, 110, 116, Dialysis, 348–350, 359
119, 147, 217, 218, 221, 224, 225, 230, Diarrhea, 41, 111, 125, 128, 133, 137–141, 143–145,
254, 354, 388 185, 224, 225, 362, 383
Corticotropin-releasing hormone (CRH), 12, 13, 116 Diastole, 235, 254, 261
Cortisol, 9, 13, 15, 115–118, 268, 269, 320, 321, 388 Diet, 9, 15, 25, 26, 68, 84, 90, 91, 94, 95, 117, 123–125,
Cromolyn sodium, 326, 327 146–152, 160, 167, 184–186, 196, 215, 284,
Crypt, 126, 152 298–300, 339, 340, 348, 349, 351–353,
Cyclic nucleotide-gated ion channel, 61 361–365, 383
Cyclooxygenase (COX) inhibitor, 316 Dietary fiber, 150, 152
Cysteinyl leukotrienes, 325, 326 Dietary heme, 152
Cystine stone, 365 Dietary modification, 152
Cystinuria, 361, 363, 365 Dietary restriction, 146, 340, 363
Cystitis, 357–358 Digestion, 123–126, 130, 139, 141, 146, 157, 160,
Cytokine, 11–15, 17, 51, 83, 94, 95, 104, 105, 108, 109, 161, 167, 173, 178
111, 115–118, 130, 134, 151, 164, 175, 176, Digestive enzyme, 124, 157, 158, 160, 161
178, 182, 183, 193–195, 200, 202, 216, 217, Digitalis, 252–254
222, 223, 225, 229, 241, 244, 252, 253, 264, Dihydropyridine, 340
265, 267, 269, 274, 275, 286, 290, 306, 308, Dihydrotestosterone, 369–372, 374, 375
309, 314, 315, 320, 321, 324, 325, 327 Dihydroxy acid leukotriene, 325
Cytotoxic T cell, 222, 223, 305, 306, 308, 310 Dimethyl fumarate, 51
Dipeptidyl peptidase-4 (DPP-4), 167
Disease-modifying osteoarthritis (OA) drugs
D (DMOADs), 107, 109, 111
Danger-associated molecular pattern (DAMP), Disrupted in schizophrenia (DISC), 17
308–310 Distal renal tubular acidosis, 363, 364
Dantrolene, 314, 316 Diuretic-induced diabetes, 342
Darbepoetin-α, 349 Dopamine (DA), 7, 8, 11, 12, 17–20, 29–32, 146,
Dashed arrow, 2 246, 247, 371
Deep brain stimulation, 31, 32, 45 agonist, 31, 32
Degranulation, 325, 327 D2 receptor, 19, 20
Dehydration, 138–141, 185, 186, 289, 291, 292 oxidation, 30
406 Index
Hypothyroidism, 53–55, 286, 299, 300 Interferon, 13, 51, 54, 115, 116, 244, 308, 309, 324, 325
Hypotonia, 53, 55 Interleukin, 13, 95, 108, 109, 115, 116, 118, 130, 164,
Hypoxemia, 211, 212, 228, 347 165, 175, 182, 193, 194, 216, 217, 222, 223,
Hypoxia, 17, 50, 200, 212, 213, 222, 228, 265, 273, 229, 253, 265, 308, 309, 314, 315, 320, 324,
274, 276, 291, 335, 347, 393, 396, 397 327, 352, 353, 382
Hypoxia inducible factor (HIF), 200, 212, 274, Interleukin-6 (IL-6), 111, 115–119, 165, 195, 216, 223,
347, 396, 397 229, 230, 314, 315, 320, 324, 325, 382
Interleukin-1β, 109, 315, 352
Interleukin (IL)-1 inhibitor, 354, 355
I International classification of diseases 10 (ICD-10), 1
IL-1β receptor antagonist, 108, 111 Interstitial fibroblast, 235
Ileum, 123–125, 127, 128, 177, 178, 301 Intima, 244, 261, 262, 274
Immune system, 305–311 Intoxication disorder, 8
anatomy and physiology of the immune Intraocular pressure (IOP), 60–64, 73–77
system, 305–306 Intrapleural pressure, 209
communication Introduction, 1–2
between immune cells, 308–310 Invasive bacterial strain, 137
of immune cells with stromal cells, 310 Ionotropic receptor, 7
of stromal cells with immune cells, 308 Ion pump, 9, 237, 247, 284
