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Cell injury


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Cell Injury

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Cell injury

  1. 1. Cell InjuryCell Injury Dr. Deepak Kr. Gupta
  2. 2. Introduction • Cell injury is defined as a variety of stresses a cell encounters as a result of changes in its internal and external environment. • Virchow’s Cellular theory of disease (1859): diseases occur due to abnormalities at the leveldiseases occur due to abnormalities at the level of cells • The cellular response to stress may vary and depends upon the following: – The type of cell and tissue involved. – Extent and type of cell injury
  3. 3. Cellular Response
  4. 4. ETIOLOGY OF CELL INJURY Genetic causes • Developmental defects: Errors in morphogenesis • Cytogenetic (Karyotypic) defects: chromosomal Acquired causes • Hypoxia and ischaemia • Physical agents • Chemical agents and drugs • Microbial agentsdefects: chromosomal abnormalities • Single-gene defects: Mendelian disorders • Multifactorial inheritance disorders • Microbial agents • Immunologic agents • Nutritional derangements • Aging • Psychogenic diseases • Iatrogenic factors • Idiopathic diseases.
  5. 5. Acquired causesAcquired causes
  6. 6. Oxygen deprivationOxygen deprivation HYPOXIAHYPOXIA Ischemia ( loss of blood supply ). Inadequate oxygenation (cardiorespiratory failure).(cardiorespiratory failure). Loss of oxygen carrying capacity of the blood ( anemia or CO poisoning ).
  7. 7. HYPOXIC INJURYHYPOXIC INJURY Loss of oxidative phosphorylation and ATP generation by mitochondria. Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis.resulting in aerobic glycolysis. Depleted glycogen. Reduced intracellular pH: Lactic acid and inorganic phosphate. Clumping of nuclear chromatin.
  8. 8. PHYSICAL AGENTS TraumaTrauma HeatHeat ColdColdColdCold RadiationRadiation Electric shockElectric shock
  9. 9. CHEMICAL AGENTS AND DRUGS •Endogenous products: urea •Exogenous agents Therapeutic drugs: hormones•Therapeutic drugs: hormones •Nontherapeutic agents: lead or alcohol
  10. 10. FREE RADICAL INITIATION Absorption of energy (UV light and x-rays) Oxidative metabolic reactions Enzymatic conversion of exogenousEnzymatic conversion of exogenous chemicals or drugs (CCl4>CCl3 .) Oxygen-derived radicals Superoxide
  11. 11. INFECTIOUS AGENTS VirusesViruses RickettsiaeRickettsiaeRickettsiaeRickettsiae BacteriaBacteria FungiFungi ParasitesParasites
  12. 12. Abnormal immunological reactions The immune process is normally protective but in certain circumstances the reaction may become deranged. – Hypersensitivity to various substances can lead to– Hypersensitivity to various substances can lead to anaphylaxis or to more localized lesions such as asthma. – In other circumstances the immune process may act against the body cells - autoimmunity.
  13. 13. Nutritional imbalances  Protein-calorie deficiencies are the most examples of nutrition deficiencies.  Vitamins deficiency.  Excess in nutrition are important causes of morbidity and mortality.morbidity and mortality.  Excess calories and diet rich in animal fat are now strongly implicated in the development of atherosclerosis.  Obesity alone leads to an increased vulnerability to certain disorders, such as atherosclerosis, coronary heart disease, diabetes mellitus
  14. 14. Aging • Programmed aging whereby after a defined number of divisions the cell undergoes terminal differentiation. • Development of an increasing population of cells irreversibly committed to senescencecells irreversibly committed to senescence and death. • Increased susceptibility to somatic mutation and a build-up of errors leading to an eventual’ error catastrophe. • Faulty DNA repair mechanisms.
  15. 15. CELLS REACT TO ADVERSE INFLUENCES  Cellular adaptation 1. Hyperplasia 2. Hypertrophy 3. Atrophy 4. Metaplasia 5. Dysplasia  Reversible injury Reversible injury 1. intracellular edema, 2. fatty change, 3. hyaline change, 4. amyloidosis, 5. mucoid degeneration, 6. pathologic pigments  Irreversible injury and dying: Necrosis, Gangrene followed by pathological calcification
  18. 18. Cellular ADAPTATION • Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment • Cells must constantly adapt, even under normal• Cells must constantly adapt, even under normal conditions, to changes in their environment. • These physiological adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical substances. – For example, as in the enlargement of the breast and induction of lactation by pregnancy.
  19. 19. Types of Adaptation • Pathologic adaptations may share the same underlying mechanisms, but they provide the cells with the ability to survive in their environment and perhaps escape injury.environment and perhaps escape injury. • Cellular adaptation is a state that lies intermediate between the normal, unstressed cell and the injured, overstressed cell.
  20. 20. Cellular Adaptation • Cell can adapt themselves by undergoing 5 different conditions 1. Hyperplasia 2. Hypertrophy2. Hypertrophy 3. Atrophy 4. Metaplasia 5. Dysplasia
  21. 21.
  22. 22. Hyperplasia An increase in theAn increase in the number of cells innumber of cells in an organ or tissue,an organ or tissue, which may thenwhich may thenwhich may thenwhich may then have increasedhave increased volume.volume.
  23. 23. Types of Hyperplasia : Physiological a. Hormonal : influence of hormonal stimulation • hyperplasiahyperplasia ofof thethe femalefemale breastbreast epitheliumepithelium atat pubertypuberty oror inin pregnancypregnancy.. • pregnant uterus • normal endometrium after a normal menstrual cycle. • Prostatic hyperplasia in old age• Prostatic hyperplasia in old age b. Compensatory: hyperplasia occurring following removal of part of an organ or a contralateral organ in paired organ • Regeneration of the liver following partial hepatectomy • Regeneration of epidermis after skin abrasion • Following nephrectomy on one side, there is hyperplasia of nephrons of the other kidney.
