Necrosis

this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.

1. General Pathology Notes (Robbins)
By Dr. Ashish Jawarkar

Chapter 1 : CELLULAR RESPONES TO STRESS AND TOXIC INSULTS:
ADAPTATION, INJURY AND CELL DEATH


TOPIC 2. CELL INJURY AND NECROSIS

Overview
1. definition
2. types – reversible, irreversible (necrosis,apoptosis)
3. causes
4. timeline
5. Mechanisms of cell injury (necrosis)
6. morphology
7. necrosis vs apoptosis
8. patterns of necrosis
9. molecular basis


*definition and types
Cells exposed to stress



Adaptation (hypertrophy/hyperplasia/atrophy/metaplasia)



Continued stress, no more adaptation possible



Cell injury



Reversible cell injury Irreversible cell injury
(necrosis & apoptosis)

2. cell
function
Biochemical
alterations Minutes
Ultrastructural
changes


Days
Light
Microscopic
Changes
Gross
Morphologic
Changes
effect


*Causes of cell injury
1. O2 deprivation, nutritional imbalances
2. Physical agents – trauma, heat, cold, UV light, shock
3. Chemical agents – cyanide, arsenic, pollutants
4. Infectious agents
5. Deranged immunity

*Timeline



Reversible irreversible cell injury
Injury
















*Mechanisms of Cell injury (Necrosis)
1. Damage to membranes (plasma, lysosomal,mitochondrial)
2. Failure of calcium pump
3. Accumulation of free radicals
4. Mitochondrial membrane damage and depletion of ATP
5. Protein misfolding and DNA damage

1. Damage to membranes

Plasma membrane damage Lysosomal membrane damage




Osmotic imbalance leakage of
Leakage of metabolites (DNAases, RNAases, Proteases etc.)

3. O2
-
H2O2 OH

Super Hydrogen Hydroxyl
Oxide Peroxide Radical


2. Failure of Ca
2+
pump


Calcium influx




Activation of leaked enzymes (DNAases, RNAases) Alteration of mitochrondrial
Membrane permeability


3. Accumulation of free radicals

Generation of free radicals
ROS
1. Redox rns in
Normal metabol SOD fenton rn
2. Radiation +Fe2+
3. Inflammn
4. CCl
4
5. Transition metals
(Fenton rn
#
)
6. NO



FENTON RN
H
20
2 + Fe
2+
Fe
3+
+ OH + OH
-
MITOCHONDRIA


Removal of free radicals done by
1. SOD (superoxide dismutase) – mitochondria
2. Glutathione peroxidase – mitochondria
3. Catalase – peroxisome

Pathologic effects of ROS

1. Fatty acid oxidation and disruption of membranes, organelles
2. Protein oxidation and loss of enzyme activity, protein misfolding
3. DNA oxidation and mutations and breaks

4. 4. Mitochondrial membrane damage and depletion of ATP

Mitochondrial membrane damaged by
1. increased cytosolic calcium
2. ROS
3. hypoxia
4. mutations in mito genes

Activation of caspases
(apoptosis)
Due to leakage of cyto c




Alteration of mitochondrial membrane permeability
Due to leakage of H
+






H
+
leakage and Loss of membrane potential


Decreased Oxidative Phosphorylation



Decreased ATP generation



Detachment of Ribosomes Failure of Na
+
pump Increased anaerobic
Glycolysis


Decreased protein synthesis Influx of Na
+
, Ca
2+
Lactic acidosis
H2O


Increased lipid deposition Cellular swelling Clumping of nuclear
ER swelling chromatin

5. *Morphology


REVERSIBLE INJURY NECROSIS
GROSS 1. Pallor
2. Turgor
3. Increased weight

Light
Microscopy
1. Cellular swelling
2. vacuolar
degeneration/hydropic
change – clear vacuoles in
cytoplasm that represent
pinched off segments of ER
1. Cytoplasm –
a. eosinophilia – due to loss of
cytoplasmic RNA
b. Glassy appearance – due to loss
of glycogen particles
c. Moth eaten app – due to
vacuolation

2. Cell membrane –
a. Myelin figures – membrane
fragments collect in cytoplasm
b. Calicification – of myelin figures

3. Nucleus –
a. Karyoloysis – lysis of chromatin
b. Pyknosis – nuclear shrinkage
c. Karyorrhexis – chromatin
condenses into solid shrunken
basophilic mass
Ultra
structure
Plasma membrane – blebs, loss of
microvilli

Nucleus – disaggregation of
granular and fibrillar elements

ER – dilatation and detachment of
ribosomes

Mitochondria – amorphous
densities
Plasma membrane – discontinuities

Cytoplasm – Myelin figures

Mitochondria - Large amorphous
densities

*Patterns of tissue necrosis

1. COAGULATIVE NECROSIS
Gross: The tissue is firm. Eg of localized coagulative necrosis is infarct.
Microscopy: preserved cell outlines, loss of nuclei, inflammatory infiltrate

2. CASEOUS NECROSIS (cheese like, in TB)
Gross: friable white app of necrotic area

6. Microscopy: Granuloma – central necrosis with lysed cells forming amorphous
debris, surrounded by inflammatory cells and epithelioid cells

3. LIQUEFACTIVE NECROSIS (necrosis in CNS)
Characterized by digestion of dead tissue – transformation into liquid viscous
mass
Gross: Abscess cavity formation with ragged margins
Microscopy: Necrotic material is creamy yellow containing dead leucocytes

4. GANGRENOUS NECROSIS
1. coagulative necrosis occurring in a limb that has lost its blood supply
2. occurs in multiple tissue planes
3. superimposed bacterial infection causes liquifactive necrosis – wet
gangrene

5. FAT NECROSIS
Refers to focal areas of fat destruction occurring due to release of pancreatic
enzymes into substance of pancreas and peritoneal cavity
Seen in acute pancreatitis
Gross: Pancreatic enzymes liquefy membranes of fat cells in peritoneum, split
triglycerides, produce saponification and deposition of calcium, chalky white
areas
Microscopy: shadowy outlines of fat cells, basophilic calcium deposits,
inflammatory reaction

6. FIBRINOID NECROSIS
Seen in immune reactions like SLE and other vasculitic syndromes
Seen in the wall of blood vessels
Microscopy: The wall of the vessels show circumferential bright pink areas of
necrosis and inflammation. Its basically immune complex deposition with
extravasated fibrin.