Progressive familial intrahepatic cholestasis: Types, genetics, and characteristics

PFIC type	Protein involved (mechanistic name)	MIM	Gene (biallelic variants)^*	Clinical characteristics	GGTP levels
PFIC type 1 (Byler disease; Greenland familial cholestasis)	FIC1 deficiency	MIM #211600	ATP8B1	Presents in infancy with cholestatic liver disease Severe pruritus; fat-soluble vitamin deficiencies Extrahepatic manifestations: diarrhea, pancreatitis, neurosensorial deafness, increased sweat electrolyte concentration Pathogenic variants mostly reported in families among the Old Order Amish and some Inuit populations	Low/normal
PFIC type 2	BSEP deficiency	MIM #601847	ABCB11	Presents in infancy with cholestatic liver disease with very high levels of serum bile acids Variable clinical course, partly predicted by genotype Risk for hepatocellular carcinoma (70% before 2 years of age) Pathogenic variants mostly reported in families in the Middle East and Europe	Low/normal
PFIC type 3	MDR3 deficiency	MIM #602347	ABCB4	Few case series Presents in infancy with cholestatic liver disease Risk of hepatocellular carcinoma and cholangiocarcinoma Milder mutations and heterozygotes may present with ICP or LPAC syndrome	Elevated
PFIC type 4	TJP2 deficiency (decreased at tight junctions in the liver)	MIM #615878	TJP2	Similar to PFIC types 1 and 2 Risk of hepatocellular carcinoma	Low/normal
PFIC type 5	FXR deficiency	MIM #617049	NR1H4	Few case reports Presents in infancy with severe, rapidly progressive cholestatic liver disease NR1H4 defects may cause secondary BSEP deficiency	Low/normal
PFIC type 6	SLC51A deficiency	MIM #619484	SLC51A	Case reports Presented in infancy with chronic malabsorptive diarrhea, coagulopathy, focal hepatocytic cholestasis, often requiring liver transplantation during childhood	Elevated
PFIC type 7	USP53 deficiency	MIM #619658	USP53	Neonatal cholestasis, with or without hearing loss Generally milder course than PFIC types 1 or 2 Variable pruritus intensity Cases reported in Saudi Arabia, Pakistan, Turkey, and China	Normal
PFIC type 8	KIF12 protein (impaired trafficking)	MIM #619662	KIF12	Few case series Presents in infancy with cholestatic liver disease Variable clinical severity	Elevated
PFIC type 9	ZFYVE19 deficiency	MIM #619849	ZFYVE19	Presents in infancy with cholestatic liver disease	Elevated
PFIC type 10	Myosin 5B (MYO5B) deficiency	MIM #619868	MYO5B	Presents in infancy or early childhood with cholestatic liver disease Variable clinical course Biallelic mutations in MYO5B also can cause congenital diarrhea (microvillus inclusion disease)	Normal
PFIC type 11	SEMA7A deficiency	MIM #619874	SEMA7A	Case report Neonatal jaundice and cholestasis, without pruritus	Normal
PFIC type 12	VPS33B deficiency	MIM #620010	VPS33B	Case series (China) Cholestasis onset in infancy; pruritus Biallelic mutations in VPS33B can also cause arthrogryposis and kidney dysfunction with cholestasis (ARC syndrome)	Normal

ARC syndrome: arthrogryposis, renal dysfunction, and cholestasis; BRIC: benign recurrent cholestasis; BSEP: bile salt export pump; FIC1: familial intrahepatic cholestasis type 1; FXR: farnesoid X receptor; GGTP: gamma-glutamyl transpeptidase; ICP: intrahepatic cholestasis of pregnancy; LPAC: low phospholipid-associated cholestasis; MDR3: multidrug resistance protein-3 P-glycoprotein; PFIC: progressive familial intrahepatic cholestasis.

* PFIC is caused by biallelic variants in these genes, with autosomal recessive inheritance. Related disorders that are associated with heterozygous variants in the same genes include BRIC, LPAC syndrome, and intrahepatic cholestasis of pregnancy.

References:

Hof WFJ, de Boer JF, Verkade HJ. Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: A focus on phase II and III trials. Expert Opin Emerg Drugs 2024; 29:305.
Online Mendelian Inheritance in Man (OMIM). https://www.omim.org (Accessed on February 3, 2025).

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Progressive familial intrahepatic cholestasis: Types, genetics, and characteristics