  24. 24. Types of Hyperplasia : Pathological • Excessive stimulation of hormones or growth factors – Endometrial hyperplasia – wound healing - of granulation tissue due to– wound healing - of granulation tissue due to proliferation of fibroblasts and endothelial cells. – skin warts from hyperplasia of epidermis due to human papilloma virus. – Pseudocarcinomatous hyperplasia of the skin
  25. 25. Hypertrophy Definition: An increase in the size of cells, and with such change, an increase in the size of the organ. Types: •• Physiologic:Physiologic: physiologic growth of the uterus during pregnancy involves both hypertrophy andduring pregnancy involves both hypertrophy and hyperplasia. • Pathologic causes: increased workload, hormonal stimulation and growth factors stimulation. • hypertrophy of heart the most common stimulus is chronic hemodynamic overload
  26. 26. Hypertrophied heart (From ROBBINS BASIC PATHOLOGY,2003)
  27. 27. Physiologic hypertrophy of the uterus during pregnancy.A, gross appearance of aPhysiologic hypertrophy of the uterus during pregnancy.A, gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed for postpartumnormal uterus (right) and a gravid uterus (left) that was removed for postpartum bleeding,bleeding, Normal uterusNormal uterus gravid uterusgravid uterus (From ROBBINS BASIC PATHOLOGY,2003)
  28. 28. The relationship between hyperplasia and hypertrophy: Although hypertrophy and hyperplasia are two distinct processes, frequently bothtwo distinct processes, frequently both occur together, and they well be triggered by the same mechanism.
  29. 29. Atrophy Definition: Acquired loss of size due to reduction of cell size or number of parenchyma cells in an organ Types: PhysiologicPhysiologic oror PathologicalPathological Left Normal Right Atrophy
  30. 30. Physiologic atrophy • A normal process of aging in some tissues, which could be due to loss of endocrine stimulation or arteriosclerosis.arteriosclerosis. – Atrophy of lymphoid tissue in lymph nodes, appendix and thymus. – Atrophy of gonads after menopause. – Atrophy of brain with aging.
  31. 31. Pathologic atrophy. • Starvation atrophy. • Ischaemic atrophy • Disuse atrophy. • Neuropathic atrophy.• Neuropathic atrophy. • Endocrine atrophy • Pressure atrophy. • Idiopathic atrophy
  32. 32. Metaplasia Definition: Metaplasia is a reversible change in which one adult cell type is replaced by another adult cell type. CausesCauses • Changes in environment • Irritation or inflammation • Nutritional
  33. 33. Types of Metaplasia • There are basically 2 types of metaplasia • EPITHELIAL METAPLASIA – Squamous metaplasia: changes in bronchus, uterine endocervix, gallbladder, prostate, renal pelvis and urinary bladder • vitamin A deficiency: squamous metaplasia in the nose, bronchi,• vitamin A deficiency: squamous metaplasia in the nose, bronchi, urinary tract, lacrimal and salivary glands – Columnar metaplasia: Intestinal metaplasia in healed chronic gastric ulcer and Barrett’s oesophagus • MESENCHYMAL METAPLASIA – Osseous metaplasia. – Cartilaginous metaplasia.
  34. 34. Squamous metaplasia in bronchitis (offered by Prof.Orr)
  35. 35. Schematic diagram of columnar to squamous metaplasia ((FromFrom ROBBINS BASIC PATHOLOGYROBBINS BASIC PATHOLOGY,,20032003))
  36. 36. DYSPLASIA • disordered cellular development. • also referred to as atypical hyperplasia • Epithelial dysplasia is characterised by cellular proliferation and cytologic changes – Increased number of layers of epithelial cells – Disorderly arrangement of cells from basal layer to the surface layer – Disorderly arrangement of cells from basal layer to the surface layer – Loss of basal polarity i.e. nuclei lying away from basement membrane – Cellular and nuclear pleomorphism – Increased nucleocytoplasmic ratio – Nuclear hyperchromatism – Increased mitotic activity. • The two most common examples of dysplastic changes are the uterine cervix and respiratory tract
  37. 37. Differences between Metaplasia and Dysplasia.
  38. 38. Reversible Injury • Intracellular edema, • Fatty change, • Hyaline change, • Amyloidosis,• Amyloidosis, • Mucoid Degeneration, • Pathologic Pigments
  39. 39. Intracellular edema • Also known as cloudy swelling. • Accumulation of watery fluid in cells. • Commonest and earliest form of cell injury • Caused by bacterial toxins, chemicals, poisons, burns, high fever, intravenous administration of hypertonichigh fever, intravenous administration of hypertonic glucose or saline. • Impaired regulation of sodium and potassium at the level of cell membrane. • Morphologic change • Gross features: cloudy swelling • M/S Changes: Parenchymal cells swollen.
  40. 40. Left Granularity change in kidney Right Hydropic change
  41. 41. Fatty change Definition: There is the accumulation of fat in non-fatty cells. • Also known as steatosis Morphologic change:Morphologic change: •• Gross features:Gross features: The organ enlarges and becomes yellow, soft, and greasy. •• M/S:M/S: An Fatty change appears as clear vacuoles within parenchymal cells.
