Alteration of

lipoprotein metabolism
 Cholesterol
 One of the main substances in the animal cell

 Origin
 exogenous
 endogenous (synthesis)

 The main organs of cholesterol synthesis

 Hepatocyte
 Nervous tissue
 Enterocytes

 Free + esterified cholesterol

 Free cholesterol
 Main structural compound cell membrane

 Parent substance for the steroid hormones synthesis

 Parent substance for the bile acids synthesis

 Necessary for the lipoprotein synthesis in the small

intestine and liver

 Necessary for the absorption of triacylglycerols and

oleovitamins from the small intestine
 Esterified cholesterol
 Cholesterol + fatty acid (linoleic acid)

 Transport and spare form of the cholesterol

 It is transported inside lipoprotein particles

 It is stored in the liver (hepatocytes)

 Triglycerides (TAG)
 Glycerol + three fatty acids (palmitic acid, linoleic acid,
oleic acid)
 Sources of TAG
 Exogenous (feeding)
 Endogenous synthesis in the liver and enterocytes
 Increased concentration of TAG is caused by abnormal
feeding, alcohol
 TAG are the main source of energy + regulation of body
temperature
 Lipoproteins
 Necessary for cholesterol and TAG transport → participate on its metabolism

 Chylomicrons (CL)
 Chylomicrons remnants
 Very low density lipoproteins (VLDL)
 Intermediate low/density lipoproteins (IDL)
 Low density lipoproteins (LDL)
 High density lipoproteins (HDL)

 Apoproteins are only weakly associated with a particular lipoprotein and are easily transferred
to another lipoprotein of a different class. Apoproteins have various functions including:
 Structural role
 Binding sites for receptors
 Activators or co-enzymes for enzymes involved with lipid metabolism
 Chylomicrons
 Assembled in intestinal mucosal cells.
 They enter the lymphatic system and enter the blood via the thoracic duct.
 They contain mostly TAG.
 Nascent chylomicrons contain apoprotein B48 but pick up others
apoproteins from high density lipoproteins (HDL) once they enter the
circulation.
Apoprotein
phospholipid

Cholesterol ester

Cholesterol

TAG (86%)
Function is to transport dietary TAG to the adipose tissues where it can be
stored as fat or to muscles where the constituent fatty acids can be used for energy.
This animation shows how chylomicrons are metabolised once
they enter the circulation from the lymphatic system

B48 Tissues

CM CII
E Lipoprotein
B48 lipase

Taken up by CII
E CMR
liver (via LDL receptors)

E CII
B48
HDL
E CMR CII Capillary wall
(endothelial surface)
 Chylomicron summary
 Synthesised in intestine.

 Contain mostly dietary TAG (with a little cholesterol,

cholesterol ester & phospholipid.

 Transport TAG to tissues and deliver remaining

cholesterol & cholesterol ester to the liver.
 Very low density lipoproteins (VLDL)
 Synthesised in the liver. Contain mostly TAG but with a significant amount of
cholesterol and cholesterol ester.
 Nascent VLDL contains apoprotein B100 but pick up others from HDL in the circulation

Protein
phospholipid

Cholesterol
ester
TAG (55%)

Cholesterol

Function is to transport endogenously synthesised TAG to the extra hepatic tissues where
it can be stored as fat or to muscles where the constituent fatty acids can be used for energy.
The cholesterol is delivered to extra hepatic tissues once VLDL has been metabolised to
LDL.
This animation shows how VLDL are metabolised once they enter
the circulation from the liver

B100 Tissues

VLDL B100

LDL Lipoprotein
Some LDL taken up lipase
E CII
by liver (LDL receptors)

Having lost TAG to

tissues LDL contains a
large proportion of
cholesterol/cholesterol
esters
Capillary wall
Some LDL taken up by (endothelial surface)
other tissues (LDL receptors).
LDL delivers cholesterol and
TAG to the extra hepatic tissues.
 VLDL summary
 Synthesised in the liver.

 Contain mostly dietary TAG (with a little cholesterol,

cholesterol ester & phospholipid.

 Converted to LDL which contain an increased proportion of

cholesterol & cholesterol ester (due to loss of TAG).

 Transport TAG and cholesterol from liver to tissues.

 Cholesterol in LDL referred to as “bad cholesterol” since LDLs

are implicated in atherosclerosis
 Role of LDL in atherosclerosis
 Damage to endothelium (hypertension, smoking etc).

 LDLs penetrate vascular wall, deposit in the intima and with

time are damaged by oxidation.

 Oxidised LDLs attract the attention of macrophages which

ingest the LDL.

 Macrophages become overloaded with lipid and become

“foam” cells which die and release pools of lipid in the vessel
wall (plaques).

