Cellular Injury Part III PDF

Cellular injury III Dr/ Sara Badawy Dr/ Sara Badawy Disturbance in pigment metabolism  Pigments are colored substances that are present in most living beings including humans. That are either classified into : ❑ Exogenous pigment (outside the body) ❑ Endogenous pigment...

Cellular injury III Dr/ Sara Badawy Dr/ Sara Badawy Disturbance in pigment metabolism  Pigments are colored substances that are present in most living beings including humans. That are either classified into : ❑ Exogenous pigment (outside the body) ❑ Endogenous pigment (inside the body). Abnormal deposition of colored substances in the tissues either intracellular or extracellular or both known as Disturbance in pigment metabolism (Pathological pigmentation).  Exogenous pigment: 1- Inhaled pigment 2- Ingested pigment 3- Injected pigment Endogenous pigment: 1- Melanin 2-Haemoprotein derived pigments 3- Lipofuscin (wear-and-tear pigment) Exogenous pigments  Def: Exogenous pigments come from outside the body either via inhalation, ingestion or inoculation. Pneumoconiosis Pneumoconiosis is a term originally describe the non-neoplastic lung reaction to inhalation of mineral dusts. The lungs and their lymph nodes are the reservoir of various dust particles that are inhaled in the air. The dust particles act as mild irritants and induce slight increase in connective tissue (fibrosis) and an accumulation of macrophages. Since pneumoconiosis are associated with certain occupations, they are considered as occupational lung diseases.  Pneumoconiosis: The presences of pigment and body reaction in lung called pneumoconiosis The three most common mineral dust pneumoconiosis are the coal dust or carbon, silica, and asbestos which always result from exposure in the workplace.  Anthracosis Anthracosis is the deposition of carbon or coal dust in the lungs. It is seen in horses and mules used in coal mines. It also frequently occurs in dogs that live in industrial areas where coal dust, soot, and smoke pollute the air.  Anthracosis Pulmonary anthracosis is the most common exogenous pigment induced pulmonary lesion in coal miners and also is commonly seen in all urban areas and smokers. Inhaled carbon pigment is engulfed by alveolar macrophages, which then accumulate in the connective tissue along the lymphatics, including the pleural lymphatics and lymph nodes. Asymptomatic anthracosis, in which pigment accumulates without a perceptible cellular reaction, but the disease divided into 2 categories: 1- Simple coal worker’s pneumoconiosis (CWP): In which accumulations of macrophages occur with little to no pulmonary dysfunction.  Simple CWP is characterized by coal macules and the somewhat larger coal nodule. The coal macule consists of dust-laden macrophages. In addition, the nodule contains small amounts of collagen fibers arrayed in a delicate network. 2- Complicated CWP or progressive massive fibrosis in which fibrosis is extensive, and lung function is compromised. Complicated CWP occurs on a background of simple CWP characterized by coal nodules and centrilobular emphysema generally requires many years to develop.  Gross picture: The carbon appears as black pigment in the lungs which either as focal or diffuse infiltration. Although these lesions are scattered throughout the lung, the ventral lobes are more heavily involved. Lungs are black in color due to multiple, intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter The regional lymph nodes are also involved and black pigment being present in the medulla. The carbon is only mild irritant.  Microscopically: Black carbon particles either present free in interalveolar space or in the alveolar walls or around the bronchioles. Also, can seen around alveolar blood vessels. Or inside macrophage. The particles are just black in color, extremely small and clustered together into globular masses.  Significant and results: Since carbon is insoluble in tissue fluids, the pigmentation persists for the life of the human and animal lung. It has little harm or cause no symptoms. Extensive deposits in the lung may cause slight respiratory distress. Heavy infiltration induce pulmonary emphysema and fibrosis cause serious pulmonary injury. Silicosis  Silicosis is the deposition of fine silica particles (silicon dioxide, i.e., stone dust) in the lungs. It is more common and important in humans than in animals. In humans, it is currently the most prevalent chronic occupational lung disease in the world. Workers in several occupations but especially those involved in sandblasting (dessert environment) and hard-rock mining are at higher risk. It as slowly progressing nodular, fibrosing pneumoconiosis ( silicotic fibrotic nodules).  