Journal Pre-Proof: Clinical Gastroenterology and Hepatology

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CANADIAN ASSOCIATION OF GASTROENTEROLOGY CLINICAL PRACTICE

GUIDELINE ON THE MANAGEMENT OF BILE ACID DIARRHEA
Daniel C. Sadowski, Michael Camilleri, William D. Chey, Grigorios I. Leontiadis,

John K. Marshall, Eldon A. Shaffer, Frances Tse, Julian R.F. Walters
PII: S1542-3565(19)31002-X
DOI: https://doi.org/10.1016/j.cgh.2019.08.062
Reference: YJCGH 56748
To appear in: Clinical Gastroenterology and Hepatology

Accepted Date: 28 August 2019
Please cite this article as: Sadowski DC, Camilleri M, Chey WD, Leontiadis GI, Marshall JK, Shaffer EA,
Tse F, Walters JRF, CANADIAN ASSOCIATION OF GASTROENTEROLOGY CLINICAL PRACTICE
GUIDELINE ON THE MANAGEMENT OF BILE ACID DIARRHEA, Clinical Gastroenterology and
Hepatology (2019), doi: https://doi.org/10.1016/j.cgh.2019.08.062.
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© 2019 by the AGA Institute

Sadowski et al. CAG CPG on BAD
CANADIAN ASSOCIATION OF GASTROENTEROLOGY CLINICAL PRACTICE

GUIDELINE ON THE MANAGEMENT OF BILE ACID DIARRHEA
Running title: Management of Bile Acid Diarrhea
Authors
Daniel C. Sadowski,1 Michael Camilleri,2 William D. Chey,3 Grigorios I. Leontiadis,4 John K.
Marshall,4 Eldon A. Shaffer,5 Frances Tse,4 Julian R.F. Walters6
Affiliations
1
Division of Gastroenterology, Royal Alexandra Hospital, Edmonton, AB; 2Division of
Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA 3Division of
Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA; 4Division of
Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster
University, Hamilton, Ontario, Canada; 5Division of Gastroenterology, University of Calgary,
Calgary, AB; 6Division of Digestive Diseases, Imperial College London, London, UK
Correspondence
Daniel Sadowski, MD
Division of Gastroenterology
University of Alberta
Edmonton, AB, T6G 2X8
Phone: 780-492-9840
Email: sadowski@ualberta.ca
Financial support
This guideline was supported through unrestricted grants to the Canadian Association of
Gastroenterology by Pendopharm and GE Healthcare Canada, neither of which had any
involvement in the development of this guideline.
Abbreviations used in this paper:

5-ASA: 5-aminosalicylate; AGA, American Gastroenterological Association; BAD, bile acid
diarrhea; BAST, bile acid sequestrant therapy; BMs, bowel movements; BSG, British Society of
Gastroenterology; CAG: Canadian Association of Gastroenterology; CI: confidence interval;
CoE: certainty of evidence; CPG: clinical practice guideline; DTA, diagnostic test accuracy;
FGF19, fibroblast growth factor; GRADE: Grading of Recommendation Assessment,
Development and Evaluation; HTA, Health Technology Assessment; HPC, hydroxypropyl
cellulose; IBS, irritable bowel syndrome; IBS-D, diarrhea predominant IBS; NPV, negative-
predictive value; OR, odds ratio; PICO, patient population, intervention, comparator, outcome;
PPV, positive-predictive value; RCT: randomized controlled trial; SeHCAT,75selenium
homocholic acid taurine or tauroselcholic acid; SIBO, small intestinal bacterial overgrowth; SR,
systematic review
1
Disclosures
NO, I do not have any industry or government relationships to report: (DS, FT, GL)
ADVISORY BOARD: Abbvie (JM), Allergan (JM, MC), American College of Gastroenterology
(WC), American Neurogastroenterology and Motility Society (WC), AstraZeneca (JM), BioKier
(MC), Boehringer-Ingelheim (JM), Celgene (JM), Celltrion (JM), Ferring (JM), Hospira (JM),
Janssen (JM), Merck (JM), Pfizer (JM), Pharmascience (JM), Rome Foundation (WC), Shire
(JM), Takeda (JM)
CONSULTING: Allergan (WC), AstraZeneca (MC), Biomerican (WC), Dignify Therapeutics

(MC), Elobix AB (MC), Enterin (MC), ENYO Pharma (JW), GE Healthcare (JW), IM Health
(WC), Intercept Pharma (JW), Ironwood (MC, WC), Lupin (JM), Merck (JM), Metacrine Inc.
(JW), Nestle (WC), Novartis Pharma (JW), Pharmascience (JM, JW), Prometheus Diagnostics
(JW, WC), QOL Medical (WC), Ritter (WC), Salix (WC), Shire (MC, WC), Takeda (MC),
Theravance (MC), Zealand Pharma (JW)
EDUCATION/RESEARCH GRANT: Allergan (MC), AstraZeneca (MC), Elira (MC), ENYO

Pharma (JW), GE Healthcare (JW), Intercept Pharma (JW), NGM Biopharma (MC), Novartis
Pharma (JW, MC), Novo Nordisk (MC), Prometheus Diagnostics (JW), Rhythm (MC)
SPEAKER'S BUREAU: Abbvie (JM), Allergan (JM), Ferring (JM), GE Healthcare (JW),
Janssen (JM), Pendopharm (ES), Shire (JM), Takeda (JM)
Writing assistance
The consensus group would like to thank Pauline Lavigne and Steven Portelance (unaffiliated)
who provided medical writing services on their behalf, supported by funds from the Canadian
Association of Gastroenterology.
Author contributions
The Clinical Practice Guideline group (DS, MC, WC, ES, JW), GL, and FT reviewed the
literature and drafted the statements. GL and FT assessed the evidence and provided GRADE
(Grading of Recommendation Assessment, Development and Evaluation) evaluations. All
members of the Consensus Group voted on the recommendations. The manuscript was initially
drafted by the chair (DS) and the methodologists (GL, FT), after which it was revised based on
input from all members of the Consensus Group, as well as the moderator (JKM). As per CAG
policy for all clinical practice guidelines, the manuscript was made available to all CAG
members for commenting before submission for publication. Members were notified that the
manuscript was available on the members-only section of the CAG website and open for
comment for a 2-week period.
2
ABSTRACT
Background & Aims: Chronic diarrhea affects about 5% of the population overall. Altered bile
acid metabolism is a common but frequently undiagnosed cause.
Methods: We performed a systematic search of publication databases for studies of assessment
and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of
recommendations were rated according to the Grading of Recommendation Assessment,
Development and Evaluation approach. Patient population, intervention, comparator, and
outcome questions were developed through an iterative process and were voted on by a group of
specialists.
Results: The certainty of evidence was generally rated as very low. Therefore, 16 of 17
recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors
(terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional
symptoms, was recommended for identification of patients with possible BAD. The group
suggested testing using 75selenium homocholic acid taurine (where available) or 7α-hydroxy-4-
cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional
diarrhea, and Crohn’s disease without inflammation. Testing was suggested over empiric bile
acid sequestrant therapy (BAST).
Once remediable causes are managed, the group suggested cholestyramine as initial therapy,
with alternate BAST when tolerability is an issue. The group suggested against BAST for
patients with extensive ileal Crohn’s disease or resection and suggested alternative anti-diarrheal
agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose,
with a trial of intermittent, on-demand administration, concurrent medication review, and
reinvestigation for patients whose symptoms persist despite BAST.
Conclusions: Based on a systematic review, BAD should be considered for patients with chronic
diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with
cholestyramine, is suggested.
KEY WORDS: SeHCAT; C4; fibroblast growth factor 19; FGF19; IBS
3
INTRODUCTION
Diarrhea is a common symptom in the general population of developed countries. Among
community dwelling persons the 1-month rate of diarrhea was 7.6% in Canada and the United
States, 6.4% in Australia, and 3.4% in Ireland; about 20% of subjects sought medical care for
this symptom.1 The prevalence of chronic diarrhea has been estimated to affect about 5% of this
population overall,2 and may be higher among older individuals.3
The most common causes of chronic diarrhea in clinical practice are functional disorders
(eg, irritable bowel syndrome [IBS]), and inflammatory diseases (eg, Crohn’s disease, celiac
disease).3 However, a common but frequently, underdiagnosed cause of chronic diarrhea is
dysregulated bile acid recycling within the enterohepatic circulation: either excessive
biosynthesis/secretion of bile acids, or malabsorption of bile acids by the ileum. Unabsorbed bile
acids in the colon appears to cause diarrhea by stimulating fluid, mucus, or sodium secretion;
increasing gastrointestinal motility; damaging the mucosa; or stimulating defecation.3,4
Three subtypes of bile acid diarrhea (BAD) have been described: Type 1, patients with
terminal ileal disease (eg, Crohn’s disease, resection) or radiation injury resulting in impaired
reabsorption of bile acids; type 2, idiopathic or primary; and type 3, other conditions (eg, celiac
disease, cholecystectomy) that alter intestinal motility or bile acid absorption.3,5 BAD has been
reported in about 25-35% of patients with chronic diarrhea or diarrhea-predominant IBS (IBS-
D).6 Rates are even higher in patients with underlying terminal ileal disease, or other conditions
such as cholecystectomy.
The diagnosis of BAD continues to be a challenge, although this may be improved in
future with the general availability of screening serological test and other diagnostic tests
discussed below. While a treatment trial with a bile acid sequestrant therapy (BAST) is often
used, this approach has not been adequately studied, and is likely imprecise, and may lead to
both under-treatment and overtreatment. Specific diagnostic tests are under investigation,
particularly radiodiagnostic measurement of bile acid pool loss with 75selenium homocholic acid
taurine (SeHCAT, GE Healthcare Canada Inc., Ontario, Canada), or measurement of serum
levels of biomarkers of bile acid synthesis including 7α-hydroxy-4-cholesten-3-one (C4) or the
ileal regulatory hormone, fibroblast growth factor 19 (FGF19). SeHCAT testing is unavailable in
some countries (including the USA).
4
BAD is generally not cured, and as is the case with many chronic gastrointestinal
diseases or disorders, many patients will require lifelong treatment.7,8 Treatment is generally with
BAST, but is also dependent on the underlying causes of BAD, severity of symptoms, or the
presence of other comorbid illnesses (eg, Crohn’s disease, celiac disease).
BAD is an understudied, often underappreciated condition, and questions remain
regarding its diagnosis and treatment. There have been guidelines on the management of chronic
diarrhea from the American Gastroenterological Association (AGA),9 and the British Society of
Gastroenterology (BSG),10 but diagnosis and management of BAD was not extensively assessed
in these publications. The BSG updated guidelines on the investigation of chronic diarrhea in
adults,11 published after the consensus meeting, addressed some issues related to BAD.
The purpose of this guideline is to critically review the literature relating to diagnostic
testing, and the induction and maintenance treatment of BAD, with the aim of developing
specific consensus recommendations for patients with BAD.
5
METHODS
Scope and purpose

These consensus statements focused on specific issues pertaining to the medical
management of BAD, which the participants and GRADE experts (FT, GL) identified a priori.
Sources, literature searches, and systematic reviews (SRs)

The Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases
Group at McMaster University performed a systematic search of MEDLINE, EMBASE, and
CENTRAL (Cochrane Central Register of Controlled Trials) for literature published between
1990 and September 2017. Key search terms were bile acid, cholecystectomy, cholestyramine,
colestipol, colesevelam, diarrhea, loperamide, malabsorption, resection, SeHCAT, and
sequestrants. An additional search of the databases for SeHCAT trials published prior to 1990
(database inception as start date) was also performed. Only human studies published in English
were considered. Further details of the search strategies are provided in Appendix 1.
Assessment of the certainty (quality) of evidence (CoE)

