Cellular Adaptations & Injury 2024 PDF

Cellular Adaptations and Injury- lecture 1  Cell specificity and homeostasis Each cell has a specific function Genetic setup Machinery and metabolic pathways Cell’s specific function The concept of homeostasis...

Cellular Adaptations and Injury- lecture 1  Cell specificity and homeostasis Each cell has a specific function Genetic setup Machinery and metabolic pathways Cell’s specific function The concept of homeostasis - equilibrium with external environment - maintenance of dynamically stable internal machinery - input orchestrated with output Concept of adaptation External disturbances - Physiologic - pathologic changes in cell machinery new steady state counteract external changes escape from cell injury preserve viability  Cellular adaptations Reactions induced by: - physiological stimuli - pathological stimuli. Aim: to escape cell injury The adaptive responses include:.Atrophy.Hypertrophy.Hyperplasia.Metaplasia.Dysplasia  Hypertrophy An increase in the size of cells resulting in increase in the size of the relevant organ. It is caused either by increased functional demand or by specific hormonal stimulation. Hypertrophy can be physiologic or pathologic. Physiological e.g. - athletes - mechanical workers - uterus in pregnancy (+ hyperplasia) Pathological e.g. - LVH in systemic hypertension Athletes as an example of muscular hypertrophy  Uterine hypertrophy in pregnancy On the left is a normal uterus showing the normal mass of smooth muscle in its wall. On the right is a uterus from a pregnant women, in which the striking increase in mass of smooth muscle is evident. At cellular level this is due to both hyperplasia and hypertrophy of uterine smooth muscle.  Normal Vs hypertrophied uterine smooth muscle cells A B A. Small spindle-shaped uterine smooth muscle cells from a normal uterus. Compare this with (B) large, plump hypertrophied smooth muscle cells from a gravid uterus (same magnification).  A 51-year-old male has a blood pressure of 150/95 mm Hg. If this condition remains untreated for years, which of the following cellular alterations will be seen in the heart? (A) Atrophy (B) Hyperplasia (C) Melaplasia (D) Hemosiderosis (E) Hypertrophy Comparison between normal heart (left) & hypertrophied heart (right)  Define hyperplasia. Give examples.  Hyperplasia Increase in the number of cells in an organ or tissue leading to an increase in its size. Hyperplasia and hypertrophy closely related; often occur together  Physiological and pathological HP Physiological hyperplasia : 1. Hormonal: Uterus in pregnancy. 2. Compensatory: Following partial liver resection Pathological hyperplasia: 1. Excessive hormonal stimulation: Estrogen induced endometrial hyperplasia 2. The effect of growth factors on target cells: e.g. Viral warts  Endometrial hyperplasia The prominent folds of endometrium in this uterus (opened to reveal the endometrial cavity) are an example of hyperplasia. The hyperplasia involves both endometrial glands and stroma.  Verruca vulgaris (Viral warts) Multiple papules with rough, pebble-like surfaces at infection sites Define atrophy. Give examples  Atrophy Decrease in the size of the cell ↓organ or tissue size (atrophic) It is an adaptive response Causes of atrophy 1. Decrease workload (e.g. immobilization of a limb) 2. Denervation (e.g. in poliomyelitis) 3. Ischemia 4. Under nutrition (e.g. Starvation) 5. Loss of endocrine stimulation (e.g. postmenopausal endometrial atrophy) A. Normal brain of a young adult. B. Atrophy of the brain in an old male with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain.  B A A. Is a normal testis. B. Atrophic testis Bilateral atrophy may complicate chronic alcoholism, hypopituitarism, atherosclerosis, chemotherapy or radiation, and severe prolonged illness.  Metaplasia Replacements of one mature cell type by another mature cell type Also represent a reversible adaptive response Examples 1. Squamous metaplasia of the - laryngeal and bronchial respiratory epithelium in heavy smokers - urothelium in the urinary bladder in bilharziasis 2. Columnar metaplasia of lower esophageal squamous epithelium in gastro-esophageal reflux disease. Metaplasia of normal columnar (left) to squamous epithelium (right) in a bronchus Barrett esophagus: Metaplastic transformation (arrow) of the normal esophageal stratified squamous epithelium (Lt) to mature columnar epithelium 8 A 34-year-old obese woman has experienced heartburn from gastric reflux for the past 5 years after eating large meals. She undergoes upper gastrointestinal endoscopy, and