16.22 ). Approximately 85% of daily production (0.2–0.3 gm) is derived from the breakdown of senescent red cells by macrophages in the spleen, liver, and bone marrow. The remainder is derived from the turnover of hepatic heme or hemoproteins (e.g., the P-450 cytochromes) and from destruction of red cell precursors in the bone marrow (Chapter 12). Whatever the source, intracellular heme oxygenase oxidizes heme to biliverdin (step 1 in
Fig. 16.22 http://ebooksmedicine.net
Table 16.4 Major Causes of Jaundice
Excess Production of Bilirubin
Hemolytic anemiasResorption of blood from internal hemorrhage (e.g., alimentary tract bleeding, hematomas)Ineffective erythropoiesis (e.g., pernicious anemia, thalassemia)
Physiologic jaundice of the newbornDiffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)
Drug-induced canalicular membrane dysfunction (e.g., oral contraceptives, cyclosporine)Hepatocellular damage or toxicity (e.g., viral or drug-induced hepatitis, total parenteral nutrition, systemic infection)
Inflammatory destruction of intrahepatic bile ducts (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease, liver transplantation)
External compression (e.g., carcinoma of the pancreas) which is immediately reduced to bilirubin by biliverdin reductase. Bilirubin thus formed is released and binds to serum albumin (step 2), which is critical since bilirubin is virtually insoluble in aqueous solutions at physiologic pH and also highly toxic to tissues. Albumin carries bilirubin to the liver, where bilirubin is taken up into hepatocytes (step 3) and conjugated with one or two molecules of glucuronic acid by bilirubin uridine diphosphate (UDP)–glucuronyltransferase (UGT1A1, step 4) in the endoplasmic reticulum. Water-soluble, nontoxic bilirubin glucuronides are then excreted into the bile. Most bilirubin glucuronides are deconjugated in the gut lumen by bacterial β-glucuronidases and degraded to colorless urobilinogens (step 5). The urobilinogens and the residue of intact pigment are largely excreted in feces. Approximately 20% of the urobilinogens formed are reabsorbed in the ileum and colon, returned to the liver, and reexcreted into bile. A small amount of reabsorbed urobilinogen is excreted in the urine.