MLS114 LEC T2 - CELLULAR INJURY AND ADAPTATION.pdf

CELL INJURY, CELL DEATH & ADAPTATIONS MIAME ROSE Y. LIMA, MD  An Overview Overview of Cellular Response to Stress and Noxious Stimuli Causes of Cell Injury Overview of Cell Injury and Cell Death Necrosis Apoptosis An Overview….. contd Cellular Adaptations Intracellular...

CELL INJURY, CELL DEATH & ADAPTATIONS MIAME ROSE Y. LIMA, MD  An Overview Overview of Cellular Response to Stress and Noxious Stimuli Causes of Cell Injury Overview of Cell Injury and Cell Death Necrosis Apoptosis An Overview….. contd Cellular Adaptations Intracellular Accumulations Pathologic Calcification OVERVIEW OF CELLULAR RESPONSES TO STRESS AND NOXIOUS STIMULI ´Adaptations are reversible functional and structural responses to changes in physiologic states (e.g., pregnancy) and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function. CAUSES OF CELL INJURY ´ Oxygen Deprivation ´ Physical Agents ´ Chemical Agents and Drugs ´ Infectious Agents ´ Immunologic Reactions ´ Genetic Abnormalities ´ Nutritional Imbalances  CAUSES OF CELL INJURY 1. Oxygen Deprivation (Hypoxia) (i) Ischemia: Loss of blood supply to a tissue (ii) Anaemia: Decreased haemoglobin, which in turns leads to decreased oxygenation 2. Physical Agents (I )Mechanical trauma. (ii) Extremes of temperature (burns and deep cold) (iii) Radiation and Electric shock 3. Chemical Agents and Drugs (i) Poisons such as Arsenic and Cyanide (ii) Glucose or salts in hypertonic concentrations (iii) Environmental or Air Pollutants (iv) Alcohol and Narcotic Drugs (v) Insecticides and herbicides  CAUSES OF CELL INJURY 4. Infectious Agents Like Viruses, Bacteria, Fungi, Parasites 5. Immunologic Reactions: Immune system serves as defense against biologic agents; Immune reactions may in fact, cause cell injury , for example: (i) Autoimmune Diseases (ii) Anaphylactic Reactions 6. Genetic Derangements: Genetic defects may result in pathologic changes as conspicuous and obvious as the congenital malformations associated with down syndrome or a subtle as the single amino acid substitution in haemoglobin S of Sickle Cell Anaemia  CAUSES OF CELL INJURY 7. Nutritional Imbalances (i) Protein Calorie Deficiencies (ii) Vitamin Deficiency (iii) Lipids excess predispose to Atherosclerosis 8. Aging Cellular senescence leads to alterations in replication and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to damage and, eventually , the death of cells and of the organism Overview of Cell Injury & Cell Death  Point of No Return Two phenomena consistently characterize irreversibility : (1)The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of original injury (2) Profound disturbances in membrane function Reversible Cell Injury: Morphologic Changes The two main morphologic correlates of reversible cell injury are: (i) Cellular Swelling: It is the result of failure of energy dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis. (ii) Fatty Change: It occurs in hypoxic injury and various forms of toxic or metabolic injury. It is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. It occurs mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells Reversible Cell Injury: Morphologic Changes (i) Cellular Swelling It is the first manifestation of almost all forms of injury to cells. It is difficult to appreciate with light microscope; it may be more apparent at the level of whole organ. Gross Examination: When it effects many cells in an organ, it causes some pallor, increased turgor, and increase in weight of the organ. Microscopic Examination: May reveal small, clear vacuoles, within the cytoplasm ; these represent distended and pinchedoff segments of the endoplasmic reticulum. This pattern of non- lethal injury is sometimes called hydropic change or vacuolar degeneration. Reversible Cell Injury: Morphologic Changes (ii) Fatty Change It is manifested by the appearance of lipid vacuoles in the cytoplasm. Injured cells may also show increased eosinophilic staining. This eosinophilic staining becomes more pronounced with progression to necrosis Ultra structural changes of Reversible Cell Injury (1)Blebbing of plasma membrane (2)Blunting or distortion of microvilli (3)Loosening of intercellular attachments (4)Swelling and appearance of phospholipid – rich amorphous densities in mitochondria (5) Dilation of endoplasmic reticulum (6) Detachment of ribosomes (7) Nuclear alterations with clumping of chromatin Morphologic changes in reversible and irreversible cell injury (necrosis) Normal kidney tubules with viable epithelial cells Morphologic changes in reversible and irreversible cell injury (necrosis) Early (reversible) ischemic injury showing surface blebs, Increased eosinophilia of cytoplasm ,and swelling of occasional cells. Morphologic changes in reversible and irreversible cell injury (necrosis) Necrotic (irreversible) cell injury of epithelial cells with loss of nuclei and fragmentation of cells and leakage of contents A normal cell and changes in reversible and irreversible cell injury (Necrosis) CELL DEATH ´ There are two principal types of cell death, necrosis and apoptosis, which differ in their mechanisms, morphology, and roles in physiology and disease. 1. Necrosis 2. Apoptosis NECROSIS “Sum of the morphologic changes that follow cell death in a living tissue or organism’’. Two mechanisms are involved in necrosis: 1. Enzymatic digestion of cells by catalytic enzymes (i) Autolysis: Catalytic enzymes derived from the lysosomes of dead cells. (ii) Heterolysis: Catalytic enzyme derived from lysosomes of immigrant leucocytes. 