Pathology Robbins Notes

CHAPTER 2

Hypoxia  O2 deficiency
Ischemia  reduced blood supply which also results in deficiency of essential
nutrients and build-up of toxic metabolites
 Most common cause of hypoxia is ischemia resulting from arterial
obstruction
 Two main morphologic correlates of reversible cell injury is:
o Cellular swelling – pallor, inc. turgor, inc. organ weight
o Fatty change – triglyceride containing lipid vacuoles in cytoplasm
o Membrane blebbing
o Loss of microvilli
o Mitochondrial swelling
o Dilation of ER
o Eosinophilia
 Hypertrophy of ER for eg. occurs in response to potentially injurious insults
 Depending on duration of injury , Cell death  ultrastructural changes 
light microscopic changes  gross morphologic changes
 NECROSIS – morphologic manifestation of accidental cell death and its
characterized by severe damage beyong salvage
o Can occur due to ischemia, exposure to toxins, trauma and infection
 APOPTOSIS – regulated cell death, when injury is less severe and cells
need to be eliminated during normal processes by activating precise set of
molecular pathways leading to death
Sometimes regulated cell death shows features of both necrosis and apoptosis -
 necroptosis

 Necrosis – always pathological indication but apoptosis – also occurs in

healthy tissues
 Cellular function may be lost long before cell death occurs

Necrosis

Form of cell death in which cellular membranes fall apart, cellular enzymes leak
out and ultimately digest the cell
 Necrosis elicits inflammation

Morphological changes which occurs during necrosis:

 Cytoplasmic changes – inc. eosinophilia (red by dye eosin), myelin figures
are prominent, cytoplasm becomes vacuolated and appears “moth-eaten”
o In electron microscopy, necrotic ells are characterized by
discontinuities in plasma and organelle membranes, marked dilation of
mitochondria associated with the appearance of large amorphous
intramitochondrial densities, disruption of lysosomes and
intracytoplasmic myelin figures
 Nuclear changes
o Pykinosis – nuclear shrinkage and inc. basophilia (DNA condenses
into dark shrunken mass)
o Karyorrhexis – pyknotic nucleus undergoes fragmentation
o Karyolysis – basophilia (blue-purple) fades
 Pyknosis, karyorrhexis, karyolysis
 Fates of necrotic cells – may persist for sometime or be digested
 Morphologic patterns of tissue necrosis –

Types of necrosis with distinctive appearances, EXCEPT fibrinoid necrosis

which is detected only by histologic examination:
 Coagulative necrosis – underlying tissue architecture is preserved for at least
several days after death of cells in the tissue – because the injury denatures
not only structural proteins but also enzymes, thereby, blocking proteolysis
of the dead cells
o Characteristic of infarcts (areas of necrosis causes by ischemia) in
all solid organs EXCEPT the brain.
 Liquefactive necrosis – dead cells are completely digested transforming
tissue into a viscous liquid which is then removed by phagocytes
o Seen in focal bacterial and fungal infections because they
stimulate rapid accumulation of inflammatory cells and the
enzymes of leukocytes digest (liquefy) the tissue
o Hypoxic death of cells within CNS causes liquefactive necrosis
(reason not known)
o In this type of necrosis is initiated by acute inflammation (e.g.
bacterial infection), the material is frequently creamy yellow and is
called PUS
 Gangrenous necrosis – refers to condition of limb that has lost blood supply
and has undergone coagulative necrosis involving multiple tissue layers
o “Wet gangrene” occurs when bacterial infection is superimposed on
normal gangrene because the destructive contents of bacteria and
attracted leukocytes causes liquefactive necrosis
 Caseous necrosis – “cheeselike”, friable (crumbly) yellow-white appearance
of the area of necrosis. Granular pink appearance with H&E stain
o Most often seen in foci of tuberculous infection
o Characterized by a nodular inflammatory lesion called a granuloma
 Fat necrosis – focal areas of fat destruction usually from the release of
activated pancreatic lipases into the substance of the pancreas and peritoneal
cavity  pancreatitis!
 (In this disorder, pancreatic enzymes that have leaked from
acinar cells and ducts cause the membranes of fat cells in the
peritoneum (the lining of the abdominal cavity) to become
liquid. Additionally, lipases, which are enzymes that break
down fats, split the fat molecules within these cells. This
process results in the release of fatty acids, which combine with
 calcium to create visible, chalky white areas in the affected
tissue. These white areas, known as fat saponification, help
surgeons and pathologists identify the damaged areas or
lesions in the tissue.)
o Histology – necrotic fat cells surrounded by basophilic calcium
deposits and an inflammatory reaction
 Fibrinoid necrosis – usually occurs in immune reactions in which
complexes of antigens and antibodies are deposited in the walls of blood
vessels but also in severe hypertension
o Deposited immune complexes and plasma proteins that leak into the
wall of damaged vessels produce a bright pink amorphous appearance
called FIBRINOID.
 Seen in polyarteritis nodosa

