Cell injury and Necrosis Flashcards

Question

Myocardial infarct In recent MI, there is extensive hemorrhage along with myocardial fiber necrosis with contraction bands and loss of nuclei

Answer 1

Myocardial infarct This myocardial infarction is 3-4 days old. There is extensive acute inflammatory cell infiltrate and myocardial fibers are so necrotic that the outlines are barely visible

Answer 2

Myocardial infarct pale white collagen within intersititum between myocardial fibers. Represents an area of remote infarcion

Answer 3

Normal heart External appearnce of a normal heart has smooth and glistening epicardial surface with normal epicardial fat. The left anterior descening coronary a. extends from apex root to apex.

Answer 4

* cardiac arrythmias 75-95% of complicated cases * left ventricular congestive failure(60%) * pulmonary edema(60%) * cardiogenic shock(10-15%) * rupture of free wall, septum or papillary m.(1-5%) * thromboembolism * aneursyms of the heart * epicarditis * death of a patient * complication of transmural myocardial infarction is rupture of the myocardium which most likely occurs in teh 1st week, 3-5 days following the initial event, when the myocardium is the softest. The white arrow maks the point of rupture in the anterior inferior MI of left ventricular free wall and septum. Dark red blood clot forms the hemopericardium which can lead to tamponade. * In the cross section the point of rupture is seen with the white arrow, in this case there was a previous MI 3 weeks before, and another myocardial infarction occurred rupturing through the thin ventricular wall 3 days later * there can be mural thrombus over myocardial infarct

Answer 5

* soft fribale necrotic tissue with white resembling cream cheese(white cottage cheese like appearance) * combination of coagulative and liquefactive necrosis * characteristic of granulomatous inflammation due to TB or systemic fungal infection(histoplasma and capsulatrum) and nocardia * gross appearance of caseous necrosis in hilar lymph node affected with tuberculosis, the node has chessy tan to white appearance * more extensive caseous necrosis, with confluent cheesy tan granulomas in the upper portion of this lung in a patient with tuberculosis. * The tissue destruction is so extensive that there are areas of cavitation (cystic spaces) being formed as the necrotic (mainly liquefied) debris drains out via the bronchi * occurs due to macrophages that wall of the infecting microorganism leading to granular debris * Caseous necrosis involves fragmented cells and debris surround lymphocytes and macrophages(granulomas) * dead cells form an amorphous proteinaceous mass but in contrast to coagulative necrosis, no original architecture can be seen histlgically * On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in H&Estained tissue sections.

Answer 6

Note the pink, amorphous region in the center of this granuloma at the upper right, and ringed by epithelioid cells at the left and lower areas of this photomicrograph. This is the microscopic appearance of caseous necrosis.

Answer 7

* Fat necrosis is necrotic adipose tissue with chalky white appearance due to deposition of calcium(saponification). * Saponification is due to fatty acids release ot lipase joining with Ca. Fat necrosis refers to focal areas of fat destruction, typically resulting from the release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. * can be enzymatic or non enzymatic * Enzymatic: acute pancreatitis due to saponification of peripancreatic fat. Damaged pancreatic cells release lipase which breaks down triglycerides, liberates fatty acids and bind calcium In this disorder, pancreatic enzymes that have leaked out of acinar cells and ducts liquefy the membranes of fat cells in the peritoneum, and lipases split the triglyceride esters contained within fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions. * Non enzymatic: trauma to breast fat due to car accident, or sports, giant cells with calcification * On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits and an inflammatory reaction.

Answer 8

* In acute pancreatitis the pancreas appears oedematous and is commonly haemorrhagic * Pancreatic tissue becomes necrotic and sometimes semi-liquid * Lipase relased from the pancreatic acini causes the development of foci of fat necrosis (white spots in mesenteric and retroperitoneal fat) with adjacent retroperitoneal infllammation * Predisposing factors of acute pancreatitis * Mechanical obstruction of pancreatic ducts (gallstones, trauma, post-operative) * Metabolic, toxic causes (alcohol, drugs, hypercalcemia, hyperlipoproteinaemia) * Vascular- poor perfusion (atherosclerosis, hypothermia) * Infections (mumps)

Answer 9

* Acute pancreatitis is a reversible inflammatory disorder that varies in severity, from focal edema and fat necrosis to widespread hemorrhagic necrosis. * This is a relatively common condition, with an annual incidence of 10 to 20 per 100,000 people in the Western world. * The most common cause of acute pancreatitis in the United States is the impaction of gallstones within the common bile duct, impeding the flow of pancreatic enzymes through the ampulla of Vater (“gallstone pancreatitis”); this is closely followed by pancreatitis secondary to excessive alcohol intake. * Overall, gallstones and alcoholism account for greater than 80% of acute pancreatitis cases, with the remaining caused by a multitude of factors (Table 17.1). These include the following: * Non–gallstone-related obstruction of the pancreatic ducts (e.g., due to pancreatic cancer or other periampullary neoplasms, pancreas divisum, biliary “sludge,” or parasites, particularly Ascaris lumbricoides and Clonorchis sinensis) * Medications including anti-convulsants, cancer chemotherapeutic agents, thiazide diuretics, estrogens, and more than 85 others in clinical use * Infections with mumps virus or coxsackievirus, which can directly infect pancreatic exocrine cells * Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states * Ischemia due to vascular thrombosis, embolism, vasculitis, or shock * Trauma, both blunt force and iatrogenic during surgery or endoscopy * Germline mutations involving genes encoding pancreatic enzymes or their inhibitors. For example, hereditary pancreatitis is a rare autosomal dominant disease with 80% penetrance that is characterized by recurrent attacks of severe pancreatitis, usually beginning in childhood. It is caused by mutations in the PRSS1 gene, which encodes trypsinogen, the proenzyme of pancreatic trypsin. The pathogenic mutations alter the site through which trypsin cleaves and inactivates itself, abrogating an important negative feedback mechanism. This defect leads not only to the hyperactivation of trypsin, but also to the hyperactivation of many other digestive enzymes that require trypsin cleavage for their activation. As a result of this unbridled protease activity, the pancreas is prone to autodigestion and injury. Loss-of-function mutations in genes that encode protease inhibitors such as SPINK1 are less commonly associated with hereditary pancreatitis