final remarks, 310 Iris, 59–61, 73
miscommunication in the immune system Iron, 30, 123, 124, 127, 150, 267, 282–286, 291, 349
as the basis of disease, 310 Irritable bowel syndrome (IBS), 143–147
primary lymphoid tissues, 306 Ischemia, 50, 139, 185, 240, 243–247, 254–256, 357
secondary lymphoid tissues, 306–307 Ischemic stroke, 267–270
specific pathways and metabolic processes Isotype switching, 325
of the immune system, 306 Ivabradine, 246, 247, 255
tertiary lymphoid tissues, 308
Immunoglobulin (Ig), 47, 69, 74, 116, 174, 210, 217,
222, 228, 305, 324, 325, 327, 375 J
Immunoglobulin E (IgE), 217, 324, 325, 327 Jejunum, 123–125, 160
Immunological synapse, 308 Joint formation, 101
Immunotherapy, 326–327, 382 Joints, 101–106
Incretin, 127, 160, 167, 285 bone, 102
Incretin homologue, 168 cartilage, 102–103
Infarction, 230, 243, 248, 251, 252, 256, final remarks, 105
267, 268, 312, 342 joint formation, 101–102
Inflammation, 11–15, 42, 43, 47, 49–51, 71, 75, 105, joints classification, 101
107–111, 115–119, 125, 127, 128, 137, 139, ligaments and tendons, 103–104
146, 147, 149–151, 164–166, 173, 181–184, metabolites affecting the joints, 105
193, 194, 211, 215–217, 221–225, 228, 230, synovium, 104–105
231, 245, 252, 263, 265, 269, 273, 274, 290, Juvenile diabetes. See Type 1 diabetes
291, 300, 308, 313, 315, 319, 320, 324–327,
348, 352–355, 357, 358, 381, 383
Inflammatory attack, 51 K
Inflammatory bowel disease (IBD), 143–147 KATP channel, 159, 240
Inhaled corticosteroids, 217–218, 224 Ketoacidosis, 166, 212
Inhaled toxic agent, 223 Ketogenesis, 175
Innate immune system, 68, 127, 164, 216, 305, 323 Ketogenic diet, 9, 25–26
Insulin, 157–161 Ketone body, 26, 50, 175, 212
resistance, 12–14, 18, 45, 74, 164–167, 194, Ketosis, 26
199–201, 241, 298, 319–321, 341, 348, Kidney, 331–337
381, 383, 386 anatomy and physiology of the kidneys, 331–333
secretory granule, 158 final remarks, 337
therapy, 166, 167, 270 kidney-specific metabolic and molecular pathways
Insulin-like growth factor-1 (IGF-1), 94, 109, 149, and processes, 333–335
253, 320, 372, 381, 386 metabolites of
Integrin, 51, 139, 178, 290 the kidney affecting other tissues, 335–336
Intensive care, 319 the kidney affecting the kidney itself, 335
Intensive care unit (ICU), 227, 229, 230, 321 other tissues affecting the kidney, 336–337
Intercritical phase, 351 transplantation, 348
410 Index
Kidney stones, 361–365 Lipolysis, 12, 13, 161, 192–194, 240, 269, 320, 321, 326
epidemiology and evaluation of Lipopolysaccharide (LPS), 182, 183, 314, 315
nephrolithiasis, 361–363 Lipoprotein lipase (LPL), 12–14, 76, 192, 295, 296
introduction to kidney stones, 361 Lipotoxicity, 164–166, 194, 195, 241
perspectives, 365 Lithium, 44
treatment Liver, 173–179
of calcium-containing stones due to anatomy and physiology of the liver, 173–174
hypocitraturia, 364 bile formation and bile acid secretion, 175–176
of calcium stones due to hypercalciuria, 364 detoxification, 176–178
of cystine stones, 365 final remarks, 179
of distal renal tubular acidosis, 364 liver and kidney dysfunction, 359
