Exploring the Effects of Bile Acid Inhibition in Cholestatic Pruritus

Abstract

Ph. D. Thesis.Pruritus (itch) is an important symptom associated with cholestatic liver diseases. The aim of this work was to study cholestatic pruritus to further our understanding of the prevalence in primary biliary cholangitis (PBC) and explore the role of inhibiting circulating bile acids (BAs) in relieving cholestatic pruritus. The cross-sectional study of pruritus from over 2800 patients from the UK-PBC research cohort showed that prevalence of pruritus in PBC is high (74%) with a significant proportion of patients reporting severe itch during the course of their disease. This study also highlighted the undertreatment of itch with inadequate use of guideline recommended drugs in the UK. The impact of inhibiting circulating BAs on cholestatic pruritus was studied in two different ways- i) via nasobiliary drainage (NBD, i.e. external diversion of bile and BAs away from the ileum), and ii) via pharmacological inhibition of the ileal bile acid transporter (IBAT) that mediates enterohepatic circulation of BAs. The retrospective cohort study of NBD showed the intervention is a highly effective treatment, but only of short-term durability and associated with high complication rate. The phase 2 clinical trial of GSK2330672, a human IBAT inhibitor agent, showed that two-weeks of treatment significantly reduced pruritus severity compared to placebo. The metabonomic and microbiome studies explored the serum metabonome and gut microbiota profile of pruritus in PBC. In addition, the effects of GSK2330672 on metabonome and gut microbiome were investigated. The study demonstrated that pruritus in PBC is associated with elevated serum total and glyco-conjugated BAs but no gut bacterial dysbiosis. Also, GSK2330672 was shown to reduce all taurine and glyco- conjugated serum BAs, increase faecal BAs and alter the gut-microbial composition. Taken together, the research studies presented in this thesis suggest: i) high prevalence of pruritus and its under-treatment in PBC, ii) removal of BAs by NBD or inhibition by IBAT inhibitor drug improves cholestatic pruritus and, iii) serum BAs but not gut microbiome are altered in cholestatic pruritus and they can be modified by IBAT inhibitor treatmentNational Institute for Health Research (NIHR), Newcastle Biomedical Research Centre (BRC