Answer 10

* **Acute pancreatitis appears to be caused by autodigestion of the pancreas by inappropriately activated pancreatic enzymes.** * Once activated trypsin is capable of converting other zymogen forms of pancreatic enzymes to their active forms. * Premature activation of trypsin within the substance of the pancreas can unleash these proenzymes (e.g., phospholipases and elastases), leading to tissue injury and inflammation. * Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems * Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis: * Pancreatic duct obstruction. Impaction of a gallstone or biliary sludge, or extrinsic compression of the ductal system by a mass blocks ductal flow, increases intraductal pressure, and allows accumulation of an enzymerich interstitial fluid. Since lipase is secreted in an active form, local fat necrosis may result. Injured tissues, periacinar myofibroblasts, and leukocytes then release proinflammatory cytokines that promote local inflammation and interstitial edema through a leaky microvasculature. Edema further compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells. * Primary acinar cell injury. This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas. * Defective intracellular transport of proenzymes within acinar cells. In normal acinar cells, digestive enzymes intended for zymogen granules (and eventually extracellular release) and hydrolytic enzymes destined for lysosomes are transported in discrete pathways after synthesis in the endoplasmic reticulum. However, at least in some animal models of metabolic injury, pancreatic proenzymes and lysosomal hydrolases become packaged together. This results in proenzyme activation, lysosomal rupture (action of phospholipases), and local release of activated enzymes. The role of this mechanism in human acute pancreatitis is not clear. * **Alcohol consumption may cause pancreatitis by several mechanisms**. Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi (the muscle regulating the flow of pancreatic juice through papilla of Vater). Alcohol also has direct toxic effects on acinar cells, including induction of oxidative stress in acinar cells, which leads to membrane damage (discussed later). Finally, chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts.

Answer 11

* **Abdominal pain is the cardinal manifestation of acute pancreatitis.** Its severity varies from mild and uncomfortable to severe and incapacitating. Acute pancreatitis is diagnosed primarily by the presence of elevated plasma levels of amylase and lipase and the exclusion of other causes of abdominal pain. In 80% of cases, acute pancreatitis is mild and self-limiting; the remaining 20% develop severe disease. * **Full-blown acute pancreatitis is a medical emergency of the first order.** Affected individuals usually experience the sudden calamitous onset of an “acute abdomen” with pain, guarding, and the ominous absence of bowel sounds. Characteristically, the pain is constant, intense and referred to the upper back, steatorrhea(oily smelly stools), weight loss; it must be differentiated from pain of other causes such as perforated peptic ulcer, biliary colic, acute cholecystitis with rupture, and occlusion of mesenteric vessels with infarction of the bowel. * The manifestations of severe acute pancreatitis are attributable to systemic release of digestive enzymes and explosive activation of the inflammatory response. The initial clinical evaluation may reveal leukocytosis, disseminated intravascular coagulation, acute respiratory distress syndrome (due to diffuse alveolar damage) , and diffuse fat necrosis. Peripheral vascular collapse (shock) can rapidly ensue as a result of increased microvascular permeability and resultant hypovolemia, compounded by endotoxemia (from breakdown of the barriers between gastrointestinal flora and the bloodstream), and renal failure due to acute tubular necrosis. **Laboratory findings include markedly elevated serum amylase during the first 24 hours, followed (within 72–96 hours) by rising serum lipase levels**. Hypocalcemia can result from precipitation of calcium in areas of fat necrosis; if persistent, it is a poor prognostic sign. The enlarged inflamed pancreas can be visualized by computed tomography (CT) or magnetic resonance imaging (MRI). The crux of the management of acute pancreatitis is supportive therapy (e.g., maintaining blood pressure and alleviating pain) and “resting” the pancreas by total restriction of oral food and fluids. In 40% to 60% of cases of acute necrotizing pancreatitis, the necrotic debris becomes infected, usually by gram-negative organisms from the alimentary tract, further complicating the clinical course. Although most individuals with acute pancreatitis eventually recover, some 5% die from shock during the first week of illness; acute respiratory distress syndrome and acute renal failure are ominous complications. In surviving patients, sequelae include sterile or infected pancreatic “abscesses” or pancreatic pseudocysts. * Pancreatic Pseudocysts * A common sequela of acute pancreatitis (and in particular, alcoholic pancreatitis) is a pancreatic pseudocyst. Liquefied areas of necrotic pancreatic tissue become walled off by fibrous tissue to form a cystic space, lacking an epithelial lining (hence the designation pseudo). The cyst contents are rich in pancreatic enzymes, and a laboratory assessment of the cyst aspirate can be diagnostic. Pseudocysts account for approximately 75% of all pancreatic cysts. While many pseudocysts spontaneously resolve, they can become secondarily infected, and larger pseudocysts can compress or even perforate into adjacent structures

Answer 12

Fat necrosis Microscopically, fat necrosis adjacent to pancreas is seen here. There are some remaining steatocytes at the left which are not necrotic. The necrotic fat cells at the right have vague cellular outlines, have lost their peripheral nuclei, and their cytoplasm has become a pink amorphous mass of necrotic material.

Answer 13

* The basic alterations in acute pancreatitis are (1) microvascular leakage causing edema, (2) necrosis of fat by lipases, (3) an acute inflammatory reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of blood vessels leading to interstitial hemorrhage. * In mild forms, there is interstitial edema and focal areas of fat necrosis in the pancreas and peripancreatic fat (Fig. 17.2A). Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids combine with calcium to form insoluble salts that precipitate in situ. * In more severe forms, such as acute necrotizing pancreatitis, the damage also involves acinar and ductal cells, the islets of Langerhans, and blood vessels. Macroscopically, the pancreas exhibits red-black hemorrhagic areas interspersed with foci of yellow-white, chalky fat necrosis (Fig. 17.2B). Fat necrosis also can occurin extrapancreatic fat,including the omentum and bowel mesentery, and even outside the abdominal cavity (e.g., in subcutaneous fat). In most cases, the peritoneum contains a serous, slightly turbid,brown-tinged fluid with globules of fat(derived from enzymatically digested adipose tissue). In the most severe form, hemorrhagic pancreatitis, extensive parenchymal necrosis is accompanied by diffuse hemorrhage within the substance of the gland

Answer 14

Foci of hard, yellow material seen in dead adipose tissue. The reaction can occur after liberation of pancreatic enzymes into the peritoneal cavity, following inflammation of the pancreas. It may also be seen after trauma to fat, for example in the breast.