Pathogenesis: After inhalation the particles interact with epithelial cells and macrophages cause activation and release of mediators including IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines.  Macroscopic features: Affected lungs are nodular (small, discrete nodules) and firm. Fibrotic lesions may also occur in the regional lymph nodes and pleura.  Microscopic features: The nodular lesions consist of concentric layers of hyalinized center. Surrounded by chronic inflammatory cells and stimulate fibroblast Necrosis and fibrosis take place. Silicotic nodules  Significant and results: Silica is insoluble in body fluids and is a powerful irritant, causing extensive fibrosis which predisposes the lungs to tuberculosis as silicosis results in a depression of cell mediated immunity. Pulmonary tissue become less resistance to infection. Alveolar emphysema may develop. Asbestosis  Its type of exogenous pigment due to inhalation of asbestos (magnesium silicate). Asbestos is a Greek word meaning ‘unquenchable’. In general, if coal is lot of dust and little fibrosis, asbestos is little dust and a lot of fibrosis. The gross of diffuse pulmonary fibrosis caused by asbestos exposure and histologic demonstration of bamboo- like asbestos bodies on asbestos fibers is termed asbestosis.  Lungs are small, grayish and firm with cartilage-like Macroscopic thickening of the pleura. features: Presence of variable degree of pulmonary fibrosis, especially in the subpleural areas and in the bases of lungs.  Microscopic features: ▪ There is diffuse pulmonary interstitial fibrosis. ▪ There is presence of characteristic asbestos bodies in the involved areas. ▪ These are asbestos fibers coated with glycoprotein and hemosiderin and appear beaded or dumbbell-shaped. ▪ The coating stains positively for Prussian blue reaction. Diffuse interstitial fibrosis Asbestos bodies  Significant and results Prolonged exposure for several years to asbestos dust produces three types of severe diseases: asbestosis of lungs, pleural disease and tumors. Siderosis  Def: Siderosis is deposition of iron in the lungs and pigmentation and cellular reaction associated with it. It results from inhalation of iron dust, and occurs in horses, mules, and dogs working in and around iron mines, smelters, and foundries. Macroscopically: Iron dust causes a brown or rusty red pigmentation, which is focal in the beginning due to the local accumulation of macrophages containing iron dust. The pigmentation becomes diffuse as more and more dust enters the lungs. Iron is mildly irritating causing only slight fibrosis. If silica (silicon) is also present in the dust, extensive fibrosis of the lung occurs. If tissues containing iron are placed in potassium ferrocyanide solution and hydrochloric acid (Prussian blue test), the tissues become blue in color.  Microscopically: The iron occurs as brown or black irregularly shaped granules (usually spherical masses) within macrophages. When Prussian blue test is applied, the granules become blue in color. There is only mild fibrosis, unless silicon is also present with the iron dust. Since iron is only slightly soluble in the tissue fluids, it persists in the tissues for the life of the individual. Siderosis is usually of no clinical significance. When iron is present in large amounts or if silicon is also present, extensive chronic inflammation of the lungs results which may lead to chronic general passive hyperemia.  Siderosis in the liver. Light micrograph of a section through a liver affected by siderosis (hepatosiderosis). This is a physiological disorder where excessive amounts of iron are deposited in body tissue  Ingested Pigments: Chronic ingestion of certain metals may produce pigmentation. i) Argyria is chronic ingestion of silver compounds (drugs) and results in brownish pigmentation in the skin, bowel, and kidney. ii) Chronic lead poisoning (plumbism) may produce the characteristic blue lines on teeth at the gumline. iii) Melanosis coli results from prolonged ingestion of certain cathartics. iv) Carotenaemia is yellowish-red coloration of the skin caused by excessive ingestion of carrots which contain carotene. Ingested pigment  Injected Pigments (Tattooing) Pigments like