Yidnekachew s(MD) - The normal cell is confined to a fairly normal range of function & structure. - It is nevertheless able to handle normal physiologic demands, maintaining steady state called homeostasis. - More severe physiologic stresses & some pathologic stimuli may bring about a number of physiologic & morphologic cellular adaptations. If the limits of adaptive response to a stimulus are exceeded, or the cell is exposed to an injurious agent or stress , a sequence of events follows that is termed cell injury The stimuli might result in a) b) c) Reversible cell injury Irreversible cell injury Cell death Cell death might be through 1) Apoptosis 2) Necrosis Adaptation Reversible Injury Normal cell Irreversible injury Cell Death - It is a new but altered steady state which preserves the viability of the cell & modulates its function as it responds to a stimuli. It is an increase in number of cells in an organ or tissue , usually resulting in increased volume of the tissue or organ. Hyperplasia takes place if the cellular population is capable of synthesizing DNA or able to undergo mitotic division (labile and stable cells). It usually, occurs together with hypertrophy It can be physiologic or pathologic. 1) Hormonal hyperplasia which increases the functional capacity of a tissue when needed. Due to ↑local production of growth factors, ↑GF receptors or activation of particular intracellular signaling pathway. In hormonal hyperplasia the hormones themselves act as GF. e.g. Breast glandular hyperplasia during puberty and pregnancy Uterine enlargement during pregnancy( due to hyperplasia and hypertrophy of the smooth muscle cells) 2. Compensatory hyperplasia, which increases tissue mass after damage or partial resection Eg. - Liver regeneration after partial resection - After unilateral nephrectomy , when the remaining kidney undergoes compensatory hyperplasia The exact mechanism of compensatory hyperplasia is unknown but it is thought to be A) Proliferation of the remaining cells B) Development of new cells from stem cells Most are caused by excessive hormonal stimulation or growth factors acting on target cells eg. Endometrial hyperplasia (due to imbalance b/n Estrogen and Progesterone), benign prostatic hyperplasia (due to androgen) N.B. Its response to normal regulatory mechanisms distinguishes benign pathologic hyperplasia from cancer( Hyperplasia ceases when the inducing agent is withdrawn but carcinomas progress despite removal of the inducing agent) However, Pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise. e.g. Endometrial hyperplasia might progress to carcinoma Hyperplasias are important in connective tissue cells during wound healing in which proliferation of fibroblasts and blood vessels aid repair. Normal bone marrow biopsy Hyperplastic marrow Normal epidermis Hyperplastic epidermis - It refers to an increase in the size of cells , resulting in an increase in the size of the organ - The increase in size is due to synthesis of more structural components - - It can be physiologic or pathologic & is caused by increased functional demand or by specific hormonal stimulation Example: ◦ The enlargement of the left ventricle in hypertensive heart disease ◦ The increase in skeletal muscle during strenuous exercise During muscle hypertrophy a) alpha-myosin heavy chain is replaced by beta –myosin heavy chain which has slow and energy conserving contraction. b) Production of atrial natriuretic peptide by both atrium and ventricle like fetal period( in normal adult it is only produced by atrium) ANP decreases hemodynamic load by ↑renal sodium excretion, ↓volume & pressure. - Shrinkage in the size of the cell by loss of cell substance - Atrophy can be physiologic or pathologic - Physiologic atrophy is common during early development . E.g Early embryonic structures such as thyroglossal duct undergo atrophy during fetal development. Uterus decreases in size shortly after parturition. can be local or generalized Common causes of atrophy are the following ◦ Decreased work load (Atrophy of disuse) ◦ Loss of innervation (denervation atrophy) ◦ Diminished blood supply ◦ Inadequate nutrition( e.g marasmus) ◦ Loss of endocrine stimulation (breast & Uterus after menopause) ◦ Aging ( especially in organs with permanent cells brain and heart) Pressure atrophy Mechanisms 1) Acid hydrolases like cathepsin in lysosomes degrade endocytosed protein from extracellular environment) 2) Ubiquitin-proteasome pathway For degrading cytosolic and nuclear proteins Protein to be degraded is conjugated with ubiqutin and then degraded by proteasome. Thyroid hormones, TNF stimulate and insulin inhibit this pathway. Proliferative endometrium form reproductive woman Atrophic endometrium from 75 years old woman - It is a reversible change in which one adult cell type is replaced by another cell type. - It is adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment. Squamous metaplasia -The most common type Is when mucin producing columnar epithelium is replaced by stratified squamous epithelium. 