Answer 15

* necrotic tissue that becomes liquified due to enzymatic lysis of cells and proteins. Dead tissue appears semi-liquid as a result of dissolution of tissue by the action of hydrolytic enzymes. * Characteristic of brain infarction due to arterial occlusion, abcesses and pancreatitis and necrosis casued by bacterial infections * In brain the huge lysosomal content in neurons, together in the relative lack of extracellular proteins leads to rapid loss of tissue architecture and activating lysosomal enzymes.In bacterial infection, mico-organisms atrract neutrophils into the area, which then relase neutrophil hydrolases. * ex: encephalomalacia- necrosis of the brain * Liquefactive necrosis is seen in focal bacterial and,occasionally, fungal infections because microbes stimulate rapid accumulation of inflammatory cells, and the enzymes of leukocytes digest (“liquefy”) the tissue. For obscure reasons, hypoxic death of cells within the central nervous system often evokes liquefactive necrosis (Fig. 2.7).Whatever the pathogenesis, the dead cells are completely digested,transforming the tissue into a viscous liquid that is eventually removed by phagocytes. If the process is initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus

Answer 16

What is the morphology of encephalomalacia? * 6 – 48 hr - the tissue is pale, swallen, soft and the corticomedullary junction becomes indistinct * 2 – 10 days – brain becomes gelatinous and friable, the border between necrotic and healthy tissue is more distinct; edema in the adjactent tissue is resolved * 10 days – 3 weeks – the tissue liquefies and eventually is removed, leaving a fluid – filled cavity lined by dark grey tissue * After 12 hr ishemic neuronal changes and edema predominate * Endothelial and glial cells swell and myelinated fibers begin to desintegrate * Activation of microglial cells, histiocytes and macrophages from circulation come near the necrotic place * The basic cells that take part in „cleaning” process are astrocytes * After several months we can see a cavity with astrocytes at the cavity wall

Answer 17

Necrosis of the brain The neurons are the most sensitive cells to anoxic injury. Seen here are red neurons which are dying as a result of hypoxia.

Answer 18

Necrosis of the brain Here is a large remote cerebral infarction. Resolution of the infarction has left a huge cystic space encompassing much of the cerebral hemisphere in this neonate.

Answer 19

Necrosis of the brain This cerebral infarction demonstrates the presence of many macrophages at the right which are cleaning up the lipid debris from the liquefactive necrosis.

Answer 20

Cessation of blood flow flow chart

Answer 21

* Characteristic of ischemia of lower limb and GI tract * Type of coagultive necrosis with mummified tissue (dry gangrene) when the lower leg has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers. and if superimposed infection occurs then liquefactive necrosis occurs (wet gangrene) because of the destructive contents of the bacteria and the attracted leukocytes. Ex of wet gangrene occurs in the foot of dibaetc patient, partial occlusion of popliteal a. due to atherosclerosis

Answer 22

* Fibrinoid necrosis is necrotic damage to blood vessel wall and leaking of proteins into the vessel wall creats bright pink staining. * Characterstic in malignant hypertension, preeclampsia(fibrinoid necrosis of placenta) or vasculitis. It usually occurs in immune reactions(PAN) in which complexes of antigens and antibodies are deposited in the walls of blood vessels. * Deposited immune complexes(type III hypersensitivity reaction) and plasma proteins(fibrin) that leak into the wall of damaged vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid (fibrinlike) by pathologists. The immunologically mediated diseases (e.g., polyarteritis nodosa) in which this type of necrosis

Answer 23

* Organ is in homeostasis with physiologic stress placed on it. Increase, decrease or change in stress on an organ can result in growth adaptations * cellular adaptations are reversible changes that are physiologic or pathologic. Persisten or excessice stress causes adaptations to progress to cell injury * In response to persistent stress, a cell dies or adapts. At the cellular level it is more appropriate to speak of chronic adaptation than of chronic injury * The major adaptive responses are atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia, and intracellular storage. * In addition, certain forms of neoplasia may follow adaptive responses. * Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment. Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy), or to the demands of mechanical stress (in the case of bones and muscles). Pathologic adaptations(myocardial hypertrophy leading o systemic hypertension) are responses to stress that allow cells to modulate their structure and function and thus escape injury, but at the expense of normal function, such as squamous metaplasia of bronchial epithelium in smokers.

Answer 24

* Hypertrophy refers to an increase in the size of cells, that results in an increase in the size of the affected organ. * Hypertrophy can be **physiologic or pathologic**; is caused by increased functional demand or by stimulation by hormones and growth factors. it involves gene activation, protein synthesis and production of organelles(increase mitochondria and other organelles or cytokeleton means increase in size which are intracellular structural components) * Hypertrophy occurs when cells have a limited capacity to divide. Hypertrophy and hyperplasia also can occur together, and obviously both result in an enlarged organ * The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen stimulated smooth muscle hypertrophy and smooth muscle hyperplasia * Only cardiac myoctyes, skeletal m and nerves undergo hypertrophy becuase permamnet tissues cannot make new cells * In contrast, in response to increased workload the **striated muscle cells in both the skeletal muscle and the heart** undergo only hypertrophy because adult muscle cells have a limited capacity to divide. Therefore, the chiseled physique of the avid weightlifter stems solely from the hypertrophy of individual skeletal muscles. * An example of pathologic hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease. The differences between normal, adapted, and irreversibly injured cells are illustrated by the responses of the heart to different types of stress. Myocardium subjected to a persistently increased workload, as in hypertension or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to generate the required higher contractile force. If, on the other hand, the myocardium is subjected to reduced blood flow (ischemia) due to an occluded coronary artery, the muscle cells may undergo injury.

Answer 25

Myocardial hypertrophy * Pressure overloaded ventricles develope concentric hypertrophy of the left ventricle, with an increased wall thickness and reduced cavity diameter * Volume overloaded ventricles develope hypertrophy accompained by dilation with increased ventricular diameter * Heart with both hypertrophy and dilation has occured may have increased, decreased or normal wall thickness (wall thickness not necessarily correlate with pathologic state) * Cardiac hypertrophy constituites a tenuous balance between adaptive characteristics (including new sarcomers) and potentially biochemical and molecular alterations (decrease capillary –to –myocyte ratio, synthesis abnormal proteins) * Sustained cardiac hypertrophy often leads to cardiac failure * Heart weigh usually ranges to 600 g, in pulmonary hypertension to 800g, in systemic hypertension to 1000g (sometimes more than 1000g) * Increased myocyte size is usually acompained by decrese capillary density, increased capillary distance, and deposition of fibrous tissue(decrease capillary –to –myocyte ratio, synthesis abnormal proteins) * The molecular and cellular changes in hypertrophied heart ( synthesis of abnormal, dysfunctional proteins) may contribute to development of heart failure * Loss of myocytes because of apoptosis may contribute to progressive myocardial disfunction

Answer 26

Myocardial Hypertrophy The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. The myocardial fibers have undergone hypertrophy.