India ink, cinnabar and carbon are introduced into the dermis in the process of tattooing where the pigment is taken up by macrophages and lies permanently in the connective tissue. The examples of injected pigments are prolonged use of ointments containing mercury, dirt left accidentally in a wound, and tattooing by pricking the skin with dyes. Endogenous pigments  Def: Endogenous pigments are either normal constituents of cells or accumulate under special circumstances e.g. melanin, hemoprotein- derived pigments, and lipofuscin  Melanin Melanin is the brown-black, non-hemoglobin derived pigment normally present in the hair, skin, choroid of the eye, meninges and adrenal medulla. It is synthesized in the melanocytes and dendritic cells, both of which are present in the basal cells of the epidermis and is stored in the phagocytic cells called the melanophores, present in the underlying dermis. Melanocytes possess the enzyme tyrosinase necessary for synthesis of melanin from tyrosine.  Melanosis Abnormal deposition of melanin pigment in various organs especially lung (pulmonary melanosis) and aorta resulting in formation of black or brown spots. Various disorders of melanin pigmentation cause generalized and localized hyperpigmentation and hypopigmentation.  Macroscopic appearance: The affected organ become brown or black in color or have dark-brown spots as in lungs, heart, liver  Microscopic appearance: Melanin appears as very minute, uniformly regular dirty-brown, spherical granules. The dopa reaction can be used to determine if certain cells in the skin or other tissues contain tyrosinase to produce melanin. The affected tissue contains macrophages filled with melanin (melanophore).  Generalized hyperpigmentation: a) In Addison’s disease, there is generalized hyperpigmentation of the skin, especially in areas exposed to light and of buccal mucosa. b) Chloasma observed during pregnancy is the hyperpigmentation on the skin of face, nipples, and genitalia and occurs under the influence of estrogen. A similar appearance may be observed in women taking oral contraceptives. c) In chronic arsenical poisoning, there is characteristic raindrop pigmentation of the skin.  Focal hyperpigmentation: 1) Melanosis coli is pigmentation of the mucosa of the colon. 2) Melanotic tumors both benign such as pigmented naevi and malignant such as melanoma, are associated with increased melanogenesis. 3) Lentigo is a pre-malignant condition in which there is focal hyperpigmentation on the skin of hands, face, neck, and arms. 4) Dermatopathy lymphadenitis is an example of deposition of melanin pigment in macrophages of the lymph nodes draining skin lesions. Generalized hypopigmentation: Albinism is an extreme degree of generalized hypopigmentation in which tyrosinase activity of the melanocytes is genetically defective and no melanin is formed. It is congenital absence of melanin. Albinos have blond hair, poor vision and severe photophobia. They are highly sensitive to sunlight.  Localized hypopigmentation: a) Leucoderma is a form of partial albinism and is an inherited disorder. b) Vitiligo is local hypopigmentation of the skin and is more common. It may have familial tendency. c) Acquired focal hypopigmentation can result from various causes such as leprosy, healing of wounds, DLE, radiation dermatitis etc Lipofuscin (Wear and Tear Pigment)  Lipofuscin or lipochrome is insoluble yellowish-brown intracellular lipid pigment (lipo= fat, fuscus= brown). The pigment is often found in atrophied cells of old age and hence the name ‘wear and tear pigment’. It is seen in the myocardial fibers, hepatocytes, Leydig cells of the testes and in neurons in senile dementia. However, the pigment may, at times, accumulate rapidly in different cells in wasting diseases unrelated to aging.  Lipofuscin represents complexes of lipid and protein that are derived from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is an important marker that indicates whether the cell suffered free radical injury. Lipofuscin represents the indigestible residue of autophagic vacuoles (residual bodies) formed during aging or atrophy.  Unlike in normal cells, in aging or debilitating diseases the phospholipid end products of membrane damage mediated by oxygen free radicals fail to get eliminated and hence are deposited as lipofuscin pigment. Considered one of age-related disease. When present in sufficient amounts, they impart a brown discoloration to the tissue (brown atrophy). Mainly in long-lived postmitotic cells, such as neurons and cardiac myocytes.  