Progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare inherited liver disorders characterized by impaired bile secretion, leading to progressive liver disease that typically begins in infancy or early childhood. Also known as Byler disease (PFIC type 1) and its related subtypes, PFIC encompasses several genetically distinct forms including PFIC1 (caused by mutations in ATP8B1), PFIC2 (caused by mutations in ABCB11), PFIC3 (caused by mutations in ABCB4), PFIC4 (caused by mutations in TJP2), PFIC5 (caused by mutations in NR1H4), and additional subtypes involving MYO5B and other genes. The condition primarily affects the hepatobiliary system, with bile acids accumulating within liver cells and the bloodstream rather than being properly excreted into the bile ducts. Key clinical features include severe pruritus (itching), jaundice, hepatomegaly (enlarged liver), failure to thrive, fat-soluble vitamin deficiency, and progressive liver fibrosis that can advance to cirrhosis and liver failure. PFIC1 and PFIC2 are characterized by low serum gamma-glutamyltransferase (GGT) levels despite significant cholestasis, while PFIC3 typically presents with elevated GGT levels. PFIC1 may also involve extrahepatic manifestations including diarrhea, pancreatitis, sensorineural hearing loss, and short stature. PFIC2 carries an increased risk of hepatocellular carcinoma and cholangiocarcinoma, even in early childhood. Treatment options include ursodeoxycholic acid (UDCA) to improve bile flow, surgical biliary diversion procedures (partial external or internal biliary diversion), and nasobiliary drainage. In 2021, odevixibat, an ileal bile acid transporter (IBAT) inhibitor, was approved for the treatment of pruritus in PFIC patients. Maralixibat is another IBAT inhibitor that has shown benefit. For patients who progress to end-stage liver disease, liver transplantation remains the definitive treatment, though PFIC1 patients may experience recurrence of extrahepatic symptoms or develop steatohepatitis post-transplant. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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