Answer 27

* The mechanisms driving cardiac hypertrophy involve at least two types of signals: mechanical triggers, such as stretch, and soluble mediators that stimulate cell growth, such as growth factors and adrenergic hormones. * These stimuli turn on signal transduction pathways that lead to the induction of a number of genes, which in turn stimulate synthesis of many cellular proteins, including growth factors and structural proteins. * The result is the synthesis of more proteins and myofilaments per cell, which increases the force generated with each contraction, enabling the cell to meet increased work demands. * There may also be a switch of contractile proteins from adult to fetal or neonatal forms. For example, during muscle hypertrophy, the α-myosin heavy chain is replaced by the fetal β form of the myosin heavy chain, which produces slower, more energetically economical contraction. * **An adaptation to stress such as hypertrophy can progress to functionally significant cell injury if the stress is not relieved.** Whatever the cause of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the increased burden. When this happens in the heart, several degenerative changes occur in the myocardial fibers, of which the most important are fragmentation and loss of myofibrillar contractile elements. Why hypertrophy progresses to these regressive changes is incompletely understood. There may be finite limits on the abilities of the vasculature to adequately supply the enlarged fibers, the mitochondria to supply ATP, or the biosynthetic machinery to provide sufficient contractile proteins or other cytoskeletal elements. The net result of these degenerative changes is ventricular dilation and ultimately cardiac failure.

Answer 28

* Hyperplasia is defined as an increase in the number of cells in an organ or tissue in response to a stimulus. * Increased stress leads to increase in organ size * Controlled proliferation of stem cells and differentiated cells which causes increase in number of cells * Hyperplasia takes place if the tissue contains cell populations capable of replication; it may occur concurrently with hypertrophy and often in response to the same stimuli. * Hyperplasia can only take place if the tissue contains cells capable of dividing. It can be **physiologic** (smooth m of uterus in pregnancy, where hypertrophy also takes place) or **pathologic** (endometrial hyperplasia to dysplasia to endometrial carcinoma, only exception is benigh prostatic hyperplasia) and cellular proliferation is stimulated by growth factors that are produced by a variety of cell types. * The two types of physiologic hyperplasia are (1) **hormonal hyperplasia**, exemplified by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and (2) **compensatory hyperplasia**, in which residual tissue grows after removal or loss of part of an organ. For example, when part of a liver is resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal size. The stimuli for hyperplasia in this setting are polypeptide growth factors produced by uninjured hepatocytes as well as nonparenchymal cells in the liver. After restoration of the liver mass, various growth inhibitors turn off cell proliferation. * Most forms of **pathologic hyperplasia** are caused by excessive hormonal or growth factor stimulation. For example, after a normal menstrual period there is a burst of uterine epithelial proliferation that is normally tightly regulated by the stimulatory effects of pituitary hormones and ovarian estrogen and the inhibitory effects of progesterone. A disturbance in this balance leading to increased estrogenic stimulation causes endometrial hyperplasia, which is a common cause of abnormal menstrual bleeding. Benign prostatic hyperplasia is another common example of pathologic hyperplasia induced in responses to hormonal stimulation by androgens. * Stimulation by growth factors also is involved in the hyperplasia that is associated with certain viral infections; for example, **papillomaviruses** cause skin warts and mucosal lesions that are composed of masses of hyperplastic epithelium. Here the growth factors may be encoded by viral genes or by the genes of the infected host cells * **An important point is that in all of these situations, the hyperplastic process remains controlled; if the signals that initiate it abate, the hyperplasia disappears**. It is this responsiveness to normal regulatory control mechanisms that distinguishes pathologic hyperplasias from cancer, in which the growth control mechanisms become permanently dysregulated or ineffective. Nevertheless, in many cases, pathologic hyperplasia constitutes a fertile soil in which cancers may eventually arise. For example, patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer

Answer 29

* Adaptive responses result in reduced mass tissue, decrease in stress of an organ means decrease in organ size and number of cells * decrease in cell number due to apoptosis * decrease in cell size due to ubiqutinin proteasome degradation of cytoskeleton or autp[hagy of cellular components * Causes: Reduced functional demand and loss of blood supply, reduction in hormonal stimuli, or reduction in nutrients are the usual stimuli which cause involution or cell atrophy. * When appropriate stimulation or demand returns, the tissue reverts to a normal pattern of growth. * For example, after immobilization of a limb in a cast as treatment for a bone fracture or after prolonged bed rest, the limb's muscle cells atrophy and muscular strength is reduced. When normal activity resumes, the muscle's size and function return.

Answer 30

* Atrophy is defined as a reduction in the size of an organ or tissue due to a decrease in cell size and number. * Atrophy can be physiologic or pathologic. * In cellular atrophy, structural proteins and organelles of a cell are destroyed with a reduction in the size and capacity of the cell. * This adaptive response allows the cell to survive in adverse conditions by reducing its metabolism. * Cell constituents are eliminated by the process of autophagy. * Atrophy is shrinkage in the size of cells by the loss of cell substance. When a sufficient number of cells are involved, the entire tissue or organ is reduced in size, or atrophic . Although atrophic cells may have diminished function, they are not dead. Causes of atrophy include a decreased workload (e.g., immobilization of a limb to permit healing of a fracture), loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging (senile atrophy). Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in menopause) and others are pathologic (e.g., denervation), the fundamental cellular changes are similar. They represent a retreat by the cell to a smaller size at which survival is still possible; a new equilibrium is achieved between cell size and diminished blood supply, nutrition, or trophic stimulation. * **Cellular atrophy results from a combination of decreased protein synthesis and increased protein degradation.** * Protein synthesis decreases because of reduced metabolic activity. * The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse may activate ubiquitin ligases, which attach multiple copies of the small peptide ubiquitin to cellular proteins and target them for degradation in proteasomes. This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including the cachexia associated with cancer. * In many situations, atrophy also is associated with autophagy, with resulting increases in the number of autophagic vacuoles. As discussed previously, autophagy is the process in which the starved cell eats its own organelles in an attempt to survive.