  42. 42. Fatty change: Liver • Since this organ plays a central role in fat metabolism, • The accumulation of fat in toxic conditions can be very dangerous.dangerous. • Depending upon the cause and amount of accumulation, fatty change may be • mild and reversible, • or severe producing irreversible cell injury and cell death
  43. 43. Etiology • Conditions with excess fat – Obesity – Diabetes mellitus – Congenital hyperlipidaemia • Liver cell damage: – Alcoholic liver disease (most common) – Starvation– Starvation – Protein calorie malnutrition – Chronic illnesses (e.g. tuberculosis) – Acute fatty liver in late pregnancy – Hypoxia (e.g. anaemia, cardiac failure) – Hepatotoxins (e.g. carbon tetrachloride, chloroform, ether, aflatoxins and other poisons) – Drug-induced liver cell injury (e.g. administration of methotrexate, steroids, CCl4, halothane anaesthetic, tetracycline etc) – Reye’s syndrome
  44. 44. MORPHOLOGIC FEATURES • Grossly – the liver in fatty change is enlarged with a tense, glistening capsule and rounded margins. – The cut surface bulges slightly– The cut surface bulges slightly and is pale-yellow to yellow and is greasy to touch • Microscopically – characteristic feature is the presence of numerous lipid vacuoles in the cytoplasm of hepatocytes.
  45. 45. Fatty change: Heart • It occurs in two patterns, • Prolonged moderate hypoxia causes intracellular deposits of fat, • grossly apparent bands of yellowed• grossly apparent bands of yellowed myocardium alterations with bands of darker, red-brown, uninvolved myocardium (tigered effect). • Profound hypoxia or diphtheritic myocarditis, the myocardial cells are uniformly
  46. 46. tigered effect Prof. (From CIBA PHARMACEUTICAL PRODUCTS, INC. 1948)
  47. 47. Fatty change: Kidney •• In most cases fatty change is confined to the epithelium of the convoluted tubules, • but in severe poisoning it may affect all structures including the glomerule. Causes:  Poisons. e. g. carbon tetrachloride, phosphorus (liver) Poisons. e. g. carbon tetrachloride, phosphorus (liver)  Chronic alcoholism (liver)  Infections  Congestive cardiac failure  Severe anaemia  Ischaemia  Diabetes mellitus  Malnutrition and wasting disease.
  48. 48. Hyaline change • Not a distinct chemical entity. • Various histological or cytological alterations characterized by homogeneous, glasslikehomogeneous, glasslike appearance in hematoxylin and eosin- stained sections. • It may be intracellular or extracellular. Hyalinization Arteriolar Sclerosis
  49. 49. INTRACELLULAR HYALINE • Its mainly seen in epithelial cells. • Hyaline droplets in the proximal tubular epithelial cells: excessive reabsorption of plasma proteins. • Hyaline degeneration of rectus abdominalis muscle called Zenker’s degeneration, occurring in typhoid fever.Zenker’s degeneration, occurring in typhoid fever. • Mallory’s hyaline represents aggregates of intermediate filaments in the hepatocytes in alcoholic liver cell injury. • Nuclear or cytoplasmic hyaline inclusions seen in some viral infections. • Russell’s bodies representing excessive immunoglobulins in the rough endoplasmic reticulum of the plasma cells
  50. 50. INTRACELLULAR HYALINE Intracellular hyaline as Russell’s bodies in the plasma cells. The cytoplasm showscytoplasm shows pink homogeneous globular material due to accumulated immunoglobulins.
  51. 51. EXTRACELLULAR HYALINE • Extracellular hyaline is seen in connective tissues. • A few examples of extracellular hyaline change are as under: – Hyaline degeneration in leiomyomas of the uterus – Hyalinised old scar of fibro-collagenous tissues.– Hyalinised old scar of fibro-collagenous tissues. – Hyaline arteriolosclerosis in renal vessels in hypertension and diabetes mellitus. – Hyalinised glomeruli in chronic glomerulonephritis. – Corpora amylacea are rounded masses of concentric hyaline laminae seen in the prostate in the elderly, in the brain and in the spinal cord in old age, and in old infarcts of the lung.
  52. 52. Extracellular Hyaline Extracellular hyaline deposit in leiomyoma uterus. The centres ofleiomyoma uterus. The centres of whorls of smooth muscle and connective tissue show pink homogeneous hyaline material (connective tissue hyaline)
  53. 53.
  54. 54. Mucoid degeneration • Mucus containing mucin (glycoprotein) secreted by mucous glands. • In certain cellular injur, there is change characterized by accumulation of mucin in intracellular or extracellular loci. • Epithelial• Epithelial – composed of sialomucin plus neutral mucopolysaccharide. – May accumulate in intracellular or extracellular (if secreted) locations. • Connective tissue – predominantly acid mucopolysaccharide, sulfated or carboxylated
  55. 55. EPITHELIAL MUCIN • Following are some examples of functional excess of epithelial mucin: • Catarrhal inflammation of mucous membrane (e.g. of respiratory tract, alimentary tract, uterus).uterus). • Obstruction of duct leading to mucocele in the oral cavity and gallbladder. • Cystic fibrosis of the pancreas. • Mucin-secreting tumours (e.g. of ovary, stomach, large bowel etc)
  56. 56. Epithelial mucin Mucinous cystadenoma of the ovary showingof the ovary showing intracytoplasmic mucinous material in the epithelial cells lining the cyst
  57. 57. CONNECTIVE TISSUE MUCIN • A few examples of disturbances of connective tissue mucin are as under – Mucoid or myxoid degeneration in some tumours e.g. myxomas, neurofibromas, fibroadenoma, soft tissue sarcomas etc myxomas, neurofibromas, fibroadenoma, soft tissue sarcomas etc – Dissecting aneurysm of the aorta due to Erdheim’s medial degeneration and Marfan’s syndrome. – Myxomatous change in the dermis in myxoedema. – Myxoid change in the synovium in ganglion on the wris
  58. 58. Connective tissue mucin Myxoid change inMyxoid change in neurofibroma
  59. 59. Amyloid degeneration • Extracellular deposition of fibrillar proteinaceous substance called amyloid – a ‘waxy substance’ composed essentially of an abnormal proteinprotein – Particularly around the supporting fibres of blood vessels and basement membranes. • Associated with a number of inherited and inflammatory disorders Primary Amyloidosis of kidneys
  60. 60. Structure of Amyloid Electron micrograph of 7.5-10 nm amyloid fibrils. Congo red staining shows an apple-green birefringence under polarized light, a diagnostic feature of amyloid.
