Cell Injury and Death PDF

CELL INJURY & DEATH Dr Leetesh Sewpaul Department of Anatomical Pathology Date: 20/01/2025 Learning Outcomes  Reversible vs irreversible cell injury  Necrosis: causes, mechanisms, morphology, clinical correlates  Apoptosis: causes, mechanisms, morphology, clinical c...

CELL INJURY & DEATH Dr Leetesh Sewpaul Department of Anatomical Pathology Date: 20/01/2025 Learning Outcomes  Reversible vs irreversible cell injury  Necrosis: causes, mechanisms, morphology, clinical correlates  Apoptosis: causes, mechanisms, morphology, clinical correlates  Distinguishing the differences between necrosis & apoptosis  Intracellular accumulations: clinical significance  Pigments: exogenous vs endogenous  Pathologic calcification: dystrophic vs metastatic DEFINITION Cell Injury: occurs when cells are stressed so severely that they are no longer able to adapt OR exposed to damaging agents OR suffer from intrinsic abnormalities REVERSIBLE CELL INJURY The functional and morphologic changes are reversible if the damaging stimulus is removed Hallmarks of reversible cell injury: Reduced oxidative phosphorylation Cellular swelling Alterations in organelles  REVERSIBLE CELL INJURY 2 morphological features on light microscopy: Cellular swelling (hydropic change) Fatty change REVERSIBLE CELL INJURY Cellular Swelling (hydropic change): First manifestation of cell injury. Caused by changes in ion concentrations and water influx. Appears whenever cells are incapable of maintaining ionic and fluid homeostasis. Result of failure of energy dependant pumps in the plasma membrane. REVERSIBLE CELL INJURY Macroscopic Features: If many cells in an organ are affected, the following features can be seen: Increased weight Increased turgor Pallor Microscopic Features: Small, clear vacuoles within cytoplasm Increased eosinophilia of the cytoplasm REVERSIBLE CELL INJURY Fatty Change (steatosis): Refers to the abnormal accumulation of lipid droplets (triglycerides) in the parenchymal cells of organs. Causes: Toxins Protein malnutrition Diabetes mellitus Obesity Hypoxia Alcohol REVERSIBLE CELL INJURY Example: FATTY LIVER In developed countries, alcohol abuse is the primary cause of fatty liver. Main causes of non-alcoholic fatty liver include diabetes and obesity. Macroscopic Findings: May not see anything if mild. If more severe the liver may appear enlarged, yellow or greasy. Microscopic Findings: Small vacuoles in the cytoplasm and around the nucleus of hepatocytes. IRREVERSIBLE INJURY With continuing damage the injury becomes irreversible, at which time the cell cannot recover and it dies It is difficult to pinpoint the exact time where reversible becomes irreversible Two phenomena consistently characterize irreversibility: Inability to reverse mitochondrial dysfunction Profound disturbances in membrane function MECHANISMS OF CELL INJURY Depletion of ATP Mitochondrial damage Calcium influx Oxidative stress (accumulation of ROS) Defects in membrane permeability Damage to DNA & proteins CAUSES OF CELL INJURY Oxygen deprivation Physical agents Chemical agents & drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances CAUSES OF CELL INJURY Oxygen Deprivation Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration. Causes of hypoxia: Reduced blood flow (ischemia). Inadequate oxygenation of the blood (cardiorespiratory failure). Decreased oxygen-carrying capacity of the blood (anemia, carbon monoxide poisoning). CAUSES OF CELL INJURY Physical Agents Mechanical trauma Extremes of temperature (burns and deep cold) Sudden changes in atmospheric pressure Radiation Electric shock CAUSES OF CELL INJURY Chemical Agents and Drugs Simple chemicals such as glucose or salt in abnormal concentrations (high or low) may injure cells directly or by deranging electrolyte balance in cells. Trace amounts of poisons (arsenic, cyanide, or mercuric salts) may damage sufficient numbers of cells within minutes or hours to cause death. Other: Environmental and air pollutants, insecticides, and herbicides Industrial occupational hazards (carbon monoxide and asbestos) Recreational drugs Therapeutic drugs CAUSES OF CELL INJURY Infectious Agents Includes viruses, rickettsiae, bacteria, fungi, parasites. Immunological Reactions Serves an essential function in defense against infectious pathogens. Immune reactions may also cause cell injury (e.g. autoimmune diseases and responses to pathogens). CAUSES OF CELL INJURY Genetic Derangements Different mechanisms: Deficiency of functional proteins, such as enzyme defects in inborn errors of metabolism. Accumulation of damaged DNA or misfolded proteins. Nutritional Imbalances e.g. Deficiencies of specific vitamins, self-imposed (anorexia nervosa), nutritional excesses (cholesterol predisposes to atherosclerosis) IRREVERSIBLE INJURY It is difficult to pinpoint the exact time where reversible becomes irreversible Two phenomena consistently characterize irreversibility: Irreversible mitochondrial dysfunction Profound disturbances in membrane function NECROSIS Definition: the death of tissues following bioenergetic failure & loss of plasma membrane integrity NECROSIS - MORPHOLOGY Cytoplasm Increased eosinophilia Glassy & homogenous Vacuolated, moth-eaten NECROSIS - MORPHOLOGY Nucleus Karyolysis Pyknosis Karyorrhexis