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.

Molecular overview of progressive familial intrahepatic cholestasis

“…FIC1 is part of the type 4 subfamily of P-type adenosine triphosphatases, which are involved in translocating phospholipids in membranes[ 18 ]. This protein, present at the apical membrane of hepatocytes, is thought to function as an aminophospholipid translocase, carrying phospholipids, specifically phosphatidylserine (PS) and phosphatidylethanolamine (PE), from the outside, ectoplasmic leaflet of the canalicular membrane, to the inside, cytoplasmic leaflet in hepatocytes[ 17 - 19 ]. When functioning normally, FIC1 protects the hepatocyte from high bile salt concentrations[ 17 ].…”

“…In hepatocytes, elevated bile salts concentrations activate FXR, which induces the expression of the BSEP[ 17 , 19 ]. BSEP allows for the pumping of bile salts out of the hepatocyte into the canalicular lumen[ 17 , 19 ]. Additionally, when expressed in the intestines, FXR represses the expression of ASBT.…”

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication

“…39 A systematic review reported that SAM improves some liver biochemical parameters and symptoms in patients with intrahepatic cholestasis, 40 which is a feature of several CLDs. 41 Furthermore, in recent years, N 6 -methyladenosine (m 6 A) modifications have been proven to be related to liver injuries. Deregulation of m 6 A regulators in host hepatocytes may contribute to the development of viral hepatitis.…”

Liver transplant for inherited metabolic disease among siblings

“…Why there was a similar fall in age at LT in siblings with SLD is not clear. Siblings with metabolic SLD may have a discordant phenotype, 3,4 but this should result in variability in age at LT rather than a progressive fall. One factor may be that when families, and their physicians, see the benefit of LT in one sibling, they are more proactive about embracing LT before deterioration, with associated complications, occurs in another.…”