a biopsy specimen of the distal esophagus is obtained. Which of the following microscopic changes, seen in the figure, has most likely occurred? A Columnar metaplasia B Goblet cell hyperplasia C Lamina propria atrophy D Squamous dysplasia E Mucosal hypertrophy Cellular Adaptations and Injury – lecture 2  Cell injury Occurs when 1. Limits of adaptive capability exceeded 2. No adaptive response is possible Cell injury is divided into 1. Reversible 2. Irreversible cell death Stages in the cellular response to stress and injurious stimuli  Reversible cell injury occurs when the injurious agent is mild or short lived; the functional and morphologic changes are reversible. although there may be significant structural and functional abnormalities, the injury has not progressed to severe damage of the cellular membranes and nucleus that are equated with cell death. With continuing damage, the injury becomes irreversible, at which time the cell cannot recover and it dies. Types of injurious agents Hypoxia a- Ischemia b- inadequate oxygenation of blood c-reduced oxygen carrying capacity of blood. Physical agents: Trauma, burns, irradiation, etc. Chemical agents: Poisons, drugs, alcohol, etc. Infectious agents Immunological reactions Genetic derangement Nutritional imbalances Aging  Factors influencing severity of injury 1. Type and severity of injurious agent 2. Duration of exposure 3. Type of affected cells - neurons (highly susceptibility to ischemic damage) : within 3-5 min - myocardial cells-hepatocytes : 30-60 min (intermediate susceptibility) - Skeletal muscles-epidermis-fibroblasts (low susceptibility) – within hours EXAMPLES OF CELL INJURY AND NECROSIS Ischemic and Hypoxic Injury Ischemia is the most common cause of cell injury in clinical medicine. Unlike hypoxia, in which energy generation by anaerobic glycolysis can continue, in ischemia the delivery of the substrates for glycolysis is also interfered with due to cut of blood supply. Consequently, anaerobic energy generation stops in ischemic tissues. Therefore, ischemia injures tissues faster than does hypoxia.  HYPOXIA & ISCHEMIA 🡪 Loss of ATP Generation 🡪 failure of many energy-dependent systems of the affected cell, including 1. Paralysis of ion pumps (causing influx of Na+ associated with Water, and exit of K+ leading to cell swelling, and influx of Ca++) 2. Anerobic glycolysis 🡪 Depletion of glycogen stores with accumulation of lactic acid 3. Reduction in protein synthesis  Functional consequences may be severe at this stage. For instance, heart muscle ceases to contract within 60 seconds of coronary occlusion ≠ mean cell death. If hypoxia continues 🡪 worsening ATP depletion 🡪 loss of microvilli and the formation of blebs 🡪 the entire cell and its organelles (mitochondria, ER) are markedly swollen, with increased concentrations of water, sodium, and chloride and a decreased concentration of potassium. If oxygen is restored, all of these disturbances are reversible.  If ischemia persists, irreversible injury and necrosis ensue which is associated with severe swelling of mitochondria & lysosomes. extensive damage to plasma membranes, The cell's components are progressively degraded, and there is widespread leakage of cellular enzymes into the extracellular space. Massive influx of calcium into the cell may occur. Death is mainly by necrosis, but apoptosis also occur.  The leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples. Cardiac muscle, for example, contains a unique enzyme creatine kinase and the contractile protein troponin. Hepatocytes contain transaminases. Irreversible injury and cell death in these tissues are reflected in increased serum levels of such proteins, and measurement of serum levels is used clinically to assess damage to these tissues.  Cellular swelling (hydropic change) The affected hepatocytes are distended by accumulated water that imparts cytoplasmic pallor. This is the histologic appearance of hepatic fatty change. The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining.  Cell necrosis Morphological changes that follow cell death in a living tissue or organ. Resulting from degrading action of enzymes on irreversibly damaged cells with denaturation of cellular proteins. Morphological changes - cytoplasmic - nuclear Cytoplasmic changes in necrosis More eosinophilia - Loss of cytoplasmic RNA - Increased binding of eosin to the denatured proteins. More homogeneous appearance - loss of glycogen particles The cytoplasm becomes vacuolated when enzymes have digested the cytoplasmic organelles,  Nuclear changes in necrosis Pyknosis karyorrhexis karyolysis Liver cell necrosis: Nuclear changes normal pyknosis karyorrhexis karyolysis  Types of cell necrosis 1. Coagulative necrosis. 