general points, 363–364 metabolites of other tissues affecting the liver, 178
of oxalate stones, 364 metabolites of the liver affecting other tissues, 178
of struvite stones, 365 nutrient metabolism, 175
of uric-acid-containing stones, 364 plasma protein synthesis, 174–175
Kupffer cell, 173–176 urea synthesis and acid-base homeostasis, 175
Long-acting bronchodilators, 224
Loop of Henle, 331–335, 342, 349
L Low-density lipoprotein (LDL), 76, 201, 243,
Lacrimal puncta, 59, 76 296–298, 348, 374
Lactase, 124, 125, 143–145, 147, 148 Lower airways, 207
Lactate, 48–50, 161, 175, 238, 239, 241, 268, Low molecular weight heparin (LMWH), 230
275, 285, 309, 321, 334, 393–395 Low sodium diet, 185, 340
Lactation, 372, 379 Lung, 207–213
Lactic acidosis, 168, 268, 269 anatomy and physiology of the lung, 207–209
Lactose intolerance, 143–148 breathing and pathologies, 211
influence of treatment on metabolism and breathing and treatment, 211
consequences for patients, 147 coordination with other organs, 212–213
introduction to lactose intolerance, 143–145 final remarks, 213
pathophysiology of lactose intolerance function under extreme conditions, 211–212
and metabolic alterations, 145–146 gas exchange, 210
perspectives, 148 lung perfusion and usage of alveoli, 213
treatment, 146–147 mechanism of breathing, 209
Lactose sensitivity. See Lactose intolerance mucus production, 209–210
Large intestine, 125, 137, 138, 144, 145, 147 reflexes and internal regulation, 213
l-dopa (l-3,4-hydroxyphenylalanine), 30–31 regulation of breathing, 210–211
l-dopa-induced dyskinesia (LID), 31 surfactant production and function, 210
Lean body mass, 319, 322, 387 Luteinizing hormone (LH), 19, 117, 370, 371
Left ventricular dysfunction, 243, 244 Lymph node, 153, 305–307, 324
Leg pain, 276 Lymphocyte, 13, 30, 48, 51, 116, 117, 164, 173, 244,
Lens, 60, 64 282, 283, 306, 310, 323–325
Leptin, 9, 12, 14, 20, 95, 164, 165, Lymphoid organ, 305–308, 310
193–195, 265, 268, 321
Leukocyte, 105, 164, 227, 240, 244, 261, 262, 265, 267,
275, 281–283, 289, 290, 306, 348, 358, 359 M
Leukocyte activation, 267, 275 Macroautophagy, 309
Leukotrienes, 222, 223, 225, 324–327 Macrophage, 14, 48, 51, 102, 104, 105, 116, 117, 164,
Levetiracetam, 24, 25 173–175, 193, 194, 200, 201, 208, 209, 216,
Leydig cell, 369, 371, 372, 375 217, 222, 223, 225, 243, 244, 274, 283, 284,
Lidocaine, 44 286, 290, 297, 305, 308, 314, 315, 324, 353
Lifestyle habits, 14, 93 Macula densa, 331, 335
Ligament, 101, 103, 104, 107 Macula lutea, 59, 60
Limbic system, 5, 12 Macular degeneration, 63, 64, 67, 69
Lipid accumulation, 275 Magnetic resonance imaging (MRI), 35, 36, 47, 48, 379,
Lipid deposition, 243 Major depressive disorder, 11–16
Lipid droplet, 191–193 association between depressive disorders
Lipid metabolite, 275 and MetS, 14
Lipid peroxidation, 53–55, 68, 69, 244, 269 autonomic nervous system, 13
Lipofuscin, 63, 67–69 HPA axis, 13
Lipogenesis, 161, 164, 165, 174, 192, 193, 321, 396, 397 inflammation, 13–14
Index 411
Nighttime modified-release glucocorticoid treatment, 118 genetic and lifestyle habit risk factors and
