Case Report
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2020; 12(2): 64-71
Published online Feb 27, 2020. doi: 10.4254/wjh.v12.i2.64
Nonsense variant of ATP8B1 gene in heterozygosis and benign recurrent intrahepatic cholestasis: A case report and review of literature
Mariano Piazzolla, Nicola Castellaneta, Antonio Novelli, Emanuele Agolini, Dario Cocciadiferro, Leonardo Resta, Loren Duda, Michele Barone, Enzo Ierardi, Alfredo Di Leo
Mariano Piazzolla, Nicola Castellaneta, Michele Barone, Enzo Ierardi, Alfredo Di Leo, Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
Antonio Novelli, Emanuele Agolini, Dario Cocciadiferro, Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy
Leonardo Resta, Loren Duda, Section of Pathology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
Author contributions: Di Leo A, Barone M and Ierardi E designed the research; Piazzolla M and Castellaneta N followed up the patient both during hospitalization and outpatient visits; Novelli A, Agolini E and Cocciadiferro D performed genetic analysis; Resta L and Duda L performed histological examination; Piazzolla M and Ierardi E wrote the paper; all authors critically revised the manuscript.
Informed consent statement: The patient gave written informed consent before the submission of the manuscript.
Conflict-of-interest statement: No conflict of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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:
Corresponding author: Enzo Ierardi, MD, Academic Fellow, Associate Professor, Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, Bari 70124, Italy.
Received: November 14, 2019
Peer-review started: November 14, 2019
First decision: December 12, 2019
Revised: December 19, 2019
Accepted: January 1, 2020
Article in press: January 1, 2020
Published online: February 27, 2020

Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters. Herein, we firstly provide the evidence that a nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygous form is involved in BRIC pathogenesis.


A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase. Acute and chronic liver diseases with viral, metabolic and autoimmune etiology were excluded. Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance. Liver biopsy showed: Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment, Kupffer’s cell activation/hyperplasia and preserved biliary ducts. Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria, ATP8B1 and ABCB11 gene analysis was performed. Surprisingly, we found a novel nonsense variant of ATP8B1 gene (c.1558A>T) in heterozygosis. The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation, showing a maternal inheritance. Immunohistochemistry confirmed a significant reduction of mutated gene related protein (familial intrahepatic cholestasis 1). The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo.


A genetic abnormality, different from those already known, could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition, thus encouraging further mutation detection in this field.

Keywords: Benign recurrent intrahepatic cholestasis, ATP8B1/ABCB11 genes, Jaundice, Heterozygous variant of ATP8B1 gene (c.1558A>T), Familial inheritance, Case report

Core tip: Benign recurrent intrahepatic cholestasis is a rare genetic disorder characterized by recurrent jaundice due to the mutation of the ATP8B1/ABCB11 genes encoding for hepato-canalicular transporters. The original finding, which characterizes the case we observed, is the association of a novel nonsense variant of ATP8B1 gene (c.1558A>T) in a heterozygous condition with hepato-canalicular transporter protein deficiency. Indeed, the disorder has been described until now as an autosomal recessive one, whereas, in this case, the patient expressed the disease despite having only one mutated allele of ATP8B1 gene.