 Leakage of intracellular proteins help in detecting tissue-specific necrosis

using blood/serum samples. Markers:
o Creatinine kinase and troponin for cardiac muscle
o Hepatic bile duct contains Alkaline phosphatase and hepatocytes
contain transaminases

Apoptosis
Pathway of cell death in which the cells activate
 APOPTOTIC CEL DEATH DOES NOT ELICIT AN INFLAMMATORY
REACTION (because the dead cell and fragments are cleared with little
leakage of cellular contents)
 Physiologic apoptosis
 Unwanted cells are eliminated
without eliciting harmful
inflammation
 In immune system, apoptosis
eliminates excess leukocytes and
lymphocytes
Apoptosis in pathologic conditions
 Eliminates cells that are
damaged beyond repair like
DNA damage
 Accumulation of misfolded
protein also triggers it
 Infectious agents esp. viruses
trigger it too

Mechanism
Regulated by biochemical pathways that control the balance of death and
survival-inducing signals and finally the activation of enzymes called
CASPASES (cysteine proteases that cleave proteins after aspartic acid
residues) .
 2 distinct pathways for caspase intersection:
 Clearance of apoptotic cells
o Apoptotic cells produce “eat-me” signals.
 Eg. Phosphatidylserine is usually on inner leaflet of plasma
membrane but in apoptotic cells they are on the outer leaflet
where it is recognized by macrophages

Other pathways of Cell Death

Necroptosis
 Kinases called receptor-interacting protein (RIP) are activated which initiates
a series of events  dissolution of cell
 Plays a role in ischemic injury

Pyroptosis
 Activation of cystosolic danger-sensing protein complex called
inflammasome  activates caspases  induce production of cytokines
(some of which induce inflammation)
 Apoptosis and inflammation coexist

Autophagy
 “self-eating”, lysosomal digestion of the cell’s own components in times of
nutrient deprivation so that the starved cell can live but eating its own
contents
 Organelles are hidden in an ER-derived vacuole which then fuses with
lysosomes to form autophagolysosome which the lysosomes digest the
cellular components
 Extensive autophagy is seen in ischemic injury and some types of
myopathies
o Inflammatory bowel disease is linked with polymorphisms in a gene
involved in autophagy
Deprivation of oxygen and nutrients (in hypoxia and ischemia)  necrosis
Damage to proteins and DNA triggers  Apoptosis

