Histological demonstration of BSEP/ABCB11 inhibition in transient neonatal cholestasis: a case report

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Idiopathic or transient neonatal cholestasis (TNC) represents a group of cholestatic disorders with unidentified origin and remains a diagnosis of exclusion. Dysfunction of hepatobiliary transporters mediating excretion of biliary constituents from hepatocytes may play a central role in the pathogenesis of cholestasis. Despite variants of bile salt (BS) export pump (BSEP /ABCB11) have already been described in TNC, the pathogenic role of BSEP dysfunction in TNC remained so far elusive.

Case presentation

We report on a newly-identified heterozygous ABCB11 missense variant (c.1345G > A, p.Glu449Lys) which was associated with prolonged cholestasis in a term infant after a complicated neonatal period. Moreover, we show for the first time almost completely abolished BSEP expression on the hepatocellular membrane in TNC.

Conclusion

This report demonstrates for the first time a close association between the prolonged cholestasis in infancy and impaired BSEP expression on the hepatocyte canalicular membrane in a heterozygous carrier of newly-identified ABCB11 variant.

Related collections

Most cited references 11

Record: found
Abstract: found
Article: not found

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response.

Shi-Ying Cai, Xinshou Ouyang, Yonglin Chen … (2017)

Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2-/- mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes from Tlr9-/- mice, while liver injury was diminished both in conventional and hepatocyte-specific Tlr9-/- mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.

0 comments Cited 87 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.

Bruno Stieger, Figen Özçay, Abdulelah F. Bassas … (2008)

Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

0 comments Cited 85 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Drug‐induced cholestasis

Vinay Sundaram, Einar S Bjornsson (2017)

Cholestatic drug‐induced liver injury (DILI) can be a diagnostic challenge due to a large differential diagnosis, variability in clinical presentation, and lack of serologic biomarkers associated with this condition. The clinical presentation of drug‐induced cholestasis includes bland cholestasis, cholestatic hepatitis, secondary sclerosing cholangitis, and vanishing bile duct syndrome. The associate mortality of cholestatic DILI can be as high as 10%, and thus prompt recognition and removal of the offending agent is of critical importance. Several risk factors have been identified for drug‐induced cholestasis, including older age, genetic determinants, and properties of certain medications. Antibiotics, particularly amoxicillin/clavulanate, remain the predominant cause of cholestatic DILI, although a variety of other medications associated with this condition have been identified. In this review, we summarize the presentation, clinical approach, risk factors, implicated medications, and management of drug‐induced cholestatic liver injury. (Hepatology Communications 2017;1:726–735)

0 comments Cited 31 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Anna Baghdasaryan:

ORCID: http://orcid.org/0000-0003-1026-706X

a.baghdasaryan@medunigraz.at

Lisa Ofner-Ziegenfuß: lisa.ofner@medunigraz.at

Carolin Lackner: karoline.lackner@medunigraz.at

Peter Fickert: peter.fickert@medunigraz.at

Bernhard Resch: bernhard.resch@medunigraz.at

Nicholas Mark Morris: nicholas.morris@medunigraz.at

Andrea Deutschmann: andrea@kinderaerztin-deutschmann.at

Journal

Journal ID (nlm-ta): BMC Pediatr

Journal ID (iso-abbrev): BMC Pediatr

Title: BMC Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2431

Publication date (Electronic): 9 July 2020

Publication date PMC-release: 9 July 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 340

Affiliations

[1 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, , Medical University of Graz, ; Auenbruggerplatz 34/2, 8036 Graz, Austria

[2 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Institute for Human Genetics, , Medical University of Graz, ; Graz, Austria

[3 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Institute of Pathology, , Medical University of Graz, ; Graz, Austria

[4 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Division of Gastroenterology and Hepatology, Department of Internal Medicine, , Medical University of Graz, ; Graz, Austria

[5 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Division of Neonatology, Department of Pediatrics and Adolescent Medicine, , Medical University of Graz, ; Graz, Austria

Author information

Anna Baghdasaryan http://orcid.org/0000-0003-1026-706X

Article

Publisher ID: 2201

DOI: 10.1186/s12887-020-02201-x

PMC ID: 7346433

PubMed ID: 32646411

SO-VID: af771dc1-4318-4f56-b232-d4c898258f8d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 November 2019

Date accepted : 12 June 2020

Custom metadata

ScienceOpen disciplines: Pediatrics

Keywords: bsep deficiency,transient neonatal cholestasis

Data availability:

ScienceOpen disciplines: Pediatrics

Keywords: bsep deficiency, transient neonatal cholestasis

Histological demonstration of BSEP/ABCB11 inhibition in transient neonatal cholestasis: a case report

Read this article at

Abstract

Background

Case presentation

Conclusion

Related collections

ScienceOpen Clinical Case Reports Collection

Most cited references 11

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response.

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.

Drug‐induced cholestasis

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 276

Most referenced authors 246