2. Liquefactive necrosis. 3. Fat necrosis 4. Caseation (caseous) necrosis 5. Gangrenous necrosis.  Coagulative necrosis Outlines of cells are still discernible, but Fine structural details lost. The nuclei are lost. The cytoplasm stains homogeneous deeply eosinophilic Sudden severe ischemia in organs cause denaturation not only of structural proteins but also of enzymes, which blocks proteolysis of the dead cells  Coagulative necrosis-kidney Normal Infarct The renal cortex has undergone anoxic injury at the left so that the cells appear pale and ghost-like. There is a hemorrhagic zone in the middle where the cells are dying or have not quite died, and then normal renal parenchyma at the far right. This is an example of coagulative necrosis Within the area of necrosis (Lt) the outlines of tubules and glomeruli are still preserved but fine structural details are lost (inset) A 63-year-old man has a 2-year history of worsening congestive heart failure. An echocardiogram shows mitral valve stenosis with left atrial dilation. A mural thrombus is present in the left atrium. One month later, he experiences left flank pain and notes hematuria. Laboratory testing shows an elevated serum AST. The representative microscopic appearance of the lesion is shown in the figure. Which of the following patterns of tissue necrosis is most likely to be present in this man? A Caseous B Coagulative C Fat D Gangrenous E Liquefactive  Coagulative necrosis Kidney Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is present  Coagulative necrosis myocardium The necrotic myocytes are intensely eosinophilic with loss of both cross striations & nuclei. The outlines of individual fibres are still maintained. There are inflammatory cells infiltration & RBCs in-between the necrotic fibers.  A 50-year-old man has experienced an episode of chest pain for 6 hours. A representative histologic section of his left ventricular myocardium is shown in the figure. There is no hemorrhage or inflammation. Which of the following conditions most likely produced these myocardial changes? A Arterial thrombosis B Autoimmunity C Blunt chest trauma D Protein-deficient diet E Viral infection  Liquefaction (liquefactive) necrosis Seen in two situations Ischemic destruction of brain tissue Bacterial infections e.g. abscesses complete digestion of dead cells by enzymes cyst filled with debris + fluid Lung abscess This is an example of liquefactive necrosis. There is confluent broncho- pneumonia (scattered pale areas) complicated by abscess formation, which is seen here as a cystic cavity (arrow). The contained pus poured off during the sectioning of the lung tissue. Brain infarction: This is an example of liquefactive necrosis; the affected area is wedge-shaped, pale, soft & cystic.  Gangrene Gangrenous necrosis A term used in surgical practice: lower limb, intestine Gangrene = coagulative necrosis (ischemia) + liquefactive necrosis (bacterial infection) Two subtypes 1- Dry gangrene 2- Wet gangrene  Ganagrene of lower limb Dry gangrene Wet gangrene  CASEOUS NECROSIS B A A- A tuberculous lung with a large area of caseous necrosis containing yellow-white and cheesy debris. B- Caseous necrosis in a hilar lymph node infected with tuberculosis. The node has a cheesy yellow to white appearance. Caseous necrosis is really just a combination of coagulative and liquefactive necrosis A screening chest radiograph of an asymptomatic 37-year-old man shows a 3-cm nodule in the middle lobe of his right lung. The nodule is excised with a pulmonary wedge resection, and sectioning shows a sharply circumscribed mass with a soft, white center. The microscopic appearance is shown in the figure. The serum interferon gamma release assay is positive. Which of the following pathologic processes has most likely occurred in this nodule? A Apoptosis B Caseous necrosis C Coagulative necrosis D Fat necrosis E Fatty change F Gangrenous necrosis G Liquefactive necrosis Caseating TB granuloma Caseous necrosis is characterized by amorphous (acellular), granular pink areas of necrosis, surrounded by a granulomatous inflammatory process.  Normal A B Identify the organ? Describe the gross pathological changes in B?  Fat necrosis of acute pancreatitis Injury to the pancreatic acini leads to release of powerful enzymes which damage fat through lipases; these liberate fatty acids which complex with calcium leading to the production of soaps, and these appear grossly as the soft, chalky white areas seen here on the cut surfaces.  