Hypoxia and Ischemia

 Compensatory mechanisms of hypoxia are induced by hypoxia inducible
factor 1 (HIF-1)  cause adaptive changes in cellular metabolism by
stimulating the uptake of glucose and glycolysis, dampening mitochondrial
oxidative phosphorylation
 Vascular endothelial growth factor (VEGF) stimulate growth of new vessels
to increase blood flow and supply of Oxygen
 rapidly proliferating normal cells and cancer cells rely on aerobic glycolysis
(instead of oxidative phosphorylation in mitochondria which is what other
cells use) to produce much of their energy because the metabolites produced
in this process serve as precursors for synthesis of proteins, lipids, nucleic
acids etc., a phenomenon referred to as the Warburg effect -Warburg effect
Ischemia-Reperfusion Injury
Under certain circumstances, the restoration of blood flow to ischemic but
viable tissues results, paradoxically, in increased cell injury.
Several mechanisms:
 Increased generation of ROS during reoxygenation
o ROS may be generated by injured cells with damaged mitochondria
that can’t carry out complete reduction of oxygen.
 Inflammation that is induced by ischemic injury inc. with reperfusion
because it enhances influx of leukocytes and plasma proteins which causes
additional injury
 Activation of the complement system also may contribute to ischemia-
reperfusion injury.

Oxidative stress
Oxidative stress refers to cellular abnormalities that are induced by ROS, which
belong to a group of molecules known as free radicals.

VIDEO NOTES
CHAPTER 4
Hemostasis is the process of blood clotting that prevents excessive bleeding
after blood-vessel damage
o Inadequate hemostasis  hemorrhage and if massive and rapid 
hypotension, shock and death

Inappropriate clotting (thrombosis) or migration of clots (embolism) can ostruct

blood vessels causing ischemic cell death (infarction)

HYPEREMIA AND CONGESTION

Hyperemia Its an active process resulting from arteriolar dilation and

increased blood inflow as occurs at sites of inflammation or in exercising
skeletal muscle
o Tissues are redder than normal
Congestion is a passive process resulting from impaired outflow of venous
blood from a tissue as in cardiac failure
o Tissues are blue-red colour (cyanosis)
o Chronic congestion can lead to:
 parenchymal cell death and secondary tissue fibrosis
 Edema
 Focal hemorrhages

EDEMA
 Accumulation of interstitial fluid within tissues
 Extravascular fluid can also collect in body cavities  effusions. Examples
include effusions in:
o Pleural cavity  hydrothorax
o Pericardial cavity  hydropericardium
o Peritoneal cavity  hydroperitoneum or ascites
 Anasarca is a severe generalized edema marked by profound swelling of
subcutaneous tissues and accumulation of fluid in body cavities
 Excess edema is removed by lymphatic drainage and is returned to the blood
stream through the thoracic duct
 The edema fluid that accumulates in the setting of increased hydrostatic
pressure or reduced intravascular colloid typically is a protein-poor
transudate; by contrast, because of increased vascular permeability,
inflammatory edema fluid is a protein-rich exudate with a high specific
gravity.

INCREASED
HYDROSTATIC
PRESSURE
Causes of Increased Hydrostatic Pressure
 Increases in hydrostatic pressure are mainly caused by disorders that impair
venous return
 Localized - causes include deep venous thrombosis (DVT) causing edema in
affected limbs.
 Generalized - in congestive heart failure leading to systemic edema.

Mechanisms in Congestive Heart Failure

 Congestive heart failure reduces heart's pumping ability, causing venous
congestion.
 Increased capillary hydrostatic pressure in tissues, leading to fluid leakage.
 Reduced cardiac output triggers renal sodium and water retention (secondary
hyperaldosteronism). The heart struggles to increase cardiac output which
sets up a cycle of fluid retention, increased venous pressure, and worsening
edema.

Management of Generalized Edema

Strategies for generalized edema management:
 Diuretics to remove excess sodium and water.
 Salt restriction to reduce water retention.
 Aldosterone antagonists to block the effects of aldosterone.

