Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.712949
Title: Disease associations of primary bile acid diarrhoea and investigations into potential treatments and a possible metabolic syndrome of low fibroblast growth factor 19
Author: Appleby, Richard
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Abstract:
The endocrine growth factor Fibroblast Growth Factor 19 (FGF19) controls bile acid (BA) synthesis and contributes to lipid and glucose metabolism. FGF19 is released in the terminal Ileum (TI) in response to BA stimulation of the Farnesoid X Receptor (FXR). Low levels are associated with bile acid diarrhoea (BAD), high serum triglycerides and obesity raising the possibility of metabolic syndrome incorporating chronic diarrhoea. The pathogenesis of low FGF19 in individuals is not known and treatments are currently not available. BAD can be reliably diagnosed with a 75Selenium–homocholic acid taurine (SeHCAT) 7 day retention < 15%, a serum FGF19 < 145pg/L or a serum level of the BA precursor; Hydroxy-4-cholesten-3-one (C4) >28 ng/mL (70nmol/L). Bile acid sequestrants are the only available treatment for BAD but may lower FGF19 further. I hypothesise that low serum FGF19 is caused by reduced ileal production, is associated with non-alcoholic liver disease (NALFD) and that treatment of BAD with BA sequestrants could lower FGF19 further. Three areas of investigation were planned: disease associations of BAD and low FGF19, FGF19 response to FXR agonist in TI explants and FGF19 response to traditional BA sequestrants and a novel colonic release cholestyramine preparation. Disease associations of BAD were studied with a retrospective database of 578 patients with known SeHCAT values and revealed an odds ratio (OR) of 2.5 for BAD and NAFLD. This finding was explored further in a prospective series of 127 patients with NAFLD that showed an OR of 6.2 for BAD. This was associated with increased BA synthesis but with normal FGF19, possibly indicating hepatic FGF19 resistance. Next, a terminal ileal (TI) explant model was used to measure FGF19 mRNA response to FXR stimulation with different compounds. Ten TI explants from patients with low SeHCAT values were stimulated with chenodeoxycholic acid (CDCA) and FGF19 mRNA measured by qPCR. Patients with BAD had lower median FGF19 mRNA fold change (16 (range 8-204)) compared to controls (185 (73-416)). Using similar methods, TI explants from asymptomatic patients were incubated. With stimulation with 50mM Cafestol these showed a 3.4 fold increase in FGF19 and the addition of 100mM ursodeoxycholic acid (UDCA) to 5mM obeticholic acid (OCA) increased FGF19 expression by 2.5 times that of OCA alone. Finally a placebo controlled trial showed that administering cholestyramine in colonic release capsules can ameliorate the FGF19 lowering effect of bile acid sequestrants. I conclude that although there are significant disease associations of primary BAD (NAFLD, gallstones, hypertriglyceridaemia), this association can’t be explained by low FGF19 alone. Since all groups appear to have dysregulated BA metabolism, it appears that there are multiple pathophysiological mechanisms underlying BAD, including reduced ileal FGF19 expression and hepatic FGF19 resistance. The novel binding mechanism of UDCA to ileal BA-binding protein may be useful therapeutic adjunct to increase the potency of OCA and colonic release BA sequestrants are a viable treatment for patients with BAD and increase FGF19 compared to traditional sequestrants.
Supervisor: Walters, Julian Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.712949  DOI: Not available
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