New hope in treating progressive familial intrahepatic cholestasis in children

Table 1 Types of progressive familial intrahepatic cholestasis with corresponding gene mutation, proteins affected, and key features

PFIC type	Gene	Protein affected	Pathophysiology	Key features	GGT	Extrahepatic symptoms
PFIC1	ATP8B1	FIC1 (flippase)	Canalicular membrane instability; impaired bile salt resistance	Cholestasis, diarrhea, growth failure, deafness	Normal	Diarrhea, short stature, deafness, pancreatitis
PFIC2	ABCB11	BSEP	Impaired bile salt excretion	Severe cholestasis, early liver failure, Increased risk of Hepatocellular carcinoma risk	Normal	None typically
PFIC3	ABCB4	MDR3	Deficient phosphatidylcholine secretion → toxic bile	Later onset, biliary fibrosis, cirrhosis	High	None typically
PFIC4	TJP2	ZO-2	Tight junction disruption → bile leaks into liver tissue	Pruritus, portal hypertension, hearing loss	Low	Hearing loss, respiratory issues
PFIC5	NR1H4	FXR	Decreased bile acid regulation and BSEP expression	Neonatal cholestasis, bleeding, ↑ International Normalization Ratio, ↑ Alpha Feto Protein	Normal	Coagulopathy (vitamin K-resistant)
PFIC6	SLC51A	OSTα	Impaired bile acid reabsorption from intestine	Diarrhea, jaundice, hepatosplenomegaly	High	Severe diarrhea, bleeding tendency
PFIC7	USP53	USP53	Tight junction dysfunction	Episodic cholestasis, vitamin deficiency, deafness	Normal	Hearing loss, developmental delay, cardiomyopathy
PFIC8	KIF12	KIF12	Disrupted intracellular transport, MRP2 mislocalization	Variable: Cholestasis to cirrhosis	High	None typically
PFIC9	ZFYVE19	ZFYVE19	Ciliopathy affecting bile duct cilia and transporter localization	Cholestasis, hepatospleno-megaly, Gastrointestinal bleeding	High	Ciliary dysfunction; systemic involvement
PFIC10	MYO5B	Myosin 5B	Defective transporter trafficking (e.g., BSEP)	Cholestasis ± microvillous inclusion disease	Normal/Low	Diarrhea, pruritus
PFIC11	SEMA7A	Semaphorin-7A	Abnormal transporter placement (via PKC pathway)	Jaundice, ↑ ALT/AST, no pruritus	Normal	None reported
PFIC12	VPS33B	VPS33B	Defective intracellular trafficking	Neonatal cholestasis, pruritus	Normal	Mild renal/skeletal issues
PFIC13	PSKH1	PSKH1	Hepatorenal ciliopathy	Cholestasis + kidney disease	Variable	Renal disease, anemia, diaphragmatic hernia

PFIC: Progressive familial intrahepatic cholestasis; BSEP: Bile salt export pump; MRP2: Multidrug resistance-associated protein 2; PKC pathway: Protein kinase C pathway; ALT: Alanine transaminase; AST: Aspartate transaminase.