Cell injury

Cell injury

1. CELLULAR INJURY DATE OF PRESENTATION: By Dr. D. VAMSHIKRISHNA, MD (H).

2. CELL INJURY Cell injury is defined as the effect of a variety of stresses due to etiologic agents a cell encounters resulting in changes in its internal and external environment.

3. CELL STRESS STRESS STRESS STRESS= ETIOLOGICAL AGENTS LIKE BACTERIA CHANGES IN INTERNAL AND EXTERNAL ENVIRONMENT OF CELL Effects Affected cell

4. CELL STRESS ALTERED FUNCTIONAL DEMAND MILD TO MODERATE STRESS SEVERE STRESS AND PERSISTANT STRESS ADAPTATIONS ATROPHY HYPERTROPHY HYPERPLASIA DYSPLASIA IRREVERSIBLE CELL INJURY -CELL DEATH REVERSIBLE CELL INJURY -DEGENERATIONS -SUBCELLULAR ALTERATIONS -INTRACELLULAR ACCUMULATIONS CELLULAR RESPONSES TO CELL INJURY.

5. ETIOLOGY OF CELL INJURY The cells may be broadly injured by two major ways: A. Genetic causes B. Acquired causes

6. 1. Hypoxia and ischemia 2. Physical agents 3. Chemical agents and drugs 4. Microbial agents 5. Immunologic agents 6. Nutritional derangements 7. Ageing 8. Psychogenic diseases 9. Iatrogenic factors 10. Idiopathic diseases.

7. HYPOXIA AND ISCHEMIA Hypoxia is the most common cause of cell injury TWO REASONS Reduced blood supply to cells due to interruption in blood flow leading to ischemia Due to defects in oxygen carrying RBC’S or due to or HEART DISEASES, LUNG DISEASES , due to increased demand from tissues .

8. INTERRUPTED BLOOD FLOW ABNORMAL RBC’S HEART DISEASES LUNG DISEASES

9. PHYSICAL AGENTS Physical agents in causation of disease are: Mechanical Trauma (e.g. Road Accidents) Thermal Trauma (e.g. By Heat And Cold) Electricity Radiation (e.g. Ultraviolet And Ionizing) Rapid Changes in atmospheric pressure

10. COLD TRAUMA ELECTRICITY TRAUMA HEAT TRAUMA RADIATION TRAUMA

11. CHEMICALS AND DRUGS Chemical poisons such as cyanide, arsenic, mercury. Strong acids and alkalis Environmental pollutants Insecticides and pesticides Oxygen at high concentrations Hypertonic glucose and salt Social agents such as alcohol and narcotic drugs Therapeutic administration of drugs.

12. MICROBIAL AGENTS Injuries by microbes include Infections caused by bacteria, rickettsiae , viruses, fungi, protozoa, metazoa , and other parasites.

13. PSYCHOGENIC DISEASES There are no specific biochemical or morphologic changes in common acquired mental diseases due to mental stress, strain, anxiety, overwork and frustration e.g. depression, schizophrenia. However, problems of drug addiction, alcoholism, and smoking result in various organic diseases such as liver damage, chronic bronchitis, lung cancer, peptic ulcer, hypertension, ischemic heart disease etc.

14. IMMUNOLOGIC AGENTS Immunity is a ‘double-edged sword’: it protects the host against various injurious agents but it may also turn lethal and cause cell injury e.g. Hypersensitivity reactions; Anaphylactic reactions; and Autoimmune diseases.

15. AGEING Cellular ageing or senescence leads to impaired ability of the cells to undergo replication and repair, and ultimately lead to cell death culminating in death of the individual.

16. PATHOGENESIS OF CELL INJURY

17. Objective of today's topic Types of Cell- injuries. Pathogenesis of Cell-injury Pathogenesis in Reversible and Irreversible Hypoxic Cell-injury in particular Outcomes/Events in Reversible and Irreversible Hypoxic Cell injury.