  61. 61. Types of Amyloid • Based on the biochemical analysis, its composed of 2 main types of complex proteins. • Fibril proteins: comprise about 95% of amyloid. – AL (amyloid light chain) protein – AA (amyloid associated) protein – Other proteins (Transthyretin (TTR), Aβ2-microglobulin (Aβ2M), β-amyloid protein (Aβ), Immunoglobulin heavy chain – Other proteins (Transthyretin (TTR), Aβ2-microglobulin (Aβ2M), β-amyloid protein (Aβ), Immunoglobulin heavy chain amyloid (AH)) • Non-fibrillar components: which include P-component predominantly; constitute the remaining 5% of amyloid – Amyloid P (AP)-component – Apolipoprotein-E (apoE) – α-1 anti-chymotrypsin. – Protein X.
  62. 62. PATHOGENESIS OF AMYLOIDOSIS • Result of immunologic mechanisms. • Multifactorial and that different mechanisms are involved in different types of amyloid. • Fundamentally a disorder of protein misfolding. • Fundamentally a disorder of protein misfolding. • More than 20 (at last count, 23) different proteins can aggregate and form fibrils with the appearance of amyloid • The dye Congo red binds to these fibrils and produces a red-green dichroism (birefringence) – commonly used to identify amyloid desposits in tissues
  64. 64. CLASSIFICATION OF AMYLOIDOSIS • Based on cause – Primary : with unknown cause and the deposition is in the disease itself – Secondary: as a complication of some underlying known disease • Based on extent of amyloid deposition – Systemic (generalised) involving multiple organs– Systemic (generalised) involving multiple organs – Localised amyloidosis involving one or two organs or sites • Based on histological basis – Pericollagenous: corresponding in distribution to primary amyloidosis – Perireticulin: corresponding in distribution to secondary amyloidosis
  65. 65. CLASSIFICATION OF AMYLOIDOSIS • Based on clinical location, – Pattern I: involving tongue, heart, bowel, skeletal and smooth muscle, skin and nerves), – Pattern II: principally involving liver, spleen, kidney and adrenals – Mixed pattern : involving sites of both pattern I and II– Mixed pattern : involving sites of both pattern I and II • Based on tissues in which amyloid is deposited, – Mesenchymal : organs derived from mesoderm – Parenchymal: organs derived from ectoderm and endoderm • Based on precursor biochemical proteins, into specific type of serum amyloid proteins.
  66. 66. CLASSIFICATION OF AMYLOIDOSIS (AL= Amyloid light chain; AA= Amyloid-associated protein; Aβ2M= Amyloid β2- microglobulin; ATTR= Amyloid transthyretin; APrP=Amyloid of prion proteins, Aβ= β- amyloid protein).
  67. 67. STAINING CHARACTERISTICS OF AMYLOID • STAIN ON GROSS – Virchow – frozen/paraffin section – Lugol’s iodine imparts mahogany brown colour to the amyloidthe amyloid – on addition of dilute sulfuric acid turns blue. • H & E – extracellular, homogeneous, structureless – Eosinophilic hyaline material, especially in relation to blood vessels
  68. 68. DIAGNOSIS OF AMYLOIDOSIS • BIOPSY EXAMINATION: commonest and confirmatory method for diagnosis in a suspected case of amyloidosis. • IN VIVO CONGO RED TEST: confirmatory• IN VIVO CONGO RED TEST: confirmatory • OTHER TESTS – supportive of amyloid disease – electrophoresis, immunoelectrophoresis of urine and serum, and bone marrow aspiration
  69. 69. Pathological effects of Amyloidosis AMYLOID DEPOSITION Pressure on adjacent cells Blood vessels Pressure on adjacent cells Blood vessels Atrophy Narrowing Increased permeability Transudation of protein out of vessels
  70. 70. MORPHOLOGIC FEATURES OF AMYLOIDOSIS OF ORGANS • Different organs shows variation in morphologic pattern, some features are applicable in general to most of the involved organs • Most commonly amyloid deposits appear at the contacts between the vascular spaces and parenchymal cells • Grossly• Grossly – affected organ is usually enlarged, pale and rubbery – Cut surface shows firm, waxy and translucent parenchyma – positive staining with the iodine test. • Microscopically – the deposits of amyloid are found in the extracellular locations, initially in the walls of small blood vessels producing microscopic changes and effects, – the deposits are in large amounts causing macroscopic changes and effects of pressure atrophy.
  71. 71. Amyloidosis of kidney The kidney is small and pale in colour. Sectioned surfaceSectioned surface shows loss of cortico- medullary distinction (arrow) and pale, waxy translucency.
  72. 72. Amyloidosis of kidney The amyloid deposits are seen mainly in the glomerular capillary tuft. The deposits are also present in peritubular connective tissue producing atrophic tubules and amyloid casts in the tubular lumina, and in the arterial wall producing luminal narrowing.
  73. 73. Amyloidosis of the spleen
  74. 74. Lardaceous amyloidosis of the spleen The sectioned surface shows presence of plae waxy translucency in a map-liketranslucency in a map-like pattern
  75. 75. Amyloidosis spleen A, The pink acellular amyloid material is seen in the red pulp causing atrophy of while pulp. B, Congo red staining shows Congophilia as seen by red-pink colour. C, When viewed under polarising microscopy the corresponding area shows apple-green birefringence.