Prior to the face-to-face meeting, the statements were converted to specific PICO (patient
population, intervention, comparator, and outcome) questions by the 2 non-voting
methodologists (FT, GL). The overall certainty of evidence (CoE) was determined using the
GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach12 to
assess risk of bias (of individual studies and overall across studies), indirectness, inconsistency,
imprecision, as well as other considerations (including publication bias). As described in
GRADE12,13 and used in previous consensus guidelines from the CAG,14-18 CoE was graded as
very low, low, moderate, or high. GRADE evaluations for each statement were provided prior to,
and discussed at, the consensus meeting.
The consensus group agreed that four statements (Statements 11, 13, 14, and 17) met
GRADE criteria for "good practice statements", that these recommendations were clinically
obvious, and that collection and GRADE assessment of evidence for these statements was not a
good use of resources.19 Although formal GRADE evaluations were not performed, details of
these statements are provided in the text.
6
Approved product labeling from government regulatory agencies varies from country to
country, and though not ignored, recommendations are based on evidence from the literature and
consensus discussion and may not fully reflect the product labeling for a given country.
Consensus process
A face-to-face consensus meeting was held in Toronto, Ontario, Canada, in February
2018. The international consensus group was comprised of 5 voting gastroenterologists
(including the chair [DS]), from Canada, the US, and the UK. Other participants included a
nonvoting moderator (JM), the 2 GRADE experts (FT, GL), and a nonvoting observer.
The consensus process was facilitated by the CAG via a web-based consensus platform
(ECD solutions, Atlanta, Georgia, USA). The platform allowed consensus participants to review
results of the initial literature searches and "tag” (select and link) the references to specific
statements. Copies of the “tagged” references were available to all members of the consensus
group. The full consensus group voted anonymously on their level of agreement with the
individual statements using a modified Delphi process.20,21 Participants suggested revisions and
commented on the statements, after which, the specific statements were revised through 2
iterations.
At the 1-day consensus meeting, evidence for each of the PICO questions was presented,
after which an Evidence-to-Decision framework was completed.22 Each PICO question was
discussed and revised, and voting members anonymously indicated their level of agreement on a
scale of 1 to 5. In favour of a specific strategy was defined as ≥75% of votes being 5 (strongly
yes) or 4 (yes). A vote against the strategy was defined as ≥75% of votes being 1 (strongly no) or
2 (no). A vote of 3 indicated neutral. Once reaching agreement on the PICO question, the
“strength” of the recommendation (strong vs. conditional) was determined based on 4
components: (a) CoE, (b) benefit/harm balance, (c) patients’ values/preferences, and (d) resource
requirements.23 When the CoE was low or very-low, unless at least 1 of the other 3 factors was
overwhelmingly strong, the strength of the recommendation would typically default (without a
vote) to “conditional”, using the phrasing “we suggest”. If the statement warranted a vote, and
≥75% of participants voted “strong, then the recommendation would be designated as “strong”
and the phrasing was “we recommend”.
7
During the meeting, consensus was not reached on 4 of the PICO questions, therefore no
statement was developed and no recommendation made. Evidence and subsequent discussion
pertaining to these 4 questions is summarized briefly in the text.
The manuscript was initially drafted by the meeting chair (DS), then reviewed and
revised by the remaining members of the consensus group. The manuscript was then made
available to all CAG members for comment over a 2-week period prior to submission for
publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest
for the 24 months prior to the consensus meeting were provided by all participants, reviewed by
the CAG ethics committee, and made available to all group members.
Role of the funding sources

Funding for the consensus meeting was provided by unrestricted, arms-length grants to
the CAG by Pendopharm and GE Healthcare Canada. The CAG administered all aspects of the
meeting, and the funding sources had no involvement in the process at any point, nor were they
made aware of any part of the process from the development of search strings and the statements,
to drafting and approval of these guidelines.
8
RECOMMENDATION STATEMENTS
The individual recommendation statements are provided and include the strength of
recommendation and certainty of supporting evidence (according to the GRADE approach), and
the voting result. This is followed by a discussion of the evidence considered for the specific
statement. A summary of the recommendation statements is provided in Table 1. See Appendix 2
for detailed CoE assessments (including description of study limitations, inconsistency,
indirectness, imprecision, publication bias) and the Evidence-to-Decision frameworks.
Diagnosis of BAD
Statement 1: In patients with chronic non-bloody 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 non-bloody 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%.
Key evidence: No published randomized controlled trials (RCTs) were available

comparing the clinical impact of using vs 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 show that history of terminal ileal resection,
cholecystectomy, or radiotherapy, are the risk factors most commonly associated with having a
positive SeHCAT test suggestive of a BAD diagnosis (Table 2).24-30
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, urgency, were similar or less frequent among
patients with BAD and those with diarrhea due to 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 high or unclear risk of bias, inconsistency (with respect to the
specific symptoms and clinical characteristics as risk factors for BAD) and imprecision.
9
Discussion: In patients presenting with non-bloody, chronic diarrhea or IBS-D, rates of

SeHCAT retention suggestive of BAD are much higher in those with risk factors compared to
those in whom other possible causes have been excluded. Rates of BAD were lower in patients
without compared to those with risk factors, specifically rates of severe BAD (SeHCAT retention
<5%) were about 10%6,36 compared to 24-48%,24,26,29 rates of at least moderate BAD (SeHCAT
retention <10%) were 19-39%6,25,34,36 compared to 38-58%,24,26,29 and rates of at least mild BAD
(SeHCAT retention <15%) were 24-27%6,24,36 compared to 46-68%.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 <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 post-cholecystectomy or post-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 post-resection.25,26,37
Other conditions such as diabetes, pancreatitis, small intestinal bacterial overgrowth
(SIBO), microscopic colitis, vagotomy, and celiac disease have been occasionally, but not
consistently, associated with an elevated risk of BAD.26,38
No symptoms have been identified that will reliably 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 While 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 non-bloody diarrhea, a history of terminal ileal resection, cholecystectomy, or
radiotherapy, but not symptom presentation, be used during initial assessment to help identify
patients with BAD.
10
Statement 3: In patients with chronic diarrhea including IBS-D and functional diarrhea, we
suggest SeHCAT testing to identify patients with BAD.
Key evidence: Data on the diagnostic accuracy of SeHCAT retention test (as initial test
for diagnosis) were derived from 2 prospective DTA studies, both conducted by Sciarretta et al
in Italy.37,40 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 (HTA) calculated the diagnostic accuracy of SeHCAT
retention for predicting response to BAST.41 In the first study, the sensitivity and specificity of
SeHCAT retention (cut-off value <5%) were 85.7% (95% CI, 42.1‒99.6) and 100% (95% CI,
54.1‒100), 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, 75.1‒99.9) and 96.2% (95% CI, 80.4‒99.9), respectively.40,41
In both studies, response to BAST was defined as 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
confidence interval 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.
Discussion: Overall, the CoE for the diagnostic accuracy of SeHCAT was determined to
be very low. As discussed in statement 1, 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 <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:
11
response to cholestyramine was 96% in patients with <5% retention, 80% at <10% retention and
70% at <15% retention.6 This was not confirmed by newer SR of 21 studies, that found response
rates with BAST of 67% at <5% retention, 73% at <8–11.7% retention and 59% at <15%
retention.42 However, one study26 published after the earlier SR, which included a large number
of patients with secondary BAD, made a disproportionately large contribution to the <5%
retention group 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 to 65.6%
of patients with a SeHCAT retention <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 were also considered. The HTA assessed the cost-
effectiveness of SeHCAT testing compared to response to BAST based on data from 3 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 cut-off
retention value <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 risks, 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 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.
While other tests show promise for the future, SeHCAT retention has been the most widely
tested, with consistent results.
12
Statement 4: In patients with small intestinal Crohn's disease without objective evidence of
inflammation who have persistent diarrhea, we suggest SeHCAT testing.
Key evidence: 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.28 SeHCAT retention was abnormal (<10%) in 54% of
patients. Of the 24 patients with abnormal SeHCAT retention, 20 received initial conventional
treatment (prednisolone ± 5-aminosalicylate [5-ASA]), 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. 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 due to very serious risk of bias (with regard to the
reference standard, patient flow, and timing) and very serious imprecision (very small sample
size).
Discussion: Although there is very low certainty evidence supporting 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 suggest 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 2-4 times greater likelihood of
having a positive SeHCAT compared to having a negative test.25,29
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.
13
Statement 5: In patients with chronic diarrhea including IBS-D and functional diarrhea, we
suggest using a C4 assay to identify possible BAD.
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 FGF19
assay to identify possible BAD.
GRADE: NO recommendation, very-low-certainty evidence; Vote on PICO question: strongly
yes, 20%; neutral, 80%.
Key evidence: The majority of published DTAs compared 7 α-hydroxy-4-cholesten-3-

one (C4)46-48 and fibroblast growth factor 19 (FGF19)32,49,50 assays to 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, which could be compared to fecal bile acid
levels. When patients with prior cholecystectomy were excluded, the sensitivity and specificity
of serum C4 were 40% and 85%, respectively, with a 40% positive-predictive value (PPV) and
an 85% negative-predictive value (NPV) for the diagnosis of BAD. For FGF19, the sensitivity
and specificity were 20% and 75%, respectively, with a 17% PPV and 79% NPV for the
diagnosis of BAD.
The CoE was downgraded to very low due to moderately serious risk of bias and very
serious imprecision (confidence interval lower limits crossing threshold for clinically useful
diagnostic tests, small sample sizes) in the DTA that used fecal bile acid levels as reference
standard.51 Similarly, there was very serious risk of bias and serious indirectness in the studies
that used SeHCAT retention as reference standard.
Discussion: 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
adequately validated as 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
14
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
Currently, there are no well-defined cut-off values for the diagnosis of BAD. In one
prospective study, C4 ≥52.5 ng/mL and FGF19 ≤61.7 pg/mL were diagnostic for BAD.51 Other
observational studies have used cut-offs of 30-48 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%
Key evidence: No direct comparative or DTA studies were found to inform this
statement. As described in statement 3, 2 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 HTA conducted by Riemsma et al.
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 cut-off retention
value 15%) varied depending on the scenario.41 The analysis provided very low CoE regarding
the optimal strategy.
Discussion: 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.
15
A poor response to a therapeutic trial of BAST could be related to non-compliance 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 (where 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, while 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.
Induction therapy for BAD
Statement 7: In patients with Type 1 or Type 3 BAD, we suggest the use of treatments for
remediable causes (eg, Crohn’s disease, microscopic colitis, SIBO) in addition to treatment for
BAD for induction of clinical response.
Key evidence: No RCTs or directly applicable cohort studies were identified in which
treatment for remediable causes was compared to BAST in patients with Type 1 or Type 3 BAD.
A cohort study (described in statement 4), included subgroups of patients with IBS-D (n=65,
n=40 treated) and unoperated Crohn’s disease in clinical remission (other than diarrhea, n= 24,
n=20 treated) who were diagnosed with BAD (SeHCAT retention <10%).28 The rates of
response to initial conventional treatment (prednisone ± 5-ASA for Crohn’s disease patients, or
anti-diarrheal agents for non-Crohn’s disease patients) were 55% among treated Crohn’s disease
patients, and 15% among treated IBS-D patients. Conventional therapy followed by BAST was
successful in 40% of treated Crohn’s disease patients and 70% of treated IBS-D patients.
This study lacked a control group and blinding, and had a subjective outcome measure.
No evidence was found for other conditions (eg, microscopic colitis, SIBO). The CoE was
downgraded to very low due to serious risk of bias, indirectness, and imprecision.
Discussion: Little data was available to define the role of other non-BAST treatments in
patients with BAST and comorbid conditions. Specific treatments for comorbid conditions that
16
may cause diarrhea (eg, Crohn’s, microscopic colitis, SIBO) may achieve control of diarrhea and
other symptoms, but conversely this may delay BAST for BAD. In addition, depending on the
condition, the treatment (eg, corticosteroids, immunosuppressive agents, biologics, or antibiotics)
may be associated with more risks or side effects than BAST treatment, and the investigations
may be more invasive and costly (eg, colonoscopy).
As mentioned in statement 4, patients with Crohn’s disease with continuing diarrhea have
a high rate of BAD. These patients were still more likely to benefit from conventional treatment,
although some did benefit from BAST.28
Some studies suggest that BAD and collagenous colitis are associated but are likely
independent diseases.57-59 In case series of collagenous colitis, BAST improved symptoms, but
had no effect on histopathology.57 In another case series, 86% of patients with microscopic
colitis who had BAD benefited from BAST, whereas no patients with collagenous colitis without
BAD improved.59 The etiology of microscopic colitis is not well defined, and may include
infectious agents, medications, or other causes in some patients, which may require other specific
treatments. Other treatments that may be beneficial include corticosteroids, antibiotics, anti-
diarrheal agents, or immunosuppressive therapies.59,60
In a large case series, 36% of patients with SIBO who were tested, had SeHCAT
retention <10%.26 These patients may benefit from BAST, but antibiotic therapy is the current
standard for SIBO.61 The etiology of SIBO is very complex and may involve disorders of
protective antibacterial mechanisms, anatomical abnormalities or motility disorders. Patients
with SIBO require treatment of the underlying disease, as well as nutritional support.62
Although there is little evidence to guide therapeutic decisions, in patients with comorbid
conditions, BAD may not be the sole cause of symptoms. Although some patients will respond to
BAST for BAD, others might not, or may have other symptoms in addition to diarrhea that will
not benefit from BAST. Therefore, the consensus group agreed that it was prudent to
individualize therapy and address other remedial causes of gastrointestinal symptoms, with the
order of therapy guided by severity of each condition.
17
Statement 8: In patients with BAD, we suggest using cholestyramine over no treatment for
induction of clinical response.
Statement 9: In patients with BAD, we suggest using cholestyramine over other BASTs as
initial therapy for induction of clinical response.
Key evidence: One RCT compared cholestyramine to hydroxypropyl cellulose (HPC).63

