Diagnosis of BAD

Statement 1. In patients with chronic nonbloody diarrhea, we recommend using risk factors (history of terminal ileal resection, cholecystectomy, or abdominal radiotherapy) as the initial assessment to identify patients with possible BAD.

GRADE: Strong recommendation, very-low-certainty evidence.

Vote: on PICO question: strongly yes, 60%; yes, 40%.

Statement 2. In patients with chronic nonbloody diarrhea, we suggest against using symptom presentation as the initial assessment to identify patients with possible BAD.

GRADE: conditional recommendation, very-low-certainty evidence.

Vote: on PICO question: no, 100%.

No published randomized controlled trials (RCTs) were available comparing the clinical impact of using versus not using risk factors or symptom presentation for the diagnosis of BAD, therefore evidence from observational, diagnostic test accuracy (DTA) studies was evaluated. Overall, studies have shown that history of terminal ileal resection, cholecystectomy or radiotherapy are the risk factors associated most commonly with having a positive SeHCAT test suggestive of a BAD diagnosis (Table 2) (24–30).

Risk factors in patients with chronic nonbloody diarrhea most commonly associated with having a positive SeHCAT test suggestive of a BAD diagnosis

BAD, bile acid diarrhea; OR, odds ratio; SeHCAT, ⁷⁵selenium homocholic acid taurine; TI, terminal ileum.

No symptoms have consistently been predictive of a greater likelihood of having SeHCAT-diagnosed BAD among patients with chronic diarrhea. Rates of abdominal pain or discomfort, distension, bloating, flatulence and urgency, were similar or less frequent among patients with BAD and those with diarrhea resulting from other causes (24,31–33). Some studies have reported an association between stool weight, consistency or frequency, and a higher risk of BAD among patients with chronic diarrhea, but no diagnostic accuracy data, or definitions, are available (7,31–35).

All studies had either a high or unclear risk of bias, inconsistency (with respect to the specific symptoms and clinical characteristics as risk factors for BAD) and imprecision.

In patients presenting with nonbloody chronic diarrhea or IBS-D, rates of SeHCAT retention suggestive of BAD are much higher in those with risk factors compared with those in whom other possible causes have been excluded. Rates of BAD were lower in patients without compared with those with risk factors, specifically rates of severe BAD (SeHCAT retention, <5%) were approximately 10% (6,36) compared with 24% to 48% (24,26,29), rates of at least moderate BAD (SeHCAT retention, <10%) were 19% to 39% (6,25,34,36) compared with 38% to 58% (24,26,29), and rates of at least mild BAD (SeHCAT retention, <15%) were 24% to 27% (6,24,36) compared with 46% to 68% (24,26,29). The risk factors most commonly identified are shown in Table 2. In patients with ileal resection, BAD appeared to be independent of resection length; resections of less than 10 cm were sufficient to cause BAD (26).

The potential harms of using clinical risk factors as a triage test for BAD could include overdiagnoses leading to unnecessary diagnostic tests and/or treatments, or underdiagnoses leading to ongoing patient suffering. In patients with ileal resection, there is an extremely high risk of BAD, and diagnostic testing may not be necessary before treatment, whereas patients with chronic diarrhea after a cholecystectomy or after radiotherapy may warrant diagnostic tests. No consistent correlation has been found between the length of resection and SeHCAT retention, therefore, all patients should be considered at high risk after resection (25,26,37).

Other conditions such as diabetes, pancreatitis, small intestinal bacterial overgrowth (SIBO), microscopic colitis, vagotomy and celiac disease have been associated occasionally, but not consistently, with an increased risk of BAD (26,38).

No symptoms have been identified that reliably will predict a diagnosis of BAD. In fact, data suggest that reliance on symptoms can lead to underdiagnosis in clinical practice; one survey found that 44% of patients reported they had experienced symptoms for more than 5 years before diagnosis (39). Although symptom presentation is inaccurate for BAD, it continues to play a role in the differential diagnosis to rule out other conditions.

Based on the available data, the consensus group recommends that in patients with chronic nonbloody diarrhea, a history of terminal ileal resection, cholecystectomy or radiotherapy, but not symptom presentation, be used during the initial assessment to help identify patients with BAD.

