What is the appropriate management for a patient diagnosed with Primary Familial Intrahepatic Cholestasis (PFIC)?

Management of Progressive Familial Intrahepatic Cholestasis (PFIC)

Initial management of PFIC should begin with ursodeoxycholic acid therapy, followed by partial external biliary diversion (PEBD) or ileal exclusion (IE) as early interventions to improve cholestasis and pruritus, with liver transplantation reserved for advanced disease or surgical failure. 1

Diagnostic Confirmation and Subtype Classification

PFIC encompasses three main genetic subtypes requiring differentiation based on gamma-glutamyl transferase (GGT) levels and genetic testing 2:

• FIC1 disease (formerly PFIC-1): ATP8B1 gene mutation, presents with severe cholestasis and normal serum GGT, typically in the first year of life 1
• BSEP disease (formerly PFIC-2): ABCB11 gene mutation, also presents with normal serum GGT 1, 2
• MDR3 deficiency (formerly PFIC-3): ABCB4 gene mutation, presents with elevated serum GGT 1

Diagnosis requires clinical manifestations, liver histology, genetic testing, and exclusion of other childhood cholestasis causes 1. Genetic panel testing should be pursued, and if negative, whole exome sequencing may identify novel mutations in the 30% of patients without identified genetic defects 1.

Stepwise Treatment Algorithm

First-Line Medical Therapy

Ursodeoxycholic acid should be initiated as first-line therapy for all PFIC subtypes 1:

• Approximately 30% of FIC1 patients respond sufficiently to delay or avoid other interventions 1
• Patients with MDR3 disease who fail to respond to ursodeoxycholic acid should proceed to liver transplant evaluation 1

Second-Line Surgical Intervention

PEBD or IE should be performed early, before cirrhosis develops, as these procedures can significantly slow disease progression 1:

• These procedures improve cholestasis, pruritus, growth, and contribute to clinical, biochemical, and histological improvement in FIC1 and BSEP patients 1
• The goal is to interrupt the enterohepatic circulation and reduce pathologic bile accumulation 3
• Longer follow-up is needed to determine whether PEBD can completely obviate the need for liver transplantation 1

Emerging Medical Therapy

Ileal bile acid transporter (IBAT) inhibitors represent a nonsurgical approach to interrupting enterohepatic circulation, demonstrating efficacy in reducing serum bile acids and pruritus 3. This provides an alternative for patients who cannot undergo or fail surgical biliary diversion.

Definitive Treatment: Liver Transplantation

Liver transplantation indications vary by PFIC subtype 1:

For FIC1 disease:

• LT should be considered only if PEBD or IE failed or could not be performed 1
• Critical caveat: Due to ATP8B1 expression in extrahepatic organs (small intestine, pancreas), short stature and diarrhea may develop or worsen following transplantation, significantly affecting quality of life 1
• Patients should be counseled that extrahepatic manifestations may persist or worsen post-transplant 1

For BSEP disease:

• LT evaluation is indicated for advanced liver disease 1
• Critical caveat: Families must be cautioned that the disease may recur following transplantation 1
• Mandatory surveillance: Regular monitoring for hepatocellular carcinoma (HCC) development is required, as BSEP patients have high risk from infancy 1, 2, 4

For MDR3 deficiency:

• LT evaluation is indicated when disease fails to respond to ursodeoxycholic acid 1
• Progressive steatohepatitis leading to cirrhosis in the allograft has been described post-transplant 1

Supportive Care Throughout Disease Course

All PFIC patients require comprehensive nutritional support 2:

• Adequate caloric intake
• Supplementation of fat-soluble vitamins (A, D, E, K) to prevent deficiency complications such as vitamin D-deficient rickets and vitamin K-deficient intracranial bleeding 1, 2
• Medium chain triglycerides supplementation 2
• Medications to relieve pruritus (cholestyramine first-line, rifampicin second-line, naltrexone third-line) 5, 2

Donor Selection Considerations

Heterozygote live donor organs from family members remain a viable and feasible option for FIC1 and BSEP patients requiring transplantation 1. This expands the donor pool while maintaining acceptable outcomes.

Critical Pitfalls to Avoid

• Do not delay PEBD/IE until cirrhosis develops, as early intervention before cirrhosis provides the best outcomes for disease modification 1
• Do not proceed with liver transplantation in FIC1 disease without first attempting PEBD/IE, as transplantation may worsen extrahepatic symptoms and quality of life 1
• Do not fail to screen BSEP patients for HCC starting in infancy, as hepatocellular carcinoma risk is significantly elevated in this subtype 1, 2, 4
• Do not assume all PFIC patients have identified genetic mutations, as approximately 30% have negative standard genetic panel testing and may benefit from whole exome sequencing 1