What is Progressive Familial Intrahepatic Cholestasis (PFIC) in pediatric patients?

What is Progressive Familial Intrahepatic Cholestasis (PFIC) in Children?

PFIC is a group of rare, autosomal recessive cholestatic liver disorders caused by genetic mutations in canalicular bile transport proteins that typically present in infancy or early childhood with severe cholestasis, intense pruritus, and progressive liver disease leading to cirrhosis and end-stage liver disease without effective treatment. 1

Genetic Classification and Underlying Defects

PFIC encompasses three main genetic subtypes, each with distinct molecular defects:

PFIC Type 1 (FIC1 Disease, formerly Byler Disease)

• Caused by mutations in the ATP8B1 gene, which encodes a phospholipid flippase (FIC1) affecting microvilli structural and functional integrity 1
• Presents typically in the neonatal period or first year of life with severe cholestasis and characteristic low or normal gamma-glutamyl transferase (GGT) levels 1, 2
• This is a systemic disorder affecting multiple organs beyond the liver, including intestine, lungs, and cochlear hair cells 1

PFIC Type 2 (BSEP Disease, formerly Byler Syndrome)

• Results from mutations in the ABCB11 gene, which encodes the canalicular bile salt export pump (BSEP) 1
• Presents similarly to PFIC1 in early childhood with progressive liver disease and characteristically low GGT levels 1
• Distinguished by significantly higher risk of hepatocellular carcinoma development, making liver transplantation particularly important 1

PFIC Type 3 (MDR3 Deficiency)

• Caused by mutations in the ABCB4 gene, encoding the canalicular phospholipid transporter (MDR3) 1
• Typically presents in the first years of childhood, though adult presentation with cirrhosis has been reported 1
• Uniquely characterized by markedly elevated GGT levels, distinguishing it from PFIC1 and PFIC2 1, 3
• May be associated with intrahepatic gallstone disease 1

Clinical Presentation

Core Hepatic Manifestations

• Severe, intractable pruritus is the hallmark symptom across all PFIC types, often presenting early and significantly impacting quality of life 1, 2
• Jaundice with conjugated hyperbilirubinemia and elevated serum bile acids 1, 4
• Hepatomegaly and splenomegaly develop as disease progresses 4
• Progressive liver fibrosis leading to cirrhosis, typically within the first decade of life if untreated 1

Extrahepatic Manifestations (Particularly PFIC1)

• Chronic diarrhea due to abnormal intestinal microvilli 1, 2
• Pancreatitis episodes 1, 2
• Growth failure and failure to thrive 1, 4
• Sensorineural hearing loss from cochlear hair cell dysfunction 1, 2
• Vitamin deficiency complications: vitamin D-deficient rickets and intracranial bleeding from vitamin K deficiency may be presenting features 1

Diagnostic Approach

Key Laboratory Findings

• Low or normal GGT with elevated bile acids and bilirubin strongly suggests PFIC1 or PFIC2, distinguishing these from biliary atresia and Alagille syndrome 1, 3
• Elevated GGT indicates PFIC3 (MDR3 deficiency) 1, 3
• Elevated serum transaminases are present across all types 1, 4

Histopathological Features

• PFIC1: Liver fibrosis without bile duct proliferation; coarse granular bile on electron microscopy 1
• PFIC2: Portal inflammation and giant cell hepatitis; amorphous bile on electron microscopy 1
• PFIC3: Portal inflammation, fibrosis/cirrhosis with massive bile duct proliferation 1

Imaging

• Abdominal ultrasound shows non-dilated bile ducts, the hallmark finding that differentiates intrahepatic cholestasis from mechanical obstruction 5
• This finding combined with low GGT and conjugated hyperbilirubinemia strongly suggests PFIC1 or PFIC2 rather than biliary atresia 5

Genetic Testing

• Genetic confirmation through targeted gene sequencing or whole exome sequencing is essential for definitive diagnosis 1, 2, 3
• Approximately 30% of patients with PFIC phenotype have no mutations in known genes, requiring whole exome sequencing 2, 3
• PFIC represents a phenotypic spectrum from mild to severe, and patients can present beyond childhood, not just in infancy 2, 3

Natural History and Prognosis

• Without effective treatment, most patients develop end-stage liver disease before the end of the first decade of life 1, 6
• PFIC2 carries particularly high risk of hepatocellular carcinoma, necessitating regular surveillance and often earlier consideration of liver transplantation 1
• Progressive deterioration in growth, development, and quality of life occurs without intervention 4, 6

Critical Diagnostic Pitfalls

• Neonatal biopsies may appear obstructive in both biliary atresia and PFIC, making histology alone unreliable for early differentiation 3
• When ultrasound shows non-dilated ducts in an infant with cholestasis, biliary atresia must still be urgently ruled out using hepatobiliary scintigraphy or intraoperative cholangiography, as early biliary atresia may not show ductal dilatation 5
• Not all PFIC presents in infancy—the disease represents a continuum with some patients presenting in adolescence or adulthood 2, 3