Nitrate, 246, 247 comorbidities, 93–94
Nitric oxide (NO), 7, 11, 12, 43, 48, 50, 109, 130, 182, immune factors, 95
183, 218, 229, 240, 243, 247, 263, 264, 286, introduction to osteoporosis, 93
290, 291, 335 nutritional factors, 95
Nitrogen homeostasis, 184 nutrition and physical activity, 95–96
Nitroprusside test, 363 osteoporosis treatment and influence on bone
N-methyl-d-aspartate (NMDA), 7, 24, 31, 38, 55 metabolism, 95
Noninfectious gastroenteritis, 137 pathogenesis of bone loss, 93
Noninvasive bacteria, 138 perspectives, 96
Noninvasive ventilation, 230 Osteoprotegerin (OPG), 82, 83, 94, 102
Nonsteroidal anti-inflammatory drug (NSAID), Ovary, 94, 369–373
44, 108, 110, 129–131, 134, 146, 153, Oxalate, 348, 361–364
182, 314, 316, 353, 354 Oxalate stone, 361, 364
Non-Th2-type asthma, 216, 218 Oxidative and nitrosidative stress (O&NS), 12
Norepinephrine (NE), 7, 11, 12, 17, 237, 263–265, 335, 340 Oxidative phosphorylation, 49, 50, 62, 237,
Norovirus, 139 244, 245, 309
Nutrient, 6, 50, 59, 70, 74, 83, 87, 104, 105, 123, 124, Oxidative stress, 8, 14, 18, 53, 54, 68, 70, 71, 73–75,
127, 130, 139, 141, 157, 158, 160–162, 173, 166, 182, 200, 222, 223, 245, 268, 348, 359
175, 178, 195, 235, 261, 262, 265, 268, 281, Oxygen, 44, 50, 53, 59, 60, 62, 63, 74, 83, 174,
282, 285, 286, 359 207–209, 212, 213, 222–225, 228, 229,
Nutrient metabolism, 175 235, 237, 238, 240, 243–247, 251, 254,
Nutritional supplementation, 70, 225 255, 261–263, 267, 268, 270, 274, 281,
282, 284, 286, 289, 290, 393, 396
deprivation, 244, 267, 268
O dissociation curve, 282, 286
Obesity, 11, 12, 14, 20, 36, 74, 75, 125, 149–153, transport, 212, 281, 282
164–166, 191, 193, 196, 199–202, 216, 218,
245, 251, 256, 265, 273, 298, 299, 316,
339–342, 357–359, 375, 379, 381, 383 P
Obesity-associated diseases, 196 p53, 396
Octreotide, 44, 185 Pain, 5, 41–45, 107–111, 129, 131–133, 137, 143–147,
Oligodendrocyte loss, 48 191, 224, 225, 227, 243, 273, 275, 276, 291,
Omalizumab, 327 301, 308, 352–354, 357, 359, 386
Orbit, 59 Pain-sensitive information, 42
Orthostatic hypotension, 342 Pancreas, 157–162
Osmotic diarrhea, 138 anatomy and physiology of the pancreas, 157
Osteoarthritis (OA), 107–113 final remarks, 161–162
disease-modifying OA drugs, 111 metabolites of other tissues affecting
introduction to OA, 107 the pancreas, 160
non-pharmacological treatment, 110 metabolites of the pancreas affecting itself, 159
OA management, 109 metabolites of the pancreas affecting
pathophysiology of OA, 107–109 other tissues, 160–161
perspectives, 111 pancreas-specific metabolic pathways
pharmacological treatment, rapid-acting and processes, 157–159
symptomatic agents, 110 Pancreatic β-cell, 14, 20, 127, 164, 178
pharmacological treatment, slow-acting Pancreatic islet (or islet of Langerhans),
symptomatic agents, 110–111 157–159, 162, 164
targeting cartilage catabolism and anabolism, 111 Paneth cell, 126, 127
targeting subchondral bone remodeling, 111 Pangastritis, 130
targeting synovial inflammation by anti-cytokine Parasympathetic neuron, 13, 42, 43, 160, 194,
therapy, 111 195, 210, 212, 237
