Genetic variants explain substantial proportion of undiagnosed cholestasis and hepatitis

Ignasi Olivas (Hospital Clínic Barcelona) and colleagues say that “[e]arly genetic testing should therefore be considered in patients remaining undiagnosed after standard evaluation to avoid unnecessary treatments.”

The study presented as a poster at the EASL Congress 2026 in Barcelona, Spain, involved 132 adults with a median age at symptom onset of 34.4 years, most of whom were women (n=90).  

The patients were classified according to their predominant phenotype. Most of the patients (n=99) had idiopathic chronic cholestasis (ICC), characterized by persistent elevations of alkaline phosphatase or gamma-glutamyl transferase for at least 1 year that were not due to primary biliary cholangitis, primary sclerosing cholangitis, or other known causes. Eighteen patients had hepatitis of unknown origin; 12 had low phospholipid–associated cholelithiasis; and three had recurrent cholestasis with two or more episodes of clinically apparent cholestasis with biochemical evidence of intermittent elevated alkaline phosphatase and/or direct bilirubin.

The researchers note that 3% of patients with ICC and 33% of those with hepatitis of unknown origin had been previously misdiagnosed.

Genetic testing of peripheral blood samples using whole exome sequencing was performed when the patients were aged a median of 49 years and variants were classified according to the American College of Medical Genetics and Genomics criteria as pathogenic, likely pathogenic, or a variant of uncertain significance (VUS).

In all, 40% of patients with ICC had a total of 43 variants, most of which were in the ABCB4 gene at a rate of 20.9%, with two of the variants pathogenic, six likely pathogenic, and one VUS. Variants in ATP7B (3 pathogenic, 4 likely pathogenic, 1 VUS) accounted for 18.6% of variants, and variants in HNF1B (2 pathogenic, 2 VUS) and PKHD1 (3 pathogenic, 1 likely pathogenic) each contributed 9.3%. The remaining genetic variants occurred in JAG1, NOTCH, USP3, HFE, H63D, ATP8A1, SCLO1B1, SCLO1B3, SCL51A, KIF12, CLDN1, and CFTR.

Among the patients with hepatitis of unknown pathology, 50% of patients had 14 genetic variants. These were found in ABCB4 (21.4%; 1 pathogenic, 2 VUS), HNF1B (21.4%; 2 pathogenic, 1 VUS), ACOX2 (14.3%; 2 pathogenic), ATP7B (14.3%; 2 VUS), TJP2 (7.1%; 1 VUS), LYST (7.1%; 1 likely pathogenic), ALG8 (7.1%; 1 VUS), and NBAS (7.1%; 1 VUS).

All but one of the patients with low phospholipid–associated cholelithiasis (92%) had a total of 12 genetic variants, primarily in ABCB4 (75.0%; 3 pathogenic, 2 likely pathogenic, 4 VUS), with the rest in SERPINA (25.0%; 1 pathogenic, 2 VUS).

All three patients with recurrent cholestasis had genetic variants, at a total of four. Three were in ABCB11, all of which were pathogenic, and one was in ATP8B1, and was also pathogenic.