1) The influences that predispose to metaplasia , if persistent, may induce malignant transformation in metaplastic epithelium e.g. a) Respiratory epithelium in heavy smokers b) Stones in salivary gland and pancreatic gland ducts c)Vitamin A deficiency 2) Columnar metaplasia Metaplasia from squamous to columnar type (Barret esophagus) may also occur. To diagnose BE presence of goblet cell is a MUST. Esophageal squamous epithelium is replaced by intestinal – like columnar under the influence of refluxed gastric acid(GERD) Cancers may arise that are typically glandular carcinoma (adenocarcinoma) BE Low and High grade dysplasia Normal ADENOCARCINOMA 3)Connective tissue metaplasia It is the formation of cartilage , bone or adipose tissue (mesenchymal tissue) in tissues that normally do not contain these elements. e.g. Myositis ossificans – bone formation in muscle after bone fracture Dysplasia Disordered cell growth or proliferation. This is farther down the road toward neoplasia, but dysplasia is still a potentially reversible process. Cellular adaptations which can undergo neoplastic transformation are 1)Hyperplasia -e.g. Endometrial hyperplasia into endometrial carcinoma 2) Metaplasia -e.g. Columnar metaplasia of the esophagus into adenocarcinoma 3)Dysplasia – e.g. Cervical epithelial dysplasia into squamous cell carcinoma Cell injury results when cells are stressed so severely that they no longer able to adapt or the cells are exposed to inherently damaging agents. These alterations may be divided into the following stages 1) Reversible cell injury – is manifested as functional & morphologic changes that are reversible if the damaging stimulus is removed 2) Irreversible injury or cell death – with continuing damage , the injury becomes irreversible 41 Oxygen deprivation Hypoxia is a deficiency of oxygen , which causes cell injury by reducing aerobic oxidative respiration. Hypoxia should be distinguished from ischemia , which is loss of blood supply from impeded arterial flow or reduced venous drainage in tissue Causes of hypoxia include Cardiorespiratory failure, Anemia, Carbon monoxide poisoning Thrombosis/Embolism Atherosclerosis Physical agents – mechanical trauma, extremes of temperature, sudden changes in atmospheric pressure Chemical agents & Drugs Infectious agents Immunologic reactions( HSR and autoimmune diseases) Genetic derangements e.g Sickle cell anemia, down’s syndrome Nutritional imbalance e.g. PEM, vit deficiency, anorexia nervosa Principles that are relevant to most forms of cell injury The cellular response to injurious stimuli depends on the type of injury, its duration & its severity. The consequences of cell injury depend on the type, state, & adaptability of the injured cell Cell injury results from functional & biochemical abnormalities in one or more of several essential cellular components. The most important targets of injurious stimuli are 1) Aerobic respiration involving mitochondrial oxidative phosphorylation & production of ATP 2) The integrity of cell membranes 3) Protein synthesis 4) The cytoskeleton 5)The integrity of the genetic apparatus of the cell Biochemical mechanisms that are responsible for cell injury induced by different stimuli a) Depletion of ATP b) Mitochondrial damage c) Influx of intracellular calcium & loss of calcium homeostasis d) Accumulation of oxygen –derived free radicals (oxidative stress) e)Defects in membrane permeability Reversible injury -Two patterns of reversible cell injury can be recognized under the light microscope 1) Cell swelling ( hydropic changes) - The first manifestation of injury - It is the result of loss of function of plasma membrane energy-dependent ion pumps Cellular swelling (synonyms: hydropic change, vacuolar degeneration, cellular edema) is an acute reversible change resulting as a response to nonlethal injuries. It is an intracytoplasmic accumulation of water due to incapacity of the cells to maintain the ionic and fluid homeostasis. It is easy to be observed in parenchymal organs : liver (hepatitis, hypoxia), kidney (shock), myocardium (hypoxia, phosphate intoxication). It may be local or diffuse, affecting the whole organ Grossly -the affected organ is enlarged, pale and soft. Mic -The cells are enlarged, with a clear cytoplasm (due to the presence of small clear or pale vacuoles, with indistinct shape and limits) and a normal nucleus in central position; blood capillaries are compressed, explaining the organ's pallor. . 