Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2020; 26(47): 7470-7484
Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7470
Molecular overview of progressive familial intrahepatic cholestasis
Sriram Amirneni, Nils Haep, Mohammad A Gad, Alejandro Soto-Gutierrez, James E Squires, Rodrigo M Florentino
Sriram Amirneni, Nils Haep, Mohammad A Gad, Alejandro Soto-Gutierrez, Rodrigo M Florentino, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
Alejandro Soto-Gutierrez, James E Squires, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States
James E Squires, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
Author contributions: All authors contributed to this paper with literature review and analysis and approval of the final version.
Supported by NIH, No. UG3TR003289 to Soto-Gutierrez A.
Conflict-of-interest statement: A.S.-G., is co-founder and have a financial interest in Von Baer Wolff, Inc. a company focused on biofabrication of autologous human hepatocytes from stem cells technology and programming liver failure and their interests are managed by the Conflict of Interest Office at the University of Pittsburgh in accordance with their policies
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: Rodrigo M Florentino, PhD, Research Fellow, Department of Pathology, University of Pittsburgh, 200 Lothrop Street S420 Biomedical Science Tower, Pittsburgh, PA 15213, United States.
Received: September 11, 2020
Peer-review started: September 11, 2020
First decision: October 27, 2020
Revised: November 5, 2020
Accepted: November 29, 2020
Article in press: November 29, 2020
Published online: December 21, 2020

Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler’s disease, is caused by mutations of the ATP8B1 gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression via variations in the ABCB11 gene. Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the NR1H4 gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the MYO5B gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Keywords: Progressive familial intrahepatic cholestasis, ATP8B1/familial intrahepatic cholestasis 1, ABCB11/bile salt export pump, ABCB4/multidrug resistance class 3, Intrahepatic cholestasis, Bile

Core Tip: Progressive familial intrahepatic cholestasis (PFIC) is an expanding group of genetically-based diseases caused by various autosomal recessive mutations which result in the inability to appropriately form and excrete bile from hepatocytes. There are three classic types of PFIC. Type 1 is caused by mutations of the ATP8B1 gene, encoding familial intrahepatic cholestasis 1. PFIC 2 is the result of mutations in the ABCB11 gene, reducing the apical membrane expression of bile salt export pump. PFIC 3 is caused by variations in the gene that encodes the multidrug resistance class 3 glycoprotein. With advances in DNA sequencing, new forms of this disease have been documented. Alterations in the NR1H4, tight junction protein 2, and MYO5B genes have been linked with new phenotypes of PFIC. Here, we provide a molecular and clinical overview of PFIC.