Newer variants of progressive familial intrahepatic cholestasis

Table 4 Comparison of clinical features, laboratory profile and outcome in progressive familial intrahepatic cholestasis 4, 5 and 6

	PFIC 4	PFIC 5	PFIC 6
Gene mutation	TJP2/Zona occludens-2 located in 9q21.11	NR1H4/FXR-located in 12q23.1	MYO5B located in 18q21.1
Clinical features
Clinical features	Cholestatic jaundice with pruritus	Rapidly progressive neonatal-onset cholestasis with uncorrectable coagulopathy	Cholestasis with pruritus, with/without transient, recurrent or progressive diarrhea (association with MVID)
Extrahepatic features	Neurological and respiratory symptoms	-	-
ICP	Yes	Yes (uncommon)	No
Laboratory parameters
AST/ALT	Elevated	Moderate elevation	Mild to moderate elevation
GGT	Normal or mild elevation	Normal	Normal
Coagulopathy	Late-onset	Early-onset	Late-onset
Alpha fetoprotein	Normal, elevated in cases with HCC	Elevated	Normal
S. Bile acids	Elevated	Elevated	Elevated
Histopathology
Canalicular cholestasis	Yes	Yes	Yes
Portal/lobular fibrosis	Yes	Yes	Yes
Giant-cell transformation	Yes	Diffuse	Sparse
Ductular reaction	No	Yes	Yes
Hepatocyte necrosis	Yes	-	-
Cirrhosis	Yes	Yes	Less common
Immunohistochemistry
BSEP	Present	Absent BSEP staining on bile canaliculus	Abnormally thick, irregular and granular positivity that overflows into subcanalicular area
MDR3	Present	Present	Thickened canalicular staining granular and patchy pattern overflows into subcanalicular area
TJP2	Absent expression in canalicular membrane	Present	Present
Claudin1	Absent or reduced staining on bile canaliculi	Present	Present
FXR	Normal	Absent staining on bile canaliculus	Normal
MYO5B/RAB11	Normal	Normal	Intense, granular staining pattern in hepatocyte cytoplasm, and weak/loss of canalicular expression
Progression	Rapid	Very rapid	Slow
Complications	Hepatocellular carcinoma	Post-transplant graft steatosis similar to PFIC1	Worsening of cholestasis post intestinal transplant
Treatment
Medical management	UDCA, Rifampicin	Minimal role	UDCA, rifampin, cholestyramine
Biliary diversion	PEBD some role	Not tried	Cholestasis subsides after BD in MVID patients with cholestasis
Liver transplant	Yes	Yes	Yes. Combined liver intestinal transplant in children with MVID and ongoing cholestasis

ALT: Alanine aminotransferase; ASBT: Apical sodium-dependent bile acid transporter; AST: Aspartate aminotransferase; BD: Biliary diversion; BSEP: Bile salt export pump; FXR: Farnesoid X receptor; GGT: Gamma-glutamyl transferase; HCC: Hepatocellular carcinoma; MDR3: Multidrug resistance class 3 glyco-protein; ICP: Intrahepatic cholestasis of pregnancy; MVID: Microvillus inclusion disease; MYO5B: Myosin-5b; NBD: Nasobiliary drainage; PEBD: Partial external biliary drainage; PFIC1Progressive familial intrahepatic cholestasis-1; RAB11: RAS-related GTP-binding protein-11; TJP2: Tight junction protein-2; UDCA: Ursodeoxycholic acid.