18. Injury to the normal cell by one or more of the above listed etiologic agents may result in a state of CELL REPAIR AND HEAL CELL DEATH

19. OUTCOME OF THE CELL-INJURY DEPENDS ON: OF TARGET CELL TYPE, DURATION, SEVERITY OF INJURIOUS AGENT TYPE, STATUS , ADAPTABILITY

20. Small Dose of Chemical/Physical Agent REVERSIBLE CELL INJURY Large Dose of Chemical/Physical Agent IRREVERSIBLE CELL INJURY BASED ON TYPE, DURATION, SEVERITY:

21. Short Duration of Ischemia REVERSIBLE CELL INJURY Long Duration of Ischemia IRREVERSIBLE CELL INJURY

22. BASED ON TYPE, STATUS, ADAPTABILITY OF TARGET CELL: IF A CELL IS HIGHLY SUSCEPTABLE TO HYPOXIA EARLY CELL INJURY EXAMPLE: Skeletal muscle can withstand hypoxic injury for long-time, While cardiac muscle suffers Irreversible cell injury if exposed to Hypoxia for > 20 mins

23. Skeletal Muscle Cardiac Muscle

24. PATHOGENESIS OF ISCHAEMIC AND HYPOXIC INJURY

25. Ischemia and hypoxia are the most common forms of cell injury. It leads to REVERSIBLE CELL INJURY IRREVERSIBLE CELL INJURY

26. REVERSIBLE CELL INJURY IN HYPOXIA

27. If hypoxia is of short duration -> the effects may be reversible on rapid restoration of circulation. Example: In coronary artery occlusion , the myocardial contractility, metabolism and ultra structure are reversed if the circulation is quickly restored

28. CORONARY ARTERY OCCLUSION

29. EVENTS IN REVERSIBLE CELL INJURY ARE: DECREASED GENERATION OF CELLULAR ATP: INTRACELLULAR LACTIC ACIDOSIS: DAMAGE TO PLASMA MEMBRANE PUMPS: REDUCED PROTEIN SYNTHESIS:

30. 1. DECREASED GENERATION OF CELLULAR ATP: All living cells require continuous supply of oxygen to produce ATP which is essentially required for a variety of cellular functions. ATP is generated from: AEROBIC PATHWAY ANEROBIC PATHWAY

31. ATP in human cell is derived from 2 sources

32. COMPLETE ATP DEPLETION BOTH OXYGEN AND GLUCOSE SUPPLY IS COMPROMISED SEVERE CELL INJURY WITH INTERRUPTED BLOOD SUPPLY WITH DEFECTS IN OXYGEN CARRYING RBC’S OR HEART OR LUNG DISEASES ONLY OXYGEN COMPROMISED ATP IS GENERATED BY ANEROBIC PATHWAY CELL INJURY IS LESS

33. Cells which depend only on Aerobic Respiration for ATP generation Hence these tissues suffer more severely and rapidly due to hypoxia

34. Low oxygen supply to the cell Mitochondria fails (No Oxygen No ATP generation) Switches to Anaerobic Glycolytic Pathway for the requirement of ATP. Accumulation of Lactic Acid Decreased Intracellular pH . Clumping of Nuclear Chromatin. 2. INTRACELLULAR LACTIC ACIDOSIS:

35. CHROMATIN CLUMPING

36. 3. DAMAGE TO PLASMA MEMBRANE PUMPS

37. DECREASED A.T.P Decreased Production of PHOSPHOLIPIDS (ATP)-Dependent Sodium pump FAILURE Repair of Cell membrane is stopped Increased accumulation of Na in cell Swelling of Cell (HYGROPIC SWELLING) Membrane damage Calcium influx into cell (Particularly mitochondria) Swelling of Mitochondria (Amorphous densities)

38. Swelling of Mitochondria HYGROPIC SWELLING

39. Endoplasmic Reticulum Golgi apparatus 4. REDUCED PROTEIN SYNTHESIS:

40. Membranes of endoplasmic Reticulum and Golgi apparatus swell up. Ribosomes are detached from granular (rough) endoplasmic reticulum Reduced protein synthesis

41. Other changes: Loss of Microvilli and Intramembranous particles Focal projections of the cytoplasm (blebs). Myelin figures may be seen lying in the cytoplasm

42. Note: Up to this point, withdrawal of acute stress that resulted in reversible cell injury can restore the cell to normal state .