Statement 3. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest SeHCAT testing to identify patients with BAD.

GRADE: Conditional recommendation, very-low-certainty evidence.

Vote: on PICO question: strongly yes, 20%; yes, 80%.

Data on the diagnostic accuracy of the SeHCAT retention test (as an initial test for diagnosis) were derived from two prospective DTA studies, both conducted by Sciarretta et al. (37,40) in Italy. These were designed as case–control studies to assess the ability of SeHCAT retention to discriminate between cases and controls. However, using other secondary results, a 2013 Health Technology Assessment calculated the diagnostic accuracy of SeHCAT retention for predicting the response to BAST (41). In the first study, the sensitivity and specificity of SeHCAT retention (cut-off value, <5%) were 85.7% (95% confidence interval [CI], 42.1 to 99.6) and 100% (95% CI, 54.1 to 100), respectively, in a subgroup of patients (n = 13) with diarrhea without evidence of intestinal or extraintestinal pathology (37,41). The second study, which included 46 patients with IBS-D or cholecystectomy, found the sensitivity and specificity of SeHCAT retention (cut-off value, <8%) were 95.0% (95% CI, 75.1 to 99.9) and 96.2% (95% CI, 80.4 to 99.9), respectively (40,41). In both studies, a response to BAST was defined as the disappearance of diarrhea. No studies were found that measured the diagnostic accuracy of SeHCAT in patients with chronic diarrhea, which avoided a case–control design and used a proven reference standard (because there is currently no such reference standard, apart from the surrogate response to BAST).

Both DTA studies were found to be at serious risk of bias with respect to the index tests and reference standards used, serious indirectness of the study populations and index tests, and very serious imprecision as a result of the very small sample sizes, and the lower limit of the CI crossing the threshold for a clinically useful diagnostic test. This suggests that the data are insufficient to support or refute the clinical utility of SeHCAT in patients with IBS-D. Therefore, other factors and indirect supportive evidence were considered.

Overall, the CoE for the diagnostic accuracy of SeHCAT was determined to be very low. As discussed in Statement 1, the prevalence data suggest that up to 40% of patients with functional diarrhea or IBS-D may have at least moderate BAD as assessed by a SeHCAT cut-off value less than 10% (6,25,34,36).

In addition, a systematic review (SR) including 15 observational studies showed a correlation between the severity of SeHCAT loss and response to treatment with BAST: response to cholestyramine was 96% in patients with less than 5% retention, 80% at less than 10% retention and 70% at less than 15% retention (6). This was not confirmed by a newer SR of 21 studies that found response rates with BAST of 67% at less than 5% retention, 73% at less than 8% to 11.7% retention and 59% at less than 15% retention (42). However, one study (26) published after the earlier SR, which included a large number of patients with secondary BAD, made a disproportionately large contribution to the group with less than 5% retention in this second analysis. Response rates were much lower in patients with negative SeHCAT tests; only 15% of patients had a good or partial response compared with 65.6% of patients with a SeHCAT retention less than 15% (29). A study has been proposed to evaluate the diagnostic accuracy of SeHCAT retention in which the test result will be concealed from clinicians and patients, and all patients will receive BAST (43).

Cost effectiveness and feasibility also were considered. The Health Technology Assessment assessed the cost effectiveness of SeHCAT testing compared with response to BAST based on data from three small trials and rather limited assumptions (41). They concluded that for the short term (first 6 months), the optimal choice between SeHCAT testing and no SeHCAT testing depended on willingness to pay, but that a trial of BAST would be more cost effective. From the long-term perspective, the optimal choice was a trial of BAST, no SeHCAT testing, or SeHCAT testing with a cut-off retention value of less than 15% depending on the scenario. Feasibility can be an issue in some areas because nuclear medicine facilities or the isotope may not be available.

BAST has poor tolerance and a high dropout rate; a positive SeHCAT test may have the additional benefit of providing the clinician with a stronger argument to encourage patients to stay on therapy when a definite diagnosis of BAD has been made (44). Other factors to consider are the potential harms of SeHCAT use, such as radiation risk, patient inconvenience and anxiety and loss of opportunity to use BAST in cases of false-negative results. Cut-off values to initiate treatment are sometimes inconsistent (45), and the role of borderline SeHCAT retention in therapeutic decisions is ill defined.