2. Denaturation of Proteins Morphologic Changes in Necrosis A. Changes in Cytoplasm Increased Eosinophilia: It is due to: a) Loss of normal basophilia imparted by RNA in the cytoplasm b) Increased binding of Eosin to denatured intracytoplasmic proteins Cell will assume a glassy homogenous appearance. It is due to loss of glycogen particles Due to digestion of cytoplasmic organelles by enzymes, the cytoplasm will appear vacuolated and appear moth-eaten Calcification of dead cell may occur Morphologic Changes in Necrosis B. Changes in Nucleus Pyknosis: Shrinkage of nucleus Karyolysis: Dissolution of nucleus Karyorrhexis: Fragmentation of nucleus  TYPES OF NECROSIS Several distinct types of necrosis are recognized: 1. Coagulative Necrosis 2. Liquefactive Necrosis 3. Caseous Necrosis 4. Gangrenous Necrosis 5. Fibrinoid Necrosis 6. Fat Necrosis  I. COAGULATIVE NECROSIS Coagulative Necrosis is the most common type of necrosis. The process of coagulative necrosis, with preservation of the general tissue architecture is characteristic of hypoxic death of cells (due to lack of blood supply) in all tissues except brain The pathogenesis of coagulative necrosis is denaturation of proteins. Myocardial Infarction is an important example of coagulative necrosis. It is also seen in infarcts of heart, kidney and spleen. Part of kidney deprived of its blood supply by an arterial embolus. This is an example of caogulative necrosis Cellular and nuclear detail has been Lost. The ghost outline of a glomerulus can be seen in the centre, with remnants of tubule elsewhere  Fig A Fig B Fig A: Normal Myocardium Fig B: Myocardium with coagulation necrosis (upper two thirds of figure), showing strongly eosinophilic anucleate myocardial fibers. Leucocytes in the interstetium are an early reaction to necrotic muscle. Compare with A and with normal fibers in the lower part of figure COAGULATIVE NECROSIS – MYOCARDIAL INFARCTION When there is marked cell injury, there is cell death. This microscopic appearance of myocardium is a mess because so many cells have died that the tissue is not recognizable. Many nuclei have become Pyknotic (shrunken and dark) and have then undergone Karorrhexis (fragmentation) and Karyoloysis (dissolution). The cytoplasm and cell borders are not recognizable  II. LIQUEFACTIVE NECROSIS Liquefactive Necrosis is characteristically seen in: (i) Hypoxic death of cells within the central nervous system (ii) Bacterial or occasionally fungal infections. Liquefaction completely digests the dead cells. The end result is transformation of the tissue into a liquid viscous mass. If the process had been initiated by acute inflammation, the material is frequently creamy yellow because of the presence of dead white cells and is called pus. A focus of liquefactive necrosis in the kidney caused by fungal seeding. The focus is filled with white cells and cellular debris, crating a renal abscess that obliterates the normal architecture  LIQUEFACTIVE NECROSIS BRAIN Grossly, the cerebral infarction at the upper left here demonstrates liquefactive necrosis. Eventually, the removal of dead tissue leaves behind a cavity.  III. CASEOUS NECROSIS A distinctive form of coagulative necrosis. It is encountered most often in foci of Tuberculosis Infection.The term caseous is derived from gross appearance of tissue (white and cheesy). Microscopic Appearance: The necrotic focus appears as amorphous granular debris composed of fragmented, coagulated cells and amorphous granular debris enclosed within a distinctive inflammatory border known a “ Granulomatous Reaction”  Gross Appearance of Caseous necrosis: Foci of caseous necrosis in Tuberculosis of Lung Microscopic Appearance of Caseation Necrosis: Characteristic Tubercle showing central necrosis, along with epithelioid cells, multinucleated Giant cells and lymphocytes EXTENSIVE CASEOUS NECROSIS LUNG IN TUBERCULOSIS Extensive caseous necrosis lung in Tuberculosis, with confluent cheesy granulomas in the upper portion.  IV. GANGRENOUS NECROSIS Gangrene is massive necrosis (Caused by acute ischemia or severe bacterial infection) followed by putrefaction Gangrene is a special type of necrosis, in which bacterial infection is superimposed on coagulative necrosis and coagulative necrosis is modified by the liquefactive action of the bacteria The bacteria proliferate in and digest the dead tissue often with the production of foul smelling gases. The tissue becomes green or black because of the production of iron sulphide from degraded haemoglobin (PUTREFACTION) There are two main types of gangrene: (i) primary ; (ii) Secondary  IV. GANGRENOUS NECROSIS There are two main types of gangrene: (i) primary ; (ii) Secondary (I) Primary (Gas Gangrene): It is due to infection of deep contaminated wounds in which there is considerable muscle damage, by bacteria of the CLOSTRIDIA group- anaerobic spore forming gram positive bacilli which produce saccharolytic and proteolytic enzymes resulting in digestion of muscle tissue with gas formation. The infection rapidly spreads and there is associated severe toxaemia (spread of poisons in the blood) (ii) Secondary Gangrene: This is due to invasion of necrotic tissue usually by a mixed bacterial flora including putrefactive organisms and occurs in two forms: a) Wet gangrene: It occurs due to Arterial and venous occlusion. The tissues are moist at the start of the process either due to oedema or venous congestion. Examples are in strangulation of viscera and occlusion of leg arteries in obese diabetic patients b) Dry Gangrene: It occurs due to Arterial occlusion. Occurs especially in the toes and feet of elderly suffering from gradual arterial occlusions; the putrefactive process is very slow and only small numbers of putrefactive organisms are present. In Dry gangrene distal to arterial occlusion, tissue fluid formation will stop, but since veins are patent, the already present tissue fluid will be drained into the veins as normal DRY GANGRENE WET GANGRENE Due to Arterial occlusion Due to Arterial and Venous occlusion Occurs n limbs in cases of Occurs in limbs in - Senile gangrene - Crush injuries - Berger's gangrene - Tight tourniquets - Raynaud’s disease - Bed sores - Sometimes in diabetic gangrene - Diabetic gangrene Does not occurs in internal organs Occurs in internal organs (intestine) Very slow Putrefaction Rapid Putrefaction decomposition of dead tissue by bacteria leading to formation of iron sulphide, which in turns impart greenish – black colour to tissue) Mild Toxemia Severe Toxemia Gangrenous part is dry and mummified Gangrenous part is swollen Prominent line of demarcation(Dead Poor line of demarcation gangrenous part separates from the living part very distinctively)  DRY GANGRENE TOES This is Gangrene, or necrosis of toes. The toes were involved in a frost bite injury. This is an example of ‘dry gangrene’ in which there is mainly coagulative necrosis due to anoxic injury.  