Expanding etiology of progressive familial intrahepatic cholestasis

Abstract

Background: 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.

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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: Benign recurrent intrahepatic cholestasis; Bile acids; Bile transport; Cholestasis; Drug induced cholestasis; Intrahepatic cholestasis of pregnancy; Progressive familial intrahepatic cholestasis.

Figure 1

Molecular mechanisms of cholestasis at the apical hepatocellular membrane. FXR: Farnesoid X receptor; RXR: Retinoid x receptor alpha; ABCB11: ATP binding cassette subfamily B member 11; MYO5B: Myosin VB; RAB11A: Ras-related protein Rab11a; FIC1: Familial intrahepatic cholestasis 1; BSEP: Bile salt export pump; MDR3: Multidrug resistance 3; TJP2: Tight junction protein 2.

Figure 2

Representative surgical interventions for progressive familial cholestasis. A: Partial external biliary diversion; B: Partial internal biliary diversion using a cholecystocolostomy approach; C: Ileal bypass/exclusion.