Systematic Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. May 27, 2019; 11(5): 450-463
Published online May 27, 2019. doi: 10.4254/wjh.v11.i5.450
Expanding etiology of progressive familial intrahepatic cholestasis
Sarah AF Henkel, Judy H Squires, Mary Ayers, Armando Ganoza, Patrick Mckiernan, James E Squires
Sarah AF Henkel, Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Atlanta, GA 30322, United States
Judy H Squires, Department of Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
Mary Ayers, Patrick Mckiernan, James E Squires, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
Armando Ganoza, Division of Pediatric Transplantation, Department of Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
Author contributions: Henkel SAF and Squires JE contributed equally to the work; Henkel SAF drafted the initial manuscript; Squires JH, Ayers M and Ganoza A helped conceptualize, design, and carry out the review; all authors reviewed and approved the final manuscript as submitted.
Conflict-of-interest statement: The authors declare that they do not have any conflict of interest to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
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:
Corresponding author: James E Squires, MD, MSc, Assistant Professor, Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States.
Telephone: +1-412-6925180 Fax: +1-412-6927355
Received: March 12, 2019
Peer-review started: March 12, 2019
First decision: March 25, 2019
Revised: April 19, 2019
Accepted: April 26, 2019
Article in press: April 27, 2019
Published online: May 27, 2019
Research background

Progressive familial intrahepatic cholestasis (PFIC) is an umbrella term originally used to describe 3 classic genetic-based cholestatic diseases in children. Recent advancements in how genetic defects in proteins affect bile acid homeostasis and caused disease has led to an expanded list of syndromes categorized as PFIC and a growing understanding of how adults can be affected. In this report, we review the literature to summarize the understanding of ‘classic’ PFIC diseases and present up-to-date information the expanding list of genetic defects that are now known to contribute to the PFIC phenotype.

Research motivation

Bile acid metabolism, homeostasis, and transport is a complex physiologic process, the importance of which is underscored when defects in the system cause disease. While recent advancements have identified critical genes and protein products that, when defective, contribute to disease, phenotypic variability persists, and treatment remains mainly supportive. Furthermore, it is clearly that additional genes and proteins are likely to be identified as the field continues to evolve. In the future, better diagnostics and precise molecular defect identification may identify individualized therapy options that will improve the care provided to these patients.

Research objectives

The objectives of this work were to thoroughly review the current published literature and present an up-to-date summarization of both the ‘’Classic’’ and ‘’Expanded’’ PFIC diseases.

Research methods

A Medline/PubMed search was performed to identify established articles relating to PFIC as well as reports of defects in PFIC-related genes contributing to morbidity in adult and pediatric populations. Data was manually extracted on disease characteristics. Associated phenotypes with other diseases relating to specific genetic defects were also collected. Treatment strategies were summarized. Data was collated and presented in text, figure, and table format.

Research results

We present a comprehensive summary of the ‘’Classic’’ PFIC disorders resulting from defects in ATP8B1 (FIC1 protein), ABCB11 (BSEP protein), and ABCB4 (MDR3 protein). We further explore and summarize the “Expanded” PFIC disorders including those related to TJP1 (TJP2 protein), NR1H4 (FXR protein), MYO5B (MYO5B protein, USP53 (USP53 protein), and LSR (LSR protein) defects. While many of these disorders have historically affected children, we also looked to present the growing literature related to the significant morbidity that these diseases cause in adults.

Research conclusions

In this review, we present a comprehensive summary of the current understanding and management of PFIC-related disorders. The recent identification of the “Expanded” disorders underscores the importance of continued exploration of the genetic basis of bile acid homeostasis. However, idiopathic disease remains a considerable challenge to patients and healthcare professionals suggesting opportunities for further investigation. Future strategies to improve the treatment provided to patients affected by these devastating diseases are also critically needed.

Research perspectives

Since their first description in 1969, the last 50 years has brought dramatic advancements in both the understanding and management of PFIC-related diseases. Still, challenges remain. Continued idiopathic disease suggest improvement in diagnostic strategies are needed and treatment options remain frustratingly small. Variability in both phenotype and response to therapy opens the possibility that specific gene defects or modifiers can identify sub-populations where more personalized approaches can be more affective. Improved disease models, both in vitro and in vivo, are needed to better understand mechanisms and identify therapeutic strategies. Finally, the growing morbidity linked to defects in PFIC-related genes identified in adults highlights the urgency, but also the opportunity, for future investigation.