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Hereditary Conjugated Hyperbilirubinaemia: 37 Years Later

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Hereditary Conjugated Hyperbilirubinaemia: 37 Years Later International Hepatology Hereditary conjugated hyperbilirubinaemia: 37 years later ⇑ Daniel Dhumeaux1, Serge Erlinger2, 1University of Paris-Est, Henri-Mondor Hospital, and INSERM U-955, Créteil, France; 2University of Paris 7, Paris, France COMMENTARY ON: of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 Complete OATP1B1 and OATP1B3 deficiency causes human Rotor and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. syndrome by interrupting conjugated bilirubin reuptake into Moreover, OATP1B1 and OATP1B3 null mutations may confer the liver. van de Steeg E, Stránecky´ V, Hartmannová H, substantial drug toxicity risks. Nosková L, Hrˇebícˇek M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH. J Clin Invest 2012 Ó 2012 European Association for the Study of the Liver. Published Feb1;122(2):519–28. Copyright Ó 2012. Abstract reprinted by Elsevier B.V. All rights reserved. with permission of American Society for Clinical Investigation. In 1975, one of us reported a case of hereditary hyperbilirubina- http://www.ncbi.nlm.nih.gov/pubmed/22232210 emia, with predominantly conjugated bilirubin. Bromosulfophtha- lein (BSP) hepatic storage capacity (S) was markedly reduced, Abstract. Bilirubin, a breakdown product of heme, is normally while BSP biliary transport maximum (Tm), reflecting excretory glucuronidated and excreted by the liver into bile. Failure of this sys- capacity, was only moderately decreased, suggesting an uptake tem can lead to a buildup of conjugated bilirubin in the blood, resulting and/or storage defect, rather than an excretory defect [1]. This in jaundice. The mechanistic basis of bilirubin excretion and hyperbil- appeared to be a ‘‘new’’ syndrome, named hepatic uptake and irubinemia syndromes is largely understood, but that of Rotor storage disease (OMIM 237550), since Rotor (OMIM #237450) syndrome, an autosomal recessive disorder characterized by conju- and Dubin–Johnson (OMIM #237500) syndromes, the two main gated hyperbilirubinemia, coproporphyrinuria, and near-absent causes of hereditary conjugated hyperbilirubinaemia [2], were hepatic uptake of anionic diagnostics, has remained enigmatic. Here, considered, at that time, excretory defects, because of the presence we analyzed 8 Rotor-syndrome families and found that Rotor of conjugated bilirubin in blood. After this first description, several syndrome was linked to mutations predicted to cause complete and groups, including ours, re-examined patients with Rotor and found simultaneous deficiencies of the organic anion transporting polypep- a markedly decreased BSP uptake and storage capacity, while BSP tides OATP1B1 and OATP1B3. These important detoxification-limiting biliary Tm was relatively normal [3,4]. Since Rotor and uptake and proteins mediate uptake and clearance of countless drugs and drug storage disease patients had a decreased BSP storage capacity and a conjugates across the sinusoidal hepatocyte membrane. OATP1B1 relatively normal BSP Tm, Rotor and uptake and storage disease polymorphisms have previously been linked to drug hypersensitivities. were considered to be the same entity [5]. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal Since then, considerable progress has been made in the under- export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates standing of hepatic transporters and in the pathophysiology of into the blood, while Oatp1a/1b transporters mediate their hepatic hyperbilirubinaemia. It has been confirmed that Rotor syndrome reuptake. Transgenic expression of human OATP1B1 or OATP1B3 cannot be explained by an excretory defect, since no mutations of restored the function of this detoxification-enhancing liver-blood ABCC2, the canalicular export pump for bilirubin glucuronide and shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle other organic anions, have been found [6]. But, in spite of these may allow flexible transfer of bilirubin conjugates (and probably advances, the reason why serum bilirubin in these patients, also drug conjugates) formed in upstream hepatocytes to downstream was predominantly conjugated remains an enigma. hepatocytes, thereby preventing local saturation of further The recent work of van de Steeg et al. probably resolves this detoxification processes and hepatocyte toxic injury. Thus, disruption mystery [7]. The authors were investigating the role of the sinusoi- dal organic anions transporting polypetides (OATPs, genes: SLCOs), Keywords: Bilirubin; Bile acids; Hepatic transport; Rotor syndrome;Dubin–Johnson which mediate the hepatic uptake of a variety of compounds, syndrome; Hepatic storage disease; Bromosulfophthalein (BSP); Organic anions including bilirubin glucuronide, bile acids, steroid and thyroid transporting polypeptide. hormones, and numerous drugs, toxins and their conjugates. In Received 14 August 2012; received in revised form 29 August 2012; accepted 30 August 2012 man, OATP1B1 and OATP1B3 are of particular importance, since ⇑ Corresponding author. Address: 1422, route des Mauvares, 13840 Rognes, they mediate hepatic uptake of a number of drugs [8]. To further France. Tel.: +33 4 42 50 27 93. study these transporters, van de Steeg et al. generated a Slco1a/ E-mail address: [email protected] (S. Erlinger). 