WET GANGRENE LEG This is Gangrene of the lower extremity. In this case the term ‘wet gangrene’ is more applicable because of the liquefactive component from superimposed infection in addition to the coagulative necrosis from loss of blood supply. This patient had Diabetes Mellitus.  V: FAT NECROSIS Fat Necrosis may be due to: (i) Direct Trauma to adipose tissue and extracellular liberation of fat. The result may be a palpable mass, particularly at a superficial site such as the breast (ii) Enzymatic lysis of fat due to release of Lipases. In Acute Pancreatitis there is release of pancreatic lipase. As a result, fat cells have their stored fat split into fatty acids, which then combine with calcium to precipitate out as white soaps.  FAT NECROSIS PANCREAS Cellular injury to the pancreatic acini leads to release of powerful enzymes which damage fat by the production of soaps (combination of calcium salts with fat; fat saponification)), and these appear grossly as the soft Chalky white areas seen in this cut surface Fat Necrosis in acute pancreatitis: The areas of chalky white deposits represents foci of fat necrosis with calcium soap formation (Saponification) at sites of lipid breakdown in the mesentery  VI. FIBRINOID NECROSIS Fibrinoid Necrosis is a type of Connective Tissue Necrosis It is seen particularly in conditions where there is Deposition of Antigen – Antibody Complexes. The important examples are Autoimmune Disorders like Systemic Lupus Erythematosus, Rheumatic Fever and Polyartirtis Nodosa. In these conditions the media and smooth muscle of blood vessels are especially involved.  VI. FIBRINOID NECROSIS Fibrinoid Necrosis is characterized by loss of normal structure and replacement by a homogenous, bright pink-staining necrotic material that resembles fibrin microscopically. Note, however, that “fibrinoid” is not the same as occurs in inflammation and blood coagulation. Areas of fibrinoid necrosis contains various amounts of Immunoglobulins, complement, albumin, break down products of collagen and fibrin Fibrinioid 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)  Differences Between Different Types of Necrosis CAGULATIVE LIQUEFACT- CASEOUS FAT FIBRINOID NECROSIS IVE NECROSIS NECROSIS NECROSIS NECROSIS Occurs due to Occurs due to Occurs due to Occurs due to Due to ischemia ischemia granuloma- trauma or vascular tous disease enzymatic fat inflammation injury In various In Brain In any tissue In Pancreas Around Blood tissues and Breast Vessels Tissue Architecture Cheesy Architecture Architecture architecture destroyed material; distorted not much preserved Architecture affected disturbed Involves Denaturation Caseation Rupture of Fat Accumulation denaturation of Proteins & cells of Fibrinoid of protein & Autolysis material lysosomal enzymes  Biochemical Markers of Necrosis Enzymes Tissue Creatinine Kinase(MB isoenzyme) Heart Certainties Kinase(BB isoenzyme) Brain Creatinine Kinase(MM isoenzyme) Skeletal Muscle Lactic Dehydrogenase(Isoenzyme 1) Heart, Erythrocytes, Skeletal Muscle Lactic Dehydrogenase (Isoenzyme 5) Liver, Skeletal Muscle Aspartate Aminotransferase(AST) Heart, Liver, Skeletal Muscle (Glutamic Oxaloacetate Transferase ; SGOT) Alanine Aminotransferase (ALT) Liver, Skeletal Muscle (Glutamic Oxaloacetic Transferase ; SGPT) Amylase Pancreas, Salivary Gland APOPTOSIS  APOPTOSIS “Programmed Cell Death” It is a form of cell death designed to eliminate unwanted host cells through activation of coordinated, internally programmed series of events effected by a dedicated set of gene products. Apoptosis occurs when a cell dies through activation of an internally controlled suicide program. It is a subtly orchestrated disassembly of cellular components designed to eliminate unwanted cells, during embryogenesis and in various physiologic processes. Doomed cells are removed with minimum disruption to the surrounding tissue. It also occurs, however, under pathologic conditions, in which it is sometimes accompanied by necrosis  Apoptosis refers to a mechanism of cell death affecting usually single cells or a group of cells scattered in a population of healthy cells. It differs from necrosis and represents most of the times a physiological or at times a pathological response by which defective cells and abnormal cells die and are eliminated. The process is rapid and (completed in few hours), and is considered in 2 stages: Stage 1 (Dying Process): a) Active metabolic changes in the cell cause cytoplasmic and nuclear condensation and nuclear membrane is intact. b) Cell disintegrates into multiple Apoptotic Bodies, each surrounded by a part of plasma membrane. Stage 2 (Elimination Process): Phagocytosis of Apoptotic Bodies by surrounding cells, e.g., liver cells, tumour cells. This is followed by rapid digestion. The surrounding cells move together to fill the vacant space leaving virtually no evidence of the process.  PATHOGENESIS OF APOPTOSIS Apoptosis results from the action of intacellular cysteine protease called CASPASES which are activated following cleavage and lead to endonuclease digestion of DNA and disintegration of the cell skeleton. There are two major pathways by which caspases are activated: (i) Activation through Death Factor (Fas Ligand): The is by signaling through membrane proteins such as Fas or TNF receptor intracellular death domain. An example of this mechanism is shown by activated cytotoxic T cells expressing Fas ligand. (ii) Release of Cytochrome – C from the Mitochondria: The second pathway is via the release of Cytochrome – C from mitochondria. Cytochrome – C binds to Apaf – 1 which then activates caspases. DNA damage induced by irradiation or chemotherapy may act through this pathway. Mechanisms of Apoptosis: the two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. In the mitochondrial pathway, proteins of Bcl-2 family, which regulate mitochondrial permeability become imbalanced and leakage of various substances from mitochondria leads to caspase activation. In the death receptor pathway , signals form plasma membrane receptors lead to assembly of adaptor protiens into a “death – inducing signaling complex” ,which activates caspases and the end result is the same  APOPTOSIS SPECIFIC GENE Gene that stimulates Apoptosis e.g., bax – gene APOPTOSIS INHIBITING GENE Gene that blocks apoptosis e.g., bcl - gene  PHYSIOLOGIC CONDIITONS HAVING EVIDENT APOPTOSIS 1.The programmed destruction of cells during embryogenesis. 