Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Table 1 Genotype, phenotype and histopathological differentiation of the various types of progressive familial intrahepatic cholestasis

	PFIC1	PFIC2	PFIC 3
Locus/gene/protein	18q21-22/ATP8B1/FIC1	2q24/ABCB11/BSEP	7q21/ABCB4/MDR3
Known mutations (n)1	50	200	300
Clinical profile
Onset	Early onset	Early onset	Second decade
Age of presentation pruritus	60% by 3 mo	72% by 3 mo	2-3 yr
Jaundice	Severe	Severe	Mild to none
Cirrhosis	Severe; By end of first decade	Severe; Majority within first 2 yr of life	Mild to moderate; By end of first decade
Growth failure	Present 90%	Present 59%
Others	Diarrhea 61%; Pneumonia 13%; Pancreatitis 12%; Deafness 31%	Gall stones in 32%	Delayed puberty
Progression	Moderate rate of progression	Rapidly progressive	Highly variable rate of progression
Associations with other cholestatic presentations	BRIC; ICP	BRIC, DIC; ICP, HCC	DIC, LPAC; ICP
Laboratory profile
TBA	High	Very high	High
GGT	Low to normal	Low to normal	High
AST/ALT	Mild elevation	Moderate elevation	Mild elevation
AFP	Normal	High	Normal
Histopathology	As disease progresses, periportal & pericentrilobular fibrosis develops; Leads to bridging fibrosis and micronodular cirrhosis	Canalicular cholestasis, lobular/portal fibrosis and inflammation with giant cells; Severe hepatocellular necrosis	Portal inflammation, portal fibrosis, cholestasis, ductular proliferation
Immunohistochemistry	Canalicular BSEP is normal or faint and MDR3 is normal bland intralobular cholestasis	BSEP expression decreased to absent in the canalicular membrane	MDR3 decreased to absent in the canalicular membrane

¹Medline genetics. BRIC: Benign recurrent intrahepatic cholestasis; BSEP: Bile salt exporter pump; ICP: Intrahepatic cholestasis of pregnancy; HCC: Hepatocellular carcinoma; DIC: Drug induced cholestasis; FIC1: Familial Intrahepatic Cholesatsis-1; LPAC: Low-phospholipid-associated cholelithiasis; MDR3: Multidrug resistant protein-3; PFIC: Progressive familial intrahepatic cholestasis; ABCB: ATP-binding cassette subfamily B.