Macroscopic appearance: Heart is Brown shrinkage coloration of ( decrease in heart. size). Microscopic appearance: The pigment is coarse, golden-brown granular and often accumulates in the central part of the cells around the nuclei. In the heart muscle, the change is associated with wasting of the muscle and is commonly referred to as ‘brown atrophy’ The pigment can be stained by fat stains but differs from other lipids in being fluorescent Lipofuscin is (autofluorescent) and having acid-fastness.  By electron microscopy, lipofuscin appears as intralysosomal electron-dense granules in perinuclear location. These granules are composed of lipid-protein complexes. Hemoprotein-derived Pigments  Hematogenous pigments are the most important endogenous pigments derived from hemoglobin, cytochromes and their break-down products derived from erythrocytes. They include hemoglobin, hematins, hemosiderin, hematoidin, bilirubin, biliverdin, and porphyrins. For an understanding of disorders of hemoproteins, it is essential to have knowledge of normal iron metabolism and its transport. In disordered iron metabolism and transport, hemoprotein-derived pigments accumulate in the body.  The average life of an erythrocyte is approximately 120 days. The physiological destruction of red cells occur within the phagocytic cells of the spleen, liver, and bone marrow and hemoglobin is released. Three components are formed in the disintegration of hemoglobin: globin, iron, and heme. Globin is soluble in the tissue fluids and is removed from the area by the blood and lymph. In cells, iron is normally stored in association with a protein, apoferritin, to form ferritin micelles. Ferritin forms hemosiderin granules, which are easily seen with the light microscope. Thus, hemosiderin pigment represents large aggregates of ferritin micelles. Hemosiderosis  Hemosiderin is a hemoglobin-derived, golden-yellow to brown granular or crystalline pigment. Under normal conditions, small amounts of hemosiderin can be seen in mononuclear phagocytes of the bone Hemosiderosis marrow, spleen, and liver. It is greatest in spleen of the horse and least in the dog. Excess of iron causes hemosiderin to accumulate within cells, either as a localized process as in hemorrhage or as a systemic derangement in case of blood hemolysis. Excessive storage of hemosiderin occurs when there is increased break-down of red cells, or systemic overload of iron due to primary (idiopathic, hereditary) haemochromatosis, and secondary (acquired) causes such as in thalassemia, sideroblastic anemia, alcoholic cirrhosis, multiple blood transfusions etc  Types of hemosiderosis  Localized hemosiderosis: This develops whenever there is hemorrhage into the tissues. With lysis of red cells, hemoglobin is liberated which is taken up by macrophages where it is degraded and stored as hemosiderin. A few examples are as under : 1) The changing colors of a bruise or a black eye are caused by the pigments like biliverdin and bilirubin which are formed during transformation of hemoglobin into hemosiderin. 2) In chronic venous congestion of liver and lung (brown induration of the lungs) as a result of small hemorrhages as occur in mitral stenosis and left ventricular failure. Microscopy reveals the presence of ‘heart failure cells’ which are hemosiderin-laden alveolar macrophages. Brown induration of lung CVC in liver  Generalized hemosiderosis: Generalized or systemic overload of iron may occur due to following causes: i) Increased erythropoietic activity: In various forms of chronic hemolytic anemia, there is excessive break-down of hemoglobin and hence iron overload. The problem is further compounded by treating the condition with blood transfusions (transfusional hemosiderosis) or by parenteral iron therapy. The deposits of iron in these cases, termed as acquired hemosiderosis, are initially in reticuloendothelial tissues but may secondarily affect other organs.  