 A complex processes mediated by cytokines and growth

factors causes smooth muscle cells to form a collagenous cap
over the lipid (mature atherosclerotic plaque).
 High density lipoprotiens
 Act as a reservoir for apoproteins which can be donated or received from
other lipoproteins.
 Also play a vital role in scavenging “used” cholesterol (reverse cholesterol
transport):

apoproteins HDL receptor mediated HDL

endocytosis by liver
HDL
HDL Liver
some cholesterol
ester transferred to
“used” cholesterol circulating VLDL
transferred to HDL and
converted to cholesterol
VLDL
ester

Cholesterol can be
LDLreceptor converted to bile salts
Peripheral mediated for excretion or
tissues LDL endocytosis LDL repackaged in VLDL
for redistribution
High density lipoprotiens summary
 HDL carries “used” cholesterol (as CE) back to the liver. Also
donate some CE to circulating VLDL for redistribution to
tissues.
 HDL taken up by liver and degraded. The cholesterol is
excreted as bile salts or repackaged in VLDL for distribution
to tissues.
 Cholesterol synthesis in the liver is regulated by the
cholesterol arriving through HDL (and dietary cholesterol
returned by chylomicron remnants).
 Cholesterol (CE) in HDL is referred to as “good cholesterol”.
 Recommended levels of lipids in blood

 Total cholesterol under 5 mmol/l

 LDL cholesterol under 3 mmol/l

 Triglycerides under 2 mmol/l

 HDL cholesterol over 1 mmol/l

Hyperlipidaemias (dyslipoproteinemias) DLP

 Metabolic disease characterized by the changes in lipids and

lipoproteins concentration in blood

 Primary (inherited) hyperlipidaemias

 Secondary hyperlipidaemias +
 Participation of enviromental factors and life style (eating, obesity,
physical activity, smoking)
 Therapeutical classification of DLP
according to EAS
 I Isolated hypercholesterolemia (LDL)

 II Combined (mixed) hyperlipoproteinemia (LDL + VLDL)

 III Isolated hypertriglyceridemia (VLDL)

+ easy to use in clinical practice

- Does not consider
- HDL concentration
- The cause of the DLP
 Classification of Dyslipidaemias
Fredrickson (WHO) Classification
Phenotype Lipoprotein Serum Serum Atherogenicity Prevalence
elevated cholesterol triglyceride
I Chylomicrons Normal to None seen Rare

IIa LDL Normal +++ Common

IIb LDL and VLDL +++ Common

III IDL +++ Intermediate

IV VLDL Normal to + Common

V VLDL and Normal to + Rare

chylomicrons

LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-

density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not considered
in the Fredrickson classification.)
(Adapted from Yeshurun et al., 1995)
 Familiar hypercholesterolemia
 The most dangerous inherited DLP → high risk of
ischemic heart disease

 Causation: gen defect in LDL receptor → increased

concentration of LDL in blood

 Clinical manifestation of disease in 40 years old male

or 55 years females
Familiar hypercholesterolemia
Familiar hypercholesterolemia
Secondary Dyslipidaemias
 Hypothyroidism
 Decreased metabolization of lipids → increased concentration
of cholesterol (LDL), TAG + decreased concetration of HDL

 Alteration of suprarenal glands (cortisol)

 Increased secretion of glucocorticoids (Cushing syndrome)
 Increased lipolysis
 Increased gluconeogenesis → Insulin resistance
 Increased production of VLDL in the liver
 Diabetes mellitus type II

a) Increased lipid catabolism

b) Increased production of VLDL in liver → ↑TAG

c) Decrease in HDL cholesterol

d) Increase in „small dense LDL“ – very atherogenic

 Kidney disease (nephrotic syndrome)

Pathophysiology

 Excretion of 3.5 g of protein in the urine per day -

proteinuria (albuminuria) →

 hypoalbuminemia → decreased oncotic pressure of

blood → formation of edema →

 hyperlipidemia (LDL, TAG) → atherosclerosis risk factor

 Obesity
 Genetic predisposition

 Increased TAG + decreased HDL

 Usually associated with metabolic syndrome

 Drugs

 glucocortikoids

 cyclosporin A

 Antihypertensive drugs
 Enviromental factors, life style

 Smoking → decrease HDL concentration

 Physical inactivity increased TAG + decreased HDL

PATHOLOGY OF THE
URINARY SYSTEM
Petr Nachtigal
 Functions of urinary (renal) system
 Excretory (production of urine, elimination of nitrogenous
substances)

 Blood pressure control (control of volume extracellular

fluid)

