Genetic Testing in Adult Cholestatic Liver Disease: Gut | June 2026

Introduction:

Advances in genetic sequencing have transformed the understanding of cholestatic liver diseases. Conditions once considered exclusive to children are now recognized in adolescents and adults, with genetic variants increasingly explaining unexplained cholestasis, recurrent pruritus, and gallstone disease.

Why was this review needed?

The widespread availability of affordable genetic testing has uncovered pathogenic variants in adults with cholestatic liver disease. Identifying these variants has important implications for diagnosis, prognosis, family screening, and selection of emerging targeted therapies.

What did the review show?

• Adult cholestatic disorders frequently harbor pathogenic variants in ABCB4, ABCB11, and ATP8B1, the same genes implicated in PFIC.
• Genetic cholestasis encompasses a broad spectrum, including PFIC, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), and low phospholipid-associated cholelithiasis (LPAC).
• Genetic testing should be considered in adults with unexplained cholestasis, recurrent cholestatic episodes, severe pruritus, early gallstone disease, or a positive family history.
• Identifying the underlying mutation enables more personalized treatment using ursodeoxycholic acid, IBAT inhibitors, or other targeted therapies.
• IBAT inhibitors have shown significant benefit in relieving cholestatic pruritus and may have an expanding role beyond pediatric PFIC.
• Genetic diagnosis also facilitates genetic counseling, family screening, and improved long-term disease management.

Clinical Impact:

Genetic evaluation is becoming an essential component of adult cholestatic liver disease rather than a test reserved for rare pediatric disorders. Integrating genomic information into routine hepatology practice enables earlier diagnosis and more individualized therapy.

Take-Home Message:

Adult cholestatic liver disease is increasingly recognized as a spectrum of inherited disorders. Genetic testing can identify the underlying cause, guide precision treatment, and improve patient outcomes, making genomics an integral part of modern hepatology.