Generalized hemosiderosis ii) Excessive intestinal absorption of iron: A form of hemosiderosis in which there is excessive intestinal absorption of iron even when the intake is normal, is known as idiopathic or hereditary haemochromatosis. It is characterized by triad of pigmentary liver cirrhosis, pancreatic damage resulting in diabetes mellitus, and skin pigmentation. On the basis of the last two features, the disease has come to be termed as bronze diabetes. iii) Excessive dietary intake of iron: A common example of excessive intake of iron is Bantu’s disease in black tribals of South Africa who conventionally brew their alcohol in cast iron pots that serves as a rich source of additional dietary iron. The excess of iron gets deposited in various organs including the liver causing pigment cirrhosis. Hemosiderin special stain Prussian blue stain Stain hemosiderin pigment dark blue in color Jaundice( Icterus)  Bilirubin metabolism  Bilirubin is the normal non-iron containing pigment present in the bile. It is derived from porphyrin ring of the heme of hemoglobin. Normal level of bilirubin in blood is less than 1 mg/dl. Excess of bilirubin or hyperbilirubinemia causes an important clinical condition called jaundice. Jaundice is a pathological condition characterized by yellow discoloration of tissue that is especially in tissue rich in elastin, such as the aorta, skin , sclera and mucous membranes. Hyperbilirubinemia may be unconjugated or conjugated.  Hepatic dysfunction is not the only cause of hyperbilirubinemia and icterus. Prehepatic causes such as intravascular hemolysis can cause icterus. It is a common cause in ruminants and likely occurs more often than hepatic damage. Horses often manifest icterus with acute hepatic dysfunction or obstruction, but icterus may or may not occur in horses with chronic hepatic disease. Interestingly, “physiologic icterus” is also common in the horse deprived of feed for several days because uptake of bilirubin from the plasma by hepatocytes is decreased. Icterus in carnivores occurs as a consequence of hemolysis, hepatic dysfunction, or biliary obstruction.  Classification of jaundice: Jaundice may appear in one of the following 3 ways depending on which part affected: a) Prehepatic or hemolytic, when there is excessive destruction of red cells. b) Posthepatic or obstructive, which results from obstruction to the outflow of conjugated bilirubin. c) Hepatic or toxic that results from failure of hepatocytes.  ❑Definition: Hemolytic Jaundice It is a yellow coloration of most body (prehepatic) tissues due to excessive hemobilirubin as a result of excessive systemic hemolysis, but the liver is normal. ❑Causes: Blood parasite (anaplasmosis) Bacterial infection (bacillus anthracis) viral diseases (equine infectious anemia) Snake venoms. Lead poisoning (chronic)  Toxic Jaundice (intrahepatic): ❑ Definition: It is characterized by intense yellowish coloration of most body tissues due to increasing of hemobilirubin & cholebilirubin. This could be attributed to damaged liver cells resulting in loss of the liver capacity to extract bilirubin, detoxicate it and secrete it in the bile. ❑ Cause: Any factors leading to toxic liver → injury of liver cells. Toxic condition due to some infectious diseases (infectious canine hepatitis).  Definition: Obstructive Jaundice It is a yellowish coloration of most body tissues due (post-hepatic): to increase of cholebilirubin. Causes: Obstruction of bile ducts (cholilithiasis). Obstruction of gall bladder ( gall stones or presence of fluke). Inflammation of bile duct (cholangitis) leading to stasis of the bile and consequently dilatation of the bile ducts, and bile canaliculi with the passage of the bile in the circulation, resulting in hypercholibilirumiaemia. Pressure on the wall of bile duct from outside as tumor, abscess, and enlarged lymph node. Disturbance in mineral metabolism Pathological Calcification The amount of calcium in bones, tissues, cells, and fluids of the body ranges constantly. Its concentration in the blood fluctuates within rather narrow limits and in general averages about 10 mg per 100 ml of blood (10 mg percent). The amount of calcium in the blood is associated with parathyroid activity. When it is low, there is increased parathyroid activity that causes calcium to be removed from the skeleton to restore blood calcium to a normal amount. When calcium content of the blood decreases to 8 mg percent, excitability occurs, when to 6 mg percent, the animal goes into tetany, and when it reaches 3 mg percent, the animal dies. On the other hand, if the calcium rises to 12 mg percent or higher, the excess precipitates in various tissues. Calcium metabolism  Pathological Calcification It is the abnormal deposition of calcium salts mainly Ca. phosphate and Ca. carbonates together with smaller amounts of iron, magnesium, and other minerals, in soft tissues other than the ossified tissue (bone and teeth). It may be classified as dystrophic and metastatic calcification  ❑ Definition: It occur when calcium deposition Dystrophic occurs in dead (necrotic) or dying calcification: tissues of any organ. It occurs in a focal area of the body. Dystrophic calcification occur in normal serum levels of calcium, and in the normal calcium metabolism. ❑ Etiology /Occurrence: Dystrophic calcification may occur due to 2 types of causes Calcification in dead tissue Calcification of degenerated tissue.  