Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2017; 23(29): 5295-5303
Published online Aug 7, 2017. doi: 10.3748/wjg.v23.i29.5295
Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation
Philipp Ellinger, Jan Stindt, Carola Dröge, Katharina Sattler, Claudia Stross, Stefanie Kluge, Diran Herebian, Sander H J Smits, Martin Burdelski, Sebastian Schulz-Jürgensen, Antje Ballauff, Jan Schulte am Esch, Ertan Mayatepek, Dieter Häussinger, Ralf Kubitz, Lutz Schmitt
Philipp Ellinger, Jan Stindt, Sander H J Smits, Lutz Schmitt, Institute of Biochemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Jan Stindt, Carola Dröge, Katharina Sattler, Claudia Stross, Stefanie Kluge, Dieter Häussinger, Ralf Kubitz, Medical Faculty, Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Diran Herebian, Ertan Mayatepek, Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Martin Burdelski, Sebastian Schulz-Jürgensen, Department of Paediatrics, University Hospital Schleswig Holstein, 24105 Kiel, Germany
Antje Ballauff, Department of Paediatrics, Helios Clinic, 47805 Krefeld, Germany
Jan Schulte am Esch, Department of General Surgery, Heinrich-Heine-University, 40225 Düsseldorf, Germany
Author contributions: Ellinger P and Stindt J contributed equally to this work; Ellinger P, Stindt J, Dröge C, Sattler K, Stross C and Kluge S performed the experiments; Herebian D and Mayatepek E carried out bile salt analysis; Burdelski M, Schulz-Jürgensen S, Ballauff A, Kubitz R and Häussinger D treated the patients; Schulte am Esch J collected human bile samples; Ellinger P, Stindt J, Kubitz R and Schmitt L designed experiments; Smits SHJ, Kubitz R and Schmitt L wrote the paper; all authors contributed to the final manuscript.
Supported by the German Research Foundation through the Clinical Research Group KFO217 “ Hepatobiliary transport and liver diseases” and the Collaborative Research Centre 974 “Communication and Systemic Relevance in Liver Damage and Regeneration”.
Institutional review board statement: The study was reviewed and approved by the Institutional Review board, the “Ethikkommission an der Medizinischen Fakultät der Heinrich-Heine-Universität Düsseldorf” (Study number 2875).
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dr. Lutz Schmitt, Professor, Institute of Biochemistry, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Telephone: +49-211-8110773
Received: January 1, 2017
Peer-review started: January 5, 2017
First decision: January 19, 2017
Revised: May 10, 2017
Accepted: June 9, 2017
Article in press: June 12, 2017
Published online: August 7, 2017

To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency.


Mutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [3H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays.


A girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients’ native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively.


In summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2 (PFIC-2).

Keywords: Familial intrahepatic cholestasis type 2, Partial external biliary diversion, Bile salt export pump, ATP binding cassette transporter, Intrahepatic cholestasis

Core tip: PFIC-2, a severe form of BSEP deficiency, is caused by mutations of the bile salt export pump (BSEP), an ATP binding cassette transporter exclusively expressed in hepatocytes. In this study we determine the functional impact of two distinct BSEP mutations on transporter localization and function in two unrelated PFIC-2 patients showing a drastically different response to partial external biliary diversion (PEBD). Our data demonstrate that residual bile salt transport by BSEP is likely required for a beneficial outcome of PEBD.