What is the recommended treatment approach for children diagnosed with Progressive Familial Intrahepatic Cholestasis (PFIC)?

Treatment Approach for Progressive Familial Intrahepatic Cholestasis (PFIC) in Children

Start ursodeoxycholic acid (UDCA) 20-30 mg/kg/day immediately upon diagnosis, proceed to partial external biliary diversion (PEBD) or ileal exclusion (IE) if medical therapy fails before cirrhosis develops, and reserve liver transplantation only for advanced cirrhosis or failed surgical diversion. 1, 2

Initial Medical Management

• Begin UDCA therapy at 20-30 mg/kg/day as first-line treatment for all PFIC types, as approximately 30% of FIC1 patients will have sufficient improvement to delay or avoid surgical intervention 1, 2
• Do not delay treatment initiation while awaiting genetic confirmation—start therapy based on clinical phenotype (cholestasis with pruritus, elevated bile acids) 2
• Monitor response to UDCA for improvements in cholestasis, pruritus, growth parameters, and liver biochemistry over 3-6 months 2

The evidence strongly supports UDCA as initial therapy despite modest response rates, as it is safe and may obviate more invasive interventions in a meaningful subset of patients 1, 2. However, physicians must recognize that 70% of patients will require escalation to surgical management 1.

Surgical Biliary Diversion

Perform PEBD or IE before cirrhosis develops if UDCA fails to adequately control cholestasis and pruritus. 1, 2

• PEBD involves creating a cholecystojejunocutaneostomy with a 10-cm jejunal segment anastomosed to the gallbladder, terminating as an end stoma for bile collection and discard 3
• 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 1, 2
• Success rates for PEBD reach 75-80% when performed before cirrhosis, with complete resolution of symptoms and normalization of conjugated bilirubin (<0.3 mg/dL) and bile acids (<10 nmol/mL) 3, 4

A critical pitfall is delaying PEBD until cirrhosis develops—patients with established bridging fibrosis or cirrhosis derive minimal benefit from biliary diversion and should proceed directly to transplant evaluation 3, 4.

Disease-Specific Considerations

FIC1 Disease (PFIC Type 1)

• PEBD or IE can be highly effective for hepatic manifestations, but extrahepatic symptoms (chronic diarrhea, short stature, hearing loss) may persist or worsen even after successful biliary diversion 1, 2
• Liver transplantation should be considered only after PEBD or IE has failed or cannot be performed, as ATP8B1 expression in extrahepatic organs means diarrhea and short stature may develop or worsen post-transplant 1, 2
• This represents a unique challenge where transplantation may improve hepatic disease but compromise quality of life through worsening extrahepatic manifestations 1

BSEP Disease (PFIC Type 2)

• Institute regular hepatocellular carcinoma (HCC) surveillance with imaging and alpha-fetoprotein from infancy, as BSEP disease carries high HCC risk 1, 2
• Families must be counseled that disease may recur in the allograft following liver transplantation, with progressive steatohepatitis potentially leading to cirrhosis 1
• PEBD remains an effective option before cirrhosis develops, with similar success rates to FIC1 disease 2, 4

MDR3 Disease (PFIC Type 3)

• Evaluate for liver transplantation when disease fails to respond to UDCA therapy 1
• MDR3 disease typically presents with elevated gamma-glutamyl transferase (GGT), distinguishing it from FIC1 and BSEP disease which have normal GGT 1, 5

Liver Transplantation

Refer for liver transplantation when PEBD or IE has failed to control disease, or when advanced liver disease (cirrhosis, hepatic decompensation) makes biliary diversion technically unfeasible. 1, 2

• Eight of 11 patients (73%) with cirrhosis at presentation who underwent orthotopic liver transplantation survived 1-5 years postoperatively 3
• PFIC heterozygote live donor organs from family members remain viable options for FIC1 and BSEP patients requiring transplantation, though ongoing monitoring is essential 1, 2
• For FIC1 disease specifically, transplantation is reserved as last resort due to risk of worsening extrahepatic manifestations 1, 2

Monitoring Disease Progression

• Measure serum bile acid levels, pruritus severity, growth parameters (height, weight), and quality of life at each visit following diagnosis and during treatment 2, 6
• Growth failure indicates inadequate disease control and should prompt escalation of therapy 2, 5
• For BSEP disease, perform HCC surveillance with ultrasound and alpha-fetoprotein every 6 months from diagnosis 1, 2
• Monitor liver biochemistry (ALT, AST, bilirubin, GGT) and coagulation parameters to assess disease progression 5, 6

Emerging Pharmacologic Options

• Ileal bile acid transporter (IBAT) inhibitors represent a newer nonsurgical approach to interrupting enterohepatic circulation, demonstrating efficacy in reducing serum bile acids and pruritus 6, 7
• A 2024 expert opinion recommends licensed IBAT inhibitors as first-line treatment for patients with PFIC, though this represents newer guidance that may not yet be universally adopted 6
• The traditional surgical approach remains the established standard of care based on decades of evidence, while IBAT inhibitors offer promise as medical alternatives to surgery 1, 2, 7

Referral and Multidisciplinary Care

• Refer all suspected PFIC patients to an experienced pediatric hepatology center for genetic testing, treatment initiation, and surgical planning 2, 6
• Approximately 30% of patients with PFIC phenotype lack mutations in known genes, requiring whole exome sequencing for definitive diagnosis 2, 8
• Coordinate care with pediatric surgery for biliary diversion procedures and transplant surgery for advanced disease 1, 2