43. IRREVERSIBLE CELL INJURY IN HYPOXIA/ISCHEMIA

44. Persistence of ischemia (i.e., reduced blood flow to a tissue/organ) or hypoxia Irreversible damage to the structure and function of the cell Even after reperfusion with oxygen i.e., CELL DEATH Continuous ↓ in ATP , ↓ in Proteins , ↓ intracellular pH , and leakage of lysosomal enzymes into the plasma.

45. CHANGES IN IRREVERSIBLE CELL INJURY ARE: 1. CALCIUM INFLUX 2. ACTIVATED PHOSPHOLIPASES 3. INTRACELLULAR PROTEASES 4. ACTIVATED ENDONUCLEASES 5. LYSOSOMAL HYDROLYTIC ENZYMES

46. 1. CALCIUM INFLUX Due to continued hypoxia - Large cytosolic influx of calcium ions occurs (Esp. after reperfusion of irreversibly injured cell) Vacuoles Formation in the Mitochondria Deposition of amorphous calcium salts in the mitochondrial matrix VACUOLES

47. 2. ACTIVATED PHOSPHOLIPASES: Increased cytosolic influx of calcium into the cell Activation of endogenous phospholipases Damage to phospholipids layer of Cell membrane Damage to membrane function

48. phospholipids bilayer Phospholipid

49. 3. INTRACELLULAR PROTEASES Activated Intracellular Proteases (released by Lysosomes) Digestion of cytoskeleton of cell Cytoskeleton Damage

50. 4. ACTIVATED ENDONUCLEASES Activated lysosomal enzymes such as Proteases and Endonucleases . Damage to DNA/Nuclear proteins 1- PYKNOSIS: Condensation and clumping of nucleus 2- KARYORRHEXIS: Nuclear Fragmentation Into small bits 3- KARYOLYSIS: Dissolution of Nucleus Three types of nuclear damage can happen :

51. 5. LYSOSOMAL HYDROLYTIC ENZYMES Lysosomal Membrane Damage Escape of lysosomal hydrolytic enzymes into cell medium Activation of hydrolytic enzymes by low pH and Low oxygen Enzymatic digestion of cellular components CELL DEATH DEAD CELLS PHAGOCYTOSED BY MACROPHAGES

52. Lysosomes Hydrolytic enzymes Digestion of cell organelles

53. Lysosome enzymes: Hydrolase , RNAase , DNAase , Protease, Glycosidase, Phosphatase , Lipase, Amylase.

54. COMMON ENZYME MARKERS IN SERUM FOR DIFFERENT FORMS OF CELL DEATH: ENZYME DISEASE Aspartate aminotransferase (AST, SGOT) Viral Hepatitis, Alcoholic Liver Disease Acute Myocardial Infarction Alanine aminotransferase (ALT, SGPT) More specific for diffuse liver cell damage than AST e.g. Viral Hepatitis Creatine Kinase -MB (CK-MB) Acute Myocardial Infarction, Myocarditis Lipase More specific for acute pancreatitis Amylase Acute Pancreatitis Sialadenitis Lactic dehydrogenase (LDH) Acute Myocardial Infarction Myocarditis Skeletal muscle injury Cardiac troponin ( CTn ) Specific for Acute Myocardial Infarction

55. Objectives of today topic - Learn the Morphological forms seen in Reversible Cell Injury and Irreversible cell Injury

