What's new in pediatric genetic cholestatic liver disease: advances in etiology, diagnostics and therapeutic approaches.

Purpose of review: To highlight recent advances in pediatric cholestatic liver disease, including promising novel prognostic markers and new therapies.

Findings: Additional genetic variants associated with the progressive familial intrahepatic cholestasis (PFIC) phenotype and new genetic cholangiopathies, with an emerging role of ciliopathy genes, are increasingly being identified. Genotype severity predicts outcomes in bile salt export pump (BSEP) deficiency, and post-biliary diversion serum bile acid levels significantly affect native liver survival in BSEP and progressive familial intrahepatic cholestasis type 1 (FIC1 deficiency) patients. Heterozygous variants in the MDR3 gene have been associated with various cholestatic liver disease phenotypes in adults. Ileal bile acid transporter (IBAT) inhibitors, approved for pruritus in PFIC and Alagille Syndrome (ALGS), have been associated with improved long-term quality of life and event-free survival.

Summary: Next-generation sequencing (NGS) technologies have revolutionized diagnostic approaches, while discovery of new intracellular signaling pathways show promise in identifying therapeutic targets and personalized strategies. Bile acids may play a significant role in hepatic damage progression, suggesting their monitoring could guide cholestatic liver disease management. IBAT inhibitors should be incorporated early into routine management algorithms for pruritus. Data are emerging as to whether IBAT inhibitors are impacting disease biology and modifying the natural history of the cholestasis.