2) Fatty change - It is manifested by the appearance of small & large lipid vacuoles in the cytoplasm & occurs in hypoxic & various toxic injury. - It is principally seen in cells involved in & dependent on fat metabolism such as hepatocytes & myocardial cells. Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver in which deranged lipoprotein transport from injury (most often alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes. - After irreversible cell injury cell death is inevitable either by necrosis or apoptosis/ both of them may occur together. Necrosis - It refers to a spectrum of morphologic changes that follow cell death in a living tissue resulting from the progressive degradative action of enzymes in lethally injured cells. - Necrosis is cell death occurring in the setting of irreversible exogenous injury. - Necrotic cells aren’t able to maintain membrane integrity & their contents leak out & elicit inflammation in the surrounding tissue Morphology - The morphologic features of necrosis is the result of denaturation of intracellular proteins & enzymatic digestion of the cell. - These processes require hours to develop so there would be no detectable change immediately. Necrotic cells show increased eosinophilia due to loss the normal basophilia imparted by RNA in the cytoplasm. Nuclear changes Karyolysis – The basophilia of the nucleus fades Pyknosis- Nuclear shrinkage & increased basophilia Karyorrhexis – Nuclear fragmentation Normal myocardium Myocardium with Coagulative necrosis Morphologic patterns of necrosis Coagulative necrosis - Most often results from sudden interruption of blood supply to an organ. - It is, in early stages, characterized by general preservation of tissue architecture atleast for few days. The necrotic cells are removed by fragmentation & phagocytosis of the cellular debris by scavenger leukocytes & by action of Proteolytic lysosomal enzymes brought in by the immigrant white cells. Coagulative necrosis is characterstic of hypoxic death of cells in all tissues except brain. Gross, cross section: A pale, whitish infarct is surrounded by a zone of hyperemia (vascular dilatation). Very low power glass slide: The area of coagulative necrosis is bright pink compared to the lighter pink viable myocardium. The bluish areas on each side of the necrotic zone represent the granulation tissue response to the necrosis. This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney. Liquefactive necrosis It is characterized by digestion of tissue. It shows softening & liquefaction of tissue. It characteristically results from ischemic injury to the CNS. It also occurs in suppurative infections characterized by formation of pus. This is liquefactive necrosis in the brain in a patient who suffered a "stroke" with focal loss of blood supply to a portion of cerebrum. This type of infarction is marked by loss of neurons and neuroglial cells and the formation of a clear space at the centre left. Gangrenous necrosis It is due to vascular occlusion & most affects the lower extremities & the bowel. It Is called wet gangrene if it is complicated by bacterial infection which leads to superimposed Liquefactive necrosis. Dry gangrene if there is only Coagulative necrosis without Liquefactive necrosis. Caseous necrosis It is type of necrosis most often seen in foci of tuberculous infection. The term Caseous is derived from the cheesy white gross appearance of the area of necrosis On microscopic examination, the necrotic focus appears as amorphous granular debris enclosed within a distinctive inflammatory border known as a granulomatous reaction Fat necrosis Focal areas of fat destruction, typically occurring as a result of release of activated pancreatic lipases into the substance of the pancreas & the peritoneal cavity. This occurs in acute pancreatitis. The activated enzymes liquefy fat cell membranes &The lipases split the triglyceride contained with in fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification) On histological examination , foci of shadow outlines of necrotic fat cells with basophilic calcium deposits & surrounded by an inflammatory reaction Pancreas with fat necrosis Fat saponification with calcification and inflammation Fibrinoid necrosis Fibrinoid necrosis is caused by immune-mediated vascular damage. It is marked by deposition of fibrin-like proteinaceous material in arterial