Calcification in dead tissue: 1. Caseous necrosis in tuberculosis is the most common site for dystrophic calcification. 2. Liquefaction necrosis in chronic abscesses. 3. Fat necrosis following acute pancreatitis or traumatic fat necrosis in the breast results in deposition of calcium soaps. 4. Chronic venous congestion (CVC) of the spleen is characterized by calcific deposits admixed with hemosiderin on fibrous tissue. 5. Infarcts may sometimes undergo dystrophic calcification. 6. Thrombi, especially in the veins, may produce phleboliths. 7. Dead parasites like in hydatid cyst, Schistosoma eggs, and cysticercosis 8. Calcification in breast cancer. 9.Congenital toxoplasmosis.  Calcification in degenerated tissues: 1. Dense old scars may undergo hyaline degeneration and calcification. 2. Atheromas in the aorta and coronaries. 3. Mönckeberg’s sclerosis shows calcification in the tunica media of muscular arteries in elderly people 4. Stroma of tumors as uterine fibroids, breast cancer, thyroid adenoma and goiter. 5. Cysts which have been present for a long time may show calcification of their walls e.g. epidermal and pilar cysts. 7. Calcinosis cutis is a condition of unknown cause in which there are irregular nodular deposits of calcium salts in the skin and subcutaneous tissue. 8. Senile degenerative changes such as in costal cartilages, tracheal or bronchial cartilages, and pineal gland in the brain etc  Calcinosis Cutis (Benign Cutaneous Calcification, Benign Nodular Calcification)  Pathogenesis: Deposition of calcium occurs in two phases: Initiation phase Propagation phase I. Initiation phase: Initiation can occur intracellularly or extracellularly Intracellular initiation phase Damaged cell has increased inflow of calcium into cytoplasm Calcium that has entered the cell has great affinity for mitochondria and gets deposited in mitochondria.  Pathogenesis: Extracellular initiation phase: Degenerated cells contain membrane bound vesicles which contain acidic phospholipids. Calcium has increased affinity for acidic phospholipids and thus calcium deposits in vesicles Once the calcium and phosphate accumulates in vesicles, it gets budded out of the cell and is released out. II. Propagation phase: In the initiation phase tiny crystals of calcium are formed. Further Calcium deposition and propagation. Macroscopic features: Organ becomes hard and nodular. Grey/white deposits in necrosed tissue looking like honey comb. Gritty sound on cutting Grossly calcium deposition occurs as fine, white granules or clumps which are gritty  Macroscopic features: In routine H &E-stained sections, calcium salts appear as deeply basophilic, irregular and granular clumps. Calcium deposits can be confirmed by special stains like silver impregnation method of von- Kossa producing black color, and alizarin red. S that produces red staining. Pathologic calcification is often accompanied by diffuse or granular deposits of iron giving positive Prussian blue reaction in Perl’s stain.  Dystrophic calcification Van Zossa stain stains calcium black  Metastatic Calcification Metastatic calcification is characterized by deposition of calcium salts in soft tissue as a result in apparently normal tissues and is associated with abnormal calcium metabolism and hypercalcemia.  ❑ Since metastatic calcification occurs in normal tissues due to hypercalcemia, its causes would include one of the following two conditions: I. Excessive mobilization of calcium from the bone. II. Excessive absorption of calcium from the gut. Etiology: I. Excessive mobilization of calcium from the bone: These causes are more common and include the following: 1. Hyperparathyroidism which may be primary such as due to parathyroid adenoma, or secondary such as from parathyroid hyperplasia, chronic renal failure etc. 2. Bony destructive lesions such as multiple myeloma, metastatic carcinoma. 3. Prolonged immobilization a patient results in disuse atrophy of the bones and hypercalcemia.  