Answer 31

* Unwanted cell organelles becomed enwrapped by membrane derived by endoplastic reticulum * They are forming the autophagic body * Autophagic body fuses with vesicles containing lysosomal acid hydrolases, formation of tubovesicular bodies, late autophagic bodies * Residual bodies (containing lamellar undigested lipid-rich cell material- lipofuscin) * Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components. It is a survival mechanism in times of nutrient deprivation, so that the starved cell can live by eating its own contents and recycling these contents to provide nutrients and energy. * In this process, intracellular organelles and portions of cytosol are first sequestered within an ER-derived autophagic vacuole, whose formation is initiated by cytosolic proteins that sense nutrient deprivation * The vacuole fuses with lysosomes to form an autophagolysosome, in which lysosomal enzymes digest the cellular components. In some circumstances, autophagy may be associated with atrophy of tissues and may represent an adaptation that helps cells survive lean times. If, however, the starved cell can no longer cope by devouring its contents, autophagy may eventually lead to apoptotic cell death. * Extensive autophagy is seen in ischemic injury and some types of myopathies. * Polymorphisms in a gene involved in autophagy have been associated with inflammatory bowel disease, but the mechanistic link between autophagy and intestinal inflammation is not known. The role of autophagy in cancer

Answer 32

* In many tissues that have undergone cellular atrophy, a brown pigment called lipofuscin accumulates in a shrunken cells * This pigment composed of a degenerate lipid material in secondary lysosomes is produced by breakdown of the cell membranes and organels through autophagy * Lipofuscin in the atrophic myocardial fibres of eldery people, giving rise to macroscopically evident brown coloration of the myocardium- BROWN ATROPHY * What is Lipofuscin? The yellow-brown granular pigment seen in the hepatocytes 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 autophagocytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome within the cell cytoplasm. * Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) with aging or atrophy. Lipofuscin represents complexes of lipid and protein that are produced by the free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is a marker of past free radical injury. The brown pigment (Fig. 2.25), when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.

Answer 33

* Thymus gland involutes during adolescens. There is involution of thymic lymphocytes by the mechanism of apoptosis. In this case, it is an orderly process and part ofnormal immune system maturation. Individual cells fragment and are consumed by phagocytes to give the appearance of clear spaces filled with cellular debris. * Myometrium involutes post partum * With reduced activity in old age, skeletal muscle fibres decrease in size * In the aging parathyroid gland, hormone- secreting cells diminish in number and are replaced by fat cells * The testis undergoes atrophy as a result of reduced gonadotrophic stimulation in old age

Answer 34

* Gradual reduction in blood suply to a tissue results in loss of functional cells through involution ischaemic atrophy) * Damage of axons supplying muscle causes atrophy of affected muscle fibres (denervation atrophy) * Atrophy secondary to endocrine insufficiency is not restricted to pathologic conditions: the endometrium atrophies when estrogen levels decrease after menopause * Following ablation of the pituitary gland by surgery, the cells of the adrenal cortex decrise in size and number owing to lack of ACTH stimulation * After trauma to the spinal cord, skeletal muscle fibres supplied by affected spinal nerve roots undergo atrophy

Answer 35

Cerebral atrophy Cerebral atrophy in a patient with Alzheimer disease. The gyri are narrowed and the intervening sulci widened, particularly pronounced toward the frontal lobe region

Answer 36

What is muscle atrophy? Some of these skeletal muscle fibers show atrophy, compared to normal fibers. The number of cells is the same as before the atrophy occurred, but the size of some fibers is reduced. This is a response to injury by "downsizing" to conserve the cell. In this case, innervation to the small, atrophic fibers was lost. A trichrome stain.

Answer 37

* Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse environment. Metaplasia is thought to arise by the reprogramming of stem cellsto differentiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cells. * Usually induced by altered differentiation pathway of tissue stem cells (it is not result from a change in the phenotype of an already differentiated cell type); * Metaplasia of laryngeal respiratory epithelium has occurred in a smoker. The chronic irritation has led to an exchanging of one type of epithelium (the normal respiratory epithelium) for another (the more resilient squamous epithelium). * Metaplasia is not a normal physiologic process and may be the first step toward neoplasia.

Answer 38

* Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium of habitual cigarette smokers, in whom the normal ciliated columnar epithelial cells of the trachea and bronchi often are replaced by stratified squamous epithelial cells * The rugged stratified squamous epithelium may be able to survive the noxious chemicals in cigarette smoke that the more fragile specialized epithelium would not tolerate. * Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance of particulate matter. * Because vitamin A(keratomalasia)is essential for normal epithelial differentiation, its deficiency also may induce squamous metaplasia in the respiratory epithelium. * Metaplasia need not always occur in the direction of columnar to squamous epithelium; in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium(Barretts esophagus can lead to adenocarcinoma if dysplasia occurs, GERD is reversible). * Metaplasia also may occur in mesenchymal cells, but in these situations it is generally a reaction to some pathologic alteration and not an adaptive response to stress. For example, bone is occasionally formed in soft tissues, particularly in foci of injury(myositis ossifcans). The influences that induce metaplastic change in an epithelium, if persistent, may predispose to malignant transformation. * In fact, squamous metaplasia of the respiratory epithelium often coexists with lung cancers composed of malignant squamous cells. It is thought that cigarette smoking initially causes squamous metaplasia, and cancers arise later in some of these altered foci.

Answer 39

* The first evidence of such damage is seen ultrastructurally as swelling of membrane-bound organelles, particulary ER and mitochondria * Mitchondrial swelling- spaces or vacuoles develop within the mitochondrion, distorting and separating the normally regular stacks of cristae (low- amlitude s.) * ER swelling- loss of ribosomes attached to the rough endoplasmatic reticulum (RER)

Answer 40

Sublethal and reversible structural abnormalities * Another manifestation of sublethal cell damage is impairment of fatty acid metabolism, affected cells acumulate lipid with cytoplasmic vacuoles, giving rise to term FATTY CHANGE. * This is seen particulary in cells that have central roles in fatty acid metabolism (i.e. hepatocytes, sometimes in myocardium and kidney)

Answer 41

* Fatty change, also called steatosis, refers to any accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but also may occur in heart, skeletal muscle, kidney, and other organs. Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations * The lipid vacuoles within hepatocytes. The lipid accumulates when lipoprotein transport is disrupted and/or when fatty acids accumulate(image).

Answer 42

* Increased peripherial mobilization of free fatty acids and uptake into cells (diabetes mellitus or nutritional deprivation) * Increased convertion of fatty acids to triglicerydes(alcohol) * Reduced oxidation of triglicerides to acetyl-CoA (hypoxia ant toxins including ethanol) * Deficiency of lipid acceptor proteins, preventing export or formed triglicerides (carbon tetrachloride and protein malnutrition)

Answer 43

Fatty change The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining. The most common cause of fatty change in developed nations is alcoholism. In developing nations, kwashiorkor in children.

