Battat R, Duijvestein M, Vande Casteele N, Singh S, Dulai PS, Valasek MA, Mimms L, McFarland L, Hester KD, Renshaw M, Jain A, Sandborn WJ, Boland BS
Clin Gastroenterol Hepatol. 2018 Nov 15. doi:10.1016/j.cgh.2018.11.012
© Ivan Lyutakov
Inflammatory Bowel Disease (IBD) comprises a heterogeneous group of chronic inflammatory disorders with two main conditions, Crohn’s Disease (CD) and Ulcerative Colitis (UC) . Bile acid malabsorption (BAM) and bile acid diarrhoea (BAD) have been recognised to be a common cause of chronic diarrhoea, and this recognition has led to the initiation of a search for new screening tests (biomarkers). BAM is one of the mechanisms leading to microscopic colitis, a key factor in the pathogenesis of irritable bowel syndrome-diarrhoea, and molecular mechanisms of BAM are found in IBD patients with or without involvement of the terminal ileum. BAM/BAD is more frequently found in CD than in UC, and the obvious aetiology for BAM in CD is either ileal resection or ileal disease . The pathophysiology of diarrhoea in CD is multifactorial but there are two key factors, colonic water and electrolyte absorption, which can be impaired directly by colonic inflammation or indirectly by increased concentrations of bile acids having secretory effects, referred to as BAD .
75Se-HCAT is the most commonly used test for the diagnosis of BAM, but it is not widely available in many countries and for this reason there has been significant research into and validation of fasting serum fibroblast growth factor 19 (FGF19), serum 7α-hydroxy-cholesten-3-one (C4), faecal bile acid test and colonic expression of farnesoid X receptor (FXR) as a surrogate measure of bile acid synthesis. In one study of 58 patients with CD , comprising 23 ileal-resected (IR-CD) patients and 35 non-resected (NR-CD) patients, reduced FGF19 levels were found to be associated with ileal resection, diarrhoea and disease activity . FGF19 may therefore have utility as a biomarker for functioning ileum in CD. Adoption of reduced FGF19 as a marker of BAD/BAM has revealed that the majority of NR-CD patients with ileal involvement, disease activity and symptoms of diarrhoea are also likely to gain symptomatic benefit from treatments for BAD . The recently published study by Battat et al., the subject of this review, compared serum concentrations of C4 and FGF19 in IR-CD, NR-CD and UC patients and the results indicate that C4 and FGF19 may become biomarkers of value in identifying patients with diarrhoea attributable to BAM in IBD.
Battat et al. collected clinical, endoscopic and histological scores from 26 patients with IR-CD, 21 patients with NR-CD and 37 patients with UC and compared serum concentrations of C4 and FGF19, using area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cut-off levels. Patients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with IR-CD with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (p compared with UC <0.0001) and patients with IR-CD without ileitis had a median concentration of 51.6 ng/mL (p compared with UC <0.001). Patients with NR-CD did not have a significantly higher median concentration of C4 than patients with UC (p=0.71), regardless of ileitis (p=0.34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhoea (72.0% vs 0 patients with inactive UC; p<0.001), but their median concentration of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; p=0.3). A C4 cut-off concentration of 48.3 ng/mL identified patients with diarrhoea attributable to BAM with 90.9% sensitivity, 84.4% specificity and an AUROC of 0.94. A significantly higher proportion of patients with concentrations of C4 above this cut-off had BAD (50.0% vs 1.8% of patients below this cut-off) (p<0.001). When only patients with diarrhoea were analysed, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC 0.99). Above this cut-off, 83.3% of patients had a serum FGF19 concentration of <60 pg/mL, compared with 4.5% below this threshold (p<0.0001). C4 concentrations correlated with the number of daily bowel movements (r=0.41; p=0.004) and correlated inversely with FGF19 concentrations (r=-0.72; p<0.0001).
There is effective treatment with bile acid sequestrants such as cholestyramine and colesevelam if diarrhoea attributable to BAM is found in IBD patients. It is worth mentioning that novel therapeutic approaches related to bile acid metabolism for patients with IBD are emerging. FXR is certainly one of these potential novel therapeutic targets because its activation inhibits inflammation, preserves the intestinal barrier, positively affects innate mucosal immunity and even decreases small intestinal bacterial overgrowth .
Interest in BAM in the context of IBD, especially in patients with ileal resection, has increased and there is a large unmet need for better diagnosis in patients with IBD and suspected BAM/BAD, as well as a need for better therapies. The test with the highest diagnostic yield for BAM/BAD is 75Se-HCAT retention, but this test is not widely available in many countries, needs special equipment and is very expensive. Serum C4 is a simple and accurate method in patients who do not have liver disease or take statins. Faecal bile acid measurement by enzymatic assay provides an estimate of total faecal bile acids, but its accuracy is considered suboptimal. Based on the recent literature it seems a reasonable starting point to explore the use of C4 and FGF19 as simple tests for BAM/BAD, given their reported high sensitivity and specificity. Secondary feedback down-regulation of colonic FXR expression is another tool that needs to be validated in further studies of BAM/BAD. The novel biomarkers for BAD/BAM need to be more widely available and serum C4, serum FGF19 and colonic FXR should be performed in patients with IBD with ileal resection. Serum C4 and FGF19 show promise as diagnostic tests for use in countries where 75Se-HCAT is not available, and identification of bile acid signalling has led to the development of new, directly acting therapeutic agents.
Ivan Lyutakov is currently performing his PhD research on serum FGF19 and C4 as biomarkers for BAM in IBD at the University Hospital “Tsaritsa Yoanna – ISUL”, Medical University Sofia, Sofia, Bulgaria, and he is interested in the treatment options for BAM in IBD patients.