Etiology: II.Excessive absorption of calcium from the gut: These causes are as under: 1. Hypervitaminosis D results in increased calcium absorption. 2. Milk-alkali syndrome caused by excessive oral intake of calcium in the form of milk and administration of calcium carbonate in the treatment of peptic ulcer. 3. Hypercalcaemia of infancy is another condition in which metastatic calcification may occur.  Sites of metastatic calcification: Metastatic calcification may occur in any normal tissue of the body but affects the following organs more commonly: 1. Kidneys, especially at the basement membrane of tubular epithelium and in the tubular lumina causing nephrocalcinosis 2. Lungs, especially in the alveolar walls. 3. Stomach, on the acid-secreting fundal glands. 4. Blood vessels, especially on the internal elastic lamina. 5. Cornea is another site affected by metastatic calcification. 6. Synovium of the joint causing pain and dysfunction.  Pathogenesis of metastatic calcification Metastatic calcification at the above-mentioned sites occurs due to excessive binding of inorganic phosphate ions with calcium ions, which are elevated due to underlying metabolic derangement. This leads to formation of precipitates of calcium phosphate at the preferential sites. Metastatic calcification is reversible upon correction of underlying metabolic disorder. Lung calcification  Metastatic calcification Lung carbolic acid Kidney uric acid Stomach hydrochloric acid  Gout (Urates & Uric Acids)  Def: It is a type of retrogressive changes (disorder of urate and uric acid metabolism) characterized by the deposition of crystals of uric acid and urates (sodium and calcium urates) in the tissues mainly joints, connective tissues and serous membranes of the internal organs, intense pain and acute inflammation. Deposition is due to an increase in the concentration of uric acid in blood (hyperuricemia) and body fluids. Gout is mainly a disease of humans and birds and has not been clearly established in other species. Clinically, the disease in humans is characterized by recurrent episodes of painful acute arthritis.  Etiology: Gout is usually divided into primary (unknown cause) and secondary forms ( known causes of hyperuricemia). Causes : 1) Renal dysfunction. 2) A high protein diet or due to an unusual type of protein. 3) Vit. A deficiency → due to deficiency of green food. 4) Insufficient exercise. 5) May be hereditary.  Pathogenesis: The uric acid is normal catabolic product of nucleoprotein of food and body tissues. It is normally present in blood in small amount 2.5mg/100ml blood and normally excreted as uric acid in urine. Excessive retention of uric acids in the blood leads to deposition of its salts in the tissues in the form of bundles or needles or crystals. Such salts inside the tissue stimulate foreign body granulomatous reaction. Gout pathogenesis Macroscopic features In articular form: The joints and surrounding tissues were covered by white chalky material known as Tophi which formed mainly from gouty deposits. The affected joints are swollen, tender and may be lost their function. In visceral form: Characterized by deposition of urates as a white powder-like substances (chalky-white, soft plagues) having a metallic sheen in the kidneys and serous membranes as pericardium.  Tophi( articular gout) Articular gout is characterized by tophi. These are deposits of urates around joints, particularly those of the feet most commonly affecting the first metatarsophalangeal joint (big toe). The joints are enlarged, and the feet appear deformed. When these joints are opened, the periarticular tissue is white due to urate deposition. White semi-fluid deposits of urates may be found within the joints Articular and visceral gout  Microscopical findings: In articular form: The calcium or sodium urate appeared as needle-shape bundles or crystals which arranged radically. The urates stimulate granulomatous reaction as macrophage aggregations beside foreign body giant cells and connective tissue proliferation with clusters of sharp a circular crystal or spaces that left after they dissolved. These reactions may lead to necrosis and fibrosis. In visceral form: Various serous surfaces are covered with finally crystalline or almost amorphous materials, that does not stain. ▪ Multinucleated foreign-body type giant cells surrounding long, slender, needle shaped shadows of the dissolved urate crystals. What is the lesion and stain?