Hyperbilirubinemia in the setting of antiviral therapy Kevin M. Korenblat, Paul D. Berk  Clinical Gastroenterology and Hepatology  Volume 3, Issue 4, Pages 303-310 (April 2005) DOI: 10.1016/S1542-3565(05)00083-2 Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 1 Efficient transfer of bilirubin from blood to bile is dependent on normal sinusoidal architecture, plasma membrane transport processes, and intracellular binding and conjugation. 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 glutathionione-S-transferases and conjugated by UGT1A1 to monoglucuronides and diglucuronides, which are actively transported across the canalicular membrane into the bile. Modified and reprinted with permission from Berk et al.3 Clinical Gastroenterology and Hepatology 2005 3, 303-310DOI: (10.1016/S1542-3565(05)00083-2) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 2 Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains at least 13 substrate-specific first exons (A1, A2, …), each with its own promoter, that encode the N-terminal substrate-specific 286 amino acids of the various UGT1-encoded isoforms and common exons 2–5 that encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2–5. The resulting message encodes a complete enzyme, in this particular case UGT1A1. Mutations in a first exon affect only a single isoform. Those in exons 2–4 affect all enzymes encoded by the UGT1 gene complex. Modified and reprinted with permission from Berk et al.3 Clinical Gastroenterology and Hepatology 2005 3, 303-310DOI: (10.1016/S1542-3565(05)00083-2) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 3 Relationship between bilirubin production, as approximated by measurements of plasma bilirubin turnover (BRT), hepatic bilirubin clearance (CBR), and the plasma concentration of unconjugated bilirubin (BR). Stippled area represents the normal range for bilirubin production; bar on the horizontal axis is the normal range (mean ± 2 standard deviations) for hepatic bilirubin clearance. A 100% increase in bilirubin production or a 50% decrease in bilirubin clearance will each result in a doubling of the plasma unconjugated bilirubin concentration. However, the absolute magnitude of the increase in bilirubin concentration depends on the initial value for bilirubin clearance. It will be appreciably greater in patients whose initial value for bilirubin clearance is reduced (eg, patients with Gilbert syndrome) than in those whose initial clearance value is normal. mg% = mg/dL. Reprinted with permission from Berk et al.10 Clinical Gastroenterology and Hepatology 2005 3, 303-310DOI: (10.1016/S1542-3565(05)00083-2) Copyright © 2005 American Gastroenterological Association Terms and Conditions