Perspectives in clinical gastroenterology and hepatology
Methods for Diagnosis of Bile Acid Malabsorption in Clinical Practice

https://doi.org/10.1016/j.cgh.2013.04.029Get rights and content

Altered concentrations of bile acid (BA) in the colon can cause diarrhea or constipation. More than 25% of patients with irritable bowel syndrome with diarrhea or chronic diarrhea in Western countries have BA malabsorption (BAM). As BAM is increasingly recognized, proper diagnostic methods are needed to help direct the most effective course of treatment for the chronic bowel dysfunction. We review the methodologies, advantages, and disadvantages of tools that directly measure BAM: the 14C-glycocholate breath and stool test, the 75selenium homotaurocholic acid test (SeHCAT), and measurements of 7 α-hydroxy-4-cholesten-3-one (C4) and fecal BAs. The 14C-glycocholate test is laborious and no longer widely used. The 75SeHCAT has been validated but is not available in the United States. Measurement of serum C4 is a simple and accurate method that can be used for most patients but requires further clinical validation. Assays to quantify fecal BA (total and individual levels) are technically cumbersome and not widely available. Regrettably, none of these tests are routinely available in the United States; assessment of the therapeutic effects of a BA binder is used as a surrogate for diagnosis of BAM. Recent data indicate the advantages to studying fecal excretion of individual BAs and their role in BAM; these could support the use of the fecal BA assay, compared with other tests. Measurement of fecal BA levels could become a routine addition to the measurement of fecal fat in patients with unexplained diarrhea. Availability ultimately determines whether the C4, SeHCAT, or fecal BA test is used; more widespread availability of such tests would enhance clinical management of these patients.

Section snippets

Clinical Utility

The 14C-glycocholate breath and stool test is a method to determine bacterial-dependent deconjugation within the gastrointestinal tract, which is due to bacterial overgrowth in the small bowel or BAM.15, 16

The 14C-glycocholate solution is orally administered and incorporates into the intraluminal pool of BAs. Bacteria can enzymatically cleave the bond between CA and glycine. 14C-glycine is released, absorbed into the portal circulation, and rapidly metabolized in the liver, and the end product

Clinical Utility

75SeHCAT uses a synthetic 75selenium homotaurocholic BA that is resistant to bacterial degradation21 and passive diffusion.22 Thus, 75selenium homotaurocholic BA can be either actively absorbed in the terminal ileum to enter the enterohepatic circulation or excreted into stool, unaltered by its passage through the colon.

Unlike 14C-glycocholate, 75selenium decays through gamma emission and thus can be measured with an external counter, a gamma camera, which does not require a collimator,

Clinical Utility

C4 was initially developed to measure BA synthesis and the associated removal of circulating low-density lipoprotein cholesterol in clinical trials investigating modalities to reduce cardiovascular risk.27 BA synthesis occurs via neutral and acidic pathways. In humans, 90% of BA synthesis occurs through the neutral pathway, which is regulated by the rate-limiting enzyme cholesterol 7α hydroxylase (CYP7A1). C4 is a downstream product of CYP7A1 (Figure 2). The correlation of C4 with BA synthesis

Clinical Utility

Apart from the fecal measurement of 14C-glycocholate, the tests discussed above indirectly assist in the diagnosis of BAM by measuring BA synthesis or retention. In contrast, it is now possible to quantify fecal total and individual BA. Increased total fecal BAs is reported in patients with chronic functional diarrhea31; moreover, recent data show that functional diarrhea and diarrhea-predominant IBS are associated with higher fecal levels of secretory BAs (CA,CDCA, DCA), whereas functional

Cross-validation of Methods to Detect Bile Acid Malabsorption

A number of studies published in the literature describe cross-validation between the various methods described; the comparative data are shown in Figures 4 and 5. Figure 4A compares 75SeHCAT retention at 3 days with total fecal BAs. The decrease in 75SeHCAT retention at day 3 is significantly associated with an increase in fecal BAs. After these initial validation studies in which the cutoff at 3 days was 34% retention, subsequent studies focused on the 75SeHCAT retention at 7 days and

Conclusions

Currently, 75SeHCAT retention, serum C4, and fecal BA measurements are the 3 viable tests available to diagnose BAM. Unfortunately, 75SeHCAT is not available in several countries, including the United States. Serum C4 is a simple and accurate method for patients who do not have liver disease or take statins and maintain a normal circadian rhythm; however, it has been studied in relatively small numbers of patients, and further validation, including response to therapy in patients selected for

Acknowledgments

The authors thank Mrs Cindy Stanislav for excellent secretarial assistance.

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    This article has an accompanying continuing medical education activity on page e74. Learning Objectives-At the end of this activity, the successful learner will be able to analyze information about tests used to diagnose BAM and interpret results of these tests to diagnose BAM in patients presenting with chronic diarrhea.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by grant RO1-DK92179 (to Dr Camilleri) from National Institutes of Health.

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