Although HPC was chosen as a placebo, it may be pharmacologically active, and a small case
series suggested it may be effective in BAD.63,64 The RCT was an 8 week study in 26 patients
with chronic functional watery diarrhea or IBS-D, of which 77% of the cholestyramine- and 54%
of HPC-treated patients had a SeHCAT retention rate ≤10%.63 There was no significant
difference in clinical remission rates (defined as <3 bowel movements /day over 1 week, with <1
watery stool/day) between treatments (53.8% vs. 38.4%; P = 0.43). However, there was a
significant improvement in the decrease in watery stools/day (-92.4±3.5% vs. -75.8±7.1%;
P=0.048). Since HPC binds bile acids and may have a bulking effect, it may have some efficacy
for BAD;63-66 this makes it difficult to interpret the lack of significant differences in clinical
remission rates with HPC compared to cholestyramine.
A SR of 23 cohort studies including 801 patients with BAD found that first-line
cholestyramine was successful in 69.8% of patients overall, 67% of those with SeHCAT
retention <5%, 73% of those with SeHCAT retention <8-11.7%, and 59% of those with SeHCAT
retention <15%.42 Study designs, patient populations, inclusion and exclusion criteria, diagnostic
tests and cut-off values for BAD, cholestyramine dosing and timing of administration, and
definitions of clinical response varied widely among the studies. An additional cohort study
published after the SR reported a response rate of 56% with first-line cholestyramine in 87
patients with BAD (defined as SeHCAT <15%).67
Although the RCT found that the rate of drug-related adverse events did not differ
between cholestyramine and hydroxypropyl cellulose,63 the SR of cohort studies reported that
11% of patients found cholestyramine intolerable due to unpalatability or side effects (range 0 to
46%).42 The most common side effects included abdominal bloating and pain, dyspepsia,
nausea/vomiting, flatulence, borborygmi, abdominal distension, constipation and increased
18
severity of diarrhea. In the additional cohort study, almost half (45%) of treatment failures were
related to medication intolerance.67 However, both studies had no control group for comparisons,
and relationships to study drug were not assessed.
RCTs assessing the efficacy of cholestyramine compared with other BAST in patients
with BAD were not found. Evidence for using cholestyramine over other BASTs as initial
therapy considered other factors such as adverse events, clinical experience, and cost. There is no
direct evidence that cholestyramine is associated with more side effects than other BAST.
However, a RCT of BAST for cardiovascular disease prevention reported higher rates of
gastrointestinal side effects (55% vs. 16%), and lower rates of compliance (53% vs. 77%) with
adjunctive cholestyramine compared to monotherapy with a statin.68 In contrast, a SR of 6 RCTs
in patients with diabetes found that adverse rates with adjunctive colesevelam were similar to
placebo (relative risk, 1.06; 95% CI, 0.97‒1.15), with the most common events with colesevelam
being GI-related (eg, constipation, dyspepsia, and nausea) and minor in nature.69 The majority of
clinical experience with BASTs in BAD has been with cholestyramine, with few data on the
other agents; in addition, colesevelam and colestipol tend to be more costly compared to
cholestyramine.
The overall CoE was very low. Very serious indirectness and serious imprecision were
found in the RCT,63 and serious risk of bias, indirectness, and imprecision in the cohort
studies.42,67
Discussion: Clear RCT evidence demonstrating the benefits of BAST was not available,
but, case series, and SRs of observational studies support a dramatic and rapid response for many
patients. Although no patient preference data was found, the high dropout rates in all of these
studies suggest that some patients may place a greater value on being free of the side effects or
unpalatability of cholestyramine compared to reduction in their diarrhea frequency or severity.
However, because BAST targets the problem, the potential higher response rates in patients with
more severe BAD (as measured by SeHCAT retention),6 and the lack of response in patients who
test negative for BAD29 (see statement 3), the consensus group suggested that patients with BAD
receive treatment with BAST over no treatment. This was a conditional recommendation because
of the very low CoE, and poor tolerability profile, making it important to discuss the benefits and
side effects with patients.
19
Although the consensus group suggested that cholestyramine be used initially over the
other BAST agents (colesevelam or colestipol), there are few comparative data. Compared with
cholestyramine, colesevelam has a 4–6 times stronger binding affinity to bile acids. It may be
better tolerated and have fewer clinical interactions.67 The majority of clinical experience to date
is with cholestyramine, with a limited number of cases using other BAST agents.29,33,38,70
Response rates with first-line use of other BAST have been reported at 67% with colesevelam,70
and 55% with colestipol.33 Although cholestyramine appears to be less costly than colesevelam
or colestipol, the lack of comparative data casts doubt on whether cholestyramine should be
preferred; therefore, this was a conditional recommendation.
Statement 10: In patients with BAD who are unable to tolerate cholestyramine, we suggest
using an alternate BAST for induction of clinical response.
GRADE: Conditional recommendation, low-certainty evidence. Vote on PICO question: strongly
yes, 40%; yes, 60%.
Key evidence: No RCT data were available comparing alternate BASTs to either placebo
or other treatments as 2nd-line therapy in patients with BAD who are unable to tolerate
cholestyramine. One RCT compared first-line colesevelam and placebo for BAD-associated
diarrhea in 26 patients with Crohn’s disease in remission.70 There was a statistically non-
significant improvement in the primary endpoint (proportion of patients with >30% reduction of
liquid stools/day) with colesevelam (66.7%) vs. placebo (27.3%) based on intention-to-treat
analysis (risk difference, 0.394; 95% CI, −0.012 to 0.706; p=0.0566). Colesevelam significantly
improved the secondary endpoints of reduction in number of liquid stools/day and improvement
in stool consistency compared to placebo. This trial did not assess colesevelam as 2nd-line
therapy, and had a very small sample size; therefore the CoE was downgraded to low for serious
indirectness and imprecision.
Additional evidence comes from a SR of 4 observational cohort studies (n=63) that
assessed the efficacy of 2nd-line colesevelam after failure of cholestyramine and reported a
success rate of 57% (range 42 to 100%).42 One other cohort study published after the SR
included 15 patients who had not responded to cholestyramine and had received 2nd-line
treatment with colesevelam.67 Of these patients, 47% had a successful response. The CoE from
the observational trials was downgraded to very low for serious risks of bias and imprecision.
20
There is no direct evidence that colesevelam is associated with a higher or lower

frequency of adverse effects than cholestyramine or other BASTs. In the RCT, colesevelam was
generally well tolerated; adverse events were mild (constipation, bloating, and nausea) and
occurred in similar proportions of colesevelam and placebo groups (40.0% vs. 36.4%).70 For
safety, the SR included 1 RCT and 4 observational cohort studies, and found that 9% were
unable to tolerate colesevelam due to unpalatability or side effects.42 In the additional
observational study, no patients reported treatment intolerance with colesevelam.67 As discussed
in statement 8, tolerability data for BASTs in non-GI conditions suggests high rates of
gastrointestinal side effects with cholestyramine, while colesevelam has side effects rates similar
to placebo.68,69
There have been limited reports describing the use of colestipol as 2nd-line therapy after
failure of cholestyramine.42,71
Discussion: Case series data have suggested that patients who fail or are unable to
tolerate cholestyramine may benefit from 2nd-line BAST.29 In a large series of patients given one
or more BAST, there were no significant differences in good/partial response rates between the
cholestyramine (74%) and colesevelam (73%). However, whether alternate BAST was used as
1st- or 2nd-line therapy was not described.29 Although, not regulatory approved for BAD, use of
2nd-line colesevelam in clinical practice appears to be quite common. In a survey of patients
followed for up to 13 years, 38% of respondents continued with cholestyramine, while 32% had
switched to colesevelam.56 The consensus group agreed that compared to cholestyramine,
colesevelam has a favourable benefit:risk profile and greater ease of administration (tablet vs.
granules/powder). However, because of the limited clinical experience, and higher cost,
suggested it be reserved for 2nd-line use.
Statement 11: In patients with BAD receiving empiric BAST, gradual daily dose titration
should be used to minimize side effects.
Designated a good practice statement
Key evidence: Good practice statement, CoE not assessed.
21
Discussion: In general, most cohort studies reported gradual dose titration for
cholestyramine to clinical response.42,67 There was, however, no mention of dose titration of
colesevelam or colestipol.
In BAD studies, cholestyramine was generally started at a low dose 2‒4 g/d and titrated
based on response (maximum 4‒24g/d).42,67 In an open-label study, the colestipol dose was
initiated at 1 g twice daily, with an increase of 1 g/day every other day.33 In BAD studies,
colesevelam has been prescribed in a dose of 2 tablets (625 mg) 3 times/day.70,72
Product labelling for BAST agents recommends that cholestyramine be started at one 4-g
dose daily and titrated to effect with a maximum of 24 g/day for all patients.73 Initiation of
colestipol granules (tablets) is recommended at 5 g (2 g) either once or twice daily, increasing by
5 g/day (2 g once or twice/day) but no more frequently than one/month, with a maximum of 30
g/day (16 g/day). No dose titration is recommended for colesevelam. Colesevelam is dosed at
3.75 g/day, as three 625-mg tablets twice daily, 6 tablets once daily, or one 3.75-g powder packet
once daily. These colestipol and colesevelam doses are regulatory approved for cholesterol-lowering
indications.
Generally, it is intuitive to gradually titrate medication to maximize symptom relief and
minimize side effects. This is particularly relevant with BAST due to the high frequency of side
effects and intolerance.42 Gradual dose titration of BAST may reduce the risks of side effects,
increase compliance, and potentially reduce costs.
Statement 12: In patients with Crohn’s disease with extensive ileal involvement or resection,
we suggest AGAINST using BAST.
GRADE: Conditional recommendation, very-low-certainty evidence. Vote on PICO question (In
patients with Crohn’s disease with extensive ileal involvement or resection, should we use BAST
vs. no BAST?): yes, 20%; no, 80%.
Key evidence: There are no long-term studies assessing the safety of cholestyramine in
patients with extensive ileal resection. It has been suggested that use of BAST in these patients
can lead to an increased rate of steatorrhea.74,75 A small series of 9 patients, in whom 3 had ileal
22
resection >100 cm and steatorrhea >20 g/day, found that the use of cholestyramine led to a small
decrease in diarrhea, but an increase in steatorrhea with substantial caloric loss.74,75
Discussion: The degree of resection that constitutes “extensive” and may carry an
increased risk of negative consequences with BAST, is unclear. In the case reports, the risk of
steatorrhea was increased in patients with resections of >100 cm.74,75
Other data have shown no correlation between the length of resection, SeHCAT
retention, and response to BAST. In case series of patients with ileal resection of up to 200 cm,
the majority had severe BAD and responded to BAST.26,76,77 In one case series, the mean length
of resection was not significantly different in those who did or did not respond to BAST (35 cm
vs. 46 cm).78
SeHCAT testing in patients with large ileal resection will almost universally indicate
severe bile acid wasting and is unlikely to be of discriminatory clinical value. Although there are
very few reports of adverse consequences of BAST use in patients with extensive resection, the
consensus group concluded that the risk of steatorrhea makes it prudent to err on the side of
caution and avoid BAST in this patient group. Furthermore, there is concern that these patients
may have extensive inflammatory disease that should be identified and treated with
antiinflammatory approaches rather than BAST. However, in some cases the benefits may
outweigh the risks, and patients should be evaluated on a case by case basis.
Maintenance therapy for BAD
Statement 13: In patients with BAD who respond to BAST, we suggest that intermittent, on-
demand dosing be tried.
Key evidence: No studies were found that directly compared different dosing strategies
in patients with BAD who had responded to BAST. Two small cohort studies suggested that for
some patients, BAD symptoms could remain controlled with on-demand therapy or no therapy at
all.7,8 In a prospective cohort study of patients with post-cholecystectomy BAD, cholestyramine
(2‒12 g/day for 1‒6 months) was effective in 23/26 patients, and 9/23 (39%) patients
experienced recurrent diarrhea when treatment was withdrawn. Bowel habit remained regular in
23
14 patients (61%) who took the drug occasionally (on demand) in the event of sporadic episodes
of slight diarrhea.8 In the other cohort study in patients with BAD and IBS-D, recurrent diarrhea
occurred in 33/35 (94%) of patients when cholestyramine (2‒8 mg/day for 1 month) was
withdrawn, and the drug was prescribed again at the dose that controlled the patient’s
symptoms.7 Only 6% of patients were able to discontinue therapy without suffering recurrent
diarrhea.
Discussion: Evidence suggests that some patients with BAD will require regular daily
dosing, whereas others may be able to discontinue completely or use on-demand therapy for
symptom control. The dose or frequency of BAST required to control symptoms may be
dependent on severity of symptoms, underlying causes of BAD, or the presence of other
comorbid illnesses (eg, gastroenteritis, Clostridium difficile infection). The need for BAST may
also be affected by use of medications that cause constipation, which may reduce the need for
BAST, or by medications that cause diarrhea, which may increase the need for BAST.
Long term use of BAST should balance the potentially high rate of relapse of diarrhea
against the high rate of adverse events, poor palatability, and uncertainty around long-term harms
(eg, malabsorption of fat and vitamins). Therefore, the consensus group suggested that during
ongoing long-term therapy, intermittent, on-demand therapy should be attempted in order to
minimize exposure to BAST, encourage compliance, and minimize costs.
Statement 14: In patients with BAD who are unable to tolerate BAST, we suggest using
alternative anti-diarrheal agents vs. no treatment for long-term symptomatic therapy.
yes, 100%
Key evidence: No studies were found that systematically assessed the effectiveness of
other anti-diarrheal agents in patients with BAD who are unable to tolerate BAST. As described
in statement 8, 1 RCT that compared cholestyramine to HPC found no difference in clinical
remission (53.8% vs. 38.4%) or adverse events.63
Three cohort studies assessed first-line loperamide in patients with BAD; however, the
effectiveness was difficult to estimate due to differences in patient populations, study designs,
and outcome measurements (mainly subjective improvement of symptoms).28,79,80 A randomized
double blind cross-over RCT in 18 patients with chronic diarrhea due to chronic radiation
24
enteritis compared loperamide (3 mg bid) and placebo for 14 days.79 The study did not include
dichotomized response rates, but did report significant improvements in stool frequency, stool
weight, and SeHCAT retention with loperamide as compared to placebo. In a prospective cohort
study of 19 patients with chronic diarrhea due to ileal irradiation and/or resection, 13 patients
with resection 20‒50 cm (n=7) or no resection (n=6), showed normalized or improved SeHCAT
retention, with symptomatic improvement while on loperamide.80 In 6 patients with resection >
80 cm, SeHCAT retention remained abnormal, and only 3 patients had “slight improvement” of
diarrhea with loperamide. In another cohort study, 27/96 (28%) of patients reported improvement
with conventional anti-diarrheal agents; however, this included codeine, loperamide, or
prednisolone (not considered an anti-diarrheal agent), and did not specify response to individual
medications.28
Discussion: Given the poor tolerability and high discontinuation rates with BAST,
alternative treatments are often needed. HPC may improve diarrhea in patients with BAD
through its bulking effects and its ability to bind bile acids.63-66 In addition, some patients may
benefit from loperamide; given its low cost and relatively good safety profile (although no cost-
effectiveness data are available), a treatment trial may be warranted.
Statement 15: In patients with BAD receiving empiric BAST, maintenance therapy should be
used at the lowest dose needed to minimize symptoms.

