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Title: The role of FGF19 in the diagnosis and pathophysiology of primary bile acid diarrhoea
Author: Johnston, Ian
ISNI:       0000 0004 5922 7875
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Introduction: PBAD is a common cause of watery diarrhoea. It is diagnosed by the SeHCAT test and is characterized biochemically by elevated bile acid biosynthesis and low fasting FGF19. FGF19 is a gut hormone produced in the terminal ileum which negatively feeds back on hepatic BA synthesis. Aims: To assess the role of FGF19 in the pathogenesis of PBAD through characterization of fasting and postprandial FGF19 levels and through identification of associations with other biochemical and genetic factors. To show an increase in the fasting level of FGF19 in PBAD patients through the use of an FXR agonist. Methods: Subjects with PBAD and idiopathic diarrhoea were recruited and their data added to a previously recruited cohort. Fasting FGF19, BA, lipids, B12, vitamins A and D were measured. A subgroup was characterized using post-prandial levels of these factors. SNP genotyping was performed in candidate genes. A subgroup had BA species characterized by UPLC-MS. 10 PBAD subjects entered a study investigating changes in FGF19 following administration of the FXR agonist obeticholic acid. Results: Low fasting and post-prandial levels of FGF19 have been demonstrated in PBAD with lowest levels in those with low SeHCAT retention. Fasting and postprandial FGF19 correlates with total BAs. No strong associations have been found between diagnosis or FGF19 with vitamins A and D or with genetic variants. Approximately 30% of PBAD subjects have been found with elevated triglycerides and normal or high FGF19. Significant improvement in FGF19 and symptoms has been shown in PBAD subjects with the use of OCA. Conclusion: Abnormalities in FGF19 levels have been explored with biochemical phenotypes described. A subset of PBAD subjects with elevated triglycerides has been identified. A central role for total BAs in the aetiology has also been shown. Potential therapeutic benefit of OCA has been found warranting further investigation.
Supervisor: Walters, Julian ; Thursz, Mark Sponsor: Bardhan Research and Education Trust
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available