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Hemostasis and Thrombosis
Accumulation of Glycogen, complex lipids and carbohydrates |
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Bilirubin is a non-iron containing yellow pigment derived from the porphyrin ring of the heme moiety of hemoglobin as a result of red cell destruction by cells of reticuloendothelial system. Bilirubin is essentially water insoluble and is kept in solution in blood plasma by binding to albumin. Since it is formed normally as a result of the turnover of red cells, there is an efficient pathway in the body for its metabolic conversion and ultimate excretion. Circulating bilirubin in plasma (normal levels range between 0.1 and 0.8 mg/dl) is removed from albumin at the surface of the hepatocytes and subsequently bound by two cytoplasmic proteins, ligandin and fatty acid binding protein. The amount of ligandin is increased by administration of phenobarbital. In the hepatocyte, bilirubin is conjugated to glucuronic acid to form the water-soluble diglucuronide. This reaction is catalyzed by glucuronyl transferase, an enzyme that is localized in the smooth endoplasmic reticulum and is one of a group of enzymes capable of modifying foreign toxic compounds by conjugation. All these enzymes, are also induced by Phenobarbital. Thus the liver handles bilirubin as a potentially toxic compound. In this regard, it is significant to note that Phenobarbital is used to treat patients with low levels of glucuronyl transferase attributable to defective gene (Gilbert’s disease and the Crigler-Najjar type of congenital jaundice). If, however, the defect is so severe that the enzyme is totally absent, such treatment is useless. Conjugated bilirubin is excreted through the biliary tract into the intestine as bile, a micellar complex of cholesterol, phospholipids, bilirubin diglucuronide, and bile salts. In the small intestine, bilirubin is changed to urobilinogen, a small amount of which is reabsorbed into the portal circulation. Most of it is excreted by the kidneys or is reduced to stercobilin in the large bowel and excreted as a brown pigment in the feces. Jaundice is a condition in which the level of bilirubin in plasma is greater than 2 mg/dl and the skin and scleras are yellow. Clinically, jaundice is classified into three major types : Hemolytic ; Obstructive ; Hepatocellular. Hemolytic jaundice: Hemolytic jaundice results from an excessive breakdown of the red blood cell membrane in a variety of conditions, which include a genetic membrane defect, an immune reaction, a severe infection, circulating intravascular toxic substances causing red cell destruction (snake venoms), or transfusion of incompatible blood. Because of the amount and rapid rate of formation of bilirubin in hemolytic crises, the liver's capacity to conjugate it is exceeded, and the level of unconjugated bilirubin rises in the plasma. However, since the liver's capacity is much greater than is normally required, even massive red cell destruction does not lead to bilirubin levels in plasma higher than 5 mg/dl. Since unconjugated bilirubin is not water soluble, its concentration in plasma can not be measured by chemical means until alcohol is added. Alcohol, a lipid solvent that allows the bilirubin to react with diazotized sulfanilic acid to form the red compound azobilirubin, which is then measured. This is the indirect van den Bergh test, which should be distinguished from the direct van den Bergh test in which water-soluble conjugate reacts directly with the reagent. In patients with hemolytic jaundice the level of unconjugated bilirubin is elevated and bilirubinurea is not present. Obstructive jaundice: Obstructive jaundice results from an obstruction of the passage of conjugated bilirubin from hepatocytes to the intestine. Clinically, this is broadly classified on the basis of the location of obstruction as : (1) Extrahepatic : Extrahepatic caused by obstruction of the common bile duct by gallstones, carcinomas of the pancreas and the common duct, and the extrinsic masses, or (2) Intrahepatic : Intrahepatic because of obstruction of normal bile flow through the bile canaliculi, most commonly caused by adverse reactions to drugs such as chlorpromazine and other phenothiazine derivatives, estrogenic hormones, and the anesthetic halothane. Ultrastructural studies have demonstrated dilatation of bile canaliculi with a sharp diminution of microvilli on the secretory surface. In obstructive jaundice, bilirubin in the plasma is predominantly the conjugated diglucuronide and results in a direct van den Bergh reaction. Hepatocellular jaundice: Hepatocellular jaundice results from failure both of hepatocytes to conjugate bilirubin and of bilirubin to pass through the liver into the intestine. Failure to conjugate may involve a primary defect in the hepatocyte because of the absence or very low levels of glucuronyl transferase, the enzyme responsible for catalyzing the reaction of uridinediphosphoglucuronic acid with bilirubin to form the diglucuronide. Jaundice in a newborn infant : Jaundice in a newborn infant, after postnatal physiologic hemolysis of red blood cells, is attributable to functional immaturity of the infant, who has had little or no need for conjugation of foreign compounds during its intrauterine existence. Enzyme levels rise a few days after birth, and the jaundice begins to subside. In severe cases of jaundice, as in prematurity, Rh incompatibility, or infection, very high levels of bilirubin can exert a toxic effect on neurons in the basal ganglia (kernicterus). This occurs because the blood-brain barrier in newborn infants, unlike that in adults, is permeable to bilirubin. Such injury can lead to mental retardation, motor dysfunction, and muscle atrophy. Low to absent levels of glucuronyl transferase resulting from a gene defect are a much rarer recurrence. The obstructive element in hepatocellular jaundice is characterized by intrahepatic cholestasis with fine structural alterations of bile canaliculi and ductules. The dual features of impaired cell function and obstruction are reflected in the fact that high levels of both indirect- and direct-reacting bilirubin are present in the plasma. The organs of patients with jaundice are deeply stained, being yellow early and becoming dark green in more protracted cases. Bilirubin is present in cells as dark mahogany brown to green droplets. In liver, bile fills the sinusoids, canaliculi, and ductules. Because of its lipid solubility and structure, bilirubin has the potential for inducing cell injury, a fact that has been documented clinically especially in the case of kernicterus. However, the precise mechanism or mechanisms by which cytotoxicity occurs is not clear. In the body, albumin has a significant protective effect by binding free bilirubin, a fact supported by experimental studies in which it was shown that albumin-bound bilirubin is nontoxic to tissue-culture cells and that albumin is capable of extracting significant amounts of cell-bound bilirubin from such cells. Free bilirubin exerts two effects - (i) uncoupling of oxidative phosphorylation and (ii) a loss of cell proteins - suggestive of a primary effect on the inner membrane of mitochondria and other cell membranes, including the plasma membrane. Clearly, there is no prominent evidence of significant cell injury in most cases of jaundice, which is probably the result of the protective effects of serum albumin and conjugation.
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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 Coagulation (Coagulative) necrosis Circulatory Anatomy, Physiology and Regulation Diagram showing Capillary System and Mechanisms of Edema Formation |