Fat necrosis Involves adipose tissue Mediated through lipases Seen in 1. acute pancreatitis 2. breast trauma (traumatic fat necrosis) Grossly chalky white Microscopically: - shadowy outlines of necrotic cells - surrounding inflammatory cells - calcium soaps: bluish deposits Acute pancreatitis A, The microscopic field shows a region of fat necrosis (right), and focal pancreatic parenchymal necrosis (center). B, The pancreas has been sectioned longitudinally to reveal dark areas of hemorrhage in the pancreatic substance and a focal area of pale fat necrosis in the peripancreatic fat (arrow).  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. A 38-year-old woman has experienced severe abdominal pain over the past day. On examination she is hypotensive and in shock. Laboratory studies show elevated serum lipase. From the representative gross appearance of the mesentery shown in the figure, which of the following events has most likely occurred? A Acute pancreatitis B Gangrenous cholecystitis C Hepatitis B virus infection D Small intestinal infarction E Tuberculous lymphadenitis  Acute pancreatitis The fat necrosis consists of fat cells that have lost their nuclei and whose cytoplasm has a granular pink appearance. Some hemorrhage is seen at the left in this case. Cellular Adaptations and Injury – lecture 3  SUBCELLULAR RESPONSES TO INJURY Certain agents and stresses induce distinctive alterations involving only subcellular organelles. Some of these occur in acute lethal injury, others are seen in chronic forms of cell injury, and still others are adaptive responses. 1- Autophagy Refers to lysosomal digestion of the cell's own components. It is a survival mechanism whenever there is nutrient deprivation; the starved cell lives by eating its own contents. In this process, intracellular organelles are first sequestered in an autophagic vacuole which fuses with lysosomes to form an autophagolysosome, & the cellular components are digested by lysosomal enzymes. Autophagy and heterophagy  Lung: coal worker’s pneumoconiosis Anthracotic pigment ordinarily is not fibrogenic, but in massive amounts (as in "black lung disease" in coal miners) a fibrogenic response can be elicited to produce excessive collagenous fibrosis impregnated with the black pigment. Skin tattoo. The pigment in tattoos is transferred to the dermis with a needle. This is the microscopic appearance of tattoo pigment (black) in the dermis. This pigment is well within the dermis in phagolysosomes of macrophages and, difficult to remove. On day 28 of the menstrual cycle in a 23-year-old female, there is menstrual bleeding that lasts for a few days She has had these regular cycles for many years. Which of the following processes is most likely happening in the endometrium just before the onset of bleeding? (A) Apoptosis (B) Caseous necrosis (C) Heterophagocytosis (D) Atrophy (E) Liquefactive necrosis  Apoptosis This form of cell death is a regulated suicide program in which the relevant cells activate enzymes (CASPASES) capable of degrading the cells' own nuclear DNA and other nuclear and cytoplasmic proteins.  Apoptotic cells may appear as round or oval masses with intensely eosinophilic cytoplasm. Nuclei show chromatin condensation and aggregation and, ultimately fragmentation (karyorrhexis). The cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytoplasm and organelles. Fragments of the apoptotic cells then break off (apoptosis = "falling off"). These fragments are quickly extruded and phagocytosed without eliciting an inflammatory response. Even substantial apoptosis may be histologically undetectable. DNA Damage: Exposure of cells to radiation or cytotoxic anticancer chemotherapeutic agents & extremes of temperature induces DNA damage. When DNA is damaged, the p53 protein accumulates in cells. It first arrests the cell cycle (at the G1 phase) to allow time for repair. However, if the damage is too great to be repaired successfully, p53 triggers apoptosis by stimulating synthesis of pro-apoptotic members of the Bcl-2 family.  