2. Hormone dependent involution in the adults, such as endometrial breakdown during menstrual cycle and regression of lactating breast after weaning 3. Cell depletion in proliferating cell population, such as intestinal crypt epithelia, in order to maintain a constant number 4. Elimination of cells that have served their useful purpose, such as neutrophils in an acute inflammatory response and lymphocytes at the end of an immune situations 5. Elimination of potentially harmful self-reactive lymphocytes either before or after they have completed their maturation, in order to prevent reactions against the body’s owns tissues  PATHOLOGIC CONDIITONS HAVING EVIDENT APOPTOSIS 6. 6. Cell death induced by cytotoxic T lymphocytes, a defense mechanism against viruses and tumours that serves to kill virus-infected and neoplastic cells. 7. DNA damage: Radiation, cytotoxic anticancer drugs, extremes of temperatures and even hypoxia can damage DNA, either directly or through production of free radicals. 8. Accumulation of misfolded proteins :Importantly folded proteins may arise because of mutations in the genes encoding these proteins or because of extrinsic factors , such as damage caused by free radicals. Excessive accumulation of these proteins in the ER leads to a condition called Endoplasmic Reticulum Stress (ER Stress), which culminates in a apoptotic death of cells  PATHOLOGIC CONDITIONS HAVING EVIDENT APOPTOSIS 9. Cell injury in certain infections, particularly viral infections, in which loss of infected cells is largely due to apoptotic death may be induced by the virus ( as in adenovirus and HIV infections) 10. Pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland and kidney MORPHOLOGIC CHANGES IN APOPTOSIS Cell Shrinkage: Cell is smaller in size; Cytoplasm is dense; organelles are tightly packed. Chromatin Condensation: Chromatin aggregates peripherally, under the nuclear membrane; nucleus may break in fragments Formation of cytoplasmic blebs and apoptotic bodies. Phagocytosis of apoptotic bodies by adjacent healthy cells MORPHOLOGIC CHANGES IN APOPTOSIS ON HISTOLOGIC SECTIONS: Apoptosis involves single cell or small clusters of cells. The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin The sequential ultra structural changes seen in coagulation necrosis (left) & Apoptosis (right). In apoptosis, the initial changes consist of nuclear chromatin condensation and fragmentation, followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. Signs of coagulation necrosis include chromatin clumping, organellar swelling, and eventual membrane damage. Apoptosis of a liver cell in viral hepatitis. The cell is reduced in size and contains brightly eosinophilic cytoplasm and a condensed nucleus  DYSREGULATED APOPTOSIS (“too little or too much’) Disorders associated with reduced apoptosis: An inappropriately low rate of apoptosis may prolong survival of abnormal cells. These accumulated cells then give rise to: a) Cancers, especially those carcinomas with p53 mutations b) Autoimmune disorders, which could arise, if autoreacitve lymphocytes are not removed after immune response. Disorders associated with increased apoptosis. These disorders are characterized by a marked loss of normal or protective cells and include: a) Neurodegenerative diseases b) Virus – induced lymphocyte depletion c) Aplastic Anaemia  COMPARISON OF CELL DEATH BY APOPTOSIS & NECROSIS FEATURE APOPTOSIS NECROSIS Cell Suicide Cell Homicide Induction May be induced by Invariably due to pathological physiological or pathological injury stimuli Extent Single cells Cell groups Biochemical events (I) Energy- dependent (i) Impairment or cessation of fragmentation of DNA by ion homeostasis endogenous endonucleases (ii) Lysosomes leak lytic (ii) Lysosomes intact enzymes Cell membrane Maintained Lost integrity Morphology Cell fragmentation to form Cell swelling and lysis apoptotic bodies Inflammatory None Usual response Fate of dead cells Ingested by neighbouring Ingested by neutrophils and cells macrophages CELLULAR ADAPTATIONS  CELLUAR ADAPTATIONS: Different Cellular adaptive responses are: (i) Hyperplasia (ii) Hypertrophy (iii) Atrophy (iv) Metaplasia  HYPERTROPHY Hypertrophy constitutes an increase in the size of cells and with such change an increase in the size of organ. Thus, there are no new cells, just large cells. Moreover, these cells are not enlarged by simple cellular edema but by the increased synthesis of more structural proteins and organelles. Hypertrophy can be Physiologic or Pathologic and is caused by increased functional demand or due to specific hormonal stimulation. Pure hypertrophy without accompanying hyperplasia occurs in muscle , and the stimulus is almost a mechanical one a) Cardiac Muscle Hypertrophy: Any demand for increased work load on cardiac muscle, i.e., in hypertension, valvular lesions or congenital heart diseases, leads to hypertrophy of the fibers of the chamber affected. b) Smooth Muscle Hypertrophy: Any obstruction to the outflow of the contents of a hollow viscus results in hypertrophy of its muscle coat. The following are examples of smooth muscle hypertrophy: (i) Bladder: Seen in Prostatic enlargement and Urethral stricture (ii) Oesophagus: Seen in carcinoma (iii) Stomach: Seen in pyloric stenosis due to ulcer or carcinoma (iv) Intestine: Stricture following Tuberculous enteritis (v) Colon: Seen in carcinoma and diverticular disease c) Skeletal Muscle Hypertrophy: The bulging muscle of the athlete provide a simple illustration of hypertrophy due to a mechanical stimulus  Cardiac Hypertrophy Cardiac Hypertrophy involving left ventricle. The number of myocardial fibres does not increase, but their size can increase in response to an increased work load leading to the marked thickening of the left ventricle in this patient with Systemic Hypertension  Benign Prostatic Hyperplasia and Hypertrophy The normal adult male prostate is about 3 to 4 cm in diameter. The number of Prostatic glands, as well as stroma, has increased in this enlarged prostate seen in cross section. The pattern of increase in this case is uniform, but nodular  Physiologic Hypertrophy of the Uterus during Pregnancy Figure Robbins page 3 A: Gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed for postpartum bleeding B: Small spindle – shaped uterine smooth muscle cells from a normal uterus C: Large , plump hypertrophied smooth muscle cells from a gravid uterus  Hypertrophy And Hyperplasia - Compared Both are cellular responses to an increased demand for work. The cells either enlarge or divide depending upon their growth potentialities. The stimulus for this is usually mechanical in hypertrophy, and chemical or hormonal in hyperplasia. When the stimulus is withdrawn, the condition regresses and the tissue reverts to normal. However, secondary structural alterations in the general architecture due to an accompanying degeneration may render a complete return to normal impossible. Hypertrophy Hyperplasia Stimulus is Stimulus in Chemical and Mechanical Hormonal Hypertrophy And Hyperplasia -Compared  HYPERPLASIA Hyperplasia constitutes an increase in the number of cells in an organ or tissue, that also leads to an increase in size of an organ and tissue Hypertrophy and Hyperplasia are closely related and often develop concurrently in tissues, so that both may contribute to an overall increase in organ size. It is important to note that those hyperplasia due to a specific stimulus persist only for so long as that stimulus is applied. When it is removed, the tissue tends to revert to its normal size. In this respect hyperplasia differs from neoplasia, for neoplastic tissue continues to grow even when the stimulus is withdrawn.  Hyperplasia can be Physiologic or Pathologic: (I) PHYSIOLOGIC HYPERPLASIA a) Hormonal Hyperplasia: Exemplified by the proliferation of glandular epithelium of the female breast at puberty and during pregnancy b) Compensatory Hyperplasia: Occurs when a portion of tissue is removed or diseased. For example, when a portion of liver is removed, hyperplasia by mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring restoring the liver to its normal weight – at which time cell proliferation ceases. The stimuli for hyperplasia in this setting are polypeptide growth factors. After restoration of the liver mass, cell proliferation is “turned Off” by growth inhibitors  PATHOLOGIC HYPEPRLASIA Pathologic Hyperplasia and Hypertrophy occur in the absence of an appropriate stimulus of increased functional demand (i) Endometrial Hyperplasia: After a normal menstrual period there is a burst of essentially physiologic hyperplasia. This proliferation is normally tightly regulated between stimulation by pituitary hormones and ovarian Estrogen, and inhibition by Progesterone. However, if the balance between estrogen and progesterone is disturbed (e.g., if there is absolute or relative increases in estrogen), Pathologic Hyperplasia results. Endometrial Hyperplasia is a common cause of abnormal menstrual bleeding. It is important to note that the hyperplasic process remains controlled. If Estrogenic stimulation abates, the hyperplasia disappears. This differentiates the process from cancer, in which cells continue to grow despite the absence of hormonal stimulus. Nevertheless, pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise. Thus patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer (ii) Compensatory hyperplasia of bone marrow: Following haemorrhage (iii) Reactive hyperplasia of lymphoid tissue in response to antigenic stimulation. (iv) Thyroid Hyperplasia (Graves’ Disease): Result from the action of auto antibodies which act on follicular cells of thyroid and then lead to hyperplasia of follicular cells, which in turn leads to increased release of T3 and T4 (v) Hyperplasia of the Prostate Gland: It is common in older age and is due to hyperplasia of both glandular and the stromal element HYPERPLASIA NEOPLASIA Excited by a stimulus A stimulus is not always detected Reversible, i.e., pathological Irreversible. i.e., cell proliferation hyperplasia stops and disappears is unlimited and progresses if stimulus is removed independent of stimuli Proliferated cells are normal Proliferated cells are abnormal in shaped shape May be useful , i.e., Harmful compensatory hyperplasia  ATROPHY Atrophy is the decrease in size of cell or of an organ by loss of cell substance Atrophy represents a reduction in the structural components of the cell. In the changing circumstances the cells adopt themselves to survive with lesser amounts of cellular substance, hence a new equilibrium is achieved. Although atrophic cells may have diminished function, they are not dead. If the blood supply is inadequate even to maintain the life of shrunken cells then atrophy may progress to the point at which cells are injured and die. The atrophic tissue is then replaced by fatty in growth.  (I) PHYSIOLOGIC ATROPHY: Physiologic Atrophy occurs at times from very early embryonic life, as part of the process of morphogenesis. The process of atrophy contributes to the physiological involution of different organs Some examples of Physiologic Atrophy are: (i) Physiologic involution of Thymus. (ii) post menopausal atrophy of Uterus and Endometrium (iii) Senile atrophy of cerebrum (iv) Bone marrow atrophy in old age  (II)PATHOLOGIC ATROPHY Pathologic atrophy depends on the basic cause and can be local or generalized. The common causes of atrophy are: (i) Decreased workload (Atrophy of Disuse): a) Skeletal muscle atrophy , when a broken limb is immobilized in a plaster cast. b) Skeletal muscle atrophy when a patient is restricted to complete bed rest. (ii) Loss of innervation (Denervation Atrophy): Damage to the nerves leads to the rapid atrophy of the muscle fibers supplied by those nerves, for example in poliomyelitis and in paraplegics. (iii) Diminished Blood Supply (Ischemia): In late adult life, the brain undergoes progressive atrophy , presumably as atherosclerosis narrows its blood supply. (iv) Inadequate Nutrition: a) Profound protein – calorie malnutrition (marasmus) is associated with marked muscle wasting. b) In starvation. c) Cachexia: An extreme form of systemic atrophy, usually seen in cancer patients (v) Loss of Endocrine Stimulation: Many endocrine glands, the breast, and the reproductive organs are dependent on endocrine stimulation for normal function. Loss of estrogen stimulation after the menopause results in physiologic atrophy of the endometrium, vaginal epithelium and breast.  (vi) Aging (Senile Atrophy): The aging process is associated with cell loss. Morphologically, it is seen in tissues containing permanent cells, particularly in the brain and heart. (vii) Pressure: Tissue compression for any length of time can cause atrophy. An enlarging benign tumour can cause atrophy in the surrounding compressed tissues. Atrophy in this setting is probably the result of ischemic changes caused by a blockade of blood supply produced by the expanding mass  Atrophy Brain Cerebral atrophy in a patient with Alzheimer disease. The gyri are narrowed and the intervening sulci widened particularly pronounced towards the frontal lobe. A. Physiologic atrophy of the brain in an 82 years old man B. Normal brain of a 36 years old male  METAPLASIA Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another cell type. Metaplasia often represents an adaptive response of a tissue to some stress, and is presumed to be due to the activation and/or repression in tissue stem cells of group of genes involved in tissue differentiation. The transdifferentiated cells replace the original cells. Metaplasia is of two types 1. Epithelial Metaplasia - Columnar to Squamous - Squamous to Columnar 2. Connective Tissue Metaplasia Schematic Diagram of Columnar to Squamous Metaplasia  Metaplasia of Respiratory Epithelium Metaplasia of laryngeal respiratory epithelium has occurred here in a smoker. The chronic irritation has led to an exchange of one type of epithelium (the normal respiratory epithelium at the right ) for another ( more resilient squamous epithelium at the left). Metaplasia is not a normal physiologic process and may be a first step toward neoplasia (ii)Columnar Metaplasia: Metaplasia from squamous to columnar type may also occur: a)Barrett Esophagitis: In this condiiton the squamous esophageal epithelium is replaced by intestinal-like columnar cells. The resulting cancers that may arise are glandular (adeno) carcinomas. b) Cervical Erosion: Squamous epithelium of cervix is replaced by columnar epithelium. Metaplastic transformation Of esophageal stratified squamous epithelium to mature columnar epithelium (so-called Barrett metaplasia) Metaplasia of the normal esophageal squamous mucosa has occurred, with the appearance of gastric type columnar epithelium  CONNECTIVE TISSUE METAPLASIA Connective tissue metaplasia is the formation of cartilage, bone or adipose tissue (mesenchymal tissues) in tissues that normally do not contain these elements. For example, bone formation in muscle, designated Myositis Ossificans , occasionally occur after bone fracture. This type of metaplasia is less clearly seen as an adaptive response.  Hyperplasia Versus Metaplasia Hyperplasia Metaplasia Definition It is an increase in the number of cells in an organ or It is a reversible change in which one type of cell is tissue usually resulting in an increase in volume of differentiated into another type of differentiated the organ or tissue epithelium Cause Physiological or Pathological Pathological Mechanism Increased production of growth factors, growth Result of reprogramming of stem cells; Precursor factor receptors, activation of signaling pathways, cells differentiate along a new pathway; Tissue production of transcription factors leading to specific and differentiation genes are involved in cellular proliferation process Examples Physiological: Uterus, breast growth during Squa mous metaplasia : gall bladder, renal pelvis pregnancy; Compensatory hyperplasia in unilateral and bladder, uterus/cervix, bronchial, prostatic nephrectomy and partial hepatectomy Columnar Metaplasia: Barret’s esophagus, cervical Pathological: Parathyroid hyperplasia occurring in erosion, chronic bronchitis, bronchiactasis, chronic renal failure; thyroid hyperplasia in graves fibrocystic disease with apocrine metaplasia disease; Benign prostatic hyperplasia ;endometrial Osseous metaplasia: Aging process in costal and hyperplasia thyroid cartilage, in scars, areas of dystrophic calcification , myositis ossificans  DYSPLASIA Dysplasia is a premalignant condition characterized by the loss of the uniformity of the individual cells as well as a loss in their architectural orientation. Dysplasia can be caused by longstanding irritation of a tissue, with chronic inflammation, or by exposure to carcinogenic substances. Dysplasia may occur in tissues which has coincident metaplasia, e.g. dysplasia developing in metaplastic squamous epithelium from the bronchus of smokers Dysplasia may also develop without co-existing metaplasia , for example in squamous epithelium of the uterine cervix, glandular epithelium of the stomach or the liver Dysplasia may be present for many years before a malignant neoplasm develops, and this observation can be used to screen populations at high risk of developing tumours Dysplatic cells exhibit following characteristic findings: I) Cellular Pleomorphism: Cells show