 Maintance of the pH

 Maintance of the osmolality

 Endocrinne function – production of erythropoietin, renin,

vitamine D
 Hemodynamics of kidney:

 blood circulation of kidney provides blood supply with

metabolities + oxygen supply

 blood circulation of kidney is ¼ of cardiac output → 1200

ml of blood
 Kidney (nephron function)
Glomerulus – glomerular filtration
Glomerular filtration depends on:

 Filtration pressure
 FP = Blood pressure - (P oncotic + P in Bowman capsula)
 FP = 6 kPa – (3,3 kPa + 1,3 kPa) = 1,3 kPa

 Structure of filtration membrane

 Endothelium of capillaries
 Basal membrane of epithelial cells of capsule
 Kidney (nephron function)

The result of glomerular filtration:

 180 l of primary urine

 Similar to plasma except protein (albumin), fat and

erythrocytes
 Kidney (nephron function)
Proximal tubulus

Tubular reabsorption
 endocytosis – small proteins
 Secondary active transport
 Na+ with glucosis, organic acids, amino acids, ions K+, Cl-, Ca2+ from
urine to blood
 Passive transport
 60-70% of water is reabsorbed with Na+
 urea
Proximal tubulus - tubular secretion
 Transport of substances from the peritubular blood into the tubules
 PAH (A) (para-amino-hippurate (hippuric acid), amonia, diuretics,
antibiotics

The results of proximal tubular processes:

 isoosmotic liquid without glucose, amino acid reduced by

reabsorption of water → maintance of volume and osmolality of
extracellular liquid
 Kidney (nephron function)
The loop of Henle
 Located in hyperosmotic medulla

Descending limb

 water permeable

 Water is reabsorbed from urine into hyperosmotic

interstitium
 Kidney (nephron function)
The loop of Henle

Ascending limb

 Water impermeable

 Only secondary active transport of ions (Na+, K+ Cl-, )

into the interstitium →
 Kidney (nephron function)
Distal tubule
 Located in isoosmotic cortex

 Activity of aldosteron
 Reabsorption of Na+, Cl- , HCO3-, water
 Secretion (elimination) K+ , H+, urea

 The results of distal tubule processes

 Regulation of blood pressure
 Controlling of pH
 Kidney (nephron function)

Collecting tubule

 Aldosteron – the same activity as in distal tubule

 Antidiuretic hormone (ADH) – reabsorption of

water
 Final urine
 For 24 hours 1,5 l of urine (pH 5,5-6,5)
 Polyuria  2 l urine
 Oliguria  0.5 l urine
 Anuria  0.1 l urine

 The urine does not contain glucose, amino acids, fat,

blood
 The urine contains substances with nitrogen (uric acid,
urea, amonia), and substances with sulphur
ALTERATIONS OF THE
URINARY SYSTEM
Petr Nachtigal
 Obstructive disorders – kidney stones
 Renal stones (nephrolithiasis) are masses of
crystals and protein responsible for the urinary tract
obstruction

 Size at least 2-3 millimeters—they can cause

obstruction of the ureter
 Obstructive disorders – kidney stones

Pathophysiology:
 High urinary concentration of stone forming substances (calcium
phosphate, calcium oxalate, uric acid)

 Urine pH – renal tubular acidosis

 Dehydratation

 Diet

 Filtration pressure
 FP = Blood pressure - (P oncotic + P in Bowman capsula)

 FP = 6 kPa – (3,3 kPa + 1,3 kPa) = 1,3 kPa

 Obstructive disorders – kidney stones
 Clinical manifestation:
 The pain located between last rib and lumbar vertebrae

 Colicky pain (stretching of the upper ureter and renal pelvis

as well as spasm of muscle, trying to move the stone)

 Nausea, vomiting (due to the embryological association of

the kidneys with the intestinal tract)

 Hematuria (bloody urine) is commonly present due to

damage in the epithelium of the urinary tract.
 Glomerulopathies
 Alterations of kidney glomeruli

 Primary
 Acute glomerulonephrities
 Chronic glomerulonephrities
 Membranous glomerulonephritis
 Nephrotic/nephritic syndrome

 Secondary
 Lupus erythematodes kidney damage
 Diabetic nephropathy
 Amyloidosis
 Nephritic syndrome

 Hematuria – macroscopical
 Proteinuria
 Increased levels of creatinine and nitrogen substances in blood
 Reduced glomerulal filtration = oligurie
 Extrarenal symtoms
 Arterial hypertension
 Edema
 Risk of acute renal failure development
 Glomerulonephritis with nephritic syndrome
Acute poststreptoccocal glomerulonephritis
 Caused by streptoccocuss A bacteria
 Associated with streptoccocal infection of throat, skin
 Usually occurs 7-10 days after streptoccocal infection
 Etiopathogenesis:
 The positively charges antigens of streptoccocus are accumulated in the negatively
charged glomerular basement membrane → attraction of neutrophils and
macrophages → the initiation of the inflammatory reaction → damage of epithelial
and endothelial cells lying on the basement membrane

