Molecular overview of progressive familial intrahepatic cholestasis

Table 1 Overview of progressive familial intrahepatic cholestasis subtypes

	PFIC 1	PFIC 2	PFIC 3	PFIC 4	PFIC 5	PFICAssociated with MYO5B defects
Gene	ATP8B1	ABCB11	ABCB4	TJP2	NR1H4	MYO5B
Molecular findings	Impaired hepatocyte bile salt secretion; canalicular cholestasis; giant cell transformation; portal and lobular fibrosis; lack of ductular proliferation	Increased intracellular bile salt concentrations; canalicular cholestasis; lobular and portal fibrosis; hepatocellular necrosis	Absence of PC from the biliary canaliculi; increased free bile salts in canaliculi; cholangiocyte damage; increased cholesterol crystallization nonspecific portal inflammation; portal fibrosis; giant cell hepatitis	Abnormal CLDN1 localization; normal CLDN2 localization; compromised tight junctions; bile salt leakage into the paracellular space; hepatocyte and cholangiocyte damage; giant cell transformation	Undetectable expression of BSEP in the bile canaliculi; intralobular cholestasis with ductular reaction; hepatocellular ballooning; giant cell transformation	Possibly mislocalized BSEP and MDR3 upon staining; portal and lobular fibrosis; giant cell transformation. Intestinal MVID findings (mislocalized apical brush border proteins, villus atrophy, presence of microvillus inclusion bodies)
Clinical findings	Low GGT cholestasis; jaundice caused by hyperbilirubinemia; pruritus; hepatosplenomegaly; diarrhea; stunted growth; exocrine pancreatic insufficiency; progressive sensorineural hearing loss; fat-soluble vitamin deficiencies; can lead to cirrhosis and end stage liver disease	Low GGT cholestasis; elevated transaminases; elevated serum bilirubin; elevated AFP; jaundice; pruritus; scleral icterus; hepatomegaly; chronic skin picking; reduced growth	Elevated GGT cholestasis; pruritus; hepatosplenomegaly; variceal bleeding; portal hypertension; jaundice; acholic stools; stunted growth; reduced bone density; learning disabilities; elevated transaminases; elevated bilirubin; elevated AP	Low GGT cholestasis; neurological and respiratory symptoms	Neonatal onset of normal GGT associated cholestasis; elevated serum bilirubin; elevated serum AFP; vitamin K independent coagulopathy; fibrosis progressing into micronodular cirrhosis	Normal GGT cholestasis; jaundice; pruritus; mildly elevated ALT and AST; elevated serum BS; hepatomegaly
Clinical outcomes	Medical management is the first line of defense, but if it is insufficient, surgical is next. Bilary diversion has been effective in around 80% of patients. The last resort is LT in patients who develop cirrhosis and liver failure. Extrahepatic symptoms can persist (or worsen) after LT	There is a 15% chance of cirrhosis developing into HCC or cholangiocarcinoma. Genetic defect(s) can aid in determination of success of biliary diversion. LT in PFIC 2 patients might lead to development of BSEP specific allo-reactive antibodies (in approximately 8% of PFIC 2 patients who undergo LT). In these cases, a second LT may be needed if BSEP deficiency develops in the new liver	HCC and cholangiocarcinoma have been associated with PFIC 3. The severity varies, with those retaining MDR3 expression responding better to medical treatment. Biliary diversion procedures aren’t as effective due to severity upon presentation, but LT is curative	There have been some reports of HCC occurrence in PFIC 4 patients, though not much is known about the mechanism. LT has been successful, with no reported recurrence of the PFIC 4 phenotype after LT	PFIC 5 is very rare (only 8 cases reported in the literature so far). LT has been used, but steatosis in the transplanted liver has been reported in some cases	MVID has been associated with MYO5B defects. Lifelong TPN is required but is associated with increased risk of sepsis and small bowel transplant. Combined bowel-liver transplants may reduce the risk of post transplant onset of cholestasis
Treatments	Medical: Vitamin supplementation; UDCA; Rifampin; Cholestyramine; CFTR folding correctors	Medical: 4PBA. Surgical: Biliary diversion procedures; LT (might need increased immunosuppression)	Medical: UDCA; Rifampin. Surgical: Biliary diversion; LT	Surgical: LT	Medical: UDCA; Rifampin; ASBT inhibitors; OCA. Surgical: LT	Medical: UDCA; rifampin; Cholestyramine. Surgical: PEBD; isolated or Combined liver-bowel transplant

PC: Phosphatidylcholine; CLDN1: Claudin-1; CLDN2: Claudin-2; BSEP: Bile salt export pump; MDR3: Multidrug resistance class 3 glycoprotein; MVID: Microvillus inclusion disease; GGT: Gamma-glutamyl transferase; AFP: Alpha-fetoprotein; AP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate transaminase; BS: Bile salt; HCC: Hepatocellular carcinoma; MYO5B: Myosin VB; TPN: Total parenteral nutrition; UDCA: Ursodeoxycholic acid; CFTR: Cystic fibrosis transmembrane conductance regulator; 4PBA: 4-phenylbutyrate; ASBT: Apical sodium-dependent bile acid transporter; OCA: Obeticholic acid; PEBD: Partial external biliary diversion; PIBD: Partial internal biliary diversion; IE: Ileal exclusion; LT: Liver transplant; PFIC: Progressive Familial Intrahepatic Cholestasis; TJP2: Tight junction protein-2.