variations in size & shape ii) Hyperchromatic Nuclei: Deeply stained nuclei, which are abnormally large for the size of cell. iii) Increased Mitotic Activity: Mitotic figures are more abundant than usual, although almost invariably they conform to normal patterns. In dysplasia the mitoses are not confined to the basal layers and may appear at all levels and even in surface cells. Dysplatic cells exhibit following characteristic findings: (iv) Architectural Anarchy : There is considerable architectural anarchy. For example, the usual progressive maturation of tall cells in the basal layer to flattened squames on the surface may be lost and replaced by a disordered scrambling of dark basal- appearing cells. This is also labeled as ‘loss of epithelial polarity’ (v) Carcinoma in situ: When dysplastic changes are marked and involve the entire thickeness of the epithelium, but the basement membrane is intact the lesion is considered as preinvasive neoplasm and is referred as carcinoma in situ.  Normal Dysplasia Invasion Carcinoma in situ Metastasis  DYSPLASIA CERVIX The normal cervical squamous epithelial at left transform to dysplastic change at right. There is also underlying chronic inflammation because abnormal epithelial surfaces do not provide the same protective barrier as normal epithelial surfaces do  PAP SMEAR CERVIX PAP SMEAR: Cytologic features of normal squamous epithelial cells can be seen at the center top bottom, with orange to pale blue plate- like squamous cells that have small pyknotic nuclei. The dysplastic cells in the center extending to upper right are smaller with darker, more irregular nuclei Intracellular Accumulations  INTRACULLAR ACCUMULATIONS One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts of various substances The stockpiled substance fall into three categories: (I) A normal cellular consistent accumulates in excess a. Fatty change liver b. Haemosidrosis c. Bilirubin accumulation (II) A normal or abnormal substance, accumulates because of the genetic or acquired defects to metabolize it: a. Glycogen Storage diseases (III) An abnormal exogenous substance accumulates because body can not metabolize it (PIGMENTATION) a. Accumulation of carbon particles in lungs b. Tattooing (IV) Specialized Accumulations a. Calcification b. Amyloidosis (i) A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it Example: Fatty Change of Liver  Fatty Change of Liver ØThe term Steatosis and Fatty Change describe abnormal accumulation of triglycerides within parenchymal cells. ØFatty change is often seen in the liver because it is the major organ involved in the fat metabolism, but it also occurs in heart, muscle, and kidney ØThe causes of fatty change include: (i) Toxins. (ii) Protein malnutrition. (iii) Diabetes mellitus. (iv) Obesity. (v) Anorexia (vi) Alcohol abuse ( In industrialized world it is the most common cause)  Fatty Change Liver Intracellular accumulation 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. Cholesterol and Cholesterol Esters accumulation Most cells use cholesterol for cell membrane synthesis, without intracellular accumulation of cholesterol esters. In several pathologic conditions intracellular accumulation of cholesterol can be manifested Atherosclerosis: In atherosclerotic plaques smooth muscle cells and macrophages are filled with fat vacuoles most of which are made of cholesterol and cholesterol esters ( Foam Cells) Xanthomas: In hereditary and acquired hyperlipedimic states clusters of foam cells are found in the sub epithelial connective tissue of the skin and tendons producing tumourous masses known as Xanthomas Inflammation and Repair: Foamy macrophages are frequently found at sites of cell injury and inflammation , owing to phagocytosis of cholesterol from membranes of injured cells Cholesterolosis: This refers to focal accumulation of cholesterol – laden macrophages in the lamina propria of gall bladder, Cholesterol and Cholesterol Esters accumulation Atheroma Xanthomas  Proteins accumulation Protein appears as eosinophilic droplets in the cytoplasms In certain disorders excessive accumulation of protein takes place: Reabsorption droplets in proximal renal tubules: Seen in renal diseases associated with protein loss in the urine (Proteinuria) Excessive synthesis of proteins: occurs in plasma cell dyscrasisias like Multple Myeloma where there is excessive immunoglobulin synthesis Multiple myeloma-Plasma Cells With Inclusions  Glycogen accumulation Excessive intracellular accumulation of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. Diabetes mellitus: It is the prime example of a disorder of glucose metabolism Glycogen storage diseases: A group of genetic disorders , In these enzymatic defects in glycogen synthesis or breakdown leads to excessive accumulation of glycogen in cells Calcification  CALCIFICATION Calcification is the abnormal deposition of Calcium salts, at sites other than osteoid and enamel along with smaller amounts of iron, magnesium and other mineral salts Calcification is of two types: 1. Dystrophic Calcification: Deposition in dead or dying tissue 2. Metastatic Calcification: Deposition in living tissue DYSTROPHIC METASTATIC CALCIFICATION CALCIFICATION Deposition of calcium Deposition of calcium in dead or dying tissue in living tissue Not associated with Associated with abnormalities in abnormalities in calcium metabolism calcium metabolism Hypercalcemia absent Hypercalcemia present Dystrophic calcification: Examples 1. In areas of necrosis. The necrosed tissue can get converted in a calcified mass 2. The atheromas of advanced atherosclerosis. 3. Aging or damaged heart valves 4. Aged pineal gland. 5. Dead parasites 6. Dead retained fetus. 7. Dystrophic Calcification can be seen in carcinomas. For example “Psammoma bodies” seen in capillary carcinoma of thyroid. Aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each cusp are seen irregular masses of pilled- up dystrophic calcification  Dystrophic Calcification This is dystrophic calcification in the wall of the stomach. At the far left is an artery with Calcification in its wall. There are also irregular bluish – purple deposits of calcium in the sub mucosa. Calcium is more likely to be deposited in the tissues that are damaged.  