Answer 44

* Iron is normally caried by specific transport proteins (transferrins); in cells it is stored with association with a protein (apoferritin) to form a ferritin micelles; * When is a local or systemic excess of iron, ferritin formes hemosiderin granules * Hemosiderin is a hemoglobin- derived, yelow to brown granular or crystaline pigment * This pigment is lying within the cells cytoplasm and is easily seen with a light microscope * Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of these ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction. Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosiderin, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis * Overload of iron could be systemic or local

Answer 45

* Systemic overload of iron- hemosiderin is deposed in many organs and tissues: * increased absorption of dietary iron * impaired use of iron * hemolytic anemias * transfusion (transfused red cells constituite an exogenous load of iron) * First the pigment is found in the mononuclear phagocytes of the liver, bone marrow, spleen, lymph nodes * With progressive acumulation, parenchymal cells through the body becomed pigmented (but iron rather does not damage this organs)

Answer 46

* Local excesses of iron results from huge hemorrhagesor a lot of minute hemorrhagies that accompany severe vascular congestion * After local hemorrhage the area is red- blue, next hemoglobin undergoes transformation to hemosiderin (with lysis of the erythrocytes)- macrophages take part in this process by phagocytizing the red cell debris and next lysosomal enzymes covert the hemoglobin * The pigmentation is first found in the reticuloendothelial cells in the area

Answer 47

Hemosiderosis These renal tubules contain large amounts of hemosiderin, as demonstrated by the Prussian blue iron stain. This patient had chronic hematuria.

Answer 48

* The hepatocytes and Kupffer cells are full of granular brown deposits of hemosiderin. * The term "hemosiderosis" is used to denote a relatively benign accumulation of iron. * The term "hemochromatosis" is used when organ dysfunction occurs. The iron accumulation may lead to a micronodular cirrhosis(so called "pigment" cirrhosis).

Answer 49

* The dark brown color of the liver, as well as the pancreas and lymph nodes is due to extensive iron deposition in a middle-aged man with hereditary hemochromatosis (HHC). HHC results from a mutation involving the hemochromatosis gene (HFE) that leads to increased iron absorption from the gut. The prevalence is between 1:200 and 1:500 persons in the U.S. * The Prussian blue iron stain reveals extensive hepatic hemosiderin deposition microscopically in case of hereditary hemochromatosis (HH). There is also cirrhosis. Excessive iron deposition in persons with HH can affect many organs, but heart (congestive failure), pancreas (diabetes mellitus), liver (cirrhosis and hepatic failure), and joints (arthritis) are the most severely affected.

Answer 50

* Hemochromatosis is caused by excessive absoprtion of iron, which is primarily deposited in parenchymal organs such as the liver and pancreas, as well as in the heart, joints, and endocrine organs. It results most commonly from an inherited disorder, hereditary hemochromatosis. * When iron accumulation occurs as a consequence of parenteral administration of iron, usually in the form of transfusions, it is called acquired hemochromatosis. Secondary iron overload also can complicate diseases that are associated with persistent ineffective erythropoiesis, particularly thalassemia and myelodysplastic syndromes * the total body iron pool ranges from 2 to 6 gm in normal adults; about 0.5 gm is stored in hepatocytes. In severe hemochromatosis, total iron may exceed 50 gm, one-third of which accumulates in the liver. Fully developed cases exhibit (1) micronodular cirrhosis; (2) diabetes mellitus (up to 80% of patients); and (3) abnormal skin pigmentation (up to 80% of patients)

Answer 51

* Because there is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. Hepcidin is a circulating peptide hormone that acts as a key negative regulator of intestinal iron uptake. Diverse mutations in several genes have been described in hereditary hemochromatosis, all of which lower hepcidin levels or diminish hepcidin function. Whatever the underlying defect, the net result is an increase in intestinal absorption of dietary iron, leading to an accumulation of 0.5 to 1 gm of iron per year. The most frequently mutated gene in patients with hereditary hemochromatosis is HFE, which is located on chromosome 6 close to the HLA gene cluster. HFE encodes an HLA class I–like molecule that regulates the synthesis of hepcidin in hepatocytes. The most common HFE mutation is a cysteine-to-tyrosine substitution at amino acid 282 (C282Y). This mutation, which inactivates the HFE protein, is present in over 70% of patients diagnosed with hereditary hemochromatosis and is most common in European populations. Several other mutations can also give rise to hemochromatosis, including other mutations in HFE as well as mutations in transferrin receptor 2 and in hepcidin itself. The associated clinical condition is milder with some of these alternative mutations and more severe with others, sometimes manifesting in young adults or even during childhood. * Whatever the underlying cause, the onset of disease typically occurs after 20 gm of stored iron have accumulated. Excessive iron appears to be directly toxic to host tissues. Mechanisms of liver injury include the following: * Lipid peroxidation via iron-catalyzed free radical reactions * Stimulation of collagen formation by activation of hepatic stellate cells * DNA damage by reactive oxygen species, leading to lethal cell injury or predisposition to HCC The deleterious effects of iron on cells that are not fatally injured are reversible, and removal of excess iron with therapy promotes recovery of tissue function

Answer 52

* Symptoms usually appear earlier in men than in women since menstrual bleeding limits the accumulation of iron until menopause. * This results in a male-to-female ratio of clinically significant iron overload of approximately 5 :1 to 7:1. In the most common form caused by HFE mutations, symptoms usually appear in the fifth and sixth decades of life in men and later in women. * With population screening, it has become clear that homozygosity for the most common HFE mutation (C282Y) shows variable penetrance; thus disease development is not inevitable, presumably because other genetic and environmental factors influence the rate of iron accumulation. * The principal manifestations include hepatomegaly, abdominal pain, skin pigmentation (particularly in sunexposed areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis. * In some patients, the presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence and loss of libido in the male). As noted, clinically apparent disease is more common in males and rarely becomes evident before 40 years of age. * Death may result from cirrhosis or cardiac disease. In those with untreated disease, the risk for HCC is increased 200-fold, presumably because of ongoing liver damage and the genotoxic effects of oxidants generated by iron in the liver. * Fortunately, hemochromatosis can be diagnosed long before irreversible tissue damage has occurred. Screening of family members of probands is important. Heterozygotes also accumulate excessive iron, but not to a level that causes significant tissue damage. * Currently most patients with hemochromatosis are diagnosed in the subclinical, precirrhotic stage due to routine serum iron measurements (as part of another diagnostic workup). * Regular phlebotomy results in steady removal of excess tissue iron, and with this simple treatment life expectancy is normal.

