Genetic etiology may explain majority of adult-onset cholestatic disorders

Their study detected a mutation in one or more of 70 different genes previously associated with cholestasis in 88% of 62 patients (mean age 56 years; 44% White, 43% African American) with cholestatic liver disease of unknown etiology despite serologic testing, magnetic resonance cholangiopancreatography (MRCP), and, in 76% of cases, liver biopsy.

Next-generation sequencing for variants in DNA sequence and copy number revealed that 26% of the cohort had one mutation, 30% had two, 24% had three, and 8% had between four and seven mutations, said Mitchell Shiffman (Liver Institute of Virginia, Richmond) and co-workers in their poster presentation.

Mutations were detected in 37 different genes, most commonly in UGTA1 (n=25), CFTR (n=10), PKHD1 (n=5), SERPINA1 (n=5), ABCB4 (n=4), and POLG (n=4). Overall, 13% of patients had a genetic mutation previously linked to progressive familial intrahepatic cholestasis or Alagille syndrome, namely ABCB4, ABCB11, MYO5B, and JAG1, the team highlighted.

The cohort included patients with elevated alkaline phosphatase, gamma-glutamyl transferase, serum bile acids and/or unexplained pruritus; a history of cholestasis of pregnancy; suspected cholestatic drug-induced liver injury without spontaneous resolution within 12 weeks; suspected primary biliary cholangitis (PBC) without diagnostic confirmation and/or no treatment response; and suspected small duct primary sclerosing cholangitis with normal MRCP.

Shiffman and co-workers reported that the majority (71%) of patients had no significant evidence of fibrosis. However, 25% of the cohort had non-specific inflammation of the portal tracts, and 23% had non-specific bile duct changes or irregularities that did not fit with a diagnosis of PBC.

In addition, 17% of the patients had steatosis and possible co-existing metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis, and 7% had cirrhosis, with most cirrhosis cases showing “no defined etiology,” the researchers said.

Of the 47 patients who underwent liver biopsy, 40% had no fibrosis; 31%, 10%, and 4% had stage 1, 2, and 3 fibrosis, respectively, and 15% had cirrhosis.

Pruritus was common in the study cohort, with mild, moderate, and severe symptoms in 16%, 19%, and 23% of patients, respectively. The researchers noted that all patients with severe pruritus, and 17% of those with moderate pruritus, did not respond to the standard escalating treatment of antihistamines, rifampin, cholestyramine, and naltrexone. However, all these patients did experience a “marked improvement or resolution” of their pruritus after initiating treatment with an ileal bile acid transporter (IBAT) inhibitor, the authors said.

“The majority of adults with a genetic cholestatic disorder do not appear to have significant liver injury or fibrosis,” Shiffman et al summarized.

Nevertheless, they concluded: “Screening for genetic cholestatic disorders in adults can provide an explanation for cholestasis of unknown etiology and in those patients with pruritus that is refractory to standard treatment an opportunity for treatment with an IBAT [inhibitor].”