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Title: Unravelling protective mechanisms of ursodeoxycholic acid in intrahepatic cholestasis of pregnancy
Author: Ovadia, Caroline Louise
ISNI:       0000 0004 7970 0017
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Introduction Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes and maternal metabolic dysfunction. Ursodeoxycholic acid (UDCA) treatment can improve itch severity and reduce bile acids in cholestatic conditions. This thesis determines how UDCA affects ICP patients by assessing its impact on adverse perinatal outcomes, its role in reducing maternal pruritus, and its involvement in maternal metabolic dysfunction secondary to altered enteroendocrine signalling. Methods To understand the magnitude of adverse perinatal outcomes in women with ICP, I performed a systematic review and aggregate data meta-analysis, comparing women with ICP (5515) and uncomplicated pregnancies (165 081), using a random-effects comparison with the DerSimonian and Laird method. To determine whether these outcomes are affected by disease severity, I analysed individual patient data from 16 published studies and two unpublished cohorts and compared results for women untreated and treated with UDCA. To identify pruritogens that are modifiable by UDCA treatment, I analysed serum samples collected longitudinally from women with ICP and benign pruritus gravidarum. Results were compared with linear and logistic regression, and predictive biomarkers for ICP were identified. To determine the effect of ICP on enteroendocrine signals, I studied murine models (0.5% cholic acid-fed ± UDCA) and samples from women with ICP, uncomplicated pregnancy, and non-pregnant controls. I used 16S rRNA sequencing and whole genome shotgun metagenomic analyses to characterise the cholestatic gut microbiota, and assessed the gut metabolome using UPLC-MS. Their effects on enteroendocrine signals were determined using qPCR and enzymatic analyses on ileal tissues and serum samples obtained following a timed dietary study. Results ICP is associated with increased adverse perinatal outcomes, compared with uncomplicated pregnancies. Women with bile acids ≥100μmol/L have significantly 24 increased risks of stillbirth (hazard ratio 30.50 (8.83 to 105.30, p < 0.0001)) compared to women with lower total bile acids. UDCA treatment did not significantly affect the observed association between total bile acid concentration and stillbirth, although the observed cohort treated with UDCA had more severe disease than untreated women, and the absolute risk of stillbirth was reduced for treated women at the equivalent disease severity (determined by bile acid concentration). Sulfated progesterone metabolites and autotaxin activity are associated with disease severity (determined by pruritus intensity) for women with ICP compared to those with benign pruritis gravidarum. They are also useful predictive biomarkers prior to hypercholanaemia developing; and their levels are reduced by treatment with UDCA. UDCA treatment of women with ICP and a murine model of cholestatic pregnancy results in enrichment of the gut microbiota with Bacteroidetes compared to Firmicutes, with associated increased bile salt hydrolase activity and intestinal bile acid deconjugation. Unconjugated intestinal UDCA is thereby modified to the metabolically-active bile acid lithocholic acid, whose levels are markedly increased in the faeces of treated women. Discussion These studies have confirmed that ICP is associated with adverse perinatal outcomes, including stillbirth; UDCA treatment may lower the stillbirth risk at an equivalent bile acid concentration, but the existing evidence does not yet support this definitive conclusion. UDCA can improve the pruritus of ICP by reducing the pruritogenic sulfated progesterone metabolites, and may improve the metabolic derangements of ICP by altering the gut microbial environment to enhance bile acid-derived enterohepatic and enteroendocrine signalling.
Supervisor: Williamson, Catherine ; Dixon, Peter ; Chappell, Lucy Charlotte Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available