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Hemostasis and Thrombosis
Accumulation of Glycogen, complex lipids and carbohydrates |
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In mammals the purine moieties of nucleic acids and nucleotides are catabolized and appear in urine as uric acid or allantoin. In humans and other primates, uric acid is the major end product of purine catabolism because of the absence of urate oxidase (uricase). Other mammals have urate oxidase in the liver and excrete allantoin as the end product. In humans, uric acid is present as the monosodium salt in the plasma at pH 7.4. The solubility of monosodium urate in body fluid is approximately 6.4 mg/dl. The serum urate concentration is in general quite stable, the average being approximately 5 mg/dl in postpubertal males and 4.1 mg/dl in postpubertal females. Although the intake of foods rich in nucleoprotein, such as liver, thymus, pancreas, and certain fish, tends to increase the serum urate concentration where as the restriction of such foods tends to reduce it, the influence of exogenous purine on the serum urate concentration is considered minor. There is complex interrelated balance among the production of purine nucleotides, catabolism of purine-containing compounds to produce free purine, oxidation of purine to uric acid by xanthine oxidase, tubular reabsorption of urate, and finally tubular secretion of urate. Disturbances of this balance can result in hyperuricemia and deposition of sodium urate crystals in the tissues, leading to painful acute arthritis, chronic gouty arthritis, tophus formation, and nephritis. Hyperurecemia is the cardinal biochemical feature of the group of clinical disorders collectively referred to as gout. Ninety-five percent of the cases occur in males. In primary gout, hyperuricemia is attributable to gene defects leading to repeated overproduction of uric acid through increased purine biosynthesis or undersecretion of uric acid by the proximal renal tubules, or in some cases both. Some of these are associated with specific genetic metabolic diseases, such as type I glycogen storage disease and the Lesch-Nyhan syndrome. In secondary gout, hyperuricemia occurs as a complication of other diseases, of the administration of certain drugs, and in some instances of both. In leukemia and lymphoma, particularly after their treatment with cytotoxic antineoplastic agents, accelerated catabolism of nucleic acids after cell death results in overproduction of uric acid. Hyperuricemia is a common feature of eclampsia. Although hyperuricemia in this condition is attributable to the frequent occurrence of tissue injury and necrosis, there are probably other mechanisms involved, specially the secretion of uric acid by the kidney. Uric acid secretion is often impaired in diseased kidneys regardless of cause. The mechanism of uric acid secretion by renal tubules is a sensitive one. It is impaired by a variety of disease states and therapeutic agents, such as - the accumulation of the keto acids acetoacetate and beta-hydroxybutyrate in diabetic ketoacidosis and starvation. - The lactic acidemia that accompanies excessive ethanol ingestion and - the thiazide diuretics used in the treatment of edema in cardiac and renal failure. In some cases of secondary gout, particularly those induced by the use of diuretics, there may be a pre-existing genetically determined disposition toward hyperuricemia. Persistent hyperuricemia results in the deposition of urate in tissues, cell injury, and an inflammatory reaction. Microcrystals of monosodium urate are phagocytized by leukocytes and eventually enter lysosomes. This is followed by increased permeability of the lysosomal membrane, which leads to leakage of hydrolytic enzymes. Since urate crystals are not degradable by lysosomal enzymes, they remain in the face of the digestion of dead cells and cellular debris. Localization of lysosomes may play an important pathogenetic role in chronic gout, particularly in the severe damage that occurs in the joint space and articular surfaces of joints. The crystals of monosodium urate initiate an inflammatory reaction by virtue of their physical presence in the interstitial fluid and tissues. Urate crystals activate Hageman factor, which in turn leads to activation of the kallikreinogen-kininogen system and ultimately increased capillary permeability. Urate crystals cause the emigration of inflammatory cells to crystalline deposits in tissues and tissue spaces by activating the complement system. The combination of these events precipitates the clinically well-known severe inflammatory reaction seen in acute bouts of gout. These are characterized by the development of hot, swollen, and very painful joints, especially those of the great toe. The most effective drug for treatment of an acute attack of gout is the plant alkaloid colchicines, which is a potent stabilizer of the lysosomal membrane and, furthermore, inhibits leukocyte motility and function by interfering with microtubules in the cytoplasm. Continued deposition of urate results in the formation of characteristic tophi - these are firm, nodular, subcutaneous deposits of urate crystals surrounded by foreign body giant cells and fibrosis. When such deposits are preserved by fixation of tissue in absolute alcohol, urate crystals can be demonstrated as brilliantly double refractile crystals by polarized light (birefringence). They can also be demonstrated by a silver-containing stain as brown-black crystals. Urate deposition tends to occur in relatively avascular tissues, such as cartilage, epiphyseal bone, and periarticular structures. In chronic gouty arthritis, both cartilage and subchondral bone are destroyed. Proliferation of fibrous tissue and marginal bone tissue leads finally to crippling immobilization of the joint. Urate deposits also occur in the kidney, leading to severe renal damage. Crystals of monosodium urate monohydrate are needle-shaped and are arranged radially in small, sheaflike clusters. Calcific material may be deposited in the matrix, rendering such deposit radiopaque. The tissues in which urate deposits commonly occur are those rich in mucopolysaccharides. Some authorities have suggested that the release of lysosomal enzymes from leukocytes may alter protein-mucopolysaccharide conjugates in connective tissues so that urates are preferentially deposited in this matrix.
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Introduction of Pathology An outline of Diagnostic Techniques available in Pathology Diagram showing Structural Changes in Reversible and Irreversible Cell Injury |