Discussion: The importance of minimizing exposure to BAST was discussed under
statement 11 (dose titration during induction), and statement 13 (use of intermittent or
discontinuing dosing during maintenance therapy).
Cohort studies have reported the use of cholestyramine for 6 to 44 months, which was
titrated to response.42 In one study, patients were allowed to titrate their own dose of
cholestyramine (between 2 to 16 g/day) and sustained responses for over 1 year.81 Colesevelam
has been used for up to 44 months with some patients titrating the dose down.72
25
Statement 16: In patients with BAD and recurrent or worsening symptoms despite stable
BAST, diagnostic re-evaluation should be conducted.

Discussion: Other diagnoses are common in patients with BAD, and a diagnosis of BAD
is frequently seen in patients with other conditions (see statement 1). As discussed in statement
7, some patients may need specific treatments for other causes of chronic diarrhea.
BAD can have a variable course, and fat intake can cause fluctuations in SeHCAT
retention, and severity of BAD. Low-fat dietary interventions can improve gastrointestinal
symptoms for some patients.82 However, sudden worsening of symptoms, not related to dietary
changes, should prompt re-evaluation. The differential diagnosis should consider conditions such
as microscopic colitis, Crohn’s disease, celiac disease, SIBO, and functional bowel disease.
Strategies in patients with worsening symptoms might include repeating SeHCAT testing with an
escalation of therapy if needed, as well as other tests, such as stool tests for infectious etiologies,
blood tests, colonoscopy, hydrogen breath tests as determined by the underlying cause of BAD,
and the patient’s history, risk factors, and symptoms.
Statement 17: In patients being considered for BAST, a review of concurrent medications
should be conducted to minimize the potential for drug interactions.

Discussion: BAST agents may bind other drugs given concurrently, which necessitates
separating administration to minimize the risk of reduced absorption of the concomitant
medication. Health Canada recommends that when a drug interaction cannot be excluded,
patients should take other drugs at least 1 hour before or 4-6 hours after the BAST.73,83,84 Gastric
emptying studies suggest that a window of 3 hours between administration of BAST and other
medications is adequate to avoid potential interactions such as binding.85
Examples of some medications that may interact when coadministered with
cholestyramine or colestipol include thyroid preparations, warfarin, hydrochlorothiazide,
furosemide, phenylbutazone, phenobarbital, tetracycline, penicillin G, digoxin, mycophenolic
26
acid, and estrogen-containing drugs.3,73,84 Colesevelam has a different structure, which

maximizes interactions with bile salt and reduces the potential for interactions with other
drugs.86,87 Colesevelam does not appear to interact with some medications (eg. digoxin,
fenofibrate, lovastatin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid,
verapamil), but has been found to reduce the absorption of others (eg, glyburide, levothyroxine,
and oral contraceptives), and may interact with warfarin and phenytoin.83
No recommendation B: In patients receiving long-term maintenance therapy with BAST, the

consensus group could not make a recommendation for or against measuring fat-soluble vitamin
levels at baseline and annually thereafter.
GRADE: NO recommendation; very-low-certainty evidence. Vote on PICO question: yes, 20%;
neutral, 80%
Key evidence: The literature search failed to identify any relevant article assessing fat-
soluble vitamin levels before and after initiation of long-term maintenance therapy with BAST.
Due to the action of BAST agents in sequestering bile acids, these agents may theoretically
interfere with normal fat absorption, thus reducing absorption of folic acid and fat-soluble
vitamins A, D and K.73,83,84 Whether this interference can result in clinical consequences is based
on rare case reports. Since 1970, there have been only a few reports of hypoprothrombinemia or
hemorrhage in adults,88,89 and of hypoprothrombinemia, hemorrhage, or folate deficiency in
pediatric patients90-92 taking cholestyramine.
Discussion: Cholestyramine has been associated with reduced vitamin and folate levels
during long term use.73 However, colestipol use for 1‒2 years had no effect on vitamin A or folic
acid levels, and only a small effect on vitamin D levels.84 Colesevelam was not associated with
significant reductions in the absorption of vitamins A, D, E or K during clinical studies of up to 1
year.83 In general, the approved product labels recommend supplementation of vitamins A, D and
K only if a deficiency occurs.73,83,84
The rare cases of vitamin K deficiency resulting in increased risk of coagulopathy have
occurred within a few weeks to months or years after the start of therapy,89 and generally can be
corrected with oral vitamin K. Although, during long-term use periodic monitoring of vitamin
levels and prothrombin time are sometimes advised,3,93 the group did not reach consensus on the
value of annual routine monitoring. Most of the consensus participants were neutral on this issue,
27
although it was suggested that performing an international normalized ratio (INR) at intervals
during long-term treatment may be prudent.
28
Future directions
The group recognised that specific, high-certainty evidence was lacking in many areas
and recommended further studies that would improve the data available in future methodological
evaluations.
In DTA studies, the diagnostic accuracy of an index test (a test under evaluation) is
determined by comparing its results with that of a reference standard (best available method to
determine the presence or absence of a target condition), by applying both in individuals who are
suspected of having the target condition of interest. Yet, if the reference standard does not
perfectly correspond to a true target condition, estimates of the accuracy of the index test can be
biased. The main challenge in conducting DTA studies for BAD is the lack of a widely accepted
or universally agreed-upon reference standard as the condition is defined and classified based on
pathophysiologic mechanisms and its response to treatment (BAST). Also, the index tests
(SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic
function. Hence, DTA studies are not the most appropriate study design.41 In studies where all
patients are tested with the index tests and all patients are treated with BAST, response to
treatment can provide an imperfect, but the best available reference standard. This is because
patients responding to BAST may be true positive patients with a true response, but may also be
false positive patients with a “placebo” response. To date, only two small DTA studies reported
information on the probability of response to treatment with BAST for people with a negative
SeHCAT test, and no DTA studies have incorporated a blinded placebo arm.37,40 Consequently,
the lack of evidence of the accuracy of SeHACT test based on a reference standard and the
variation in cut-off values of test results led to important uncertainties in the cost-effectiveness
analyses in determining the optimal strategy in investigating BAD.41 Therefore, one of the
research priorities in BAD is for the scientific and clinical communities to agree upon a reference
standard that best represents BAD (e.g. response to BAST), with full understanding that the
reference standard is and will likely be imperfect.
Given the paucity of high certainty evidence on diagnostic tests, there is also a need for
well-designed DTA studies comparing SeHCAT, C4 assay, FGF19, total and primary bile acid
measurement in stool, with a reference standard for BAD (eg, response to BAST) by applying
both the index tests and reference standard to all patients, 94,95 as well as RCTs comparing
29
SeHCAT testing vs empiric trial of BAST in patients with suspected BAD including assessment
of objective clinical efficacy and safety outcome measures. A placebo-controlled RCT of BAST
(colesevelam) in patients with evidence of BAD, based on fecal bile acid measurements, is
ongoing (NCT03270085) and its results will help to inform the role of fecal bile acids as a
diagnostic test for BAD.96
It is important to note that the diagnostic accuracy of total and primary bile acid excretion
has not been formally assessed by GRADE for this guideline, because it was not a topic initially
proposed for inclusion a priori. Nevertheless, there have been recent publications on assessing
48-hour total and primary bile acid fecal excretion (a test available in North America) as a
diagnostic test for BAD. 95 Recent advances also assessed whether this test could be optimized
by including assays of primary bile acids.95 Most (if not all) are observational studies that have
found significant correlation or association between elevated fecal bile acids and certain
conditions that can cause diarrhea (i.e. IBS-D, chronic functional diarrhea).95,97-99 While
observational studies can provide evidence of significant association or correlation between
predictor and outcome variables, they cannot prove causality because there are always residual
confounding variables (unmeasured or imprecisely measured) that may have affected the results.
Spurious associations can also arise with reverse causality. Future prospective studies are
required to validate the diagnostic accuracy for BAD of primary bile acids at various cut-off
concentrations in a single stool sample against a reference standard (ie, the ability of this test to
accurately predict response to BAST).
RCTs are needed to compare cholestyramine to other BAST for the treatment of BAD. In
addition, evidence is needed to guide dosing schedules. This includes assessment of whether
there is any advantage to morning vs. evening dosing and once-daily vs. divided doses of BAST
to maximize benefits and minimize interactions with other medications. Theoretically, there may
be some efficacy benefits to targeting dosing to times of maximum gallbladder emptying, such as
postprandially or in the morning, but more research is needed. In hypercholesterolemia there
were no significant variations in the hypocholesterolemic effects when cholestyramine was timed
with meals to optimize exposure to bile in the duodenum that followed gallbladder emptying.100
However, the relevant mechanisms in BAD may be different, particularly as the therapeutic aim
is to reduce the effects of free, secretory bile acid in the colon.
30
In conclusion, current evidence suggests that the accuracy of diagnostic tests (e.g.
SeHCAT, C4) in predicting BAD or response to treatment are highly uncertain. Economic
evaluation suggests that strategies of either empiric trial of BAST or performing SeHCAT testing
may be cost-effective depending on the scenarios and the society’s willingness-to-pay.
Therefore, either strategy may be used to identify patients with possible BAD depending on cost,
available resources, local expertise, and patient preferences.
31
ACKNOWLEDGEMENTS
The CAG would like to thank Pendopharm and GE Healthcare Canada, for their generous
support of the guideline process. The consensus group would like to thank the following people
for their contributions: Paul Sinclair, Cindy Roll, and Adria Cehovin (CAG representatives:
administrative and technical support, and logistical assistance), Pauline Lavigne and Steven
Portelance (unaffiliated, editorial assistance).
Canadian Association of Gastroenterology Statement