walls, which appears smudgy and eosinophilic on light microscopy. Necrosis can be followed by A) B) C) Release intracellular enzymes into the blood (creatinine kinase or troponin in myocardial infarction ) –clinically very important Inflammation or Dystrophic calcification ( if necrotic cells are not phagocytosed , they tend to attract calcium salts ) - It is a pathway of cell death that is induced by tightly regulated intracellular program in which cells destined to die activate enzymes that degrade the cells’ own nuclear DNA & nuclear & cytoplasmic proteins Apoptosis in physiologic situations 1) Programmed destruction of cells during embryogenesis 2) Hormone –dependent involution in the adult such as endometrial cell breakdown during menstrual cycle , the regression of the lactating breast after weaning 3) Cell deletion in proliferating cell populations 4) Death of host cells that have served their useful purpose such as neutrophils in acute inflammatory response 5) Elimination of potentially harmful self reactive lymphocytes 6) Cell death induced by cytotoxic T cells that serves eliminate virus infected & tumor cells Apoptosis in Pathologic conditions Cell death produced by a variety of injurious stimuli such as radiation & cytotoxic anticancer drugs Cell injury in certain viral diseases such as viral hepatitis Pathologic atrophy in parenchymal organs after duct obstruction Cell death in tumors The following morphologic features characterize cells undergoing apoptosis Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs & apoptotic bodies. The apoptotic cell undergoes fragmentation into membrane bound apoptotic bodies Phagocytosis of apoptotic cells or cell bodies usually by macrophages On histologic examination , apoptosis involves single cells or small cluster of cells . The apoptotic cells appear as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis Karyorrhexis – Karyolysis- Fragmentation into nucleosome size fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of Certain conditions are associated with distinctive alteration in cell organelles or the cytoskeleton. Lysosomal catabolism Primary lysosomes are membrane bound intracellular organelles that contain different enzymes . They fuse with membrane bound vacuoles that contain material to be digested forming secondary lysosomes. 1) Heterophagy It is the process of lysosomal digestion of materials ingested from the extracellular environment. Extracellular materials are taken up through general process of endocytosis. Uptake of particulate material is known as phagocytosis; uptake of soluble smaller macromolecules is called pinocytosis. It is common in professional phagocytes such as neutrophils & macrophages 2) Autophagy It refers to lysosomal digestion of the cells’ own components Lysosomal enzymes digest all proteins & CHO but Some lipids may remain undigested by lysosomal enzymes & persist in cells as residual bodies eg. Lipofuscin pigment – It represents undigested material derived from intracellular lipid perioxidation . Autophagy is a common phenomenon involved in a) Removal of damaged organelles during cell injury and the cellular remodeling of differentiation b) Cells undergoing atrophy induced by nutrient deprivation or hormonal involution. Lysosomes may sequester abnormal substances which cannot be completely metabolised. 1) Hereditary lysosomal storage disorders, caused by deficiencies of enzymes that degrade various macromolecules, It result in the accumulation of abnormal amounts of these compounds in the lysosomes of cells all over the body, particularly neurons, leading to severe abnormalities. 2) Acquired or drug-induced (iatrogenic) lysosomal diseases. E.g. Chloroquine ↑ internal pH of the lysosomes, thus inactivating its enzymes ↓Tissue damage in inflammatory reactions, which are mediated in part by enzymes released from leukocytes; This action is the basis of the use of the drug (Chloroquine) in autoimmune diseases like rheumatoid arthritis, SLE,… The same inhibition of enzymes, however, can result in abnormal accumulation of glycogen and phospholipids in lysosomes, causing toxic myopathy and neuropathy. The smooth ER is involved in the metabolism of various chemicals & cells exposed to these chemicals show hypertrophy of the ER as an adaptive response that may have functional consequences. E.g. protracted use of barbiturates leads to a state of tolerance , with decrease in the effects the drug & the need to use increasing doses . This is due to hypertrophy of smooth ER hepatocytes that metabolize the drug of It consists of 1) Microtubules, 2) Microfilaments (thin actin and thick