Methods for diagnosis of bile acid malabsorption in clinical practice

Abstract

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 (14)C-glycocholate breath and stool test, the (75)selenium homotaurocholic acid test (SeHCAT), and measurements of 7 α-hydroxy-4-cholesten-3-one (C4) and fecal BAs. The (14)C-glycocholate test is laborious and no longer widely used. The (75)SeHCAT 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.

Keywords: (75)SeHCAT; (75)selenium homotaurocholic acid test; 7 α-hydroxy-4-cholesten-3-one; ASBT; BA; BAM; C4; CA; CDCA; CYP7A1; DCA; Diarrhea; Fecal; GC-MS; Glycocholate; HPLC; IBAT; IBS; LCA; MS; NADH; Na(+)-dependent bile salt transporter; SeHCAT; bile acid; bile acid malabsorption; chenodeoxycholic acid; cholesterol 7α hydroxylase; cholic acid; deoxycholic acid; gas chromatography–mass spectrometry; high-performance liquid chromatography; ileal BA transporter; irritable bowel syndrome; lithocholic acid; mass spectrometry; reduced nicotinamide adenine dinucleotide.

Figure 1

Bile acid (BA) chemistry: chenodeoxycholic acid (CDCA), cholic acid (CA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA). Reproduced from Bajor A, et al. Scand J Gastroenterol 2010;45:645-664.

Figure 2

Hepatic synthesis of BA from cholesterol involves entry into hepatocytes of lowdensity lipoprotein (LDL) cholesterol by binding to LDL receptors on the hepatocyte cell surface. Upregulation of hepatic BA synthesis promotes maintenance of BA pool size and leads to an increase in serum 7 α-hydroxy-4-cholesten-3-one (C4), a surrogate for the activity of cholesterol 7 α-hydroxylase, the rate-limiting enzyme in hepatic BA synthesis. Adapted from Wong BS, et al. Am J Gastroenterol 2011;106:2154-2164.

Figure 3

Variation in BA excretion per gram fecal weight in each bowel movement (BM) in a single patient. Data show median, interquartile range, 5^th and 95^th percentiles, and each individual value. Reproduced from Mitchell WD, et al. Gut 1973;14:348-353.

Figure 4A and B

(A) ⁷⁵SeHCAT values and total fecal bile acids of nine patients. Vertical dotted line marks the lower normal limit for total fecal bile acids (250mg/day). Reproduced from Sciaretta G, et al. Gut 1987;28:970-975. (B) Relationship between half-life of ⁷⁵SeHCAT and HCO (7 α-hydroxy-4-cholesten-3-one) serum concentrations in patients with diarrhea of unknown origin. The response to treatment is indicated by different symbols ( = response to treatment, ■ = no response to treatment, ● = response not evaluated). The hatched area denotes pathologic values for both tests; the dotted area denotes normal values for both tests. Reproduced from Sauter GH, et al. Dig Dis Sci 1999;44:14-19.

Figure 5A, B and C

(A and B) Quantification of serum C4 and total stool bile acids in IBS-C, IBS-D and healthy controls. Data show median and interquartile ranges, 5th and 95th percentiles. Note the higher serum C4 and fecal total bile acids excreted over 48 hours in patients with IBS-D. (C) Relationship between fasting serum C4 and total 48 hour stool BA excretion. Adapted from Wong BS, et al. Clin Gastroenterol Hepatol 2012;10:1009-1015.