This clinical practice guideline (CPG) on the management of BAD was developed under
the direction of Dr. Dan Sadowski, in accordance with the policies and procedures of the
Canadian Association of Gastroenterology (CAG) and under the direction of CAG Clinical
Affairs. It has been reviewed by the CAG Practice Affairs and Clinical Affairs Committees and
the CAG Board of Directors. The CPG was developed following a thorough consideration of
medical literature and the best available evidence and clinical experience. It represents the
consensus of a Canadian, US, and UK panel comprised of experts on this topic. The CPG aims to
provide a reasonable and practical approach to care for specialists and allied health professionals
are charged with the duty of providing optimal care to patients and families, and can be subject
to change as scientific knowledge and technology advance and as practice patterns evolve. The
CPG is not intended to be a substitute for physicians using their individual judgment in
managing clinical care in consultation with the patient, with appropriate regard to all the
individual circumstances of the patient, diagnostic and treatment options available, and available
resources. Adherence to these recommendations will not necessarily produce successful
outcomes in every case.
32
TABLES
Table 1: Summary of consensus recommendations for the management of BAD*

Diagnosis of BAD
Statement 1: In patients with chronic non-bloody diarrhea, we recommend using risk factors (history of terminal
ileal resection, cholecystectomy, or 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 non-bloody 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%.
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%.
Statement 4: In patients with small intestinal Crohn's disease without objective evidence of inflammation who have
persistent diarrhea, we suggest SeHCAT testing.
yes, 80%.
Statement 5: In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest using a C4 assay
to identify possible BAD.
yes, 60%; neutral, 20%
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: yes, 20%; no, 40%;
strongly no, 40%
Induction therapy for BAD (BAST)
Statement 7: In patients with Type 1 or Type 3 BAD, we suggest the use of treatments for remediable causes (eg,
Crohn’s disease, microscopic colitis, SIBO) in addition to treatment for BAD for induction of clinical response.
yes, 20%.
Statement 8: In patients with BAD, we suggest using cholestyramine over no treatment for induction of clinical
response.
yes, 40%.
Statement 9: In patients with BAD, we suggest using cholestyramine over other BASTs as initial therapy for
induction of clinical response.
GRADE: Conditional recommendation, very low-certainty evidence. Vote on PICO question: yes, 80%; neutral,
20%.
Statement 10: In patients with BAD who are unable to tolerate cholestyramine, we suggest using an alternate BAST
for induction of clinical response.
GRADE: Conditional recommendation, low-certainty evidence. Vote on PICO question: strongly yes, 40%; yes,
60%.
Statement 11: In patients with BAD receiving empiric BAST, gradual daily dose titration should be used to
minimize side effects.
Statement 12: In patients with Crohn’s disease with extensive ileal involvement or resection, we suggest AGAINST
using BAST.
GRADE: Conditional recommendation, very low-certainty evidence. Vote on PICO question (Should we use
BAST?): yes, 20%; no, 80%.
33
Maintenance therapy for BAD (BAST)

Statement 13: In patients with BAD who respond to BAST, we suggest that intermittent, on-demand dosing be tried.
GRADE: Conditional recommendation, very low-certainty evidence. Vote on PICO question: yes, 80%; neutral,
20%.
Statement 14: In patients with BAD who are unable to tolerate BAST, we suggest using alternative anti-diarrheal
agents vs. no treatment for long-term symptomatic therapy.
GRADE: Conditional recommendation, very low-certainty evidence. Vote on PICO question: yes, 100%.
Statement 15: In patients with BAD receiving empiric BAST, maintenance therapy should be used at the lowest
dose needed to minimize symptoms.
Statement 16: In patients with BAD and recurrent or worsening symptoms despite stable BAST, diagnostic re-
evaluation should be conducted.
Statement 17: In patients being considered for BAST, a review of concurrent medications should be conducted to
minimize the potential for drug interactions.
Statements with no recommendations
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 FGF19 assay to identify possible BAD.
GRADE: NO recommendation, very low certainty evidence; Vote on PICO question: strongly yes, 20%; neutral,
80%.
No recommendation B: In patients receiving long-term maintenance therapy with BAST, the consensus group could
not make a recommendation for or against measuring fat-soluble vitamin levels at baseline and annually thereafter.
GRADE: NO recommendation; very low-certainty evidence. Vote on PICO question: yes, 20%; neutral, 80%.
*The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong
(“we recommend...”) or conditional (“we suggest...”). A recommendation could be classified as strong despite low-
certainty evidence to support it, or conditional despite the existence of high certainty evidence due to the 4
components considered in each recommendation (risk:benefit balance, patients’ values and preferences, cost and
resource allocation, and certainty of evidence).
34
Table 2: Risk factors in patients with chronic non-bloody diarrhea most commonly associated
with having a positive SeHCAT test suggestive of a BAD diagnosis
Risk Factor SeHCAT <10% SeHCAT <15%
(at least moderate) (at least mild)
Cholecystectomy 78%26 86% (CI, 71%–95%)26
68% - OR 5.70 (95% CI, 2.42–13.46)25 68% - OR 2.51 (99% CI, 1.10–5.77)24
21%24 57% - OR 2.54 (95% CI, 1.36–4.74)29
TI resection or right 100%44 92% - OR 12.4 (99% CI, 2.42–63.8)24
hemicolectomy for 97%28 91% (95% CI, 78%–87%)26
Crohn’s disease 91% - OR 15.83 (95% CI, 2.62–95.69)25 87% - OR 5.0 (95% CI, 2.20–11.4)29
87%24
TI resection or right 76%24 82% - OR 7.94 (99% CI, 1.02– 61.6)24
hemicolectomy for 71%29
reasons other than
Crohn’s disease
Radiotherapy without 18%30 62%27
resection 36%30
Radiotherapy with 71%30 88%30
resection
CI, confidence interval; OR, odds ratio; TI, terminal ileum.
35
Table 3: Prevalence of positive SeHCAT tests in patients with ileal Crohn’s disease who have
not undergone resection
SeHCAT Prevalence
<10% 80% - OR 3.76 (95% CI, 1.10–12.60)25
(at least moderate) 54%28
52%26
43%29
35%24
<15% 76% (95% CI, 57%–90%)26
(at least mild) 52% - OR 1.88 (95% CI, 1.04‒3.41)29
35%24
CI, confidence interval; OR, odds ratio.
36
FIGURE LEGEND
Figure 1: 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 acids; C4, 7 α-hydroxy-4-cholesten-3-one; CDCA, chenodeoxycholic acid; CA, cholic acid; FGF19,
fibroblast growth factor 19; LCA, lithocholic acid. Reprinted from Gastroenterology, Vol 156, Vijayvargiya P,
Camilleri M. Current practice in the diagnosis of bile acid diarrhea, Pages 1233-1238, ©2019, with permission from
Elsevier.53
37
REFERENCES
1. Scallan E, Majowicz SE, Hall G, et al. Prevalence of diarrhoea in the community in
Australia, Canada, Ireland, and the United States. Int J Epidemiol 2005;34:454-60.
2. Fine KD, Schiller LR. AGA technical review on the evaluation and management of
chronic diarrhea. Gastroenterology 1999;116:1464-86.
3. Barkun AN, Love J, Gould M, et al. Bile acid malabsorption in chronic diarrhea:
pathophysiology and treatment. Can J Gastroenterol 2013;27:653-9.
4. Schiller LR, Pardi DS, Sellin JH. Chronic diarrhea: diagnosis and management. Clin
Gastroenterol Hepatol 2017;15:182-193 e3.
5. Mottacki N, Simren M, Bajor A. Review article: bile acid diarrhoea - pathogenesis,
diagnosis and management. Aliment Pharmacol Ther 2016;43:884-898.
6. Wedlake L, A'Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic
bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-
predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30:707-17.
7. Galatola G, Ferraris R, Pellerito R, et al. The prevalence of bile acid malabsorption in
irritable bowel syndrome and the effect of cholestyramine: An uncontrolled open
multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7.
8. Sciarretta G, Furno A, Mazzoni M, et al. Post-cholecystectomy diarrhea: evidence of bile
acid malabsorption assessed by SeHCAT test. Am J Gastroenterol 1992;87:1852-4.
9. American Gastroenterological Association medical position statement: guidelines for the
evaluation and management of chronic diarrhea. Gastroenterology 1999;116:1461-3.
10. Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic
diarrhoea, 2nd edition. Gut 2003;52 Suppl 5:v1-15.
11. Arasaradnam RP, Brown S, Forbes A, et al. Guidelines for the investigation of chronic
diarrhoea in adults: British Society of Gastroenterology, 3rd edition. Gut 2018;67:1380-
1399.
12. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ 2008;336:924-6.
13. Sultan S, Falck-Ytter Y, Inadomi JM. The AGA institute process for developing clinical
practice guidelines part one: grading the evidence. Clin Gastroenterol Hepatol
2013;11:329-32.
14. Enns RA, Hookey L, Armstrong D, et al. Clinical practice guidelines for the use of video
capsule endoscopy. Gastroenterology 2017;152:497-514.
15. Nguyen GC, Seow CH, Maxwell C, et al. The Toronto consensus statements for the
management of inflammatory bowel disease in pregnancy. Gastroenterology
2016;150:734-757 e1.
16. Fallone CA, Chiba N, van Zanten SV, et al. The Toronto consensus for the treatment of
Helicobacter pylori infection in adults. Gastroenterology 2016;151:51-69 e14.
38
17. Bressler B, Marshall JK, Bernstein CN, et al. Clinical practice guidelines for the medical
management of nonhospitalized ulcerative colitis: the Toronto consensus.
Gastroenterology 2015;148:1035-1058 e3.
18. Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention,
and treatment of venous thromboembolism in inflammatory bowel disease: Canadian
Association of Gastroenterology. Gastroenterology 2014;146:835-848 e6.
19. Guyatt GH, Schunemann HJ, Djulbegovic B, et al. Guideline panels should not GRADE
good practice statements. J Clin Epidemiol 2015;68:597-600.
20. Dalkey N. An experimental study of group opinion: the Delphi method. Futures
1969;1:408-426.
21. Cook DJ, Greengold NL, Ellrodt AG, et al. The relation between systematic reviews and
practice guidelines. Ann Intern Med 1997;127:210-6.
22. Alonso-Coello P, Schunemann HJ, Moberg J, et al. GRADE Evidence to Decision (EtD)
frameworks: a systematic and transparent approach to making well informed healthcare
choices. 1: Introduction. BMJ 2016;353:i2016.
23. Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to recommendations. BMJ
2008;336:1049-51.
24. Gracie DJ, Kane JS, Mumtaz S, et al. Prevalence of, and predictors of, bile acid
malabsorption in outpatients with chronic diarrhea. Neurogastroenterol Motil
2012;24:983-e538.
25. Kurien M, Evans KE, Leeds JS, et al. Bile acid malabsorption: an under-investigated
differential diagnosis in patients presenting with diarrhea predominant irritable bowel
syndrome type symptoms. Scand J Gastroenterol 2011;46:818-22.
26. Borghede MK, Schlutter JM, Agnholt JS, et al. Bile acid malabsorption investigated by
selenium-75-homocholic acid taurine ((75)SeHCAT) scans: causes and treatment
responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern
Med 2011;22:e137-40.
27. Ludgate SM, Merrick MV. The pathogenesis of post-irradiation chronic diarrhoea:
measurement of SeHCAT and B12 absorption for differential diagnosis determines
treatment. Clin Radiol 1985;36:275-8.
28. Smith MJ, Cherian P, Raju GS, et al. Bile acid malabsorption in persistent diarrhoea. J R
Coll Physicians Lond 2000;34:448-51.
29. Murray IA, Murray LK, Woolson KL, et al. Incidence and predictive factors for positive
(75)SeHCAT test: improving the diagnosis of bile acid diarrhoea. Scand J Gastroenterol
2017;52:698-703.
30. Valdes Olmos R, den Hartog Jager F, Hoefnagel C, et al. Imaging and retention
measurements of selenium 75 homocholic acid conjugated with taurine, and the carbon
14 glycochol breath test to document ileal dysfunction due to late radiation damage. Eur J
Nucl Med 1991;18:124-8.
39
31. Ung KA, Kilander AF, Lindgren A, et al. Impact of bile acid malabsorption on
steatorrhoea and symptoms in patients with chronic diarrhoea. Eur J Gastroenterol
Hepatol 2000;12:541-7.
32. Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 in patients with bile
acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.
Aliment Pharmacol Ther 2013;38:967-76.
33. Bajor A, Tornblom H, Rudling M, et al. Increased colonic bile acid exposure: a relevant
factor for symptoms and treatment in IBS. Gut 2015;64:84-92.
34. Stotzer PO, Abrahamsson H, Bajor A, et al. Are the definitions for chronic diarrhoea
adequate? Evaluation of two different definitions in patients with chronic diarrhoea.
United European Gastroenterol J 2015;3:381-6.
35. Williams AJ, Merrick MV, Eastwood MA. Idiopathic bile acid malabsorption--a review
of clinical presentation, diagnosis, and response to treatment. Gut 1991;32:1004-6.
36. Aziz I, Mumtaz S, Bholah H, et al. High prevalence of idiopathic bile acid diarrhea
among patients with diarrhea-predominant irritable bowel syndrome based on Rome III
criteria. Clin Gastroenterol Hepatol 2015;13:1650-5 e2.
37. Sciarretta G, Vicini G, Fagioli G, et al. Use of 23-selena-25-homocholyltaurine to detect
bile acid malabsorption in patients with illeal dysfunction or diarrhea. Gastroenterology
1986;91:1-9.
38. Lin S, Sanders DS, Gleeson JT, et al. Long-term outcomes in patients diagnosed with
bile-acid diarrhoea. Eur J Gastroenterol Hepatol 2016;28:240-5.
39. Bannaga A, Kelman L, O'Connor M, et al. How bad is bile acid diarrhoea: an online
survey of patient-reported symptoms and outcomes. BMJ Open Gastroenterol
2017;4:e000116.
40. Sciarretta G, Fagioli G, Furno A, et al. 75Se HCAT test in the detection of bile acid
malabsorption in functional diarrhoea and its correlation with small bowel transit. Gut
1987;28:970-5.
41. Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for
the investigation of bile acid malabsorption and measurement of bile acid pool loss: a
systematic review and cost-effectiveness analysis. Health Technol Assess 2013;17:1-236.
42. Wilcox C, Turner J, Green J. Systematic review: the management of chronic diarrhoea
due to bile acid malabsorption. Aliment Pharmacol Ther 2014;39:923-39.
43. Reid F, Peacock J, Coker B, et al. A multicenter prospective study to investigate the
diagnostic accuracy of the SeHCAT test in measuring bile acid malabsorption: research
protocol. JMIR Res Protoc 2016;5:e13.
44. Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption in Crohn's disease and
indications for its assessment using SeHCAT. Gut 1994;35:90-3.
45. Summers JA, Peacock J, Coker B, et al. Multicentre prospective survey of SeHCAT
provision and practice in the UK. BMJ Open Gastroenterol 2016;3:e000091.
40
46. Sauter GH, Munzing W, von Ritter C, et al. Bile acid malabsorption as a cause of chronic
diarrhea: diagnostic value of 7alpha-hydroxy-4-cholesten-3-one in serum. Dig Dis Sci
1999;44:14-9.
47. Farkkila MA, Kairemo KJ, Taavitsainen MJ, et al. Plasma lathosterol as a screening test
for bile acid malabsorption due to ileal resection: correlation with 75SeHCAT test and
faecal bile acid excretion. Clin Sci (Lond) 1996;90:315-9.
48. Brydon WG, Nyhlin H, Eastwood MA, et al. Serum 7 alpha-hydroxy-4-cholesten-3-one
and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile
acid induced diarrhoea. Eur J Gastroenterol Hepatol 1996;8:117-23.
49. Johnston IM, Nolan JD, Pattni SS, et al. Characterizing factors associated with
differences in FGF19 blood levels and synthesis in patients with primary bile acid
diarrhea. Am J Gastroenterol 2016;111:423-32.
50. Borup C, Syversen C, Bouchelouche P, et al. Diagnosis of bile acid diarrhoea by fasting
and postprandial measurements of fibroblast growth factor 19. Eur J Gastroenterol
Hepatol 2015;27:1399-402.
51. Vijayvargiya P, Camilleri M, Carlson P, et al. Performance characteristics of serum C4
and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-
diarrhoea and functional diarrhoea. Aliment Pharmacol Ther 2017;46:581-588.
52. Camilleri M. Physiological underpinnings of irritable bowel syndrome: neurohormonal
mechanisms. J Physiol 2014;592:2967-80.
53. Vijayvargiya P, Camilleri M. Current practice in the diagnosis of bile acid diarrhea.
Gastroenterology 2019;156:1233-1238.
54. Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 and 7alpha-hydroxy-4-
cholesten-3-one in the diagnosis of patients with possible bile acid diarrhea. Clin Transl
Gastroenterol 2012;3:e18.
55. Brydon WG, Culbert P, Kingstone K, et al. An evaluation of the use of serum 7-alpha-
hydroxycholestenone as a diagnostic test of bile acid malabsorption causing watery
diarrhea. Can J Gastroenterol 2011;25:319-23.
56. Damsgaard B, Dalby HR, Krogh K, et al. Long-term effect of medical treatment of
diarrhoea in 377 patients with SeHCAT scan diagnosed bile acid malabsorption from
2003 to 2016; a retrospective study. Aliment Pharmacol Ther 2018;47:951-957.
57. Ung KA, Kilander A, Nilsson O, et al. Long-term course in collagenous colitis and the
impact of bile acid malabsorption and bile acid sequestrants on histopathology and
clinical features. Scand J Gastroenterol 2001;36:601-9.
58. Pardi DS. Diagnosis and management of microscopic colitis. Am J Gastroenterol
2017;112:78-85.
59. Fernandez-Banares F, Esteve M, Salas A, et al. Bile acid malabsorption in microscopic
colitis and in previously unexplained functional chronic diarrhea. Dig Dis Sci
2001;46:2231-8.
41
60. Baert D, Coppens M, Burvenich P, et al. Chronic diarrhoea in non collagenous

