Newer variants of progressive familial intrahepatic cholestasis

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.

Keywords: Biliary diversion; Hepatocellular carcinoma; Microvillous inclusion disease; Progressive familial intrahepatic cholestasis; Tight junction protein.

Figure 1

Pathogenesis of progressive familial intrahepatic cholestasis 1, 2 and 3. Familial intrahepatic cholestasis protein 1 is a flippase that helps in movement of phosphatidylserine and phosphatidylethanolamine from the outer to inner leaflet of the plasma membrane of hepatocyte; Bile salt exporter pump exports bile acid from hepatocytes to bile canaliculus; Multidrug resistance protein 3 is a floppase involved in transporting phosphatidylcholine into bile canaliculus. PFIC: Progressive familial intrahepatic cholestasis; FIC1: Familial intrahepatic cholestasis protein 1; BSEP: Bile salt exporter pump; MDR3: Multidrug resistance protein 3.

Figure 2

Diagrammatic representation of interaction between various tight junction proteins in hepatocytes. Claudin, tight junction proteins (TJP2), and actin form intercellular cytoskeletal support. Tight junctions prevent mixing of bile and blood. Absence of TJP2 causes a failure of claudin-1 localization at the canalicular membrane, leading to loss of compactness of the tight junctions and leakage of the bile through the paracellular space. TJP2: Tight junction proteins 2.

Figure 3

Schematic representation of role of farnesoid X receptor in hepatocyte. Bile acids are transported into the hepatocyte by NTCP. De novo synthesis of bile acids from cholesterol is mediated by CYP7A1. Bile acids and farnesoid X receptor (FXR) interact and enter the nucleus to promote expression of bile salt export protein and short heterodimer partner (SHP). SHP suppresses expression of NTCP and CYP7A1. FXR also induces FGF-19 in ileal enterocytes which inhibits CYP7A1 via FGFR4. ASBT: Apical sodium bile transporter, BSEP: Bile salt export pump; FGF-19: Fibroblast growth factor-19; FGFR-4: Fibroblast growth factor receptor-4; FXR: Farnesoid X receptor; NTCP: Na+-taurocholate co-transporting polypeptide; OST α/β: Organic solute transporter; RXR: Retinoid X receptor; SHP: Short heterodimer partner.

Figure 4

Diagrammatic representation of role of MYO5B and RAS-related GTP-binding protein 11A interaction and endosome recycling pathway and bile salt export pump expression. MYO5B and RAS-related GTP-binding protein 11A (RAB11A) interaction is essential for epithelial cell polarization and BSEP localization to the canalicular membrane. Diminished MYO5B/RAB11A recycling endosome pathway leads to disruption of bile salt export pump localization. ABCB11: ATP Binding Cassette Subfamily B Member 11; BSEP: Bile salt export pump; FXR: Farnesoid X receptor; RAB11A: RAS-related GTP-binding protein 11A; RXR: Retinoid X receptor.