myosin) 3) Various classes of intermediate filaments Microtubules Defect in microtubules can a) Inhibit sperm motility causing male sterility b) Immobilize the cilia of respiratory epithelium causing interference with the ability to clear inhaled bacteria, leading to bronchiectasis (kartagener’s syndrome – immotile cilia syndrome ) c) Microtubules are also important for leukocyte migration & phagocytosis. Drugs such as colchicine bind to tubulin & prevent the assembly of microtubules . It is used in acute attacks of gout. D) They are also important component of the mitotic spindle . Drugs (eg vinca alkaloids) can be antiproliferative & so act as antitumor agents Thin filaments They are important for leukocyte movement or for phagocytosis to occur adequately. Some drugs & toxins can affect these processes Intermediate filaments These components provide a flexible intracellular scaffold that organizes the cytoplasm & resist forces applied to the cell. Intermediate filaments are divided into five classes 1) Keratin filaments (characteristics of epithelial cells) 2) Neurofilaments (neurons) 3) Desmin filaments (muscle cells) 4) Vimentin filaments (connective tissue cells) 5) Glial filaments (astrocytes) Mallory body (alcoholic hyaline) is eosinophilic intracytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease and it is composed predominantly of keratin intermediate filaments. Intracellular Accumulations One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts of various substances - They fall into three categories 1) A normal cellular constituent accumulated in excess such as lipids, water, CHO or proteins 2) An abnormal substances , either exogenous such as mineral or product of infectious agents or endogenous such as product of abnormal synthesis or metabolism 3) Pigments Accumulation may be permanent or transient It may be harmless to the cell or very toxic In cytoplasm(especially in phagolysosome) or within nucleus Lipids Fatty change (Steatosis) It implies abnormal accumulation of triglycerides within parenchymal cells It is caused by an imbalance between the uptake, utilization, & secretion of fat It is often seen in liver because it is the major organ involved in fat metabolism. It also occurs in heart, muscle & kidney. The causes of steatosis include A) Alcohol abuse and toxins( hepatotoxic), B) Protein malnutrition(decrease apoprotein production), C) Diabetes mellitus, obesity and starvation ( increased FFA release) , & D) Anoxia( prevent FFA oxidation) Morphology - Fatty change is most often seen in the liver & heart - It appears as clear vacuoles within parenchymal cells. - Intracellular accumulation of water or polysaccharides (glycogen) may also produce clear vacuoles . - To distinguish b/n them, special stains are used Fat – Sudan IV or oil Red-O both impart orange –red color to the contained lipids Glycogen – periodic acid –Schiff (PAS) Water – when neither glycogen or fat can be demonstrated , it is presumed to contain water Cholesterol 1) Atherosclerosis – Cholesterol & cholesterol esters fill smooth muscle cells & macrophages within the intimal layer of the aorta & large arteries 2) Xanthoma – intracellular accumulation of cholesterol within macrophages in the subepithelial connective tissue of the skin & in tendons. 3) Cholesterolosis – focal accumulation of cholesterol laden macrophages in the lamina propria of the gallbladder Proteins Intracellular accumulation of proteins usually appear as rounded, eosinophilic droplets, vacuoles or aggregates in the cytoplasm Excess protein accumulation has various causes Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria) Synthesis of excessive amounts of normal secretory protein such as plasma cells engaged in active synthesis of immunoglobulin. The ER becomes hugely distended, producing large , homogenous eosinophilic inclusions called Russell bodies. Hyaline change The term hyaline refers to an alteration within cells or in the extracellular space , which gives a homogenous, glassy, pink appearance in routine histologic sections stained with hematoxylin & eosin. Eg intracellular accumulation of protein Pigments Pigments are colored substances , some of which are normal constituents of cells (eg melanin) whereas others are abnormal Pigments can be endogenous or exogenous Exogenous pigments Accumulation of carbon or coal dust blacken lung tissue & involved lymph nodes called as anthracosis. When inhaled , it is picked up by alveolar macrophages & is transported through lymphatic channels to the regional LNs in tracheobronchial region. Aggregates of excess carbon dust (as in coal miners) may induce a