56. MORPHOLOGY OF REVERSIBLE CELL INJURY

57. Morphologic Forms Of Reversible Cell Injury: 1. Hydropic change 2. Hyaline change 3. Mucoid change 4. Fatty change

58. 1. HYDROPIC CHANGE/DEGENERATION Accumulation of water within the cytoplasm of the cell. Synonym= CLOUDY SWELLING , VACUOLAR DEGENERATION (Due to cytoplasmic vacuolation ). It is entirely reversible . Commonest form in cell injury Earliest form in cell injury

59. Etiology: Hypoxia Microbes Chemicals agents Physical agents Etc…

60. PATHOGENESIS Cloudy swelling results from impaired regulation of sodium and potassium at the level of cell membrane.

61. MORPHOLOGIC FEATURES: Grossly, the affected organ such as kidney, liver, pancreas, or heart muscle is enlarged due to swelling. The cut surface bulges outwards and is slightly opaque. MICROSCOPICALLY: The features of Hydropic swelling of kidney are as under The tubular epithelial cells are swollen cytoplasm contains small clear vacuoles Small cytoplasmic blebs may be seen.

62. 2. HYALINE CHANGE/DEGENERATION The word ‘hyaline’ or ‘ hyalin ’ means glassy. Hyalinisation is a common descriptive histologic term. It means glassy, homogeneous, eosinophilic appearance of proteinaceous material in haematoxylin and eosin-stained sections. It does not refer to any specific substance.

63. Hyaline change is seen in heterogeneous pathologic conditions and may be intracellular or extracellular.

64. INTRACELLULAR HYALINE Intracellular hyaline is mainly seen in epithelial cells. A few examples are as follows: Hyaline droplets in the proximal tubular epithelial cells due to excessive reabsorption of plasma proteins in proteinuria .

65. Hyaline droplets in proximal tubular epithelial cells

66. 2. Hyaline degeneration of rectus abdominalis muscle called Zenker’s degeneration, occurring in typhoid fever. Zenker’s degeneration

67. 3. Mallory’s hyaline/Mallory bodies- seen in the hepatocytes in alcoholic liver cell injury.

68. 4. Russell’s bodies representing excessive immunoglobulin in the rough endoplasmic reticulum of the plasma cells RUSSELL’S BODIES

69. EXTRACELLULAR HYALINE Extracellular hyaline commonly seen in connective tissues. A few examples of extracellular hyaline change are as under:

70. 1. Hyaline degeneration in leiomyomas of the uterus

71. 2. Hyalinised old scar of fibrocollagenous tissues. 3. Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes mellitus.

72. 3. MUCOID CHANGE/ DEGENERATION Mucoid means mucus-like Mucin (constituent of mucus) is a glycoprotein normally produced by epithelial cells of MUCUS MEMBRANES and MUCUS GLANDS and by some CONNECTIVE TISSUE (CT) cells. The mucin produced by CT cells is called MYXOID.

73. MUCUS GLANDS MUCUS

74. What is Mucoid Degeneration? Excessive mucus production by the Epithelial cells of mucous membranes and mucous glands (EPITHELIAL MUCIN) Connective tissues ( CONNECTIVE TISSUE MUCIN)

75. EPITHELIAL MUCIN Examples of functional excess of epithelial Mucin: Catarrhal inflammation of mucous membrane (e.g. of respiratory tract, alimentary tract). Cystic fibrosis of the pancreas/Lungs. Mucin-secreting tumors (e.g. of ovary, stomach, large bowel etc)

76. RESPIRATORY TRACT CATARRAL INFLAMMATION - EXCESS MUCUS PRODUCTION

77. CYSTIC FIBROSIS OF THE LUNGS.

78. CONNECTIVE TISSUE MUCIN Connective tissue mucin or myxoid change are as under: Mucoid or myxoid change in some tumours like fibroadenoma . Myxomatous change in the dermis in Myxoedema .