microscopic colitis: therapeutic effect of cholestyramine. Acta Clin Belg 2004;59:258-62.
61. Fan X, Sellin JH. Review article: Small intestinal bacterial overgrowth, bile acid
malabsorption and gluten intolerance as possible causes of chronic watery diarrhoea.
62. Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome.
World J Gastroenterol 2010;16:2978-90.
63. Fernandez-Banares F, Rosinach M, Piqueras M, et al. Randomised clinical trial:
colestyramine vs. hydroxypropyl cellulose in patients with functional chronic watery
diarrhoea. Aliment Pharmacol Ther 2015;41:1132-40.
64. Brydon WG, Walters JRF, Ghosh S, et al. Hydroxypropyl cellulose as therapy for chronic
diarrhoea in patients with bile acid malabsorption – possible mechanisms [Letter].
65. Torcello-Gómez A, Fraguas CF, Ridout MJ, et al. Effect of substituent pattern and
molecular weight of cellulose ethers on interactions with different bile salts. Food Funct
2015;6:730-739.
66. Tsuchida E, Yamamoto K, Miyatake K, et al. Molecular assembly of cholesterol-bearing
poly (allylamine) for binding bile salts in water. Macromolecules 1997;30:4235-4237.
67. Orekoya O, McLaughlin J, Leitao E, et al. Quantifying bile acid malabsorption helps
predict response and tailor sequestrant therapy. Clin Med (Lond) 2015;15:252-7.
68. Eriksson M, Hadell K, Holme I, et al. Compliance with and efficacy of treatment with
pravastatin and cholestyramine: a randomized study on lipid-lowering in primary care. J
Intern Med 1998;243:373-80.
69. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus. Cochrane Database Syst Rev
2012;12:CD009361.
70. Beigel F, Teich N, Howaldt S, et al. Colesevelam for the treatment of bile acid
malabsorption-associated diarrhea in patients with Crohn's disease: a randomized,
double-blind, placebo-controlled study. J Crohns Colitis 2014;8:1471-9.
71. Ung KA, Gillberg R, Kilander A, et al. Role of bile acids and bile acid binding agents in
patients with collagenous colitis. Gut 2000;46:170-5.
72. Wedlake L, Thomas K, Lalji A, et al. Effectiveness and tolerability of colesevelam
hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective chart
review and patient questionnaire. Clin Ther 2009;31:2549-58.
73. Olestyr (cholestyramine) Product Monograph. Pharmascience Inc., February 16, 2017.
74. Hofmann AF, Poley JR. Role of bile acid malabsorption in pathogenesis of diarrhea and
steatorrhea in patients with ileal resection. I. Response to cholestyramine or replacement
of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology
1972;62:918-34.
42
75. Poley JR, Hofmann AF. Role of fat maldigestion in pathogenesis of steatorrhea in ileal
resection. Fat digestion after two sequential test meals with and without cholestyramine.
Gastroenterology 1976;71:38-44.
76. Williams CN, Dickson RC. Cholestyramine and medium-chain triglyceride in prolonged
management of patients subjected to ileal resection or bypass. Can Med Assoc J
1972;107:626-31.
77. Ford GA, Preece JD, Davies IH, et al. Use of the SeHCAT test in the investigation of
diarrhoea. Postgrad Med J 1992;68:272-6.
78. Worobetz L, Wilkinson A, Chmielowiec C, et al. Evaluation of SeHCAT test in
determining ileal involvement and dysfunction in Crohn’s disease. Can J Gastroenterol
1993;7:597-601.
79. Yeoh EK, Horowitz M, Russo A, et al. Gastrointestinal function in chronic radiation
enteritis--effects of loperamide-N-oxide. Gut 1993;34:476-82.
80. Valdés Olmos RA, Taal BG, Hoefnagel CA, et al. 75SeHCAT in the assessment of
improved bile acid absorption in patients with ileal damage by delaying bowel motility
with loperamide. Eur J Gastroenterol Hepatol 1993;5:941-946.
81. Menon S, Jones BJ. Postinfective bile acid malabsorption: is this a long-term condition?
Eur J Gastroenterol Hepatol 2011;23:308-10.
82. Watson L, Lalji A, Bodla S, et al. Management of bile acid malabsorption using low-fat
dietary interventions: a useful strategy applicable to some patients with diarrhoea-
predominant irritable bowel syndrome? Clin Med (Lond) 2015;15:536-40.
83. Lodalis (colesevelam) Product Monograph. Valeant Canada LP, October 16, 2014.
84. Colestid (colestipol) Product Monograph. Pfizer Canada Inc., October 7, 2013.
85. Camilleri M. Drug-resin drug interactions in patients with delayed gastric emptying:
What is optimal time window for drug administration? Neurogastroenterol Motil
2016;28:1268-71.
86. Scaldaferri F, Pizzoferrato M, Ponziani FR, et al. Use and indications of cholestyramine
and bile acid sequestrants. Intern Emerg Med 2013;8:205-10.
87. Steinmetz KL, Schonder KS. Colesevelam: potential uses for the newest bile resin.
Cardiovasc Drug Rev 2005;23:15-30.
88. Gross L, Brotman M. Hypoprothrombinemia and hemorrhage associated with
cholestyramine therapy. Ann Intern Med 1970;72:95-6.
89. Vroonhof K, van Rijn HJ, van Hattum J. Vitamin K deficiency and bleeding after long-
term use of cholestyramine. Neth J Med 2003;61:19-21.
90. Shojania AM, Grewar D. Hypoprothrombinemic hemorrhage due to cholestyramine
therapy. CMAJ 1986;134:609-10.
91. Sadler LC, Lane M, North R. Severe fetal intracranial haemorrhage during treatment with
cholestyramine for intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol
1995;102:169-70.
43
92. West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut
1975;16:93-8.
93. Westergaard H. Bile acid malabsorption. Curr Treat Options Gastroenterol 2007;10:28-
33.
94. Camilleri M, Busciglio I, Acosta A, et al. Effect of increased bile acid synthesis or fecal
excretion in irritable bowel syndrome-diarrhea. Am J Gastroenterol 2014;109:1621-30.
95. Vijayvargiya P, Camilleri M, Chedid V, et al. Analysis of fecal primary bile acids detects
increased stool weight and colonic transit in patients with chronic functional diarrhea.
Clin Gastroenterol Hepatol 2019;17:922-929 e2.
96. Camilleri M. Trial to understand efficacy of colesevelam in diarrhea predominant IBS
patients with bile acid malabsorption. Last Update 2017. Available at:
https://clinicaltrials.gov/ct2/show/NCT03270085. Accessed December 6, 2018.
97. Dior M, Delagreverie H, Duboc H, et al. Interplay between bile acid metabolism and
microbiota in irritable bowel syndrome. Neurogastroenterol Motil 2016;28:1330-40.
98. Hou RG, Fan L, Liu JJ, et al. Bile acid malabsorption is associated with diarrhea in acute
phase of colitis. Can J Physiol Pharmacol 2018;96:1328-1336.
99. Arya LA. Rationale for investigating stool metabolites and microbiota in women with
fecal incontinence. Dis Colon Rectum 2017;60:249-252.
100. Sirtori M, Pazzucconi F, Gianfranceschi G, et al. Efficacy of cholestyramine does not
vary when taken before or during meals. Atherosclerosis 1991;88:249-52.
44
What You Need to Know
Background and context: Chronic diarrhea affects about 5% of the population, and can be
related to bile acid diarrhea (BAD), a condition that is frequently underdiagnosed.
New findings: The group recommended using risk factors, but not additional symptoms to help
diagnose BAD. Testing using 75selenium homocholic acid taurine (SeHCAT) or 7α-hydroxy-4-
cholesten-3-one (C4) was suggested, and was preferred over empiric bile acid sequestrant
therapy (BAST) depending on cost, available resources, local expertise, and patient preferences.
Cholestyramine was suggested as initial therapy, with alternate BAST when tolerability was an
issue. BAST maintenance treatment should be used at the lowest effective dose, with a trial of
intermittent, on-demand dosing.
Limitations: The main challenge in BAD is the lack of a universally agreed-upon reference
standard for diagnosis. Currently the condition is defined based on pathophysiologic mechanisms
and its response to BAST.
Impact: This consensus provides guidance on the appropriate evidence-based use of diagnostic
tests and medical therapies to help improve outcomes for patients with BAD. The gaps in
evidence highlight the need for further research in this chronic condition.
Appendix 1: Search strategies for BAD
Final search strategy for BAD:
(from 1990 we have 1511 hits, then it was separated into RCTs or SRs, n=451; non-RCTs non
SRs, n=1060).
Database: Embase <1974 to 2017 September 05>, OVID Medline Epub Ahead of Print, In-Process &
Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present, EBM
Reviews - Cochrane Central Register of Controlled Trials <July 2017>, EBM Reviews - Cochrane
Database of Systematic Reviews <2005 to August 30, 2017>
Search Strategy:
--------------------------------------------------------------------------------
1 diarrhea/ or chronic diarrhea/ (250921)
2 (diarrhea or diarrhoea or malabsorption).tw,kw. (251236)
3 1 or 2 (385404)
4 exp "Bile Acids and Salts"/ or exp bile acid/ (86671)
5 (bile acid or bile acids or biliary acid).tw,kw. (50328)
6 (SeHCAT or tauroselcholic acid).tw,kw. (381)
7 (Cholestyramine or colestyramine or Colestipol or Colestid or Colestipid or Colesevelam or
Cholestagel or Welchol or Lodalis or Questran or Cholybar or Olestyr).tw,kw. (8017)
8 or/4-7 (107151)
9 3 and 8 (5049)
10 Conference Abstract.pt. or Congresses as Topic/ (2795323)
11 note/ or editorial/ or letter/ or Comment/ or news/ or (note or editorial or letter or Comment or
news).pt. (4054984)
12 (exp animals/ or exp animal/ or exp nonhuman/ or exp animal experiment/ or animal model/ or
animal tissue/ or non human/ or (rats or mice or mouse or cats or dogs or animal* or cell lines).ab.) not
(humans/ or human/ or (human* or men or women or patients or subjects).ab.) (10259693)
13 (child/ or Pediatrics/ or Adolescent/ or Infant/ or adolescence/ or newborn/ or (baby or babies or
child or children or pediatric* or paediatric* or peadiatric* or infant* or infancy or neonat* or newborn*
or new born* or kid or kids or adolescen* or preschool or pre-school or toddler*).ti.) not (adult/ or aged/
or (aged or adult* or elder* or senior* or men or women).ti.) (4123598)
14 or/10-13 (20145364)
15 9 not 14 (3682)
16 limit 15 to english language [Limit not valid in CDSR; records were retained] (3093)
17 limit 16 to yr="1990 -Current" (2101)
18 remove duplicates from 17 (1511)
***************************
Note: cholestyramine (colestyramine, trade names Questran, Questran Light, Cholybar, Olestyr);
colestipol (Colestid, Colestipid); colesevelam (Cholestagel in Europe, Welchol in the USA,
Lodalis in Canada)
We then performed a separate search for SeHCAT before 1990, without limiting to adults,
we have 13 hits:
Database: Embase <1974 to 2017 September 06>, OVID Medline Epub Ahead of Print, In-Process &
Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present, EBM
Reviews - Cochrane Central Register of Controlled Trials <August 2017>, EBM Reviews - Cochrane
Database of Systematic Reviews <2005 to September 7, 2017>
Search Strategy:
--------------------------------------------------------------------------------
1 diarrhea/ or chronic diarrhea/ (251595)
2 (diarrhea or diarrhoea or malabsorption).tw,kw. (252683)
3 1 or 2 (387037)
4 (SeHCAT or tauroselcholic acid).tw,kw. (383)
5 Conference Abstract.pt. or Congresses as Topic/ (2801365)
6 note/ or editorial/ or letter/ or Comment/ or news/ or (note or editorial or letter or Comment or
news).pt. (4065461)
7 (exp animals/ or exp animal/ or exp nonhuman/ or exp animal experiment/ or animal model/ or
animal tissue/ or non human/ or (rats or mice or mouse or cats or dogs or animal* or cell lines).ab.) not
(humans/ or human/ or (human* or men or women or patients or subjects).ab.) (10306801)
8 3 and 4 (314)
9 5 or 6 or 7 (16741255)
10 8 not 9 (202)
11 limit 10 to english language [Limit not valid in CDSR; records were retained] (179)
12 limit 11 to yr="1860 - 1989" (24)
13 remove duplicates from 12 (13)
***************************
Appendix 2: PICO questions and GRADE assessments of evidence on the
management of bile acid diarrhea (BAD)
Frances Tse & Grigorios Leontiadis
Feb 8, 2018 (Updated Oct 12, 2018, updated Jul 22, 2019)
Summary table
Role of risk factors and symptom presentation in the diagnosis of bile acid diarrhea (BAD)
PICO 1: In patients with chronic non-bloody diarrhea, should risk factors (history of terminal ileal resection, cholecystectomy, or radiotherapy) be used as
the initial assessment to identify patients with possible BAD?
GRADE: Very low-quality evidence. Vote: strongly yes, 60%; yes, 40%.
PICO 2: In patients with chronic non-bloody diarrhea, should symptom presentation be used as the initial assessment to identify patients with possible
BAD?
GRADE: Very low-quality evidence. Vote: no, 100%.
Role of laboratory tests in the diagnosis of BAD
PICO 3: In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use SeHCAT testing to identify patients with BAD?
PICO 4: In patients with small intestinal Crohn's disease without objective evidence of inflammation who have persistent diarrhea, should we use SeHCAT
testing?
PICO 5: In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use a C4 assay to identify possible BAD?
GRADE: Very low-quality evidence. Vote: strongly yes, 20%; yes, 60%; neutral, 20%.
Role of BAST in the Diagnosis of BAD
PICO 6: In patients with suspected BAD, should we initiate empiric BAST over performing SeHCAT to establish a diagnosis of BAD?
GRADE: Very low-quality evidence. Vote: yes, 20%; no, 40%; strongly no, 40%.
Role of BAST in the induction treatment of BAD
PICO 7: In patients with Type 1 or Type 3 BAD, should we use treatments for remediable causes (eg, Crohn’s, microscopic colitis, SIBO) in addition to
treatment for BAD for induction of clinical response?
PICO 8: In patients with BAD, should we use cholestyramine over no treatment for induction of clinical response?
1
PICO 9: In patients with BAD, should we use cholestyramine over other BASTs as initial therapy for induction of clinical response?
GRADE: Very low-quality evidence. Vote: yes, 80%; neutral, 20%.
PICO 10: In patients with BAD who are unable to tolerate cholestyramine, should an alternate BAST be used for induction of clinical response?
GRADE: Low-quality evidence. Vote: strongly yes, 40%; yes, 60%.
PICO 11: In patients with BAD receiving empiric BAST, should gradual daily dose titration vs. no titration be used to minimize side effects?
DESIGNATED A GOOD PRACTICE STATEMENT.
PICO 12: In patients with Crohn’s disease with extensive ileal involvement or resection, should we use BAST vs. no BAST?
GRADE: Very low-quality evidence. Vote: yes, 20%; no, 80%.
Role of BAST in the maintenance treatment of BAD
PICO 13: In patients with BAD who respond to BAST, should intermittent, on demand dosing be tried?
GRADE: Very low-quality evidence. Vote on PICO question: yes, 80%; neutral, 20%.
PICO 14: In patients with BAD who are unable to tolerate BAST, should alternative anti-diarrheal agents vs. no treatment be used for long-term
symptomatic therapy?
GRADE: very low-quality evidence. Vote: yes, 100%
PICO 15: In patients with BAD receiving BAST, should maintenance therapy be used at the lowest dose needed to maintain symptom response vs. no dose
titration?
PICO 16: In patients with BAD and recurrent or worsening symptoms despite stable BAST, should diagnostic re-evaluation or dose escalation be used?
PICO 17: In patients being considered for BAST, should concurrent medications be reviewed to minimize the potential for drug interactions?
PICO questions with no recommendations

