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In this segment of Liver Lineup, experts discuss genetic testing in cholestatic disease, highlighting real-world cases demonstrating the value of these tests.
Genetic testing is increasingly finding a place in the hepatology toolkit, but questions remain about who to test and when these panels offer the greatest clinical value. In this segment from an episode of Liver Lineup: Updates & Unfiltered Insights, Robert Gish, MD, provides practical guidance rooted in real-world experience, highlighting how genetic testing can uncover hidden drivers of liver disease across a range of clinical scenarios.
0:14:01 - Who to test & overall rules
0:15:15 - Drug‑induced cholestasis & pregnancy
0:16:30 - ICP case with dual variants
0:18:00 - Case: COPD + dual heterozygote (CFTR + Alpha‑1)
0:19:15 - Case: PEX mutation & transition to broader practice
Drawing on his experience ordering more than 80 genetic panels, Gish emphasized a broad, pragmatic approach. Rather than limiting testing to classic cholestatic presentations, he applies genetic evaluation to patients with unexplained liver disease more generally, including those with hepatocellular patterns of injury, reflecting a growing recognition that genetic contributions to liver disease are not always limited to traditional phenotypes.
However, he notes that certain clinical presentations should raise particular suspicion. Patients with antimitochondrial antibody-negative primary biliary cholangitis, lean metabolic dysfunction-associated steatotic liver disease accompanied by pruritus, or atypical biochemical patterns such as elevated alkaline phosphatase with normal gamma-glutamyl transferase may warrant genetic evaluation. These features can point toward underlying transporter defects, including variants associated with progressive familial intrahepatic cholestasis.
Gish also underscored the relevance of genetic testing in drug-induced cholestasis and intrahepatic cholestasis of pregnancy. In one case, a young pregnant patient with pruritus and fluctuating liver enzymes was found to carry variants in ABCB4 and a bile acid synthesis gene. While her laboratory values normalized without treatment, the identification of these variants provided critical context for monitoring and risk assessment as her pregnancy progressed. Rather than relying solely on standard biomarkers, her care plan incorporated periodic liver tests and bile acid monitoring, reflecting a more personalized approach.
In another patient with severe pulmonary disease disproportionate to smoking history, genetic testing revealed heterozygous variants linked to cystic fibrosis and alpha-1 antitrypsin deficiency, offering a unifying explanation for both pulmonary and hepatic findings. In a separate case, identification of a mutation associated with a rare metabolic disorder prompted targeted follow-up testing, demonstrating how genetic panels can guide downstream diagnostic pathways.
Importantly, Gish noted that most patients tested will have ≥ 1 genetic variants. The challenge, therefore, lies not in detection but in interpretation, reinforcing the need for hepatologists to become comfortable navigating genetic data, even when results are not definitive.
As this discussion makes clear, genetic testing is no longer reserved for rare or pediatric cases. When used thoughtfully, it can provide meaningful insights into otherwise unexplained liver disease, helping clinicians refine diagnoses and tailor management strategies in an increasingly complex clinical landscape.
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.