Taking all of these issues together, the consensus group concluded that SeHCAT retention is a relatively safe test, BAST is a relatively safe treatment (although poorly tolerated), and the anticipated benefit of SeHCAT retention testing likely outweighs the uncertainty of the evidence. Although other tests show promise for the future, SeHCAT retention has been the most widely tested, with consistent results.

Statement 4. In patients with small intestinal Crohn’s disease without objective evidence of inflammation who have persistent diarrhea, we suggest SeHCAT testing.

GRADE: Conditional recommendation, very-low-certainty evidence.

Vote: on PICO question: strongly yes, 20%; yes, 80%.

An observational cohort study included a subgroup of 44 patients with unoperated Crohn’s disease in clinical remission (other than diarrhea) who had normal hematology and C-reactive protein levels (28). SeHCAT retention was abnormal (<10%) in 54% of patients. Of the 24 patients with abnormal SeHCAT retention, 20 received initial conventional treatment (prednisolone ± mesalamine), followed by BAST when conventional treatment failed. Response rates were 55% with conventional treatment, and 40% with BAST, with 5% failing both treatments. The treatment duration and outcome assessments, as well as the use of BAST in patients with normal SeHCAT retention, were not clearly described. The diagnostic accuracy and the effects of using test results to inform management choices could not be calculated because of the lack of a control group.

The CoE was downgraded to very low because of a very serious risk of bias (with regard to the reference standard, patient flow and timing) and very serious imprecision (very small sample size).

Although there is very-low-certainty evidence supporting the use of SeHCAT testing to guide management decisions in patients with Crohn’s disease, testing may play a role in patients with ileal Crohn’s disease in complete remission who have ongoing chronic diarrhea.

Observational studies have suggested that almost half of the patients with ileal Crohn’s disease who have not undergone resection will have a positive SeHCAT, suggestive of a diagnosis of at least moderate BAD (Table 3) (25,26,28,29). These patients may have a two to four times greater likelihood of having a positive SeHCAT compared with having a negative test (25,29).

Prevalence of positive SeHCAT tests in patients with ileal Crohn’s disease who have not undergone resection

OR, odds ratio; SeHCAT, ⁷⁵selenium homocholic acid taurine.

Given the association between positive SeHCAT testing and response to BAST in patients with Crohn’s disease who continue to have persistent diarrhea despite conventional treatments, the consensus group made a conditional recommendation in favour of SeHCAT testing in patients with Crohn’s disease who have no objective evidence of active inflammation.

Statement 5. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest using a C4 assay to identify possible BAD.

GRADE: Conditional recommendation, very-low-certainty evidence.

Vote: on PICO question: strongly yes, 20%; yes, 60%; neutral, 20%.

No recommendation A: In patients with chronic diarrhea including IBS-D and functional diarrhea, the consensus group could not make a recommendation for or against the use of the FGF19 assay to identify possible BAD.

GRADE: No recommendation, very-low-certainty evidence.

Vote: on PICO question: strongly yes, 20%; neutral, 80%.

The majority of published DTAs compared C4(46–48) and FGF19(32,49,50) assays with SeHCAT testing. These showed good inverse correlation between C4 and SeHCAT testing, and between FGF19 and SeHCAT testing, however, the overall CoE for the diagnostic accuracy of SeHCAT was assessed for Statement 3 and determined to be very low. Therefore, the true diagnostic accuracy of these tests cannot be estimated from these studies.

One study assessing C4 and FGF19 assays used direct measurement of 48-hour fecal bile acid as a reference standard (51). This prospective DTA study included 30 patients with IBS-D who had replicate C4 and FGF19 samples 5 years apart that could be compared with fecal bile acid levels. When patients with a prior cholecystectomy were excluded, the sensitivity and specificity of serum C4 were 40% and 85%, respectively, with a 40% positive predictive value and an 85% negative predictive value for the diagnosis of BAD. For FGF19, the sensitivity and specificity were 20% and 75%, respectively, with a 17% positive predictive value and a 79% negative predictive value for the diagnosis of BAD.