79. MYXOEDEMA

80. 4. FATTY DEGENERATION (STEATOSIS) Intracellular accumulation of neutral fat within parenchymal cells. Fatty change is particularly common in the liver but may occur in other non-fatty tissues as well e.g. in the heart, skeletal muscle, kidneys (lipoid nephrosis ) and other organs.

81. FATTY LIVER

82. MORPHOLOGY OF IRREVERSIBLE CELL INJURY (CELL DEATH)

83. Cell death is a state of irreversible injury. LOCALLY 1- AUTOLYSIS 2- NECROSIS 3- APOPTOSIS CHANGES FOLLOWING LOCAL CHANGE 1- GANGRENE 2- CALCIFICATION PROCESSES INVOLVED IN CELL DEATH

84. AUTOLYSIS ( self-digestion) Disintegration of the cell by its own hydrolytic enzymes liberated from Lysosomes RAPID in tissues rich in hydrolytic enzymes- PANCREAS, GASTRIC MUCOSA INTERMEDIATE in tissues like the HEART, LIVER AND KIDNEY SLOW in fibrous tissue. PACE OF AUTOLYSIS

85. NECROSIS Necrosis is defined as a localized area of death of tissue followed later by degradation/breakdown of tissue by hydrolytic enzymes liberated from dead cells; it is invariably accompanied by inflammatory reaction.

86. ETIOLOGICAL AGENTS: Hypoxia, Chemical Physical agents Microbial agents Immunological etc…

87. 5 TYPES OF NECROSIS: Coagulative Liquefaction (Colliquative) Caseous Fat Fibrinoid Necrosis Based on Etiology and Morphologic appearance

88. 1. COAGULATIVE NECROSIS Most common type of necrosis caused by irreversible focal injury. Cause: From sudden cessation of blood flow (ischemic necrosis) Less often from bacterial and chemical agents. The organs commonly affected are the heart, kidney, and spleen.

89. APPEARANCE GROSSLY/MACROSCOPICALLY Pale Firm Slightly swollen EARLY STAGE LATE STAGE Yellowish Softer Shrunken. INFARCT

90. MICROSCOPICALLY Hallmark of coagulative necrosis = ‘TOMB STONES’ i.e. outlines of the cells are retained and the cell type can still be recognized but their cytoplasmic and nuclear details are lost.

91. OTHER FINDINGS MICROSCOPICALLY: Nuclear changes of pyknosis , karyorrhexis and karyolysis Cell digestion and liquefaction fail to occur . Eventually, the necrosed focus is infiltrated by inflammatory cells and the dead cells are phagocytosed leaving granular debris and fragments of cells

92. 2. LIQUEFACTION (COLLIQUATIVE) NECROSIS Due to ischemic injury and bacterial or fungal infections Liquefaction is due to Hydrolytic enzymes. The common examples are infarct brain and abscess cavity.

93. Grossly, the affected area is soft with liquefied centre containing necrotic debris. Later, a cyst wall is formed.

94. Microscopically, the cystic space contains necrotic cell debris and macrophages filled with phagocytosed material. The cyst wall is formed by Proliferating capillaries, Inflammatory cells, and Gliosis (proliferating glial cells) in the case of brain and Abscess cavity - Proliferating fibroblasts

95. 3. CASEOUS NECROSIS Caseous (caseous= cheese-like) necrosis is found in the centre of foci of tuberculous infections. It combines features of both coagulative and liquefactive necrosis.

96. 4. FAT NECROSIS Fat necrosis is a special form of cell death occurring at mainly fat-rich anatomic locations in the body. Examples are: Traumatic fat necrosis of the breast, Mesenteric fat necrosis due to acute pancreatitis.

97. TRAUMATIC FAT NECROSIS OF BREAST

98. MESENTERIC FAT NECROSIS

99. In fat necrosis: HYDROLYSIS AND RUPTURE OF ADIPOCYTES CHANGES INTO GLYCEROL & FREE FATTY ACIDS. Free fatty acids complex with Calcium to form CALCIUM SOAPS (SAPONIFICATION) Release of neutral fat

100. SAPONIFICATION Fat necrosis appears as yellowish- white and firm Deposits. Formation of calcium soaps imparts the necrosed foci FIRMER AND CHALKY WHITE APPEARANCE.

