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 (UDCA) 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

Initial Diagnostic Confirmation and Subtype Classification

• Confirm PFIC diagnosis through genetic testing identifying mutations in ATP8B1 (FIC1 deficiency/PFIC1), ABCB11 (BSEP deficiency/PFIC2), or ABCB4 (MDR3 deficiency/PFIC3), combined with clinical manifestations and liver histology. 1

• Measure serum gamma-glutamyl transferase (GGT) to distinguish subtypes: normal GGT indicates FIC1 or BSEP deficiency, while elevated GGT suggests MDR3 deficiency. 1, 2

• Assess for extrahepatic manifestations in FIC1 disease, including chronic diarrhea, asthma-like symptoms, and sensorineural hearing loss due to systemic microvilli dysfunction. 1

Stepwise Medical Management Algorithm

First-Line Therapy: Ursodeoxycholic Acid

• Initiate UDCA therapy immediately at 13-15 mg/kg/day for all PFIC subtypes, recognizing that approximately 30% of FIC1 patients respond sufficiently to delay or avoid other interventions. 1

• UDCA efficacy varies by subtype: low efficacy in FIC1 deficiency, variable response (none to high) in MDR3 deficiency related to specific genotype, and generally poor response in BSEP deficiency. 1

Second-Line Therapy: IBAT Inhibitors

• Consider ileal bile acid transporter (IBAT) inhibitors (maralixibat or odevixibat) to interrupt enterohepatic circulation, reduce serum bile acids, and improve pruritus when UDCA fails. 1, 3

• IBAT inhibitors work by blocking bile acid reabsorption in the terminal ileum, mimicking the effect of surgical biliary diversion pharmacologically. 1

Adjunctive Pruritus Management

• Treat severe pruritus sequentially: start with cholestyramine (bile acid sequestrant), escalate to rifampicin if inadequate response, then consider antihistamines (chlorpheniramine, alimemazine) for sedative effect. 1

• Consider experimental therapies including 4-phenylbutyrate or glycerol phenylbutyrate as chaperone molecules for specific missense mutations, though evidence remains limited to case reports. 1

Surgical Intervention Timing

Biliary Diversion Procedures

• Perform PEBD or IE early, before cirrhosis develops, as these procedures significantly slow disease progression with improvements in cholestasis, pruritus, growth, and histological findings in FIC1 and BSEP patients. 1

• PEBD/IE interrupts enterohepatic circulation surgically, normalizing serum bile acids and reducing liver injury, though longer follow-up is needed to determine if transplantation can be completely avoided. 1, 3

Liver Transplantation Considerations

FIC1 Deficiency-Specific Concerns

• Reserve liver transplantation for FIC1 disease only when PEBD or IE has failed or cannot be performed, as ATP8B1 expression in extrahepatic organs (small intestine, pancreas) means short stature and diarrhea may develop or worsen post-transplant, significantly affecting quality of life. 1

BSEP Deficiency-Specific Concerns

• Counsel families that BSEP disease may recur following transplantation due to progressive steatohepatitis developing in the allograft liver. 1

• Monitor BSEP deficiency patients regularly for hepatocellular carcinoma (HCC) development starting from infancy, as this subtype carries high malignancy risk. 1, 4

MDR3 Deficiency Management

• Proceed to liver transplant evaluation for MDR3 disease when UDCA therapy fails, as this subtype typically requires definitive surgical management. 1

General Transplant Indications

• List for transplantation when patients develop decompensated liver disease, end-stage cirrhosis, or hepatocellular failure despite medical and surgical interventions. 1, 2

• Heterozygote live donor organs from family members remain viable and feasible options for FIC1 and BSEP patients requiring transplantation. 1

Nutritional and Supportive Care

• Provide adequate caloric intake with medium-chain triglyceride supplementation and fat-soluble vitamin replacement (A, D, E, K) to address malabsorption from cholestasis. 2, 5

• Monitor specifically for vitamin D-deficient rickets and vitamin K deficiency-related intracranial bleeding, which may be presenting features of FIC1 disease. 1

Critical Monitoring Requirements

• Screen BSEP deficiency patients for HCC with regular surveillance imaging given the elevated malignancy risk throughout childhood. 1

• Assess growth parameters, liver biochemistry, and pruritus severity at regular intervals to guide escalation of therapy. 2, 5

Important Clinical Pitfalls

• Do not delay biliary diversion procedures until cirrhosis develops, as PEBD/IE performed before advanced fibrosis provides maximal benefit in slowing disease progression. 1

• Recognize that approximately 30% of PFIC patients have no identifiable mutations in known genes, requiring whole-exome sequencing for novel gene discovery. 1, 6

• Avoid liver transplantation as first-line therapy in FIC1 disease due to worsening extrahepatic manifestations post-transplant; exhaust medical and surgical biliary diversion options first. 1