PICO A: In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use a FGF19 assay to identify possible BAD?
GRADE: Very low-quality evidence. Vote: strongly yes, 20%; neutral, 80%.
PICO B: In patients receiving long-term maintenance therapy with BAST, should fat-soluble vitamin levels be measured at baseline and annually, thereafter?
GRADE: very low-quality evidence. Vote: yes, 20%; neutral, 80%
2
PICO questions that were not voted on, and for which no additional recommendation statements were developed
PICO I: In patients with chronic diarrhea, should we use the absence of inflammatory markers or prior surgery to identify patients with possible primary bile
acid diarrhea (Type II BAD)?
(Note: This PICO was not voted on, and no recommendation statement was developed because “prior surgery” was included in PICO 1, and no data were
found regarding the use of inflammatory markers to identify patients with possible BAD)
PICO II: In patients with chronic diarrhea, should we use appropriate risk factors (e.g. ileal disease/disorders, post-surgical syndromes, enteropathies), to
identify patients with likely bile acid malabsorption?
(Note: This PICO was not voted on, and no additional recommendation statement was developed because “risk factors” were included in PICO 1)
PICO III: In patients with BAD, should BAST be taken once daily to minimize interaction with other medications?
(Note: This PICO was not voted on, and no additional recommendation statement was developed because “drug interactions” were included in PICO 17)
PICO IV: In patients with BAD, should BAST be taken AM (or PM/ HS)?
(Note: This PICO was not voted on, and no recommendation statement was developed because there were no data to inform this issue, which is discussed in
terms of future research needs)
Role of risk factors and symptom presentation in the diagnosis of bile acid diarrhea (BAD)
PICO 1: In patients with chronic non-bloody diarrhea, should risk factors be used as the initial assessment to identify patients with bile acid
diarrhea (BAD)?
PICO 2: In patients with chronic non-bloody diarrhea, should symptom presentation be used as the initial assessment to identify patients with
possible bile acid diarrhea (BAD)?
Evidence for this PICO can be derived from two types of studies:
A. Diagnostic test accuracy (DTA) studies that assessed what is the diagnostic accuracy of “symptom presentation and/or risk factors” for
the diagnosis of BAD - compared to a reference standard (positive SeHCAT, with/without positive response to BAS treatment)
B. RCTs that randomized patients to one strategy (assessing “symptom presentation and/or risk factors”) vs. another strategy (not
assessing “symptom presentation and/or risk factors”) and then treated the patients according to the resulting diagnoses and captured
clinical outcomes.
No such RCTs have been published; therefore the evidence will be derived from DTA studies.
Notes:
3
• Bannaga BMJ Open Gastro 20171 (UK): Online survey of patients with self-reported BAD. Serious limitations (only the first 100 responses out
of 1300 members of the Bile Salt Malabsorption Facebook Group were analyzed; self-reported BAD). It does not directly answer this
diagnostic PICO question, but it provides insight to patients’ values: esp. the disappointment they felt because they “felt like they were not
taken seriously by the medical professionals consulted” (35%) and because of the delay in diagnosis (“symptoms had been experienced for
more than 5 years before diagnosis in 44% of respondents”).
• We have also included 2 untagged studies that were cited in Gracie 20122 (see below):
o Borghede EJIM 20113
o Ung EJGH 20004
DTA studies (QUADAS-II risk of bias domains)