Answer 53

* Abnormal deposition of calcium salts, together with small amounts of iron, magnesium and other mineral salts * There are two forms of pathologic calcification: * dystrophic * metastatic

Answer 54

* Formation of crystalline calcium phosphate mineral; the process has two phases: initiation and propagation * It occurs in changed, injured cells * Intracellular initiation- occurs in mitochondria of dead or dying cells * Extracellular initiation- include phospholipids found in membrane- bound vesicles which are derived from degenerating or ageing cells * Propagation of crystal formation depends of the concentration of Ca +2 and PO 4 and the presence of inhibitors * Is encountered in areas of necrosis, whether they are of coagulative, caseous or liquefactive type and in foci of enzymatic necrosis of fat. * Occurs in atheromas of advanced atherosclerosis * Developes in ageing or damaged heart valves * Macroscopically- white granules or clumps, offten felt as gritty deposites. * Sometimes –tuberculous lymph node is virtually converted to stone * 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 submucosa.

Answer 55

* Dystrophic calcification. In this form, calcium metabolism is normal but it deposits in injured or dead tissue, such as areas of necrosis of any type. It is virtually ubiquitous in the arterial lesions of advanced atherosclerosis (Chapter 10). * Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury, it also may be a cause of organ dysfunction. For example, calcification can develop in aging or damaged heart valves, resulting in severely compromised valve motion. * Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in elderly persons (Chapter 11). * Dystrophic calcification is initiated by the extracellular deposition of crystalline calcium phosphate in membrane-bound vesicles, which may be derived from injured cells, or the intracellular deposition of calcium in the mitochondria of dying cells. * It is thought that the extracellular calcium is concentrated in vesicles by its affinity for membrane phospholipids, whereas phosphates accumulate as a result of the action of membranebound phosphatases. The crystals are then propagated, forming larger deposits * 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 in tuberculosis. Sometimes a tuberculous lymph node is essentially converted to radiopaque stone. On histologic examination,

Answer 56

* Metastatic calcification- may occur in normal tissue whenever there is hypercalcemia * Increased secretion of parathyroid hormone (parathyroid tumors or ectopic secretion of PTH) * Destruction of bone tissue (primary tumors or metastasis, immobilization) * Vitamine D related disorders * Renal failure (retention of phosphate leading to secondary hyperparathyroidism) * Mainly affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins * All of these tissues loss acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification * Morphologicaly- noncrystalline amorphous deposites or hydroxyapatite crystals

Answer 57

* Metastatic calcification * This form is associated with hypercalcemia and can occur in normal tissues. The major causes of hypercalcemia are (1) increased secretion of parathyroid hormone, due to either primary parathyroid tumors or production of parathyroid hormone–related protein by other malignant tumors; (2) destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (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); and (4) renal failure, in which phosphate retention leads to secondary hyperparathyroidism. * Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa.The calcium deposits morphologically resemble those described in dystrophic calcification. Although they generally do not cause clinical dysfunction, extensive calcifications in the lungs may be evident on radiographs and may produce respiratory deficits, and massive deposits in the kidney (nephrocalcinosis) can lead to renal damage

Answer 58

* This disease is diagnosed by the presence of small nodules, in the lung fields on chest radiograph * The pattern of disease is not associated with any clinically significant impairment of respiratory function * Histologically there is acumulation of anthrosilicotic dust in macrophages at the center of acinus, with associated with emphysema of local dust type * coal workers have progressive massive fibrosis . This disease is characterized by large nodules in the lungs, greater than 10 mm in diameter, they are most common in the upper lobes, they become so extensive as to occupy 30% of the lung fields * The nodules are usually surrounding irregular emphysema * Coal Worker’s Pneumoconiosis Worldwide dust reduction in coal mines has greatly reduced the incidence of coal dust–induced disease. The spectrum of lung findings in coal workers is wide, ranging from asymptomatic anthracosis, in which pigment deposits without a perceptible cellular reaction; to simple coal worker’s pneumoconiosis (CWP), in which macrophages accumulate with little to no pulmonary dysfunction; to complicated CWP or progressive massive fibrosis (PMF), in which fibrosis is extensive and lung function is compromised (see Table 13.3). Although statistics vary, it seems that less than 10% of cases of simple CWP progress to PMF. Of note, PMF is a generic term that applies to a confluent fibrosing reaction in the lung; this can be a complication of any of the pneumoconioses discussed here. Although coal is mainly carbon, coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica. The ratio of carbon to contaminating chemicals and minerals (“coal rank”) increases from bituminous to anthracite coal; in general, anthracite mining has been associated with a higher risk for CWP. * Clinical features * CWP usually is a benign disease that produces little decrement in lung function. In those in whom PMF develops, there is increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale. Progression from CWP to PMF has been linked to a variety of variables including higher coal dust exposure levels and total dust burden. Unfortunately, once established PMF has a tendency to progress even in the absence of further exposure. After taking smoking-related risk into account, there is no increased frequency of lung carcinoma in coal miners, a feature that distinguishes CWP from both silica and asbestos exposures

Answer 59

* Diseases of lungs caused by inhalation of dust is termed pneumoconiosis, the maiority of cases being caused by nonfibrous mineral dust * Lung damage occurs when the dust interacts with defence mechanisms in the lung * If dust is toxic to macrophages, ther is local inflammation, secretion of cytokines and stimulation of fibrosis * The main dusts causing industrial pulmonary fibrosis are various forms of silicates, often mixed with other materials such as iron oxid or coal * Pneumoconiosis is a term originally coined to describe lung disorders caused by inhalation of mineral dusts. The term has been broadened to include diseases induced by organic and inorganic particulates, and some experts also regard chemical fume- and vapor-induced lung diseases as pneumoconioses. The mineral dust pneumoconioses—the three most common of which are caused by inhalation of coal dust, silica, and asbestos—usually stem from exposure in the workplace. Asbestos is the exception, as with this mineral the increased risk for cancer extends to family members of asbestos workers and to individuals exposed outside of the workplace. Table 13.3 indicates the pathologic conditions associated with each mineral dust and the major industries in which the dust exposure may produce disease.

Answer 60

Pneumoconiosis Anthracotic pigment in macrophages in a hilar lymph node. Pathogenesis The reaction of the lung to mineral dusts depends on many variables, including the size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10 µm are unlikely to reach distal airways, whereas particles smaller than 0.5 µm move into and out of alveoli, often without substantial deposition and injury. Particles that are 1 to 5 µm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable. Silica, asbestos, and beryllium are more reactive than coal dust, resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the particles become impacted at alveolar duct bifurcations, where macrophages accumulate and engulf the trapped particulates. **The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of inflammation, lung injury and fibrosis.** Following phagocytosis by macrophages, many particles activate the inflammasome and induce production of the pro-inflammatory cytokine IL-1 as well as the release of other factors, which initiates an inflammatory response that leads to fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/ or to self-proteins that are modified by the particles. This then leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than other particles.