  76. 76. Amyloidosis of the liver A, The deposition is extensive in the space of Disse causing compression and pressure atrophy of hepatocytes. B, Congo red staining shows congophilia which under polarising microscopy. C, shows apple-green birefringence.
  77. 77. Pathologic Pigments • Pigments are coloured substances present in most living beings including humans.including humans. • There are 2 broad categories of pigments: endogenous and exogenous.
  78. 78. Endogenous Pigmentation • Melanin – Generalised hyperpigmentation: Addison’s disease, Chloasma, chronic arsenical poisoning – Focal hyperpigmentation: Cäfe-au-lait spots, Peutz- Jeghers syndrome, Melanosis • Melanin-like pigment – Alkaptonuria – Dubin-Johnson syndrome • Haemoprotein-derived pigments – Haemosiderin – Acid haematin (Haemozoin)Jeghers syndrome, Melanosis coli, Melanotic tumours, Lentigo , Dermatopathic lymphadenitis – Generalised hypopigmentation: Albinism – Localised hypopigmentation: Leucoderma, Vitiligo , Acquired focal hypopigmentation, leprosy, healing of wounds, DLE, radiation dermatitis – Acid haematin (Haemozoin) – Bilirubin – Porphyrins • Lipofuscin (Wear and tear pigment)
  79. 79. Endogenous Pigmentation Brown atrophy of the heart. The lipofuscin pigment granules are seen in the cytoplasm of the myocardial fibres, especially around the nuclei.
  80. 80. Endogenous Pigmentation Compound naevus showing clusters of benign naevus cells in the dermis as well as in lower epidermis. These cells contain coarse, granular, brown-black melanin pigment
  81. 81. EXOGENOUS PIGMENTS • Inhaled pigments – Atmospheric pollutants and of smokers – Pneumoconiosis: occupational lung diseases – Anthracosis: deposition of coal • Ingested pigments – Argyria : silver compounds - brownish pigmentation in the skin, bowel, and kidney. – Argyria : silver compounds - brownish pigmentation in the skin, bowel, and kidney. – Burtonian Lines: Chronic lead poisoning - blue lines on teeth at the gumline. – Melanosis coli : cathartics (stimulates evacuation of the bowels) – Carotenaemia: yellowish-red colouration of the skin - ingestion of carrots which contain carotene. • Injected pigments (Tattooing): India ink, cinnabar and carbon deposited in dermis
  82. 82. EXOGENOUS PIGMENTS Anthracosis lung: There is presence of abundant coarse black carbon pigment in the septal walls and around the bronchiole
  83. 83. Irreversible InjuryIrreversible Injury
  84. 84. Irreversible Injury • Cell death is a state of irreversible injury, • It may occur in the living body as a local or focal change: autolysis, necrosis and apoptosis • The changes that follow it: gangrene and• The changes that follow it: gangrene and pathologic calcification
  85. 85. NECROSIS • Defined as a localised area of death of tissue followed by degradation of tissue by hydrolytic enzymes liberated from dead cells. • It is invariably accompanied by inflammatory reaction. Various agents such as hypoxia, chemical and• Various agents such as hypoxia, chemical and physical agents, microbial agents, immunological injury, etc • Two essential changes characterise irreversible cell injury in necrosis of all types – Cell digestion by lytic enzymes – Denaturation of proteins
  86. 86. Types of Necrosis Morphologically, there are five types of necrosis • Cogulative • Liquefaction• Liquefaction • Caseous • Fat • Fibrinoid
  87. 87. COAGULATIVE NECROSIS • It’s a form of tissue necrosis in which the component cells are dead but the basic tissue architecture is preserved for at least several days. • The affected tissues take on a firm texture • Presumably the injury denatures not only• Presumably the injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells – as a result, eosinophilic, anucleate cells may persist for days or weeks – Ultimately, the necrotic cells are removed by phagocytosis of the cellular debris.
  88. 88. COAGULATIVE NECROSIS • Most common type of necrosis • Mostly from sudden cessation of blood flow (ischaemia) • Less often from bacterial and• Less often from bacterial and chemical agents. • It’s characteristic of infarcts (areas of ischemic necrosis) in all solid organs except the brain. • The organs commonly affected are the heart, kidney, and spleen Coagulative necrosis of the left ventricular wall
  89. 89. Morphology • Gross – foci of coagulative necrosis in the early stage are pale, firm, and slightly swollen. – With progression, they become more yellowish, softer, and shrunken. • Microscopically – the hallmark of coagulative necrosis - the conversion of normal cells into their ‘tombstones’cells into their ‘tombstones’ • outlines of the cells are retained so that the cell type but their cytoplasmic and nuclear details are lost. – The necrosed cells are swollen and appear more eosinophilic than the normal, along with nuclear changes described above. – But 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
  90. 90. COAGULATIVE NECROSIS Infarct Kidney The affected area on right shows cells with intensely eosinophilic cytoplasm of tubular cells but the outlines of tubules are still maintained. The nuclei show granular debris. The interface between viable and non-viable area shows nonspecific chronic inflammation and proliferating vessels
  91. 91. LIQUEFACTION (COLLIQUATIVE) NECROSIS • Due to ischaemic injury and bacterial or fungal infections • degradation of tissue by the action of powerful hydrolytic enzyme. • The common examples are infarct brain• The common examples are infarct brain and abscess cavity. • Whatever the pathogenesis, liquefaction completely digests the dead cells, resulting in transformation of the tissue into a liquid viscous mass. • If the process was initiated by acute inflammation, the material is frequently creamy yellow and is called pus
  93. 93. Morphology • Gross – The affected area is soft with liquefied centre containing necrotic debris. – Later, a cyst wall is formed. • Microscopically,• 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 – proliferating fibroblasts in the case of abscess cavity
  94. 94. LIQUEFACTION NECROSIS Liquefactive necrosis brain The necrosed area on right side of the field shows a cystic space containing cell debris, while the surrounding zone shows granulation tissue and gliosis.
