Inherited disorders of bilirubin clearance

Abstract

Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), (iii) bilirubin excretion into bile (Dubin-Johnson syndrome), or (iv) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy.

Figure 1

Schematic view of transporters and enzymes involved in hepatic bilirubin clearance. (Alb, albumin; BCRP, breast cancer resistance protein; BMG, bilirubin monoglucuronide; BDG, bilirubin diglucuronide; GST, glutathione-S-transferase; MRP, multidrug resistance-associated protein; OATP, organic anion transport protein; UCB, unconjugated bilirubin; UGT, uridine diphosphate glucuronosyl transferase).

Figure 2

Schematic representation of the UGT1 gene locus and the UGT1A1 protein. (Chr, chromosome; PR, promoter regions; UGT, uridine diphosphate glucuronosyl transferase).

Figure 3

Schematic view of transporters and enzymes involved in inherited disorders of bilirubin clearance. (Alb, albumin; BCRP, breast cancer resistance protein; BMG, bilirubin monoglucuronide; BDG, bilirubin diglucuronide; CN, Crigler-Najjar; DJS, Dubin-Johnson syndrome; GS, Gilbert syndrome; GST, glutathione-S-transferase; MRP, multidrug resistance-associated protein; OATP, organic anion transport protein; RS, Rotor syndrome; UCB, unconjugated bilirubin; UGT, uridine diphosphate glucuronosyl transferase).