Psamomma Bodies - Dystrophic Calcification Seen in Malignant Tumours Psamomma Bodes: Are lamellated bodies of dystrophic calcification. Seen in: -Papillary carcinoma thyroid -Meningioma Serous ovarian malignant tumours  Metastatic Calcification: Examples There are four principal causes in groups of patients with Hypercalcemia who can have Metastatic Calcification: 1. Increased secretion of Parathyroid Hormone with subsequent bone resorption seen in a. Hyperparathyroidism due to parathyroid tumours b. Ectopic secretion of Parathyroid hormone by malignant tumours 2. Destruction of bone tissue seen with a. primary tumours of bone marrow like: - Multiple Myeloma - Leukaemias b. Diffuse skeletal metastasis (e.g., breast cancer) c. Accelerated bone turn over like in Paget disease or in immobilization. 3. Renal Failure, which causes retention of Phosphate, leading to secondary hyperparathyroidism. 4. Vitamin – D related disorders including Vitamin- D intoxication and Sarcoidosis.  Calcification: Morphology Regardless of the site, calcium salts are seen on gross examination as fine white granules or clumps. Often felt as gritty deposits Dystrophic calcification is common in areas of caseous necrosis. On histologic examination calcification appears as intracellular and/or extracellular basophilic deposits. Overtime, heterotrophic bone may be formed in the focus of calcification Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs and gastric mucosa. Calcium deposits, in metastatic calcification, morphologically resemble those as in dystrophic calcification.  Metastatic Calcification Metastatic calcification in the lung of a patient with a very high serum Calcium level (Hyperplasia) Metastatic calcification, lung Pigments  PIGMENTS Pigments are colured substances which accumulate in cells. Based on the source pigments can be of two types 1. Exogenous pigments 2. Endogenous pigments  PIGMENTS (I) Endogenous Pigments 1.Lipofuscin 2. Melanin 3. Bilirubin 4. Haemosidrin (II) Exogenous Pigments 1. Anthracosis 2. Pneumoconiosis 3. Tattoing  (i) ENDOGENOUS PIGMENTS These are the pigments which are synthesized inside the body a. Lipofuscin or Wear and tear pigment: It is composed of polymers of lipid and phospholipids complexed with proteins , suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of sub cellular membranes. It is the tell tale sign of free radical injury. Microscopic appearance: Yellow brown intracytoplasmic granules. b. Melanin: Brown black pigment derived from melanocytes of skin. Examples of melanin accumulation; - Suntan - Melasma - In pregnancy c. Haemosidrin: Golden yellow to brown granular pigment. It is the form in which iron is accumulated in cells. The main storage form of iron is ferritin. But when there is local or systemic excess of iron, ferritin aggregates in the form of haemosidrin. Haemosidrosis ( increased sysmteimic accumulation of iron) is seen in: (i) Increased absorption of dietary iron. (ii) Impaired use of iron. (iii) Haemolytic anaemias , for example beta thalassaemia major (iv) Repeated blood transfusions. d. Bilirubin: Jaundice is the common clinical disorder caused by excesses of Bilirubin within cells and tissues.  Lipofuscin Accumulation The yellow brown granular pigment seen in the hepatocytes here is Lipochrome (LIpofuscin) which accumulates over time in cells (particularly liver and heart) as a result of “wear and tear” with aging. It is of no major consequence , but illustrates the end result of the process of autophago- cytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome within the cell cytoplasm  Jaundice The Sclera of the eye is yellow because the patient has jaundice, or Icterus. The normally white sclera of the eyes is a good place on physical examination to look for jaundice. Bilirubin: Yellow – green globular material seen in small bile ductules in liver  Haemosidrin granules in liver cells A: H& E showing golden brown , finely granular pigment B: Prussian Blue , specific for iron Suntan Melasma  (ii) EXOGENOUS PIGMENTS These are the pigments which come from outside the body. Anthracosis (Carbon or coal dust accumulation): It is the main pollutant of the urban life. When inhaled, it is picked up by macrophages within the alveoli and is then transported through lymphatic channels to regional lymph nodes. Accumulation of this pigment blackens the tissues of lung ( Anthracosis). b. Coal worker’s pneumoconiosis: In coal miners and those living in heavily polluted environments , the aggregates of carbon dust may induce a fibroblastic reaction or even emphysema and thus cause a serious lung disease known as coal worker’s pneumoconiosis. c. Tattooing: A form of localized exogenous pigmentation. The pigments inoculated are ingested by dermal macrophages, where they reside permanently. Anthrocosis pigment in macrophages in hilar lymph node: Anthrocosis is accumulation of carbon pigment from breathing bad sir. Smokers have the most pronounced Anthrocosis. Exogenous pigment Anthracosis of lung Tattooing Endogenous substances accumulating in tissues as a result of deranged metabolism Accumulated Effects in Effects in Substance Parenchymal cells interstitial cells Water Cloudy swelling Edema Hydropic changes Triglycerides Fatty change Cholesterol Atherosclerosis Xanthomas Complex lipids Lipid storage diseases Protein -Ubiquitin/ Protein Amylodosis complexes Glycogen Glycogen storage diseases Mucopolysaccharides Mucopolysaccharidoses Myxoid degeneration Endogenous substances accumulating in tissues as a result of deranged metabolism Accumulated Effects in Effects in Substance Parenchymal cells interstitial cells Iron Hemochromatosis Localized Haemosidrosis Calcium Contributes to necrosis Calcification Copper Wilson’s disease Wilson’s disease Bilirubin Kernicterus Jaundice Lipofuscin Brown Atrophy in old age Urate Gout Homogensitic Acid Alkaptonuria