  95. 95. CASEOUS NECROSIS • found in the centre of foci of tuberculous infections. • It combines features of both coagulative and liquefactive necrosis.liquefactive necrosis. • term "caseous" (cheese- like) is derived from the friable yellow-white appearance of the area of necrosis
  97. 97. Morphology • Grossly – foci of caseous necrosis, – as the name implies, resemble dry cheese and are soft, granular and yellowish. – This appearance is partly attributed to the histotoxic effects of lipopolysaccharides present in the capsule of the tubercle bacilli, Mycobacterium tuberculosis. lipopolysaccharides present in the capsule of the tubercle bacilli, Mycobacterium tuberculosis. • Microscopically – the necrosed foci are structureless, eosinophilic, and contain granular debris – The surrounding tissue shows characteristic granulomatous inflammatory reaction • Consisting of epithelioid cells with interspersed giant cells of Langhans’ or foreign body type • And peripheral mantle of lymphocytes.
  98. 98. CASEOUS NECROSIS Caseous necrosis lymph node There is eosinophilic, amorphous, granular material, while the periphery shows granulomatous inflammation.
  99. 99. FAT NECROSIS • Refers to focal areas of fat destruction – Acute pancreatic necrosis, – traumatic fat necrosis commonly in breasts • Pancreatic enzymes that have leaked out of acinar cells and ducts Pancreatic enzymes that have leaked out of acinar cells and ducts – liquefy the membranes of fat cells in the peritoneum. – lipases split the triglyceride esters contained within fat cells to fatty acid. – These combines calcium to produce grossly visible chalky white areas (fat saponification)
  100. 100. FAT NECROSIS Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.
  101. 101. Morphology • Grossly – fat necrosis appears as yellowish-white and firm deposits. – Formation of calcium soaps imparts thesoaps imparts the necrosed foci firmer and chalky white appearance. • Microscopically – the necrosed fat cells have cloudy appearance – surrounded by an inflammatory reaction. Formation of calcium soaps is identified in the tissue sections as amorphous, granular and basophilic material
  102. 102. FIBRINOID NECROSIS • Characterised by deposition of fibrin-like material which has the staining properties of fibrin. • It is encountered in various examples of• It is encountered in various examples of immunologic tissue injury – immune complex vasculitis, – autoimmune diseases, – Arthus reaction • Arterioles in hypertension, peptic ulcer
  103. 103. FIBRINOID NECROSIS Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation (dark nuclei of neutrophils).
  104. 104. Morphology • Microscopically – identified by brightly eosinophilic, hyaline-like deposition in the vessel wall. – Necrotic focus is surrounded by nuclear debris of neutrophils (leucocytoclasis) – Local haemorrhage may occur due to rupture of the blood vessel. Fibrinoid necrosis in autoimmune vasculitis. The vessel wall shows brightly pink amorphous material and nuclear fragments of necrosed neutrophils
  105. 105. Gangrene • A form of necrosis of tissue with superadded putrefaction. • All types of gangrene, necrosis undergoes liquefaction by the action of putrefactive bacteria. • It may be caused either ischemic or inflammatory • Coagulative Necrosis due to ischaemia• Coagulative Necrosis due to ischaemia – gangrene of the bowel, – gangrene of limb • Gangrenous or necrotising inflammation: primarily inflammation provoked by virulent bacteria resulting in massive tissue necrosis. – Gangrenous appendicitis, – Gangrenous stomatitis (noma, cancrum oris)
  106. 106. Types of Gangrene • 2 main forms of gangrene • Dry gangrene • Wet Gangrene• Wet Gangrene – Gas gangrene: a kind of wet gangrene
  107. 107. Dry Gangrene • begins in the distal part of a limb due to ischaemia. • The gangrene spreads slowly upwards until it reaches a point where the blood supply is adequate to keep the tissue viable. • A line of separation is formed at this point between• A line of separation is formed at this point between the gangrenous part and the viable part. – Toes and feet of an old patient due to arteriosclerosis. – Thromboangiitis obliterans (Buerger’s disease), – Raynaud’s disease, – Trauma – Ergot poisoning
  108. 108. Dry Gangrene Dry gangrene
  109. 109. Morphology • Grossly – the affected part is dry, shrunken and dark black, resembling the foot of a mummy. – It is black due to liberation of haemoglobin from haemolysed red blood cells which is acted upon by hydrogen disulfide (H2S) produced by bacteria resulting in formation of black iron sulfide. – The line of separation usually– The line of separation usually brings about complete separation with eventual falling off of the gangrenous tissue if it is not removed surgically • Histologically – Necrosis with smudging of the tissue. – The line of separation consists of inflammatory granulation tissue
  110. 110. Wet Gangrene • Naturally moist tissues and organs such as the mouth, bowel, lung, cervix, vulva. • develops rapidly due to blockage of venous, and less commonly, arterial blood flow from thrombosis or embolism.thrombosis or embolism. • The affected part is stuffed with blood which favours the rapid growth of putrefactive bacteria. • The toxic products formed by bacteria are absorbed causing profound systemic manifestations of septicaemia, and finally death.
