Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review

Abstract

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity. This article provides a comprehensive review on the pathophysiology of Dubin-Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.

Keywords: ABCC2/MRP2; Dubin-Johnson syndrome; Rotor syndrome; SLCO1B1/OATP1B1; SLCO1B3/OATP1B3; conjugated hyperbilirubinemia.

FIGURE 1

Mechanisms of bile formation and hepatobiliary transport systems in human liver. Bile formation begins in the hepatocyte, at the canalicular level (75% of daily bile production), followed by modifications along the bile ducts (25% of daily production). The uptake of various substances across the basolateral membrane is followed by conjugation reactions mediated by the enzyme UGT1A1 (Phase II). Posteriorly, excretion occurs and substances, including conjugated bilirubin, are secreted into the bile–this process is mediated by Multidrug Resistance‐associated Protein 2 (MRP2) with possible minor contribution of other transports at the canalicular (apical) membrane of hepatocytes. The hepatobiliary transport of bile salts is performed by a different system (their excretion occurs through bile salt export pump (BSEP) transport). In addition, even under physiologic conditions, a fraction of bilirubin conjugates is secreted by MRP3 across sinusoidal (basolateral) membrane into the blood, from where they can be subsequently reuptaken by sinusoidal membrane‐bound OATP1B1 and OATP1B3 transporters. MRP: Multidrug resistance‐associated protein; OATP: Organic anion transporting polypeptide; UGT: Uridine diphosphate glucuronosyltransferase; NTCP: Na⁺ taurocholate cotransporter; BSEP: Bile salt export pump; ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; UB: unconjugated bilirubin; HCO₃ ⁻: Bicarbonate; Na⁺: Sodium

FIGURE 2

Schematic representation of the Multidrug Resistance‐associated Protein 2 (MRP2) protein. MRP2 is a multispecific organic anion transporter, exclusively located on the apical membrane of polarized cells, especially in the hepatocyte. A bidimensional schematic representation of its proposed structural topology is shown–MRP2 contains an extra membrane spanning domain (MSD0) of 5 transmembrane helices in the NH2 terminal region, along with two other membrane‐spanning domains (MSD‐0) (MSD 1 and MSD2) of six transmembrane helices and two nucleotide binding domains (NBD1 and NBD2). Cytoplasmic loops (L‐1 and L‐2); Connecting Regions (CR1, CR2); N‐terminal (NH₂) and C‐terminal (COOH)

FIGURE 3

Schematic representation of the OATP1B protein. OATP1B encompass a subfamily of membrane transport proteins. OATP1B1/1B3 are expressed on the basolateral membrane of hepatocytes. A bidimensional schematic representation of its core structure is shown–OATP1B proteins include 12 transmembrane domains (TM1–TM12) and a conserved signature sequence of (D‐X‐RW‐(I,V)‐GAWWX‐G‐(F,L)‐L). N‐terminal (NH₂) and C‐terminal (COOH)