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

Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.


To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.


We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.


Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.


We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.

Keywords: Cholestasis, Progressive familial intrahepatic cholestasis, Benign recurrent intrahepatic cholestasis, Intrahepatic cholestasis of pregnancy, Drug induced cholestasis, Bile acids, Bile transport

Core tip: Progressive familial intrahepatic cholestasis is a heterogeneous cohort of diseases that present both diagnostic and treatment challenges for clinicians. Significant advancement in the knowledge base related to the genetic underpinnings regulating bile acid transport physiology has enabled new diseases to be identified with a breadth of phenotypes from neonates to adults.