  111. 111. Wet Gangrene • Diabetic foot – high sugar content in the necrosed tissue which favours growth of bacteria.of bacteria. • Bed sores – bed-ridden patient due to pressure on sites like the sacrum, buttocks and heels
  112. 112. Wet gangrene Intestine
  113. 113. MORPHOLOGIC FEATURES • Grossly, – the affected part is soft, swollen, putrid, rotten and dark. – The classic example is gangrene of bowel, commonly due to strangulated hernia, volvulus or intussusception. – The part is stained dark due to the same mechanism as in dry gangrenegangrene • Histologically, – coagulative necrosis with stuffing of affected part with blood. – There is ulceration of the mucosa and intense inflammatory infiltration. – Lumen of the bowel contains mucus and blood. – The line of demarcation between gangrenous segment and viable bowel is generally not clear-cut
  114. 114. Wet gangrene of the small bowel Coagulative necrosis of the affected bowel wall and thrombosed vessels while the junction with normal intestine is indistinct and shows an inflammatory infiltrate
  115. 115. Contrasting Features of Dry and Wet Gangrene
  116. 116. GAS GANGRENE • Special form of wet gangrene caused by gas-forming clostridia (gram-positive anaerobic bacteria). • gain entry into the tissues through open contaminated wounds, • especially in the muscles, or as a complication of• especially in the muscles, or as a complication of operation on colon which normally contains clostridia. • It produce various toxins which produce necrosis and oedema locally • Also absorbed producing profound systemic manifestations.
  117. 117. GAS GANGRENE
  118. 118. MORPHOLOGIC FEATURES • Grossly – the affected area is swollen, oedematous, painful and crepitant due to accumulation of gas bubbles within the tissues. – Subsequently, the affected tissue becomes dark black and foul smelling.foul smelling. • Microscopically – the muscle fibres undergo coagulative necrosis with liquefaction – Large number of gram-positive bacilli can be identified. – At the periphery, a zone of leucocytic infiltration, oedema and congestion are found. – Capillary and venous thrombi are common.
  119. 119. GAS GANGRENE
  120. 120. Pathologic calcification DefinitionDefinition:: Abnormal deposits of calcium salts occur in any tissues except bones and teeth. • Two distinct types of pathologic calcification: – Dystrophic calcification: characterised by deposition– Dystrophic calcification: characterised by deposition of calcium salts in dead or degenerated tissues with normal calcium metabolism and normal serum calcium levels. – Metastatic calcification: apparently normal tissues and is associated with deranged calcium metabolism and hypercalcaemia.
  121. 121. Morphological Features • Etiology and pathogenesis of the two are different. • But morphologically the deposits in both resemble normal minerals of the bone. • H and E stained sections, – Calcium salts appear as deeply basophilic, irregular and granular clumps.clumps. – The deposits may be intracellular, extracellular, or at both locations. – Occasionally, heterotopic bone formation (ossification) may occur. – Calcium deposits can be confirmed by special stains • Silver impregnation method of von-Kossa producing black colour, • Alizarin red S that produces red staining. – Pathologic calcification is often accompanied by diffuse or granular deposits of iron • Positive Prussian blue reaction in Perl’s stain.
  122. 122. Dystrophic calcification • Encountered in areas of necrosis of any type • Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury,insignificant past cell injury, it may also be a cause of organ dysfunction • May occur due to 2 types of causes: – Dead tissue – Degenerated tissue. Calcification of the aortic valve
  123. 123. Dystrophic Calcification: Dead Tissue • Caseous necrosis in tuberculosis is the most common site • Liquefaction necrosis in chronic abscesses may get calcified. • Fat necrosis following acute pancreatitis or traumatic fat necrosis in the breast results in deposition of calcium soaps. • Gamna-Gandy bodies in chronic venous congestion (CVC) of the spleen is characterised by calcific deposits admixed with haemosiderin on fibrous tissue.on fibrous tissue. • Infarcts may sometimes undergo dystrophic calcification. • Thrombi, especially in the veins, may produce phleboliths. • Haematomas in the vicinity of bones may undergo dystrophic calcification. • Dead parasites like in hydatid cyst, Schistosoma eggs, and cysticercosis. • Calcification in breast cancer detected by mammography. • Congenital toxoplasmosis involving the central nervous system visualised by calcification in the infant brain.
  124. 124. Dystrophic calcification: Degenerated Tissues • Dense old scars may undergo hyaline degeneration and subsequent calcification. • Atheromas in the aorta and coronaries frequently undergo calcification. • Mönckeberg’s sclerosis shows calcification in the tunica media of muscular arteries in elderly people • Stroma of tumours such as uterine fibroids, breast cancer, thyroid adenoma, goitre etc show calcification.etc show calcification. • Psammoma bodies or calcospherites: characteristic spherules of calcification such as in meningioma, papillary serous cystadenocarcinoma of the ovary and papillary carcinoma of the thyroid. • Cysts which have been present for a long time e.g. epidermal and pilar cysts. • Calcinosis cutis is a condition of unknown cause in which there are irregular nodular deposits of calcium salts in the skin and subcutaneous tissue. • Senile degenerative changes may be accompanied by dystrophic calcification such as in costal cartilages, tracheal or bronchial cartilages, and pineal gland in the brain etc.
  125. 125. Dystrophic calcification Fibrosis and dystrophicFibrosis and dystrophic calcifications of the pancreatic parenchyma.
  126. 126. Dystrophic calcification Mitral Stenosis: Gross natural color openedcolor opened valve with commissure fusion dystrophic calcification
  127. 127. Dystrophic calcification Degenerated tunica media of muscular artery of uterine myometrium in Mönckeberg’s arteriosclerosis Caseous necrosis in tuberculous lymph node. In H & E, the deposits are basophilic granular while the periphery shows healed granulomas.