Osteoblast, 81–85, 93–97, 102, 103 Parathyroid hormone (PTH), 84, 94, 102, 333, 335,
Osteoclast, 82, 83, 85, 93–97, 102, 103, 111, 374, 375 336, 346, 347, 363, 374
Osteocyte, 81–83, 96 Parathyroid hormone (PTH) analogue, 349
Osteopenia, 119, 183, 375 Parenchymal cell (PC) hydration, 178
Osteophyte formation, 107, 108 Parkinson’s disease (PD), 29–33
Osteoporosis, 93–98 influence of treatment on metabolism and
anti-osteoporosis drugs, 96 consequences for patients, 31–32
endocrine factors, 94–95 introduction to PD, 29
Index 413
Sodium glucose linked transporter-2 (SGLT-2) T-cell, 95, 116, 216, 217, 223, 306–309, 324–326, 374
inhibitor, 168 Teeth, 81–85
Somatic recombination, 306 anatomy and physiology of teeth and bone, 81
Somatostatin, 43, 44, 130, 133, 157–159 bone and tooth: roles in calcium–phosphate
Space of Disse, 173, 174 homeostasis, 84–85
Sputum specimen, 227 calcium and phosphate metabolism and physiological
Statin, 153, 230, 247, 269, 290, 300, 301 reactions in bone and teeth, 83–84
Steroid hormone, 115, 117, 119, 326, 336, 369, calcium metabolism in teeth, 84
370, 372, 373, 376 final remarks, 85
deficiency, 119 tooth growth, 82–83
receptor, 372 Temperature, 5, 64, 152, 195, 282, 286, 313–316, 320
Stomach, 123–125, 127, 129, 130, 132, 133, 137, Tendon, 103, 104, 298, 299
138, 147, 186, 195, 285, 286 Tertiary lymphoid tissue, 305, 308, 309
Storage disorder, 8 Testis, 369–372, 386, 388
Streptococcus, 227–229 Testosterone, 9, 116, 195, 369–376, 382, 386, 388
Stress TGR5 activation, 178
hyperglycemia, 320 Thalamus, 5, 6, 42, 43
management, 147 Theca cell, 371
response, 11, 13, 14, 178, 319, 321, 322 T helper cell (Th-cell), 306, 324
Stroke, 267–271 Thiazide diuretics, 269, 341, 342, 352, 364
influence of treatment on metabolism, 269 Thrombocyte (platelet), 281
introduction to stroke, 267 Thrombolytic drug, 269, 270
pathological changes in metabolism following Thrombosis, 49, 110, 166, 243, 264, 273, 275, 283, 297
stroke onset, 267–269 Thrombospondin-1 (TSP-1), 54
perspectives, 270 Thrombus formation, 200, 248, 264, 270
secondary treatment options, 269–270 Th2-type asthma, 216–218
treatment, 269 Thyroid dysfunction, 15, 53–55
Stromal cell, 193, 308–310 Thyroid hormone, 55, 111, 194, 286, 374
Strontium ranelate, 96, 97, 111 Timolol, 44, 74, 75
Struvite stone, 363, 365 Tiopronin, 362, 365
Stunned myocardium, 244 Tiotropium bromide, 224, 225
Subchondral bone remodeling, 107–109, 111 Tissue plasminogen activator (tPA), 269, 283
Substance P, 7, 43, 44, 263, 265 Tobacco, 215, 221–223
Substantia nigra, 5, 9, 29, 30, 32 Topical β-blocker, 76
Sucralfate, 133 Trachea, 102, 207, 208, 374
Sulfonylurea, 159, 167, 168 Translocation of bacteria, 125, 182–184, 228
Sumatriptan, 44 Translocation of proteins, 13, 149, 238, 239, 337, 380
Suprachiasmatic nucleus (SCN), 63–64 Translucent zone, 88–90
Surfactant, 209, 210, 212 Transporter symbol, 2
Surgical stone removal, 365 Trauma, 36, 73, 104, 107, 108, 315
Sympathetic nervous system (SNS), 251–253 Tremor, 29, 31, 224
Sympathetic neuron, 13, 95, 160, 178, 183, 194, Triacylglycerol, 191, 200, 201, 241, 285.
