Progressive familial intrahepatic cholestasis: From childhood to adulthood

Table 2 Mechanism-based clinical classification of progressive familial intrahepatic cholestasis integrating variant type, phenotype, and therapeutic implications

	Residual function present	Severe loss-of-function variants
Typical variant type	Missense variants; partial loss of function; reduced but preserved protein activity	Nonsense variants; frameshift variants; canonical splice-site variants; biallelic null variants
Mechanistic contexts	Canalicular transport defects: Selected ABCB11, ABCB4 variants. Membrane lipid homeostasis/canalicular stability: Selected ATP8B1 variants. Tight junction/epithelial barrier dysfunction: Selected TJP2, USP53 variants. Intracellular trafficking/polarity defects: Selected MYO5B variants	Canalicular transport defects: Truncating ABCB11, severe ABCB4. Membrane lipid homeostasis/canalicular stability: Severe ATP8B1. Tight junction/epithelial barrier dysfunction: Severe TJP2. Nuclear receptor/transcriptional regulation: NR1H4. Intracellular trafficking/polarity defects: Severe MYO5B, VPS33B
Genotype-phenotype correlation	Missense variants are often associated with residual protein activity. Genotype-phenotype correlation is evident in selected genes (e.g., ABCB11, ABCB4). Clinical severity varies widely depending on residual function. Milder or later-onset phenotypes may be observed	Truncating or null variants are associated with absent protein function. Strong genotype-phenotype correlation with severe clinical presentation. Early-onset disease and rapid progression are common. Higher risk of complications (e.g., liver failure, malignancy in selected subtypes)
Clinical implications	Variable severity. Later onset or slower progression may occur. Residual transporter activity may still permit bile flow	Early-onset, often neonatal or infantile. Rapid progression. Higher risk of advanced liver disease and complications
Therapeutic implications	IBAT inhibitors: More likely to be beneficial. UDCA: Especially relevant in ABCB4-related disease. Rifampicin/symptomatic therapy: May be useful for pruritus. PEBD/internal diversion: Can be considered in refractory cases with preserved native liver function	IBAT inhibitors: Limited or less predictable benefit. PEBD/internal diversion: Earlier consideration in progressive disease. Liver transplantation: Often required in severe or rapidly progressive cases. Multidisciplinary management: Especially important when extrahepatic involvement is present
Key determinant: Residual protein function is the primary driver of disease severity and therapeutic response across all PFIC mechanisms

PFIC: Progressive familial intrahepatic cholestasis; IBAT: Ileal bile acid transporter inhibitors; UDCA: Ursodeoxycholic acid; PEBD: Partial external biliary diversion.