  128. 128. Dystrophic calcification: Pathogenesis • Denatured proteins in necrotic or degenerated tissue bind phosphate ions, which react with calcium ions to form precipitates of calcium phosphate. • It involves 2 steps • Initiation (or nucleation)• Initiation (or nucleation) – phase in which precipitates of calcium phosphate begin to accumulate intracellularly in the mitochondria, – or extracellularly in membrane-bound vesicles: matrix vesicles • Propagation – phase in which minerals deposited in the initiation phase are propagated to form mineral crystals
  129. 129. Metastatic calcification • Calcification in normal tissue whenever there is hypercalcemia. • These may be due to• These may be due to – Excessive mobilisation of calcium from the bone – Excessive absorption of calcium from the gut
  130. 130. Excessive mobilisation of calcium from the bone • Hyperparathyroidism – Primary : parathyroid adenoma, – Secondary: parathyroid hyperplasia, chronic renal failure • Bony destructive lesions• Bony destructive lesions – Multiple myeloma – Metastatic carcinoma – leukemia • Prolonged immobilisation – Disuse atrophy of the bones and hypercalcaemia.
  131. 131. Excessive absorption of calcium from the gut • Hypervitaminosis D • Milk-alkali syndrome – Excessive oral intake of calcium in the form of milk – And administration of calcium carbonate in the– And administration of calcium carbonate in the treatment of peptic ulcer. • Hypercalcaemia of infancy • Sarcoidosis: macrophages activate a vitamin D precursor
  132. 132. Sites of Metastatic calcification • May occur in any normal tissue of the body but affects the following organs more commonly: • Kidneys, especially at the basement membrane of tubular epithelium and in the tubular lumina causing nephrocalcinosiscausing nephrocalcinosis • Lungs, especially in the alveolar walls. • Stomach, on the acid-secreting fundal glands. • Blood vessels, especially on the internal elastic lamina. • Cornea: another site affected by metastatic calcification. • Synovium of the joint causing pain and dysfunction. Tubular basement membrane in nephrocalcinosis due to hypercalcaemia
  133. 133. Metastatic calcification Lung:Lung: Metastatic Calcification
  134. 134. Differences between Dystrophic and Metastatic Calcification
  135. 135. CELL DEATH
  136. 136. APOPTOSIS • a form of ‘coordinated and internally programmed cell death’ • pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading theto die activate enzymes capable of degrading the cells' own nuclear DNA and nuclear and cytoplasmic proteins • Apoptosis is responsible for mediating cell death in a wide variety of physiologic and pathologic processes
  137. 137. APOPTOSIS
  138. 138. APOPTOSIS • The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes. • The dead cell is rapidly cleared before its contents have leaked out, and therefore cell death by thishave leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host • Thus, apoptosis differs from necrosis • However, apoptosis and necrosis sometimes coexist, and apoptosis induced by some pathologic stimuli may progress to necrosis
  139. 139. Apoptosis V/S Necrosis
  140. 140. Physiologic Processes • Organised cell destruction in sculpting of tissues during development of embryo. • Physiologic involution of cells in hormone- dependent tissues Endometrial shedding during mensuration– Endometrial shedding during mensuration – 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.
  141. 141. Pathologic Processes • Cell death in tumours exposed to chemotherapeutic agents. • Cell death by cytotoxic T cells in immune mechanisms such as in graft-versus-host disease and rejection reactions. • Progressive depletion of CD4+T cells in the pathogenesis of AIDS. • Cell death in viral infections e.g. viral hepatitis.• Cell death in viral infections e.g. viral hepatitis. • Pathologic atrophy of organs and tissues on withdrawal of stimuli e.g. prostatic atrophy after orchiectomy, atrophy of kidney or salivary gland on obstruction of ureter or ducts, respectively. • Cell death in response to injurious agents involved in causation of necrosis e.g. radiation, hypoxia and mild thermal injury. • In degenerative diseases of CNS e.g. in Alzheimer’s disease, Parkinson’s disease, and chronic infective dementias
  142. 142. A,Apoptosis in the skin in an immune-mediated reaction B,High power of apoptotic cell in live in immune-mediated hepatic cell injury.
  143. 143. Recognition of Cell death Ultrastructural changes • Margination or progressive loss of nuclear chromatin • Focal rupture of the nuclear membrane • Breakdown of the plasmalemma. • Development of flocculent densities in mitochondria. Changes in the nucleus Pyknosis: condensation of chromatin of chromatin and Changes in the nucleus • Pyknosis: condensation of chromatin of chromatin and shrinkage of the nucleus. • Karyorrhexis: fragmentation of the nucleus. • Karyolysis: dissolution of the nucleus. Normal Pyknosis Karyorrhexis Karyolysis
  144. 144. Recognition of Cell death Changes in cytoplasm staining • Positive staining with vital dyes such as Trepan blue which reflects abnormal membrane permeability. • Opacification: denaturation of proteins lead to aggregation with resultant opacification of the cytoplasm. • Eosinophilia: exposure of basic amino groups results in increased affinity for acidic dyes such as eosin.affinity for acidic dyes such as eosin. Biochemical changes • Release of K+ by dead cells. • Release of enzymes into the blood. e. g. increased plasma levels of creatine kinases, lactic dehydrogenase and aspartate aminotransferase. • Release of protein or protein breakdown products into the blood.
  145. 145. Recognition of Cell death Postmortem change • Tissues in dead body can be distinguished from necrosis by being diffuse and not associated with inflammatory response.associated with inflammatory response. Autolysis • Digestion of cell by enzymes released from lysosome; occurs after cell dies.
  146. 146. References • Robbinson's basic pathology 8 ed • Harsh Mohan - Textbook of Pathology 6th Ed. • Color atlas of pathology