195, 202, 210, 212, 237, 251–253, 262, 320, See also Triglyceride (TG)
321, 335, 340, 342, 346 Tri- and tetracyclic antidepressant (TCA), 14, 15
Synapse, 6, 7, 25, 31, 35, 36, 38, 54, 61 Tricarboxylic acid (TCA) cycle, 26, 49, 239,
Synaptic cleft, 6, 7, 15 245, 393–398
Synovial fluid, 101, 104, 107, 109, 110, 116 Trigeminocervical complex, 42, 43
Synovial inflammation, 107–109, 111, 116 Trigeminovascular system, 5, 42, 43
Synovial joint (diarthrosis), 101, 103, 104 Triglyceride (TG), 13, 14, 76, 173, 175, 191–193,
Synovial membrane, 101, 103–105, 107–109 199–202, 241, 274, 285, 295–301, 341,
Synoviocyte, 104, 105, 108, 109 375, 394. See also Triacylglycerol
Synovium, 104, 105 Trimetazidine, 246–247
Synthetic phenotype, 274 Triptan, 44, 146, 147
Systemic inflammation, 12, 164, 183, 222, 228, 252, 315 Trisomy 21. See Down syndrome (DS)
Systole, 235, 254 Tubuloglomerular feedback, 335
Tumor necrosis factor α (TNFα), 13, 43, 95, 105, 108,
109, 115, 116, 118, 130, 164, 165, 175, 182,
T 193, 194, 200, 222, 223, 229, 253, 264, 314,
Tau, 35–38 315, 320, 324, 382
Taurocholate, 176, 177 Tunica adventitia, 261
416 Index
Tunica intima, 261 Vasoactive intestinal peptide (VIP), 43, 181, 183
Tunica media, 261 Vasoconstriction, 44, 166, 186, 212, 213, 228, 251, 252,
Type A synoviocyte, 104, 105 255, 264, 286, 290, 291, 314, 335, 340
Type B synoviocyte, 104, 105 Vasodilation, 42–44, 130, 166, 182, 183, 185, 202, 240,
Type 1 diabetes mellitus (T1DM), 117, 163, 164, 166, 299 246, 247, 264, 265, 342
Type 2 diabetes mellitus (T2DM), 148, 163–165, 167, Vasodilator, 42, 183, 228, 229, 240, 246, 263, 264, 276,
199, 202, 265, 299, 342, 359, 383 341, 342
Type 1 pili, 359 Vasoocclusion, 289–291
Vasopressin (antidiuretic hormone, ADH), 8, 182, 183,
186, 252, 332–334, 336, 337, 371
U Vasoregulation, 262, 263, 265
Upper airways, 207, 325 VEGF inhibition, 68, 69
Urate crystal, 352 Vein, 42, 45, 61, 74, 173, 177, 181, 184, 200,
Urea cycle, 175, 183, 184 208, 235, 236, 261, 263–265, 273–276,
Urea synthesis, 174, 175 331–333
Urea transport, 334 Vein wall hypoxia, 274
Uremia, 345, 348, 350, 357, 358 Venoactive drug, 275
Ureterorenoscopy, 363 Venous valve failure, 273
Uric acid, 361–364 Ventilation, 209–213, 228, 230, 374
Uric acid stone, 363, 364 Ventilation-perfusion (VA/Q) mismatching, 228
Uricase, 351, 353–355 Ventricle, 18, 50, 235, 236, 240, 251, 261
Uricosuric, 353–355 Verapamil, 44, 340
Urinary tract infection (UTI), 357–360 Very-low-density lipoprotein (VLDL),
influence of treatment on metabolism, 359 201, 202, 295–299
introduction to UTI, 357 Vigabatrin, 24, 25
pathophysiology of UTI and metabolic Villus, 126, 139
alterations, 357–359 Virus, 139–141, 145, 148, 164, 184, 215, 227, 229,
perspectives, 359–360 308–310, 315
treatment, 359 Visceral fat, 13, 199–202, 341, 386
Urine, 94, 127, 163, 175, 176, 192, 285, 286, 331–335, Visceral obesity, 11, 12, 200, 201
347, 348, 350, 355, 357, 359, 361–365 Vision, 59, 67, 70, 73, 74
Urine pH, 363, 364 Vitamin A, 61, 64, 173
Uropathogen, 357–360 Vitamin D endocrine system, 115, 117
Uropathogenic Escherichia coli, 357 Vitreous body, 60
Vomiting, 38, 41, 44, 110, 127, 129, 131, 137, 138,
140, 143, 146, 147, 323, 374
V
Valproic acid, 24, 25, 44
Valve, 235, 236, 263, 273 W
Varicose veins, 273–277 Warburg effect, 393, 394, 396
histological changes, 274 Weight gain, 15, 20, 31, 32, 44, 168, 339,
introduction to varicose veins, 273 341, 342, 382, 398
metabolic changes, 275 White adipose tissue (WAT), 164, 191–193, 265
molecular changes, 274–275 White blood cell (leukocyte), 281, 321
pathophysiology of varicose veins and metabolic
alterations, 273
perspectives, 276 X
pharmacological treatments and their influence Xanthine oxidase, 351–353
on metabolism, 275–276
treatment, 275
Vascular endothelial growth factor (VEGF), Z
51, 68–71, 130, 153, 193, 274 Zolmitriptan, 44