Liver Lineup: Navigating Genetic Testing in Cholestatic Liver Disease

Genetic testing is rapidly reshaping the diagnostic and therapeutic landscape of cholestatic liver disease, but for many practicing hepatologists, its clinical application remains uncertain. In the latest episode of Liver Lineup, hosts Nancy Reau, MD, and Kimberly Brown, MD, are joined by Saul Karpen, MD, PhD, inaugural chief scientific officer for the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University and president of AASLD, and Robert Gish, MD, medical director of the Hepatitis B Foundation and the American Pacific Health Foundation, to unpack the evolving role of genetic testing in cholestatic disorders and provide practical guidance for integrating these tools into routine care.

Karpen, a pediatric hepatologist with decades of experience in cholestasis, outlined the historical arc of genetic testing in liver disease. Early approaches were laborious and limited, often requiring single-gene sequencing following invasive biopsies and yielding inconclusive results. However, advances over the past decade, particularly the advent of exome-based sequencing panels, have enabled clinicians to assess dozens of relevant genes simultaneously.

This shift has transformed genetic testing from a niche diagnostic tool into a foundational component of pediatric hepatology. Today, Karpen emphasized, such panels are “part of the fabric” of clinical evaluation in children with unexplained cholestasis.

For adult hepatologists, adoption has been slower, in part due to differences in clinical expectations. While pediatric providers may accept a modest diagnostic yield, adult clinicians often seek higher certainty before ordering specialized tests. Yet, as Gish highlighted, this mindset may need to evolve.

Drawing on his own experience ordering genetic panels, he noted that the majority of patients demonstrate ≥ 1 genetic variants, findings that can meaningfully inform diagnosis, risk stratification, and management.

Both experts emphasized that genetic testing should not be reserved solely for rare or refractory cases. Instead, it should be considered in a range of clinical scenarios, including unexplained cholestatic or mixed-pattern liver enzyme abnormalities, antimitochondrial antibody (AMA)-negative primary biliary cholangitis, atypical drug-induced liver injury, intrahepatic cholestasis of pregnancy, and even lean metabolic dysfunction-associated steatotic liver disease (MASLD). Importantly, these tests can uncover underlying genetic susceptibilities that may not have been clinically apparent.

A key challenge, however, lies in interpretation. Results frequently include variants of uncertain significance (VUS), which can create confusion and anxiety for both clinicians and patients. Karpen and Gish acknowledged this limitation but stressed that uncertainty is not unique to genetics—hepatologists routinely navigate ambiguous findings in imaging, histology, and laboratory testing. The critical step is correlating genetic results with the clinical phenotype, using them as one piece of a broader diagnostic puzzle.

Among the most clinically relevant genes discussed were ABCB4 and ABCB11, both of which play central roles in bile formation and transport. Variants in these genes can predispose patients to a spectrum of cholestatic conditions, sometimes manifesting only under physiologic stressors such as pregnancy, infection, or medication exposure. Notably, even heterozygous variants, traditionally considered benign, may contribute to disease in certain contexts, underscoring the concept of “synergistic heterozygosity.”

The conversation also highlighted the growing therapeutic implications of genetic insights. Identification of specific variants may guide treatment decisions, including the use of ursodeoxycholic acid or newer agents such as ileal bile acid transporter (IBAT) inhibitors. In some cases, genetic findings can explain treatment resistance or predict response, enabling more personalized care.

Despite these advances, both speakers agreed that collaboration remains essential. While geneticists can provide valuable support, particularly for complex cases requiring whole-exome sequencing, hepatologists must develop a working knowledge of key genes and interpretation principles. As Karpen noted, the field is still evolving, and variant classifications may change over time as new data emerge.

Editors’ note: Relevant disclosures for Reau include AbbVie, Gilead, Salix, Arbutus, and VIR. Relevant disclosures for Brown include Mallinckrodt Pharmaceuticals, Gilead, Salix, Intercept, Ipsen, and Madrigal. Relevant disclosures for Karpen include Mirum and Ipsen. Relevant disclosures for Gish include Abbott, AbbVie, Aligos, Altimmune, Arrowhead, AstraZeneca, Corcept, Genentech, Gilead Sciences, GSK, Intercept, Janssen, Merck, Perspectum, Pfizer, and others.

References

1. Hasegawa S, Yoneda M, Kurita Y, et al. Cholestatic Liver Disease: Current Treatment Strategies and New Therapeutic Agents. Drugs. 2021;81(10):1181-1192. doi:10.1007/s40265-021-01545-7

2. Brooks A. FDA Approves Linerixibat (Lynavoy) As First Treatment for Cholestatic Pruritus in PBC. HCPLive. March 19, 2026. Accessed April 7, 2026. https://www.hcplive.com/view/fda-approves-linerixibat-lynavoy-as-first-treatment-for-cholestatic-pruritus-in-pbc