 Clinical symptoms

 Nephritic syndrome like symtoms

 Chronic glomerulonephritis
 Several glomerular diseases with progressive course leading to chronic renal failure

Pathophysiology
 Autoimmune mechanism contribute to the glomerular injury
 Deposition of circulating soluble antigen-antibody complexes
 Activation of inflammation → damage of glomerular filtration membrane
 progressive destruction of the glomeruli (sclerosis)

Clinical manifestation
 Hematuria
 Proteinuria
 Decreased glomerular filtration → edema, hypertension
 After 10-20 years it leads to renal insufficiency
 Nephrotic syndrome
 glomerular injury + damage of filtration barrier (basement membrane)

Pathophysiology = group of symptoms

 Excretion of 3.5 g of protein in the urine per day - proteinuria (albuminuria) →
 hypoalbuminemia → decreased oncotic pressure of blood → formation of edema
 Generally around the eyes
 In the extremities, especially the feet and ankles
 Decrased volume of blood → decreased glomerular filtration → acute renal failure

 Decreased oncotic pressure → increase lipoprotein synthesis → hyperlipidemia

(↑LDL, ↑TAG) → atherosclerosis risk factor
 Glomerulonephritis with nephrotic syndrome

 Membranous glomerulonephritis
 Immunocomplexes induced inflammation in glomeruli

 The most common glomerulonephritis related to nephrotic

syndrome

 2/3 are idiopathic – no precise cause (unknown)

 1/3 part of other diseases

 Systemic lupus erythematodes

 Nádory
 Acute renal failure

 Reversible reduction in renal function = accumulation of

nitrogenous substances in body
 Possible causes
 Prerenal (hypoxia, ischemia, hypoperfusion)
 Systemic decrease of blood pressure
 Hypovolemia (blood loss, vomiting diarrhea)

 Cardiac failure

 Stenosis or obstruction of renal artery

 Acute renal failure

 Reversible reduction in renal function = accumulation of

nitrogenous substances in body
 Possible causes
 Intrarenal
 Acute tubular necrosis (ischemia of kidney)

 Glomerulapathies

 Nephrotoxicity (heavy metals)

 Postrenal
 Ureteal destruction

 Obstructive uropathies (renal stones)

 Pathophysiology, clinical symptoms- initial phase:

 It takes hours
 Symptoms usually related to the cause of renal
failure

 Shock

 Poisons, heavy metals

 Kidney disease
Pathophysiology, clinical symptoms– anuric-oliguric phase:

 It takes 1-2 weeks

 Oliguria ( < 300ml/day), anuria (< 100 ml/day)
 Decreased elimination of nitrogenous substances→

 Uremia
 Nauzea, vomiting
 Azotemia (foetor azotemicus)
 Metabolic acidosis
 Decreased elimination H+
 Compensatory deep acidotic breathing

 Hyperkalemia
 Decreased elimination of pottasium
 Alteration of heart rhythm
Pathophysiology, clinical symptoms– anuric-oliguric phase:

 Hyperhydratation
 Arterial hypertension

 Lung edema (dyspnea, shortness of breath)

 Brain edema (restlesness, irritability, convulsion)
Pathophysiology, clinical symptoms – early diuretic phase:

 Diuresis increase over 300 ml/day

 Decreased concentration of urea

Pathophysiology, clinical symptoms – later diuretic phase

 Decreased urea concentration in blood

 Polyuria appears (hypotension, dehydratation, hypokalemia)

Pathophysiology, clinical symptoms – recovering phase Kidney

functions are recovered within 3-6 months
 Chronic renal failure
Chronic renal failure = irreversible loss of nephrons = uraemia
Causation
 glomerulonephritis
 diabetic nephropathy
 nephrosclerosis

 Pathophysiology
 Degeneration of glomeruli → decreased glomerular filtration →
azotemia → uraemia → alteration of ions transport especially
Na+ → alteration of Na/K pump
 Chronic renal failure
 Clinical manifestation
 Retention of Na+ and water
 hypertension

 edema

 cardiac failure (volume overload)

 Alteration of nervous system (PNS + CNS)

 Disturbances in behaviour

 Convulsions

 Neuropathy

 Dementia
 Chronic renal failure
 Clinical manifestation
 Dysfunction of leukocytes
 Infection

 Sepsis

 Anemia
 Low hematocrit

 Lethargy

 Dizziness

 Alteration of bones (alteration of calcium and phosphate and vitamin D

synthesis