Simplified algorithm may aid genetic diagnosis of unexplained adult cholestatic disease

A substantial number of adults present to gastroenterologists and hepatologists with cholestatic liver diseases, the team explains, but a subset of those remain “undiagnosed despite exhaustive serological, histopathological and imaging evaluations.”

Although “there are currently no formal AASLD guidelines,” Arvind Murali (Orlando Health Digestive Health Institute, Florida) and colleagues recommend that “adult patients with cholestatic liver diseases, in whom extensive evaluation has not revealed a diagnosis, be tested for gene cholestatic syndromes.”

At AASLD The Liver Meeting 2026 in Denver, Colorado, USA, they reported their experience of using cholestatic gene panel analysis in patients referred to their liver center at Orlando Health with cholestatic liver disease between April 2023 and April 2026.

They excluded patients with cholestatic hepatitis due to congestive hepatopathy, drug-induced liver injury, biliary obstruction, and infiltrative conditions.

In all, 123 patients underwent an exhaustive work-up, of whom 75 were diagnosed with primary biliary cholangitis (PBC) based on the detection of antimitochondrial antibodies (AMA) or the presence of anti-SP100 or anti-GP210 antibodies, while 27 were diagnosed with primary sclerosing cholangitis (PSC) using magnetic resonance cholangiopancreatography.

The remaining 21 patients had unexplained cholestatic liver disease and underwent a cholestatic gene panel analysis to identify genetic mutations, alongside which demographic and laboratory testing data were collected.

A genetic mutation was implicated in the development of cholestasis for nine (43%) of these 21 patients, noted the researchers. The genetic variants included ABCB4, ABCB11, ATP8B1, NOTCH-2, CFTR, and MYO5B. The age of the patients ranged from 19 to 72 years, and 78% were women.

Seven of the nine patients had no evidence of PBC, PSC, or infiltrative liver disease on liver biopsy, although all of them had pruritus, elevated alkaline phosphatase (ALP) levels (peak levels 190–897 U/L), and raised bile acids (peak levels 19–263 µmol/L), the researchers report.

All nine patients began treatment with ursodiol. ALP levels improved after treatment, with peak levels ranging from 76 to 801 U/L, and five (56%) of the patients had levels less than 1.5 x upper limit of normal, indicating mild or well-controlled cholestasis. An additional three (33%) patients had a partial response, and one had no improvement in ALP levels.

In addition, four (44%) of the nine patients had an improvement in pruritus and bile acids while receiving ursodiol. The remaining five (56%) showed no improvement and were started on other therapies.

The researchers declare: “Personalized medicine has arrived as a defining paradigm in modern hepatology.”

Based on their experience, they summarize a diagnostic algorithm to guide the diagnosis and treatment of adults with unexplained cholestatic liver disease:

• Rule out drug-induced liver injury and request AMA and magnetic resonance cholangiopancreatography assessment to rule out PBC and PSC;
• Test for anti-SP100 or anti-GP210 antibodies and, if negative, carry out liver biopsy and cholestatic gene panel analysis;
• If the gene panel is suggestive of a genetic cholestatic syndrome, initiate targeted pharmacological therapy and simultaneously manage pruritus;
• Monitor ALP, monitor liver fibrosis and liver function periodically, and monitor for pruritus improvement.