The CoE was downgraded to very low because of the moderately serious risk of bias and very serious imprecision (CI lower limits crossed the threshold for clinically useful diagnostic tests, small sample sizes) in the DTA that used fecal bile acid levels as the reference standard (51). Similarly, there was very serious risk of bias and serious indirectness in the studies that used SeHCAT retention as the reference standard.

Although there appears to be a good correlation (inverse) between C4 and SeHCAT results, and between FGF19 and SeHCAT results, SeHCAT retention has not been validated adequately as a reference standard. Theoretically, C4 and FGF19 should be good markers of bile acid loss. C4 is a metabolic intermediate in the rate-limiting step for the synthesis of bile acids from hepatic cholesterol. FGF19 is a hormone released by ileal enterocytes after stimulation of nuclear farnesoid X receptors, typically by absorbed bile acids. Both markers have been correlated with fecal loss of bile acids (Figure 1) (51–53). In addition, FGF19 levels have been shown to correlate with C4 levels (54).

Enterohepatic circulation of bile acids. C4 is a metabolic intermediate in the rate-limiting step for the synthesis of bile acids from hepatic cholesterol. FGF19 is a hormone released by ileal enterocytes after stimulation of nuclear farnesoid X receptors by absorbed bile acids. BA, bile acid; C4, 7 α-hydroxy-4-cholesten-3-one; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FGF19, fibroblast growth factor 19; LCA, lithocholic acid. Reprinted with permission from Vijayvargiya and Camilleri (53).

Currently, there are no well-defined cut-off values for the diagnosis of BAD. In one prospective study, a C4 level of 52.5 ng/mL or greater and a FGF19 level of 61.7 pg/mL or less were diagnostic for BAD (51). Other observational studies have used cut-off values of 30 to 48 ng/mL for C4 (46,55). One study found a wide range of normal values for C4 (corrected for cholesterol) from 0.76 to 8.0 mg/mol and for FGF19 from 48 to 343 pg/mL (33).

Insufficient evidence is available with C4, and even less with FGF19. In addition, the FGF19 assay was not available as a commercial clinical test at the time of the meeting, which impacts the feasibility of implementing that test. Therefore, the consensus group made a conditional recommendation in favour of C4, but was unable to make a recommendation for or against the use of the FGF19 assay to identify BAD.

Statement 6. In patients with suspected BAD, we suggest against initiating empiric BAST over performing SeHCAT to establish a diagnosis of BAD.

GRADE: Conditional recommendation, very-low-certainty evidence.

Vote: on PICO question (in patients with suspected BAD, should we initiate empiric BAST over performing SeHCAT to establish a diagnosis of BAD?): yes, 20%; no, 40%; strongly no, 40%.

No direct comparative or DTA studies were found to inform this statement. As described in Statement 3, the two studies on the diagnostic accuracy of SeHCAT testing for predicting response to BAST yielded very low-certainty evidence in favour of using SeHCAT testing (37,40). The cost-effectiveness analysis included in the Health Technology Assessment conducted by Riemsma et al. (41) found that in the short term, a trial of BAST may be the optimal choice. However, over the long term, the optimal choice (trial of BAST, no SeHCAT testing, or SeHCAT at a cut-off retention value 15%) varied depending on the scenario. The analysis provided very low CoE regarding the optimal strategy.

There is very little evidence to determine the relative role of testing with SeHCAT testing versus using an empiric trial of BAST to make a diagnosis of BAD. Other factors were considered when making a conditional recommendation against empiric treatment.

A poor response to a therapeutic trial of BAST could be related to noncompliance and early discontinuation, which could result in a falsely negative diagnosis with patients being denied other effective alternative BAST that may be better tolerated (38,56). As discussed in Statement 3, a definitive diagnosis of BAD may help educate and motivate patients to adhere to treatment (38,44).

Conversely, in patients in whom there is a very high index of suspicion (in whom a positive SeHCAT test is found in >90%), such as terminal ileum resection or right hemicolectomy, early initiation of therapy may be preferred. In addition, although a test-and-treat strategy was preferred for most patients, it was recognized that SeHCAT testing or other diagnostic tests are not available in some areas. In these cases, a trial of BAST may be the only option.