April 02, 2014
Bile acid malabsorption (BAM) has been associated with diarrhea for nearly 50 years, yet it remains an under-recognized and underdiagnosed cause of chronic diarrhea. It is estimated that BAM occurs in one-third of patients diagnosed with irritable bowel syndrome with diarrhea (IBS-D) and up to 50 percent of those with functional diarrhea. Even so, few gastroenterologists consider BAM in chronic diarrhea cases.
Bile acids are synthesized in the liver primarily through the classical microsomal cholesterol 7α-hydroxylase (CYP7A1) pathway. They are conjugated with taurine and glycine in a series of steps and stored in the gallbladder until released into the small intestine where they solubilize dietary lipids.
The great majority of bile acids are eventually reabsorbed by the distal ileum and returned to the liver for recycling. When they aren't reabsorbed into the enterohepatic circulation — due to ileal resection, Crohn's disease or disrupted feedback control of bile acid synthesis — they spill into the colon, causing watery stools, urgency and fecal incontinence.
Michael Camilleri, M.D., of Mayo Clinic in Minnesota, says the main problem in evaluating for BAM is the limited availability of reliable diagnostic tests.
"The gold standard is the 75 selenium homocholic acid taurine (SeHCAT) retention test, but it's not available in many countries, including the United States, where the isotope it uses hasn't been approved by the FDA," he notes.
In the SeHCAT test, a radio-labeled homolog of a natural bile acid is administered orally and retention measured after seven days. The test is able to evaluate BAM with 80 to 90 percent sensitivity and 70 to 100 percent specificity.
One alternative to SeHCAT is a therapeutic trial of a bile sequestrant, such as cholestyramine, colestipol or colesevelam, which binds to bile acids in the gut. If symptoms improve, the response is seen as indirect proof of BAM. But some drugs, especially cholestyramine, are often poorly tolerated and not recommended for use without a definitive diagnosis. As a result, other tests for diagnosing bile acid malabsorption are being developed and validated.
One involves the measurement of serum levels of the marker 7α-hydroxy-4-cholesten-3-one (C4) — a measure of bile acid synthesis. In head-to-head comparisons with the SeHCAT retention test, increased serum C4 had a sensitivity of 90 percent and specificity of 79 percent in diagnosing bile acid malabsorption. The test is noninvasive, requiring only a blood sample from patients, and is relatively inexpensive. "It's wonderful to be able to screen for bile acid malabsorption with a serum test. It was not developed at Mayo, but we have continued to validate and perfect the assays, proving that it's a useful test," Dr. Camilleri says.
A paper describing Mayo's development of a serum C4 assay appeared in the March 2009 issue of Neurogastroenterology & Motility.
Bile acid excretion test
Another option is a total bile acid excretion test based on quantification of bile acids in a 48-hour stool collection. The bile acid test can be run on the same sample used for a fecal fat excretion test, and the assay using high-performance liquid chromatography and mass spectrometry is extremely accurate. "The proportions of the primary and secondary bile acids are determined on the same sample, and it is especially important to assess the proportion of the secretory bile acids, mainly deoxycholic acid and chenodeoxycholic acid, in the stool sample," Dr. Camilleri explains.
The fecal bile acid excretion test will likely have multiple uses, including evaluation of Crohn's disease patients with diarrhea, especially after ileal resection or when diarrhea persists after inflammation has been controlled. The test will be available through Mayo Medical Laboratories by mid-2014.
"We've broken the ice and conclusively demonstrated that a large subgroup of patients with chronic diarrhea needs to be diagnosed properly and treated more specifically and effectively with bile sequestrants," Dr. Camilleri says, adding, "Welchol is a newer drug that is FDA-approved for hypercholesterolemia and as an adjunct treatment for type 2 diabetes. It comes in a tablet form, so medication compliance is likely to be better than with cholestyramine."
He notes that in the future a more targeted therapy, such as a class of medications called farnesoid X receptor agonists, may become available and increase the feedback inhibition of bile acid synthesis.
For more information
Camilleri M, et al. Measurement of serum 7α-hydroxy-4-cholesten-3-one (or 7αC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterology & Motility. 2009;21:734.