1bÀ/À mouse model and noted that these mice exhibited Abbreviations: BSP, bromosulfophthalein; S, hepatic storage capacity; Tm, biliary marked conjugated hyperbilirubinaemia. They postulated that transport maximum; ABCC2 (or 3), ATP-binding cassette protein, family C, member 2 (or 3); OATP, organic anion transporting polypeptide; SLCO, solute carrier organic sinusoidal Oatps in the normal mouse function in ‘‘tandem’’ with anion transporter family; MRP2, multi drug-resistance associated protein 2. the sinusoidal efflux transporter Abcc3 (the sinusoidal equivalent Journal of Hepatology 2013 vol. 58 j 388–390 JOURNAL OF HEPATOLOGY AB Blood Hepatocyte Bile Blood Hepatocyte Bile Alb Ligandin Alb Ligandin UCB? UCB UGT1A1 UCB ? UCB UGT1A1 MRP2/ABCC2 MRP2/ABCC2 BG BG BG BG BG BG ABCC3 ABCG2 ABCC3 ABCG2 Bile Bile canaliculus canaliculus OATP1B1/3 OATP1B1/3 BG Fig. 1. Hepatic transport of bilirubin in normal subjects (A) and in patients with Rotor syndrome (B). Normally, unconjugated bilirubin (UCB) is present in plasma bound to albumin. It enters the hepatocyte mostly by passive diffusion across the sinusoidal membrane. Transporters like OATP1B1/3 or others (?) may also play a role. In the hepatocyte, UCB is bound to ligandin, then conjugated into bilirubin glucuronide (BG) by the enzyme UDP-glucuronyl transferase 1A1 and excreted either into bile by the canalicular conjugate export pump MRP2/ABCC2, or back into blood by the sinusoidal efflux carrier ABCC3. Finally, it is retaken up into the hepatocyte by the sinusoidal transporters OATP1B1/3. In Rotor syndrome, OATP1B1/3 are defective, BG cannot re-enter the hepatocyte and accumulates in blood. of the canalicular conjugate export pump Abcc2) to mediate suc- Pathogenic homozygous mutations of both SLCO1B1 and cessively hepatic efflux (by Abcc3) and reuptake (by Oatps) of bil- SLCO1B3 are found in Rotor syndrome patients irubin glucuronide. Their recent work is a combination of functional studies in mice to test this hypothesis and genetic stud- Finally, the authors scanned the whole genome and mapped the ies in humans to elucidate the genetic basis of Rotor syndrome. The candidate gene intervals in 11 Rotor syndrome patients from 8 dif- main results can be summarised as follows: ferent families (4 Central European, 3 Saudi-Arabian and 1 Fili- pino). Homozygosity mapping identified a single genomic region on chromosome 12 for which 8 tested index patients and no Abcc3 mediates bilirubin glucuronide excretion from liver to healthy siblings were homozygous, suggesting inheritance of both blood and Oatp1a/b mediate its hepatic reuptake mutated alleles from a common ancestor. Sequence analysis revealed predictably pathogenic mutations affecting both SLCO1B3 The authors generated double knockout mice whose Slco1a/b and and SLCO1B1 in each of the tested subjects. The identified muta- Abcc3 genes (coding, respectively, for the sinusoidal transporters tions generally introduced a stop codon in the genes, thus severely Oatp1a/b, functionally close to human OATP1B1/3, and Abcc3, sim- disrupting or, even, annihilating protein expression and function. ilar to human ABCC3) were inactivated. The marked conjugated They all showed autosomal recessive segregation in the Rotor syn- hyperbilirubinaemia observed in Slco1a/bÀ/À mice (with only inac- drome investigated families. The severity of the mutations was tive Oatp1a/b but functional Abcc3) [9] was absent or markedly supported by nearly absent immunostaining of OATP1B proteins reduced in the double knockout mice (with inactive Oatp1a/b in liver biopsy specimens of Rotor syndrome patients. and Abcc3). This shows that Abcc3 is necessary for most of the In summary, in normal subjects (Fig. 1A), bilirubin, after entry increase in plasma conjugated bilirubin. The result is consistent into hepatocytes, is conjugated into bilirubin glucuronide by with the view that Abcc3 excretes bilirubin glucuronide back into uridine glucuronyl transferase 1A1, and then excreted into bile blood and Oatp1a/b mediate their hepatic reuptake. by the canalicular MRP2/ABCC2 conjugate export pump. In addi- tion, this landmark study elegantly demonstrates that bilirubin Human OATP1B1
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