fibroblastic reaction or emphysema & cause serious lung disease known as coal worker’s pneumoconiosis. Tattooing is a form of localized exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages Endogenous pigments Lipofuscin - It is an insoluble pigment & wear-and-tear or A. - - aging pigment It is composed of polymers of lipids & phospholipids complexed with protein It is seen in cells undergoing slow, regressive changes & is particularly prominent in liver & heart of aging patients or patients with severe malnutrition or cancer cachexia In tissue sections, it appears as a yellow – brown finely granular intracytoplasmic perinuclear pigment B. Melanin Melanin is a brownish-black pigment produced by the melanocytes found in the skin. Increased melanin pigmentation is caused by sun tanning & certain diseases e.g. nevus, or malignant melanoma. Decreased melanin pigmentation is seen in albinism & vitiligo. Albinism Vitiligo Melanoma cells with intracytoplasmic melanin C. Bilirubin Bilirubin is a yellowish pigment, mainly produced during the degradation of hemoglobin. Excess accumulation of bilirubin causes yellowish discoloration of the sclera, mucosa, & internal organs. Such a yellowish discoloration is called jaundice. Jaundice is most often caused by i. Hemolytic anemia Hemolytic anemia is characterized by increased destruction of red blood cells ii.Biliary obstruction This is obstruction of intrahepatic or extrahepatic bile ducts. It can be caused by gallstones. iii. Hepatocellular disease This is associated with failure of conjugation of bilirubin. D. Hemosiderin Hemosiderin is a hemoglobin-derived ,golden yellow to brown, granular or crystalline pigment in which form iron is stored in cells & is identified by its staining reaction (blue color) with the Prussian blue dye. In cells, It is stored in in form of ferritin . When there is a local or systemic excess of ion , ferritin forms hemosiderin granules Hemosiderin exists normally in small amounts within tissue macrophages of the bone marrow, liver, & spleen as physiologic iron stores. It accumulates in tissues in excess amounts in certain diseases. It can be local or systemic derangement. - Local excesses result from gross or minute hemorrhages eg bruise - Systemic overload of iron can be seen Increased absorption of dietary iron Impaired use of iron Hemolytic anemia Transfusions This excess accumulation is divided into 2 types i. Hemosiderosis When accumulation of hemosiderin is primarily within tissue macrophages & is not associated with tissue damage, it is called hemosiderosis. ii. Hemochromatosis When there is more extensive accumulation of hemosiderin, often within parenchymal cells, which leads to tissue damage, scarring & organ dysfunction, it is called hemochromatosis. Primary (hereditary condition) or secondary Liver, pancreas and heart are commonly affected. It is the abnormal tissue deposition of calcium salts together with small amounts of iron, magnesium and other mineral salts. There are two forms of pathologic calcification 1) Dystrophic calcification 2) metastatic calcification Dystrophic calcification It is occurs in previously damaged tissue It occurs in a) b) c) Areas of necrosis (Coagulative , Liquefactive, Caseous, Fat necrosis) Atheroma of advanced atherosclerosis Aging or damaged heart valves Typically, the serum calcium level is normal. Gross Whatever the site of deposition, it appears as white granules or clumps, often felt as gritty deposits. Microscopy By H & E stains it is basophilic, amorphous granular sometimes clumped. Intracellular or extracellular or both Heterotrophic bone might be formed at the focus calcification. Psammoma bodies are dystrophic calcifications with laminated configuration. Psammoma bodies can be seen in some neoplastic conditions like a) b) c) Papillary thyroid carcinoma, Serous papillary cyst adenocarcinoma of ovary and Meningioma. Final common pathway of dystrophic calcification is formation of crystalline calcium phosphate mineral. The process has two steps 1) 2) Initiation( nucleation) Propagation Dystrophic calcification is sure sign of previous cell injury It can result functional dysfunction (narrowing heart valves and great vessels) Metastatic calcification It occurs in normal tissue whenever there is hypercalcemia. There are four principal causes of hypercalcemia 1) ↑secretion of parathyroid hormone(PTH) with subsequent bone resorption (parathyroid tumors and some lung carcinomas) 2) Destruction of bone tissue occurring with primary tumors of bone marrow (multiple myeloma) or diffuse skeletal metastasis(by breast carcinoma,…) 3) Vitamin D related