BILIRUBIN METABOLISM



About 4 mg/kg of bilirubin is produced each day, mainly (80 to 85 per cent) derived from the catabolism of the hemoglobin heme group of se­nescent red blood cells. The heme group is cleaved in the reticuloendothelial system to form biliverdin, which in turn is oxidized to bilirubin, a waterinsoluble, linear tetrapyrrole (Fig. 36-5). A smaller proportion of bilirubin (15 to 20 per cent) is derived from the destruction of maturing eryth-roid cells in the bone marrow (ineffective eryth-ropoiesis) and from the heme groups of predom­inantly hepatic hemoproteins such as cytochrome P-450 and cytochrome c.

Bilirubin liberated into the plasma is trans­ported to the liver bound tightly but reversibly to albumin. Three phases of hepatic bilirubin me­tabolism are recognized: (1) uptake, (2) conjuga­tion, and (3) excretion into the bile, the last step being overall rate-limiting (Fig. 36-6). Uptake is reversible and follows dissociation of bilirubin from albumin. Unconjugated bilirubin is insolu­ble in water and is virtually incapable of being excreted in bile. This apolar molecule, however, dissolves in lipid-rich environments and readily traverses the blood-brain barrier and placenta.

The major physiological process for rendering bilirubin water-soluble, and hence capable of being excreted in the aqueous bile, is its conju­gation with the sugar glucuronic acid. Mono and diglucuronides of bilirubin are formed in the he­patic endoplasmic reticulum catalyzed by the en­zyme UDP-glucuronyl transferase. If the biliary excretion of conjugated bilirubin is impaired, the pigment from hepatocytes regurgitates into plasma. Conjugated bilirubin is both watersolu­ble and less tightly bound to albumin than un­conjugated pigment, so that it is readily filtered by the glomerulus and appears in the urine when plasma levels are increased. Unconjugated bili­rubin is not excreted in urine. With sustained con­jugated hyperbilirubinemia (e.g., obstructive jaundice), a proportion of the conjugated bilirubin becomes covalently bound to albumin and is therefore unavailable for renal or biliary excre­tion.

Conjugated bilirubin excreted in the bile is not reabsorbed by the intestine but is converted by bacterial action in the gut to colorless tetrapyr-roles termed urobilinogens. Up to 20 per cent of urobilinogen is reabsorbed and undergoes an enterohepatic circulation, a proportion being ex­creted in the urine. Thus, both impaired hepatocellular excretion and marked overproduction of bilirubin lead to increased appearance of urobi­linogen in the urine.







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