When p53 is mutated or absent, it is incapable of inducing apoptosis, so that cells with damaged DNA are allowed to survive. This enhances the possibility of mutations or translocations that lead to neoplastic transformation and subsequently providing the tumor cells with a growth advantage. Accumulation of Misfolded Proteins In normal protein synthesis, chaperones (escorters) in the ER control the proper folding of newly synthesized proteins Misfolded polypeptides are targeted for proteolysis. If, unfolded or misfolded proteins accumulate in the ER because of inherited mutations or stresses, they induce "ER stress" that triggers a number of cellular responses ( called the unfolded protein response) a- activation of signaling pathways that increase the production of chaperones and retard protein translation, thus reducing the levels of misfolded proteins in the cell. b- Failing to cope with the accumulation of misfolded proteins🡪 the activation of caspases 🡪 apoptosis. Intracellular accumulation of abnormally folded proteins is a feature of a number of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases, and possibly type II diabetes. The cytoplasm is intensely esoniphilic (pinkish) and the nucleus condensed (pyknotic) MECHANISMS OF INTRACELLULAR ACCUMULATIONS Abnormal metabolism, as in fatty change in the liver. Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly. Failure to degrade a metabolite a. A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases. a b. An inability to degrade phagocytosed particles, as in carbon pigment accumulation.  Effects 1. No effect (harmless) 2. Severe toxicity Sites of accumulation 1. Nuclear 2. Cytoplasmic (lysosomal)  Lipid accumulations (fatty change) This is the abnormal accumulation of triglycerides within parenchymal cells, most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in the heart. Causes of fatty change include 1. Toxins including alcohol 2. Diabetes mellitus 3. Obesity 4. Protein malnutrition 5. Anoxia Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations. Normal Fatty change  Severe fatty changes In the liver mild fatty change shows no gross changes, but with progressive accumulation, the organ enlarges and become increasingly yellow, soft and greasy to touch. This is the histologic appearance of hepatic fatty change. The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining.  A 46-year-old man has noted increasing abdominal size for the past 6 years. On physical examination his liver span is increased to 18 cm. An abdominal CT scan shows an enlarged liver with diffusely decreased attenuation. Laboratory findings include increased total serum cholesterol and triglyceride levels, increased prothrombin time, and a decreased serum albumin concentration. The representative microscopic appearance of his liver is shown in the figure. Which of the following activities most likely led to these findings? A Drinking beer B Ingesting aspirin C Injecting heroin D Playing basketball E Smoking cigarettes A coronary artery has been opened longitudinally; it is surrounded by epicardial fat. This coronary shows occasional yellow-tan lipid plaque and no narrowing.  Coronary atherosclerosis A B A B A: the lumen of the artery is at the top, and the band of smooth muscle at the bottom is the atrophic media. The intima is enormously thickened, by the presence of amorphous material containing large numbers of cholesterol crystals (the unstained clefts). There are many foamy (lipid-filled) macrophages. B: This high magnification of the atheroma shows numerous foam cells and an occasional cholesterol cleft. Xanthoma tuberosum multiplex Cutaneous xanthoma showing in patient with ill-defined collection of foamy hypercholesterolemia macrophages in the dermis  Protein accumulations Seen in Plasma cells : excessive accumulation of immunoglobulins 🡪 round eosinophilic Russel bodies. In Alzheimer disease The neurofibrillary tangle found in the brain in is an aggregated protein inclusion that contains microtubule-associated proteins and neurofilaments, a reflection of a disrupted neuronal cytoskeleton  Protein reabsorption droplets in the renal tubular epithelium In nephrotic syndrome, there is a abnormally large reabsorption of the protein. Pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets  Alcoholic hepatitis Eosinophilic Mallory bodies are seen in hepatocytes in alcoholism. (arrows) They represent aggregated non-degradable intermediate filaments  Glycogen accumulations Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. In poorly controlled diabetes mellitus, glycogen accumulates in : renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans.  