Answer 61

Pneumoconiosis * By polarized light microscopy can be seen the etiology for most pneumoconioses (even those in coal miners)--silica crystals. * Bright white crystals of varying sizes. The silica induces a fibrogenic response by macrophages to produce the nodular foci of collagen deposition.

Answer 62

* Amorphous collection of acellular proteinaceous material containing little collagen and abundant carbon pigment, which frequently cavitates and liquefies (it is response to a coal with a low silica content) * Dense collagenous tissue and macrophages, heavily pigmented by carbon dust (response to coal with high silica content) * Caplan‘s syndrome occurs in miners with rheumatoid disease, nodules have the apperance of large, carbon pigmented rheumatoid nodules

Answer 63

* Caused by inhalation of silicon dioxide (quartz) * The main occupational exposure is from slate mining, metal foundaries, stone masonry, tunneling, granite quarying, coal mining through granit rocks * RTG- small nodules, may also be calcification of the periphery of hilar lymph nodes * Short heavy doses produce acute silicosis with pulmonary oedema and alveolar exudation * Prolonged exposure leads to formation of multiple fibrous nodules composed with collagen * Development of tuberculosis is a common complication of silicosis * Silicosis is currently the most prevalent chronic occupational disease in the world. It is caused by inhalation of crystalline silica, mostly in occupational settings. Workers involved in sandblasting and hard-rock mining are at particularly high risk. Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz, cristobalite, and tridymite) are by far the most toxic and fibrogenic. Of these, quartz is most commonly implicated in silicosis. After inhalation, the particles interact with epithelial cells and macrophages. Ingested silica particles cause activation of the inflammasome and the subsequent release of inflammatory mediators by pulmonary macrophages, including IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines. When mixed with other minerals, the fibrogenic effect of quartz is reduced. This fortuitous situation is commonplace, as quartz in the workplace is rarely pure. Thus, for example, miners of the iron-containing ore hematite may have abundant quartz in their lungs yet have relatively mild lung disease because of the protective effect of hematite.

Answer 64

Silicosis usually is detected in asymptomatic workers on routine chest radiographs, which typically show a fine nodularity in the upper zones of the lung. Most patients do not develop shortness of breath until late in the course, after PMF is present. Many patients with PMF develop pulmonary hypertension and cor pulmonale as a result of chronic hypoxia–induced vasoconstriction and parenchymal destruction. The disease is slowly progressive, often impairing pulmonary function to such a degree that physical activity is severely limited. Silicosis is associated with an increased susceptibility to tuberculosis. It is postulated that silicosis depresses cell-mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria. Nodules of silicotuberculosis often contain a central zone of caseation. The relationship between silica and lung cancer is unsettled, but most studies suggest that silica exposure is associated with some increase in risk.

Answer 65

* Silicotic nodule is composed mainly of bundles of interlacing pink collagen(second image). There is a minimal inflammatory reaction. * The greater the degree of exposure to silica and increasing length of exposure determine the amount of silicotic nodule formation and the degree of restrictive lung disease. * Silicosis increases the risk for lung carcinoma about 2-fold. * Anthracosilicosis(1st image)

Answer 66

* Caused by heavy exposure to asbestos, usually with a latent period of 25 years before clinical symptoms become evident * Long and heavy, exposure increases risk * Fibres longer then 8 μm are very pathogenic * Two main forms of asbestos: * serpentine asbestos (including white asbestos)- most * common form, the fibres persist in lung for a limited time * amphibole asbestos (including blue and brown asbestos) * main cause of malignant mesothelioma * Asbestos is a family of crystalline hydrated silicates with a fibrous geometry. On the basis of epidemiologic studies, occupational exposure to asbestos is linked to (1) parenchymal interstitial fibrosis (asbestosis); (2) localized fibrous plaques, or, rarely, diffuse fibrosis in the pleura; (3) pleural effusions; (4) lung carcinoma; (5) malignant pleural and peritoneal mesothelioma; and (6) laryngeal carcinoma. An increased incidence of asbestos-related cancers in family members of asbestos workers has alerted the general public to the potential hazards of asbestos in the environment. * Asbestosis pathogenesis * As with silica crystals, once phagocytosed by macrophages, asbestos fibers activate the inflammasome and damage phagolysosomal membranes, stimulating the release of proinflammatory factors and fibrogenic mediators. In addition to cellular and fibrotic lung reactions, asbestos probably also functions as both a tumor initiator and a promoter. Some of the oncogenic effects of asbestos on the mesothelium are mediated by reactive free radicals generated by asbestos fibers, which preferentially localize in the distal lung close to the mesothelial layer. However, potentially toxic chemicals adsorbed onto the asbestos fibers also undoubtedly contribute to the pathogenicity of the fibers. For example, the adsorption of carcinogens in tobacco smoke onto asbestos fibers may be the basis for the remarkable synergy between tobacco smoking and the development of lung carcinoma in asbestos workers.

Answer 67

* The asbestos fiber becomes coated with iron and calcium, which is why it is often referred to as a "ferruginous body" -iron stain. Ingestion of these fibers by macrophages sets off a fibrogenic response via release of growth factors that promote collagen deposition by fibroblasts. * Another gross lesion typical for pneumoconioses, and asbestosis in particular, is a fibrous pleural plaque. Seen here on the pleural side of the diaphragmatic leaves are several tan-white pleural plaques.

Answer 68

Microscopically, the fibrous pleural plaque is composed of dense layers of collagen.

Answer 69

The clinical findings in asbestosis are indistinguishable from those of any other chronic interstitial lung disease. Progressively worsening dyspnea appears 10 to 20 years after exposure. It is usually accompanied by a cough and production of sputum. The disease may remain static or progress to congestive heart failure, cor pulmonale, and death. Pleural plaques are usually asymptomatic and are detected on radiographs as circumscribed densities. Both lung carcinoma and malignant mesothelioma develop in workers exposed to asbestos. The risk for developing lung carcinoma is increased about 5-fold for asbestos workers; the relative risk for mesothelioma, normally a very rare tumor (2–17 cases per 1 million individuals), is more than 1000 times greater. Concomitant cigarette smoking greatly increases the risk for lung carcinoma but not for mesothelioma. Lung or pleural cancer associated with asbestos exposure carries a particularly poor prognosis

Answer 70

* One form of hypersensitivity pneumonitis is known as farmer's lung because the farmer inhales thermophilic actinomycetes in moldy hay that set off the reaction. * Bird dust (bird fancier's disease) and molds in air conditioners may produce similar problems. The bales in this field near * Sterling are of good quality and less likely to produce this disease.