101. 5. FIBRINOID NECROSIS Fibrinoid necrosis is characterized by deposition of fibrin-like material which has the staining properties of fibrin such as phosphotungistic acid haematoxylin (PTAH) stain. It is encountered in various examples of immunologic tissue injury. E.g. - Immune Complex Vasculitis Autoimmune Diseases Arthus Reaction Etc

102. APOPTOSIS

103. Apoptosis is a form of ‘coordinated and internally programmed cell death’ . When the cell is not needed, pathway of cell death is activated (‘cell suicide’). Unlike necrosis, apoptosis is not accompanied by any inflammation and collateral tissue damage.

104. APOPTOSIS IN BIOLOGIC PROCESSES Physiological apoptosis Pathological apoptosis

105. Physiologic Processes: Physiologic involution of cells in hormone-dependent tissues e.g. endometrial shedding, regression of lactating breast after withdrawal of breast-feeding. Normal cell destruction followed by replacement proliferation such as in intestinal epithelium. Involution of the thymus in early age.

106. Pathologic Processes: Cell death in tumors exposed to chemotherapeutic agents. Progressive depletion of CD4+T cells in the pathogenesis of AIDS. Pathologic atrophy of organs and tissues on withdrawal of stimuli e.g. prostatic atrophy after orchiectomy .

107. 5. Cell death in response to low dose of injurious agent involved in causation of necrosis e.g. radiation, hypoxia and mild thermal injury. 6. In degenerative diseases of CNS e.g. in Alzheimer’s disease, Parkinson’s disease, and chronic infective dementias. 7. Heart diseases e.g. in acute myocardial infarction (20% necrosis and 80% apoptosis).

108. MOLECULAR MECHANISMS OF APOPTOSIS Several physiologic and pathologic processes activate apoptosis in a variety of ways. Molecular events involved in apoptosis: 1- INITIATORS OF APOPTOSIS 2- INTIAL STEPS IN APOPTOSIS 3- FINAL PHASE OF APOPTOSIS 4- PHAGOCYTOSIS

109. 1. Initiators of apoptosis: All cells have inbuilt effector mechanisms for cell survival and signals of cell death. It is the loss of this balance that determines survival or death of a cell.

110. A cell may be initiated to programmed cell death by: Withdrawal of normal cell survival signals: e.g. absence of certain hormones, growth factors, cytokines . Agents of cell injury e.g. Heat, Radiation, Hypoxia, Toxins, Free Radicals . OR

111. 2. Initial steps in apoptosis After the cell has been initiated into self-destruct mode, Cell death signaling mechanisms gets activated from Intrinsic (mitochondrial) pathway Extrinsic (cell death receptor initiated) pathway. However, finally mediators of cell death are activated caspases. Caspases are a series of proteolytic or protein-splitting enzymes which act on nuclear proteins and organelles containing protein components.

112. Intrinsic (mitochondrial) pathway Increased mitochondrial permeability activates this pathway Cytochrome - c (protein) released from mitochondria into the cytoplasm of the cell Cytochrome - c triggers the cell into apoptosis. activates Caspases -9 APOPTOSIS

113. The major mechanism of regulation of this mitochondrial protein (Cytochrome- c) is by pro-apoptotic and anti-apoptotic members of Bcl proteins.

114. BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. BCL-2 proteins (Anti-apoptotic proteins) Bad Bim BH3-only proteins (Pro- apoptotic proteins)

115. Extrinsic (cell death receptor initiated) pathway It works by Activation of death receptors on the cell membrane. Cell Death Receptors are: Type 1 Tumour Necrosis Factor Receptor (TNF-R1) and a related transmembrane protein called Fas (CD95) and its ligand (FasL). (Fas belongs to TNF Receptor family)

116. TNFR1 Receptor TNF- α   (Death Ligand) Extracellular Intracellular Cell membrane ADAPTER Tumor Necrosis Factor Receptor Type 1-associated Death Domain (TRADD) Activation of Caspases 8 and 10 ADAPTER Fas-associated protein Death domain (FADD) Fas Receptor FasL (Ligand) APOPTOSIS

117. 3. Final phase of apoptosis The activated caspases have proteolytic action Proteolytic actions lead to Nucleus damage Chromatin clumping Cytoskeleton damage Disruption of endoplasmic reticulum Mitochondrial damage Disturbed cell membrane. CELL DEATH

118. 4. Phagocytosis Thrombospondin molecules Dead Apoptotic Cell Phosphatidylserine molecule phagocyte Phagocytosed dead cell

119. CHANGES AFTER CELL DEATH

120. Two types of pathologic changes may superimpose following cell injury: Gangrene (after necrosis) Pathologic calcification (after degenerations as well as necrosis).

121. GANGRENE Gangrene is Necrosis of tissue associated with superadded Putrefaction Combination of Coagulative necrosis, due to ischemia (dry gangrene); and Liquefactive necrosis (wet gangrene) if a bacterial infection is superimposed.

122. There are 2 main types of gangrene: Dry Gangrene Wet Gangrene, and - Gas gangrene- a variant of wet gangrene

123. Dry Gangrene This form of gangrene begins in the distal part of a limb due to ischemia. Seen in: 1. Severe atherosclerosis: causes dry gangrene in the toes and feet of an old patient.

124. 2. Buerger’s disease (thrombosis of artery due to smoking) 3. Ergot Poisoning . 4. Raynauds Disease.

125. It is usually initiated in one of the toes which is farthest from the blood supply, Dry gangrene is not accompanied by infection (containing so little blood that even the invading bacteria find it hard to grow in the necrosed tissue) The gangrene spreads slowly upwards until it reaches a point where the blood supply is adequate to keep the tissue viable.

126. A line of separation is formed at this point between the gangrenous part and the viable part

127. MORPHOLOGIC FEATURES DRY, SHRUNKEN AND DARK BLACK, resembling the foot of a mummy. Hemoglobin + Hydrogen disulfide (H2S) BLACK IRON SULFIDE. (produced by bacteria)

128. The line of separation usually brings about complete separation with eventual falling off of the gangrenous tissue if it is not removed surgically ( i.e. spontaneous amputation)

129. Wet Gangrene Wet gangrene usually develops due to blockage of both venous as well as arterial blood flow. More rapid. The affected part is saturated with stagnant blood, which promotes the rapid growth of bacteria. It is Dangerous: The toxic products formed by bacteria are absorbed, causing systemic manifestation of sepsis and finally death.

130. Wet gangrene occurs in naturally moist tissues and organs such as the bowel, lung, mouth, cervix, vulva etc. The spreading wet gangrene generally lacks clear-cut line of demarcation.

131. Examples: Diabetic foot which is due to high glucose content in the necrosed tissue which favors growth of bacteria. Bed sores occurring in a bed-ridden patient due to pressure on sites like the sacrum, buttocks and heel.

132. MORPHOLOGIC FEATURES Grossly : Soft, Swollen, Putrid, Rotten And Dark Dark black due to the same mechanism as in dry gangrene.

133. GAS GANGRENE Gas gangrene is a  bacterial infection that produces gas in gangrene tissue. Caused by gas-forming clostridia: (anaerobic bacteria) This deadly form of gangrene usually is caused by  Clostridium perfringens bacteria. 

134. Gross oedematous , painful and crepitant due to accumulation of gas bubbles of carbon dioxide within the tissues formed by fermentation of sugars by bacterial toxins. Dark black and is foul smelling.