https://theartofmed.wordpress.com/2015/05/29/pathologic-cell- injury-and-cell-death-ii-necrosis/ 034/01/2018 NECROSIS - TYPES Coagulative Liquefactive Caseous Fibrinoid Fat necrosis Gangrene NECROSIS - COAGULATIVE Architecture preserved for days Anucleate eosinophilic cells Enzymes are denatured preventing proteolysis of dead cells Localised area of coagulative necrosis = infarct NECROSIS - LIQUEFACTIVE Transformation of the tissue into a liquid viscous mass Occurs in the brain because of a lack of supporting stroma & high lipid content Also occurs with infections (proteolysis by leukocytes) NECROSIS - CASEOUS Most often in TB Refers to gross appearance Microscopically: amorphous eosinophilic granular debris FIBRINOID Seen in immune reactions involving blood vessels & malignant hypertension Circumferential, deeply eosinophilic, amorphous appearance of blood vessel wall FIBRINOID Example: Malignant hypertension: Arterioles are under a lot of pressure  necrosis of the smooth muscle wall  seepage of plasma into the media with subsequent deposition of fibrin  fibrinoid necrosis. NECROSIS – FAT NECROSIS May occur with direct trauma eg. Fat necrosis of the breast Or with the release of lipases eg. pancreatitis NECROSIS - GANGRENOUS Coagulative necrosis (ischaemia) with superimposed bacterial infection resulting in putrefaction Infarction of mixed tissues in bulk Often occurs in the lower limbs https://www.news- medical.net/health/What-is- and bowel gangrene.aspx 04/01/2018 May be wet or dry APOPTOSIS Definition: a pathway of cell death induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells own DNA & proteins APOPTOSIS - CAUSES Physiologic Pathologic Destruction of cells during DNA damage embryogenesis Accumulation of misfolded proteins Involution of hormone-dependent tissues upon hormone withdrawal Cell death in certain infections Cell loss in proliferating cell populations Pathologic atrophy in parenchymal Elimination of potentially self-reactive organs after duct obstruction lymphocytes Death of host cells that have served their useful purpose APOPTOSIS – MORPHOLOGY Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs & apoptotic bodies Phagocytosis of apoptotic bodies Appears as a mass of intensely eosinophilic cytoplasm with fragments of dense nuclear chromatin APOPTOSIS - MECHANISMS Two pathways: Involves the activation of Intrinsic (mitochondrial) caspases Extrinsic (death-receptor Interactions between mediated) sensors ,pro-apoptotic & Two phases: anti-apoptotic molecules Initiation Execution APOPTOSIS – CLINICAL CORRELATES Decreased apoptosis Increased apoptosis Malignancy Neurodegenerative diseases Autoimmune diseases Death of virus-infected cells NECROSIS VS APOPTOSIS FEATURE NECROSIS APOPTOSIS Induction Invariably pathologic Physiologic or pathologic Extent Cell groups Single cells Biochemical events Energy failure Energy dependent Cell size Swelling Shrinking Plasma membrane Disrupted Intact, altered structure Cellular contents Leakage Intact Nucleus Karyolysis/karyorrhexis/ Fragmentation into pyknosis nucleosome-size fragments Inflammation Frequent None AUTOPHAGY Definition: A process in which a cell eats its own contents AUTOPHAGY Can be physiologic or Cancer pathologic Neurodegenerative Aging, exercise, atrophy diseases Maintains cellular integrity Infectious diseases under stress conditions Inflammatory bowel diseases INTRACELLULAR ACCUMULATIONS Accumulations of abnormal Can be reversible or amounts of substances progressive leading to cell within a cell injury & death May be within the cytoplasm, nucleus, other organelles INTRACELLULAR ACCUMULATIONS Lipids Steatosis (fatty change) Cholesterol & cholesterol esters (atherosclerosis) INTRACELLULAR ACCUMULATIONS Proteins: appear as rounded eosinophilic droplets, vacuoles or aggregates within the cytoplasm Eg. amyloid INTRACELLULAR ACCUMULATIONS Glycogen: appears as clear vacuoles within the cytoplasm Diabetes mellitus, glycogen storage diseases PIGMENTS Coloured substances Some are normal constituents of cells Others are abnormal https://za.pinterest.com/pin/365565694735749845/?lp=true May be exogenous or 03/01/2018 endogenous PIGMENTS Exogenous Carbon (coal dust): anthracosis Tattooing PIGMENTS Endogenous Lipofuscin Melanin Haemosiderin http://www.clinicaladvisor.com/pediatrics/diffuse-alveolar- hemorrhage/article/622562/ 03/01/2018 PATHOLOGIC CALCIFICATION The abnormal tissue Two types: deposition of calcium salts, Dystrophic together with smaller Metastatic amounts of other mineral salts PATHOLOGIC CALCIFICATION - DYSTROPHIC Occurs locally in diseased or necrotic tissue Advanced atherosclerosis, aging/damaged heart valves Normal serum calcium; normal calcium metabolism PATHOLOGIC CALCIFICATION - METASTATIC Occurs in normal tissues Increased PTH secretion Hypercalcaemia Resorption of bone Altered calcium metabolism Vitamin D-related disorders Renal failure References 1. Kumar V, Abbas AK, FaustoN, Aster JC, editors. Robbins and CotranPathologic Basis of Disease. 10thEdition. Philadelphia: Saunders Elsevier; 2020. 2. General & Systemic Pathology, 5th Edition. J.C.E Underwood & S.S Cross 3. Muir’s Textbook of Pathology, 15th Edition. C. Simon Herrington 4. Underwood JCE, Cross SS, editors. General and Systematic Pathology. 5thEdition. London: Churchill Livingstone Elsevier; 2009.