In the genetic disorders collectively referred to as glycogen storage diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive intracellular accumulations, with secondary injury and cell death Seen as clear cytoplasmic vacuoles. PAS stain routinely used for demonstration  Pigments Colored substances Divided into 1. normal constituents e.g. melanin 2. Abnormal a. endogenous b. exogenous. Exogenous pigments The most common of these is carbon (an example is coal dust), a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes 🡪 (anthracosis). Heavy accumulations may induce fibroblastic reaction that can result in a serious lung disease called coal workers' pneumoconiosis  Lung: coal worker’s pneumoconiosis Anthracotic pigment ordinarily is not fibrogenic, but in massive amounts (as in "black lung disease" in coal miners) a fibrogenic response can be elicited to produce excessive collagenous fibrosis impregnated with the black pigment.  Pigmented nevi Melanin is an endogenous, brown-black pigment produced in melanocytes By a tyrosinase-catalyzed oxidation of tyrosine to dihydroxyphenylalanine. In the epidermis it acts as a screen against harmful ultraviolet radiation. Although melanocytes are the only source of melanin, adjacent basal keratinocytes  Hemosiderin is a hemoglobin-derived iron containing granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. The iron can be identified by the Prussian blue histochemical reaction (Perl’s stain) Local excesses of iron, and consequently of hemosiderin, result from hemorrhage, bruises, hematomas, etc.  In systemic overload of iron, hemosiderin is deposited in many organs and tissues including their macrophages. This condition is called hemosiderosis. With progressive accumulation, parenchymal cells throughout the body (but principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment. Hemosiderosis occurs in the setting of 1. Increased absorption of dietary iron 2. Impaired utilization of iron 3. Hemolytic anemias, and 4. Excessive blood transfusions (the transfused red cells constitute an exogenous load of iron). In most instances of systemic hemosiderosis, the iron pigment does not damage the parenchymal cells or impair organ function despite an impressive accumulation. However, more extensive accumulations of iron are seen in hereditary hemochromatosis, with tissue injury including liver fibrosis, heart failure, and diabetes mellitus. Hemochromatosis: liver, pancreas, and lymph node The dark brown color of the liver, as well as the pancreas (bottom center) and lymph nodes (bottom right) on sectioning is due to extensive iron deposition in a middle-aged man with hereditary hemochromatosis.  Hemosiderin granules liver cells A B A: H&E stained section showing hemosiderin as yellow-brown finely granular pigment within hepatocytes. B: same section stained with an iron stain (Prussian blue); the hemosiderin granules are deep blue.  Calcification Pathologic calcification implies the abnormal deposition of calcium salts. Dystrophic calcification occurs in the absence of calcium metabolic abnormalities. It is noted in - Areas of necrosis - Advanced atherosclerosis - Aging or damaged heart valves Gross features - fine, white granules or chalky gritty material. Microscopic features - basophilic (bluish), amorphous granules or larger clumps. - Sometimes as rounded lamellar fashion at a nidus of necrotic cells (psammoma bodies) as in papillary carcinoma and meningioma  Calcification of the aortic valve. A view looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each cusp are large, irregular masses of dystrophic calcification that will prevent normal opening of the cusps.  A 72-year-old man died suddenly from congestive heart failure. At autopsy, his heart weighed 580 g (normal 330 g) and showed marked left ventricular hypertrophy and minimal coronary arterial atherosclerosis. A serum chemistry panel ordered before death showed no abnormalities. Which of the following pathologic processes best accounts for the appearance of the aortic valve seen in the figure? A Amyloidosis B Dystrophic calcification C Hemosiderosis D Hyaline change E Lipofuscin deposition Metastatic calcification seen in cases of hypercalcemia of any cause principally affects - blood vessels - kidneys (nephrocalcinosis) 🡪 renal damage - lungs (radio-opaque deposits) - gastric mucosa. The four major causes of hypercalcemia are 1. Increased secretion of parathyroid hormone, (primary parathyroid tumors or production of parathyroid hormone-related protein by other malignant tumors) 2. Destruction of bone (effects of accelerated turnover as in Paget disease, immobilization, or tumors due to increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases 3. vitamin D-related disorders including vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor) 4. Renal failure, in which phosphate retention leads to secondary hyperparathyroidism.