135. PATHOLOGIC CALCIFICATION Deposition of calcium salts in tissues other than osteoid or enamel is called pathologic or heterotopic calcification. Two distinct types of pathologic calcification: 1- Dystrophic calcification 2- Metastatic calcification

136. Dystrophic calcification is characterized by deposition of calcium salts in dead or degenerated tissues with normal calcium metabolism and normal serum calcium level . Metastatic calcification, on the other hand, occurs in apparently normal tissues and associated with deranged calcium metabolism and hypercalcaemia.

137. DYSTROPHIC CALCIFICATION ETIOLOGY: Dystrophic calcification may occur due to 2 types of causes: 1- Calcification in Dead tissue 2- Calcification in Degenerated tissue.

138. 1. Calcification in Dead tissue Caseous necrosis in tuberculosis is the most common site for dystrophic calcification. Living bacilli may be present even in calcified tuberculous lesions

139. Liquefaction necrosis in chronic abscesses may get calcified.

140. Fat necrosis following acute pancreatitis or traumatic fat necrosis in the breast results in deposition of calcium soaps.

141. Gamna -Gandy bodies in chronic venous congestion (CVC) of the spleen is characterized by calcific deposits admixed with haemosiderin on fibrous tissue.

142. Infarcts may sometimes undergo dystrophic calcification.

143. Haematomas in the vicinity of bones may undergo dystrophic calcification

144. Dead parasites like in hydatid cyst, Schistosoma eggs, and cysticercosis are some of the examples showing dystrophic calcification.

145. cysticercosis

146. Microcalcification in breast cancer detected by mammography.

147. 2. Calcification in Degenerated tissues Atheromas in the aorta and coronaries frequently undergo calcification.

148. Mönckeberg’s sclerosis shows calcification in the degenerated tunica media of muscular arteries in elderly people

149. Calcinosis cutis is a condition of unknown cause in which there are irregular nodular deposits of calcium salts in the skin and subcutaneous tissue

150. Senile degenerative changes may be accompanied by dystrophic calcification Eg: pineal gland calcification

151. Pathogenesis of Dystrophic calcification In cell injury (Degeneration or Necrosis) Phosphatases breaks phospholipids of cell membrane and this causes release of phosphatases Damaged mitochondria increase Uptake of calcium into it. CALCIUM PHOSPHATES Precipitates as CALCIUM PHOSPHATES

152. METASTATIC CALCIFICATION Since metastatic calcification occurs in normal tissues due to hypercalcaemia include either of the following two groups of causes: Excessive mobilization of calcium from the bone. Excessive absorption of calcium from the gut.

153. 1. Excessive mobilization of calcium from the bone. Hyperparathyroidism:

154. Prolonged immobilization of a patient results in disuse atrophy of the bones and hypercalcaemia. Bony destructive lesions such as multiple myeloma.

155. 2. Excessive absorption of calcium from the gut. Less often, excess calcium may be absorbed from the gut causing hypercalcaemia and metastatic calcification. Causes: Hypervitaminosis D from excessive intake or Sarcoidosis Milk-alkali syndrome caused by excessive oral intake of calcium in the form of milk and administration of calcium carbonate in the treatment of peptic ulcer.

156. Sites of metastatic calcification: Metastatic calcification may occur in any normal tissue of the body but preferentially affects the following organs and tissues : Kidneys: especially at the basement membrane of tubular epithelium and in the tubular lumina causing nephrocalcinosis

157. Lungs: especially in the alveolar walls (Alveolar calcinosis )

158. Cornea Synovium

159. Pathogenesis of Metastatic Calcification Rapid changes in pH levels at tissues (of Lungs, Stomach, Kidney) Elevated Calcium ions Inorganic phosphate Ions (in serum) Excessive binding Formation of CALCIUM PHOSPHATE CALCIFICATION

160. Metastatic calcification is reversible upon correction of underlying metabolic disorder, but Dystrophic calcification is not reversible/Irreversible.