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A source for healthcare professionals to access the latest data and information on the diagnosis, treatment and management of patients with gut related disorders
Professor Julian R.F. Walters
Consultant Gastroenterologist and Professor of Gastroenterology, Imperial College London, London, UK
In a healthy individual, fibroblast growth factor 19 (FGF19) regulates of the size of the bile acid pool by suppressing bile acid synthesis in response to bile acid absorption. Individuals with bile acid diarrhoea (BAD), either primary, or secondary to ileal dysfunction, produce excess bile acids due to lack of negative feedback from FGF19.1
In patients with ileal resection or dysfunction, there is a failure in absorption of bile acids (bile acid malabsorption, [BAM]) which is thought to be the major factor in BAD. Patients with Crohn's disease have low levels of FGF19. FGF19 values are lower in these patients if they have undergone ileal resection or have active disease, and are further reduced in those with concomitant diarrhoea.1 FGF19 levels increase when treatment with steroids has been given.1
The causes of reduced FGF19 in primary BAD are still uncertain and require further research. Study of polymorphisms in candidate genes, such as FGF19, fibroblast growth factor receptor 4, beta-klotho and farnesoid X receptor (FXR), in patients with BAD, have failed to show clear associations. Gene expression in ileal tissue shows correlations between the values of the tauroselcholic (75selenium) acid (SeHCAT) test, and both the basal and stimulated expression of FGF19.2
Bile acids are FXR agonists, and this action has been widely studied in basic systems.3 In studies looking at human ileal gene expression, the stimulation of FGF19 by FXR agonists is significant. Stimulation occurs with natural bile acids such as chenodeoxycholic acid and with the more potent analogue, obeticholic acid.3 FXR agonists could be an effective treatment for BAD. A proof-of-principle study has shown that treatment with obeticholic acid helped restore FGF19, reduced bile acid synthesis and produced clinical improvement of symptoms in patients with BAD.4
BAD can be thought of as an endocrine disorder and if compared to another endocrine disease, such as diabetes, we can observe the presence of numerous parallels. Both disorders have a main symptom (polyuria in diabetes and diarrhoea in BAD), a metabolism problem (glucose and BAs, respectively), and involve hormone regulation of remission (insulin and FGF19, respectively) through receptor-mediated pathways. There are also tests that detect the disease in both cases (measurement of HbA1c and the SeHCAT test, respectively).5
There are therapeutic strategies that help reduce the quantities of the hormone-regulated product, such as low-carbohydrate diets in diabetes and low-fat diets in BAD. Drugs such as sulfonylureas, metformin and insulin address the metabolic pathway in diabetes. In BAD, colestyramine only reduces the effects of the excess bile acid, whereas FXR agonists could provide therapy by stimulating the hormonal pathway.6
Job number: JB57410GBl Date of Preparation: June 2019
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Brief report: length of ileal resection correlates with severity of bile acid malabsorption in Crohn’s disease
In patients with Crohn’s disease who had a prior surgical resection there was a modest correlation between the length of ileal resection and the severity of bile acid malabsorption (BAM), as defined by tauroselcholic (75selenium) acid (SeHCAT) retention values. Response to bile salt sequestrant therapy was not dependent on SeHCAT retention values.
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