disorders( Vit D intoxication, sarcoidosis, idiopathic hypercalcemia of infancy) 4) Renal failure ( causing phosphate retention resulting secondary hyperparathyroidism) Amyloid is a pathologic proteinaceous substance deposited between cells in various tissue & organs of the body in a wide variety of clinical settings. Amyloidosis is not a single disease rather it is a group of diseases having in common deposition of similar–appearing proteins Clinical diagnosis depends on morphologic identification of this distinctive substance(Amyloid) in appropriate biopsy specimens On light microscopy & standard tissue stains , amyloid appears as an amorphous , eosinophilic , hyaline, extracellular substance with progressive accumulation, encroaches on & produces pressure atrophy of adjacent cells. To differentiate it from other proteins ,Congo Red stain is used, it imparts a pink or red color to tissue deposits under ordinary light microscope. Under polarizing microscopy green birefringence of the stained amyloid is seen. Congo red stain by light microscope By polarizing microscopy Physical & chemical nature of amyloid - Amyloid material consists of mainly fibril proteins with characteristics cross -β pleated sheet conformation The three most common forms of amyloid proteins include AL (amyloid light chain) is derived from plasma cells & contains immunoglobulin light chains AA (amyloid-associated) synthesized by liver is protein Aβ amyloid is found in the cerebral lesions of Alzheimer disease Classification of Amyloidosis 1) Primary Amyloidosis It is usually systemic distribution & is characterized by deposition of the AL type Most patients have some form of plasma cell dyscrasia such as multiple myeloma. 2) Reactive systemic Amyloidosis The amyloid deposits in this pattern are systemic in distribution & are composed of AA protein It occurs secondary to an associated inflammatory conditions like(Tuberculosis, bronchoectasis , chronic osteomyelitis, rheumatoid arthritis) Old age is a consequence of civilization Aging must be distinguished from mortality on the one hand and from disease on the other. Death is a random event Even in the absence of specific diseases or vascular abnormalities, beginning in the 4th decade of life there is a progressive decline in many physiologic functions, including such easily measurable parameters as muscular strength, cardiac reserve, nerve conduction time, pulmonary vital capacity, glomerular filtration, and vascular elasticity. With age there are physiologic & structural alteration in almost all organ systems. Aging in individuals is affected to great extent by genetic factors, diet, social conditions & occurrence of age related diseases Aging –induced alterations in cells are an important components of the aging the organism Cellular aging is the result of a a) b) Progressive decline in the proliferative capacity & life span of cells The effects of continuous exposure to exogenous influences that result in progressive accumulation of cellular & molecular damage. These include A number of cellular functions decline progressively with age Reduction in oxidative phosphorylation & synthesis of nucleic acids & structural & enzymatic proteins , cell receptors & transcription factors . Decreased capacity of uptake of nutrients & repair of chromosomes Accumulation of Lipofuscin pigment as sign of oxidative damage Replicative senescence Cells have limited capacity for replication,this may be due to a limited number of cellular divisions that can take place. Telomeres are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome ends and protecting chromosomal termini from fusion and degradation. An enzyme called telomerase, which counteracts the tendency of the ends of chromosomes to shorten with each cellular division, may have decreased activity so that the telomeric ends of chromosomes shorten, and the ability of chromosomes to replicate is lost. The process of programmed cell death (apoptosis) may be part of a sequence of cell maturation Telomerase activity decreases with age But cancer cells have maintained activity of telomerase. Presence of genes that influence the aging process Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase — a protein involved in DNA replication and repair Accumulation of metabolic & genetic damage Cellular life span can determined by the balance b/n cellular damage resulting from metabolic events occurring with in a cell & counteracting molecular responses that can repair the damage . One of these metabolic products are reactive oxygen species whose damage increases with age
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