What are the management options for a pediatric patient with Progressive Familial Intrahepatic Cholestasis (PFIC)?

Management of Progressive Familial Intrahepatic Cholestasis (PFIC)

Ursodeoxycholic acid (UDCA) should be initiated as first-line medical therapy, followed by partial external biliary diversion (PEBD) or ileal exclusion (IE) if medical management fails, with liver transplantation reserved for advanced cirrhosis or failed surgical diversion. 1

Initial Medical Management

Start UDCA therapy immediately upon diagnosis as it improves cholestasis sufficiently to delay or avoid surgical intervention in approximately 30% of FIC1 patients and may benefit some PFIC2 patients. 1 The typical dosing is 20-30 mg/kg/day. 2

Supportive Care Requirements

• Provide aggressive nutritional support including adequate calories, fat-soluble vitamin supplementation (A, D, E, K), and medium chain triglycerides to address malabsorption. 3
• Monitor for vitamin deficiencies as vitamin D-deficient rickets and intracranial bleeding from vitamin K deficiency can be presenting features. 1
• Manage pruritus with rifampicin or bile acid binding resins when UDCA alone is insufficient. 1, 3

Surgical Intervention Algorithm

When to Proceed with Biliary Diversion

Perform PEBD or IE before cirrhosis develops if UDCA fails to adequately control cholestasis and pruritus. 1 This timing is critical—biliary diversion performed prior to established cirrhosis significantly slows disease progression with improvements in cholestasis, pruritus, growth, and histological findings in both FIC1 and BSEP disease patients. 1

The success rate of PEBD is approximately 80% when performed before cirrhosis is established. 4

Type-Specific Considerations

For FIC1 disease: PEBD or IE can be highly effective, but be aware that extrahepatic manifestations (diarrhea, short stature) may persist or worsen even after successful biliary diversion. 1 These patients should undergo biliary diversion before considering transplantation. 1

For BSEP disease: PEBD or IE follows the same algorithm as FIC1, but institute hepatocellular carcinoma (HCC) surveillance from infancy due to high malignancy risk. 1, 3

For MDR3 disease: If UDCA fails to produce adequate response, proceed directly to liver transplant evaluation rather than biliary diversion. 1

Liver Transplantation Indications

Clear Indications for Transplant Evaluation

Refer for liver transplantation when:

• Established cirrhosis is present at diagnosis 4
• PEBD or IE has failed to control disease 1
• Advanced liver disease makes biliary diversion technically unfeasible 1
• Decompensated liver disease develops 1

Critical Type-Specific Transplant Warnings

For FIC1 disease: Liver transplantation should be considered only after PEBD or IE has failed or cannot be performed, as ATP8B1 expression in extrahepatic organs means that diarrhea and short stature may develop or worsen post-transplant, significantly affecting quality of life. 1 Even total external biliary diversion combined with transplant may not prevent PFIC-related complications. 5

For BSEP disease: Counsel families that disease recurrence can occur post-transplant due to antibody development against the BSEP protein in the graft, potentially leading to graft failure. 1, 5

For MDR3 disease: Transplant outcomes are generally favorable without the recurrence issues seen in BSEP or extrahepatic complications of FIC1. 5

Donor Considerations

PFIC heterozygote live donor organs from family members remain viable options for FIC1 and BSEP patients, though ongoing monitoring is essential. 1

Disease Monitoring Protocol

Essential Surveillance

• Measure serum bile acids and liver function tests regularly to assess disease progression and treatment response 6
• Monitor growth parameters as failure to thrive indicates inadequate disease control 1, 6
• Assess pruritus severity using validated scales, as this directly impacts quality of life 6
• For BSEP disease specifically: Perform regular HCC surveillance with imaging and alpha-fetoprotein from infancy 1

Genetic Testing Approach

Initiate treatment based on clinical phenotype while awaiting genetic confirmation. 6 Approximately 30% of patients with PFIC phenotype lack mutations in known genes, requiring whole exome sequencing. 7 Do not delay treatment for genetic results when the clinical presentation (low GGT with elevated bile acids, severe pruritus, early-onset cholestasis) strongly suggests PFIC1 or PFIC2. 7, 2

Common Pitfalls to Avoid

Do not perform liver transplantation as first-line therapy in FIC1 disease—the extrahepatic manifestations will persist or worsen, making the patient's quality of life potentially worse than with successful biliary diversion. 1

Do not delay biliary diversion until cirrhosis develops—the 80% success rate drops dramatically once cirrhosis is established, and these patients will require transplantation anyway. 4

Do not assume all PFIC types respond similarly to interventions—MDR3 disease should proceed to transplant if UDCA fails, while FIC1 and BSEP benefit from biliary diversion attempts first. 1