Cholestasis genetic variants prevalent in unexplained chronic cholestatic liver disease

The researchers found that such variants, which included those linked and not linked to progressive familial intrahepatic cholestasis (PFIC), were present in 89% of 81 adults with CCLD of unknown etiology.

Presenting the findings at AASLD The Liver Meeting in Denver, Colorado, USA, Mitchell Shiffman (Bon Secours Mercy Health, Richmond, Virginia, USA) explained that “the etiology for cholestatic liver diseases in adults encompasses a wide array of disorders,” and “despite extensive testing the etiology for chronic cholestatic liver disease remains undefined in many patients.”

They hypothesized that genetic causes for PFIC and Alagille syndrome, which are recognized in children, may also underlie less severe forms of these conditions in adults.

The team retrospectively analyzed 81 patients in their clinic who had CCLD, defined by the presence of at least two of the following: persistent or intermittent elevation in alkaline phosphatase (ALP) levels for more than 6 months; raised levels of gamma glutamyl transferase levels; increased serum bile acids; and unexplained pruritus.

All the patients received extensive biochemical, serologic, radiologic, and histologic assessments, and 54 individuals underwent liver biopsy, while 65 received vibration-controlled transient elastography.

The researchers excluded patients who had confirmed diagnoses of CCLD, such as primary sclerosing cholangitis, primary biliary cholangitis, sarcoidosis, and autoimmune hepatitis, according to serology, magnetic resonance cholangiopancreatography, or liver biopsy.

Genetic testing with Prevention Genetics Cholestasis Panel was conducted in the remaining patients with CCLD of unknown etiology. This panel “screens for variants in 70 genes involved in pathways associated with cholestasis and in the synthesis, uptake, intracellular transplant, and secretion of BA [bile acid],” the researchers note.

The patients had a mean age of 55 years, and the majority (77%) were women. They had a mean ALP level of 278.0 IU/L, a mean alanine aminotransferase (ALT) level of 65.6 IU/L, mean gamma glutamyl transferase levels of 262 IU/L, and their bile acid level was 40.9 µmol/L. The total bilirubin level was a mean of 1.1 mg/dL. Most of the patients had a fibrosis stage of 0 or 1, at rates of 36% and 30%, respectively, but 15% had cirrhosis.

Prior to genetic testing, the patients had been monitored for an average of 42 months.

High rate of cholestatic gene variants

Genetic testing showed that 29% of patients had at least one genetic variant in PFIC-related genes, the most common of which were ABCB4 (Multi Drug Resistance 3; 25%), MYO5B (vesicle movement cell polarity; 14%), and PLEC (cytoskeleton; 14%), while 1% had a JAG1 Alagille gene variant.

At least one non-PFIC gene variant was found in 59% of patients, with the average number of gene variants per patient of 2.3. The most common of these mutations were UGT1A1 (UDP-glucuronosyltransferase 1A1; 58%) and CFTR (cystic fibrosis transmembrane regulator conductor; 25%). The remaining 11% of patients had no genetic variants.

PFIC variants linked to pruritus severity

Shiffman and colleagues report that 33% of patients had pruritus, with 16 patients (20% of the overall cohort) experiencing severe pruritus, defined as resistance to up to two standard medications. These individuals were significantly more likely than patients with less severe pruritus to have PFIC genetic variants, they highlight. The proportion with PFIC genetic variants was 44%, compared with 26% of 34 patients without pruritus, 27% of 22 with mild pruritus (intermittent, and not requiring treatment), and 22% of nine patients with moderate pruritus (controlled with up to two standard medications).

While the rate of moderate and severe pruritus was higher among patients with PFIC gene variants, at 37%, there was still a proportion of individuals with non-PFIC gene variants who had pruritus of this severity, at 23%, the team notes.

ALP and ALT levels increased significantly in line with pruritus severity, increasing from a mean of 242.5 IU/L and 37.8 IU/L, respectively, in patients with no pruritus to 385.9 IU/L and 107.1 IU/L in those with severe pruritus. However, there was no stepwise increase in serum bile acids.