The details of bilirubin metabolism are presented in Chap. 42. However, the hyperbilirubinemias are best understood in terms of perturbations of specific aspects of bilirubin metabolism and transport, and these will be briefly reviewed here as depicted in Fig. 303-1.
Hepatocellular bilirubin transport. Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell it is bound to glutathione-S-transferases and conjugated by bilirubin-UDP-glucuronosyltransferase (UGT1A1) to monoand diglucuronides, which are actively transported across the canalicular membrane into the bile. ALB, albumin; BDG, bilirubin diglucuronide; BMG, bilirubin monoglucuronide; BT, proposed bilirubin transporter; GST, glutathione-S-transferase; MRP2, multidrug resistance–associated protein 2; UCB, unconjugated bilirubin; UGT1A1, bilirubin-UDP-glucuronosyltransferase.
Bilirubin is the end product of heme degradation. Some 70–90% of bilirubin is derived from degradation of the hemoglobin of senescent red blood cells. Bilirubin produced in the periphery is transported to the liver within the plasma, where, due to its insolubility in aqueous solutions, it is tightly bound to albumin. Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes. Transfer of bilirubin from blood to bile involves four distinct but interrelated steps (Fig. 303-1).
Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics. Although a number of candidate bilirubin transporters have been proposed, the actual transporter remains elusive.
Intracellular binding: Within the hepatocyte, bilirubin is kept in solution by binding as a nonsubstrate ligand to several of the glutathione-S-transferases, formerly called ligandins.
Conjugation: Bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronosyltransferase to form bilirubin mono- and diglucuronide, respectively. Conjugation disrupts the internal hydrogen bonding that limits aqueous solubility of bilirubin, and the resulting glucuronide conjugates are highly soluble in water. Conjugation is obligatory for excretion of bilirubin across the bile canalicular membrane into bile. The UDP-glucuronosyltransferases have been classified into gene families based on the degree of homology among the mRNAs for the various isoforms. Those that conjugate bilirubin and certain other substrates have been designated the UGT1 family. These are expressed from a single gene complex by alternative promoter usage. This gene complex contains multiple substrate-specific first exons, designated A1, A2, etc. (Fig. 303-2), each with its own promoter and each encoding the amino-terminal half of a specific isoform. In addition, there are four common exons (exons 2–5) that encode the shared carboxyl-terminal half of all of the UGT1 isoforms. The various first exons encode the specific aglycone substrate binding sites for each isoform, while the shared exons encode the binding site for the sugar donor, UDP-glucuronic acid, and the transmembrane domain. Exon A1 and the four common exons, collectively designated the UGT1A1 gene (Fig. 303-2), encode the physiologically critical enzyme bilirubin-UDP-glucuronosyltransferase (UGT1A1). A functional corollary of the organization ...