A Genes & Health pilot recall study of intrahepatic cholestasis of pregnancy and cholestatic liver disease

BackgroundCholestatic liver disease disproportionately affects South Asians, yet they remain underrepresented in genomic studies. This recall study aimed to recall volunteers from a British South Asian genetic cohort that were considered to be at high risk of cholestatic liver disease based on their genotype or phenotype. MethodsCases were defined as participants with rare (minor allele frequency <1%) heterozygous loss of function (LoF) variants in ABCB4 and ABCB11 (genotype re-call) or with a previous intrahepatic cholestasis of pregnancy (ICP) diagnosis (ICD10 O26.6). Cases were matched 1:1 to controls. A detailed medical and family history was taken along with fasting anthropometric and transient elastography (TE) measurements and blood samples. ResultsOut of 22 eligible volunteers, 9 (41%) participated in the recall (8/9 genotype and 1/9 phenotype recall). Among the cases there were 5 ABCB4 LoF, 3 ABCB11 LoF, and 1 ICP phenotype. Of these, 6/9 (66.7%) were newly identified with a cholestatic phenotype (genotype re-call). Specifically, 3/6 (50%) had increased liver stiffness on TE with one also demonstrating abnormal liver blood tests. 2/6 (33.3%) experienced at least 2 cholestatic symptoms and an additional 1/6 (16.7%) demonstrated abnormal liver blood tests without increased liver stiffness. ConclusionThis pilot study demonstrated new evidence of cholestatic liver disease in 66.7% of volunteers, underscoring the potential of rare heterozygous ABCB4/11 variants as markers for identifying individuals at high risk of developing cholestatic liver disease. Consequently, individuals at higher genetic risk benefit from monitoring, personalised treatment and prevention strategies for cholestatic liver disease. Plain language summaryWe aimed to identify British South Asians at high risk of liver disease due to specific genetic factors, such as issues with bile production or liver problems during pregnancy. We invited these individuals to a clinic, where we collected their medical and family history, conducted liver blood tests, and performed a scan to check for early signs of liver scarring. We found that nearly two out of three participants had undetected liver disease. This finding suggests that genetic factors are linked to developing liver disease, highlighting the importance of early detection and monitoring for those at risk.