REDUCED PLASMA OSMOTIC PRESSURE

Reduction of plasma albumin concentrations leads to decreased colloid osmotic
pressure of the blood and loss of fluid from the circulation
Causes of Reduced Plasma Osmotic Pressure:
 Nephrotic Syndrome: This syndrome, characterized by leaky glomerular
capillaries in the kidneys, results in the loss of albumin and other proteins in
the urine, leading to generalized edema.
 Liver Disease (e.g., Cirrhosis): Severe liver disease can reduce albumin
synthesis, contributing to reduced plasma osmotic pressure.
 Protein Malnutrition: Inadequate protein intake can lead to lower albumin
levels.

Consequences of Reduced Albumin:

Reduced albumin levels lead to a stepwise sequence of events:
 edema, decreased blood volume, reduced kidney perfusion, and secondary
hyperaldosteronism.
 Hyperaldosteronism results in increased salt and water retention by the
kidneys  which worsens edema

LYMPHATIC OBSTRUCTION
Edema may result from lymphatic obstruction that compromises resorption
(removing) of fluid from interstitial spaces.

Causes of Lymphedema
Lymphedema commonly results from conditions such as inflammation or
tumors. These conditions can obstruct the flow of lymphatic fluid, leading to
swelling.
Examples:
Filariasis: This parasitic infection can lead to massive edema in the lower
extremities and external genitalia, a condition known as "elephantiasis." It does
so by causing fibrosis in inguinal lymphatic vessels and nodes.
Breast Cancer: Breast cancer can infiltrate and obstruct superficial lymphatics,
causing edema in the overlying skin. This results in a characteristic "peau
d’orange" appearance, resembling orange peel.
Therapeutic Complications: Lymphedema can also occur as a complication of
therapy. For instance, women with breast cancer who undergo axillary lymph
node removal or radiation therapy may experience lymphatic disruption and
severe lymphedema in the arm.

SODIUM AND WATER RETENTION

Sodium and water retention can lead to can lead to edema by increasing
hydrostatic pressure (because of expansion of the intravascular volume – means
more blood) and reducing plasma osmotic pressure.

CLINICAL FEATURES
Variability in Effects: Edema can range from being a minor annoyance to a
rapidly fatal condition.

Subcutaneous Edema:

 Important for recognizing underlying cardiac or renal diseases.

 Can impair wound healing and the body's ability to clear infections when
significant.

Pulmonary Edema:
 Commonly associated with left ventricular failure.
 lso seen in renal failure, acute respiratory distress syndrome, and lung
inflammatory and infectious disorders.
 Interferes with normal breathing, hinders oxygen diffusion, and promotes
infection within the lungs.

Brain Edema:
 Life-threatening condition
 Severe brain swelling can cause herniation (extrusion) through the foramen
magnum.
 Increased intracranial pressure can compress the brain stem's vascular
supply, potentially leading to death due to injury to vital centers controlling
functions like respiration.

MORPHOLOGY

Gross Inspection: Edema is easily recognizable through visual examination. It

appears as swelling and can be observed by the naked eye.

Microscopic Examination: Microscopic examination reveals clearing and

separation of the extracellular matrix (ECM) elements within the affected tissue.

Common Sites of Edema:

 Subcutaneous tissues
 Lungs
 Brain
 Dependent Edema:
Edema is most pronounced in body parts located farthest below the heart, where
hydrostatic pressures are highest. Thus, edema typically is most pronounced in
the legs with standing and the sacrum with recumbency, a relationship termed
dependent edema. This is known as "dependent edema."

Pitting Edema:
When pressure is applied to edematous subcutaneous tissue, it displaces
interstitial fluid, leaving a depression that can be indented by finger pressure.

Specific Types of Edema:

 Edema resulting from renal dysfunction or nephrotic syndrome often
first manifests in loose connective tissues, such as the eyelids, causing
periorbital edema.
 Pulmonary edema leads to increased lung weight and contains frothy fluid
consisting of air, edema fluid, and red blood cells.
 Brain edema can be localized or generalized, depending on the nature and
extent of the underlying pathological process or injury. With generalized
edema, the gyri of the brain swell and flatten against the skull, narrowing the
sulci.