Study Patient Index test (here: risk Reference standard Flow and Comments
selection factors and symptom (here: SeHCAT) timing
presentation)
Gracie NGM The criteria for Retrospective cohort Unclear if the SeHCAT OK (UK): Retrospective cohort study of 373 patients with chronic diarrhea
20122 referring some - design: the data on results were interpreted undergoing SeHCAT scan. BAM = retention <15%:
but not all - risk factors were without knowledge of ● Overall: 50.9% had BAM
chronic collected from the results of the index ● Previous cholecystectomy: 68.4% had BAM (OR 2.51; 99% CI 1.10–5.77)
diarrhea medical records. With test (risk factors and ● TI resecNon or right hemicolectomy: 89.1% had BAM
patients for the exception of the symptoms): probably - TI resection or right hemicolectomy for Crohn’s disease: OR 12.4; 99% CI
SeHCAT were PMH of surgery, these not. 2.42–63.8
not defined. data cannot be - TI resection or right hemicolectomy for other reasons: OR 7.94; 99% CI
adequately accurate. 1.02– 61.6
Unclear if the index ● IBS-D: 27.3% had BAM
test results were ● Patients with no risk factors for a positive SeHCAT scan, other than chronic
interpreted without diarrhea: 37.5% had BAM
knowledge of the - Significantly fewer individuals with BAM reported bloating (15.3% vs 24.9%,
results of the P = 0.02), or abdominal pain or discomfort (33.9% vs 43.6%, P = 0.05), and
reference standard (it fewer met criteria for IBS-D (11.1% vs 30.6%, P < 0.001).
is not clear if medical ● History of acute enteric illness: 40.9% had BAM (not significantly associated
records collected after with BAM)
the diagnosis of BAM, ● There were very few patients with microscopic colitis or celiac disease
were also taken into ● So, overall this study confirmed that (among patients with chronic diarrhea)
account when data on previous cholecystectomy, and TI resection or R hemicolectomy were risk
risk factors and factors for BAM. Interestingly, patients with bloating, abdominal pain or
symptoms were discomfort (among those with chronic diarrhea) were less likely to have BAM.
extracted for this
study: recall bias and
directly questioning
patients already
diagnosed with BAM
for recognized risk
factors, would inflate
4
the importance of
these factors)
Kurien SJG The criteria for Retrospective cohort Unclear if the SeHCAT OK (UK): Retrospective cohort study of 273 patients undergoing SeHCAT scan.
20115 referring for design: the data on results were interpreted 39.2% had BAM = retention <10%. It was unclear how many patients had
SeHCAT were risk factors were without knowledge of chronic diarrhea. Only in the Discussion section it reads that “38% of patients
not defined. collected from the results of the index with chronic diarrhea had evidence of BAM based on their SeHCAT result”.
Not all patients medical records = test (risk factors and ● Predictive factors reported in the pasted table below (for all patients, with or
had chronic inaccuracy. symptoms): probably without diarrhea):
diarrhea. Unclear if the index not.
test results were
interpreted without
knowledge of the
results of the
reference standard
● 33.6% of patients who had a positive SeHCAT also had Rome II D-IBS, but D-
IBS was not a predictive factor.
Fernandez- OK. OK Unclear if the SeHCAT OK (Spain): prospective cohort study of 62 patients with a) non-bloody chronic
Banares AJG results were interpreted watery diarrhea, defined as more than 3 loose or liquid BMs a day for at least 4
20076 without knowledge of wk and a stool weight >200 g/day; (b) fulfilling the Rome II criteria of either
the results of the index functional diarrhea or diarrhea predominant IBS. They were assessed with a
test (risk factors and series of tests including SeHCAT (BAM=retention >11%).
symptoms): probably ● 59.7% had BAM by SeHCAT. The final diagnosis of BAD was given to those
not. patients with BAM who responded to cholestyramine.
● Final diagnoses: 45.2% had BAD; an additional 3% had both BAD and sugar
malabsorption.
● There were no significant differences between patients with functional
diarrhea vs IBS-D in the final diagnoses: BAD was 46.7% vs. 43.8% respectively.
Galatola EJGH OK OK Unclear if the SeHCAT OK (Italy): prospective study on 98 patients with IBS-D: they all had SeHCAT scan:
19927 results were interpreted 56 patients (57.1%) had BAM (retention > 11.2%): of those 42 completed a
without knowledge of course of cholestyramine and of those only 3 did not respond to the treatment.
the results of the index ● Predictive factor for BAM was fecal wet weigh > 200 g/day.
test (risk factors and
symptoms): probably
not.
Aziz CGH OK OK Unclear if the SeHCAT OK (UK): cross-sectional study that showed that the prevalence of BAD (SeHCAT
20158 results were interpreted <15%) was 23.7% in 118 patients with Rome III IBS-D. No clinical characteristic
without knowledge of was associated with BAD, other than BMI (patients with BAD had a higher
the results of the index mean BMI than patients without BAD (31.6 vs 26.4; P = .003)
test (risk factors and
symptoms): probably
not.
Stotzer UEGJ OK High risk for Unclear if the SeHCAT OK (Sweden): Prospective cohort study. Assessed which of two definitions for
20159 differential results were interpreted diarrhea (≥3 loose stools/day vs. stool consistency mushy or loose) is the best
verification bias: without knowledge of predictor of having an organic cause of the diarrhoea.
because the patients the results of the index The most common of the organic causes of diarrhea in this study was BAD (48
with less severe test (risk factors and out of 91 patients with organic diarrhea). Among patients with BAD 44% had ≥3
5
diarrhea were less symptoms): probably loose stools/day and 81% had mushy or loose stools; among functional
rigorously investigated not. diarrhea patients the proportions were 21% and 35%. Therefore, the
and therefore were consistency of stools would have a better discriminator ability than the
less likely to be frequency. The diagnostic accuracy for BAD among patients with diarrhea was
diagnosed with not calculated but it is obvious that this criterion alone cannot be extremely
organic diarrhea. useful in clinical practice.
Borghede The criteria for Retrospective cohort Unclear if the SeHCAT OK (Denmark): Retrospective cohort study of 289 patients with chronic watery
EJIM 20113 referring for design: the data on results were interpreted diarrhea undergoing SeHCAT scan. BAM = retention <15%:
SeHCAT risk factors were without knowledge of ● Overall: 68% had BAM
patients with collected from the results of the index ● Previous cholecystectomy: 89% (CI 71%–95%) had BAM
chronic watery medical records = test (risk factors and ● Crohn's disease in TI without resecNon: 76% (CI 57%–90%) had BAM
diarrhea were likely inaccurate. symptoms): probably ● Crohn's disease with ileal resecNon: 91% (CI 78%–87%) had BAM
not defined. Unclear if the index not. ● Patients with no known cause for diarrhea (and no risk factors for BAM other
test results were than chronic diarrhea): 60% (CI 52%–67%) had BAM
interpreted without
knowledge of the
results of the
reference standard
Ung EJGH OK OK Unclear if the SeHCAT Data on (Denmark): Prospective cohort study of 94 patients with chronic diarrhea
20004 results were interpreted symptoms were undergoing SeHCAT scan. BAM = retention <10%:
without knowledge of missing in 22% ● Overall: 44.6% had BAM
the results of the index of the patients ● PaNents with BAD type II had more frequent and looser stools compared to
test (risk factors and patients with functional diarrhea, but there was no difference in abdominal
symptoms): probably pain, distention or flatulence.
not.
Williams Gut The criteria for Retrospective cohort Unclear if the SeHCAT Data on clinical (UK): retrospective study on 181 patients with chronic diarrhoea (that
199110 referring for design: the data on results were interpreted characteristics remained unexplained after full investigation), who had SeHCAT scan, and if,
SeHCAT were clinical characteristics without knowledge of (as shown in positive, were treated with cholestyramine.
not defined. were collected from the results of the index tables I-III) were ● 11.6% had mild BAM (SeHCAT retention 10-15%)
medical records = test (risk factors and missing for ● 8.8% had moderate BAM (SeHCAT retention 5-10%)
likely inaccurate. symptoms): probably many patients. ● 12.7% had severe BAM (SeHCAT retention < 5%)
Unclear if the index not. No predictive factors for BAM were reported
test results were It was noted that the nocturnal component of the diarrhea was only present in
interpreted without severe BAM (11 out of 23) and in no patient with moderate or mild BAM.
knowledge of the However, the prevalence of the nocturnal component in non-BAM patients was
results of the not reported. Therefore, it is unknown if this criterion has any diagnostic value
reference standard. when trying to predict if a patient which chronic diarrhea is likely to have BAM
or not.
Very serious indirectness.
QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies- 2) tool

Domain 1: Patient Selection
Risk of Bias: Could the Selection of Patients Have Introduced Bias?
• Signaling question 1: Was a consecutive or random sample of patients enrolled?
6
• Signaling question 2: Was a case–control design avoided?
• Signaling question 3: Did the study avoid inappropriate exclusions?
Applicability: Are There Concerns That the Included Patients and Setting Do Not Match the Review Question?
Domain 2: Index Test
Risk of Bias: Could the Conduct or Interpretation of the Index Test Have Introduced Bias?
• Signaling question 1: Were the index test results interpreted without knowledge of the results of the reference standard?
• Signaling question 2: If a threshold was used, was it prespecified?
Applicability: Are There Concerns That the Index Test, Its Conduct, or Its Interpretation Differ From the Review Question?
Domain 3: Reference Standard
Risk of Bias: Could the Reference Standard, Its Conduct, or Its Interpretation Have Introduced Bias?
• Signaling question 1: Is the reference standard likely to correctly classify the target condition?
• Signaling question 2: Were the reference standard results interpreted without knowledge of the results of the index test?
Applicability: Are There Concerns That the Target Condition as Defined by the Reference Standard Does Not Match the Question?
Domain 4: Flow and Timing
Risk of Bias: Could the Patient Flow Have Introduced Bias?
• Signaling question 1: Was there an appropriate interval between the index test and reference standard?
• Signaling question 2: Did all patients receive the same reference standard?
• Signaling question 3: Were all patients included in the analysis?
Quality of evidence assessment
Overall
Other Quality of
Studies Risk of bias Inconsistency Indirectness Imprecision quality of
considerations Evidence
evidence
TI resection, TI disease or cholecystectomy as risk factors for BAM among patients with chronic diarrhea
Multiple
⊕⊝⊝⊝ ⊕⊝⊝⊝
observational Serious a Not serious Not serious Not serious None VERY LOW VERY LOW
studies
Symptom presentation
Multiple
⊕⊝⊝⊝ ⊕⊝⊝⊝
observational Serious b Serious c Not serious Serious d None VERY LOW VERY LOW
studies
a. All studies are at either high or unclear risk of bias
b. The studies that identified specific symptoms and clinical characteristics as risk factors for BAM (among patients with chronic diarrhea) were all at high risk of bias. There were only three
studies at unclear risk of bias (Fernandez-Banares AJG 2007, Galatola EJGH 1992, Aziz CGH 2015) but these included selected sub-populations with chronic diarrhea (functional diarrhea
and/or IBS-D) and did not identify any symptoms as risk factors for BAM. There were no studies at low risk of bias.
c. The specific symptoms and clinical characteristics were inconsistently identified as risk factors for BAM among the studies
d. Small sample size, the studies were not powered to identify weak risk factors.
7
Overall QoE for PICO 1:
There are no diagnostic-strategy RCTs informing this PICO.
There are several observational studies that have not been designed and executed as diagnostic accuracy studies, but diagnostic accuracy data
can still be extracted.
• There is VERY LOW quality evidence supporting the use of TI resection, TI disease or cholecystectomy as the initial assessment to
identify patients at higher risk for having BAD. The quality of evidence was downrated for study limitations (risk of bias) but the results
of the studies were consistently in favor of this PICO
• There is VERY LOW quality evidence supporting the use of symptom presentation as the initial assessment to identify patients at higher
risk for having BAD. The quality of evidence was downrated for study limitations (risk of bias), inconsistency and imprecision: it remains
very uncertain if symptom presentation has any diagnostic/prognostic utility in this clinical setting.
Other factors that should influence the strength (or direction) of recommendation:
• Balance between benefits and harms: Consider the potential harms (clinical consequences of false positive (unnecessary diagnostic
tests and /or treatments) or false negative classifications (missed diagnoses)) when using clinical risk factors as triage test for BAM
• Patient values and preferences: See Bannaga BMJ Open Gastro 2017.1
• Cost: The cost of using clinical risk factors as triage test for BAM is very low.
Articles that were initially tagged as potentially eligible, but did not directly contribute to the GRADE assessment of the quality of evidence
for this PICO
• Wedlake APT 2009 (Wedlake L, A'Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in
patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30:707-17): Systematic review and meta-analysis that allows estimation
of the prevalence of BAM among patients with IBS-D:
o 5 studies (429 patients) indicated that 10% (CI: 7–13) patients had severe bile acid malabsorption (SeHCAT 7-day retention <5% of baseline value)
o 17 studies (1073 patients) indicated that 32% (CI: 29–35) patients had moderate bile acid malabsorption (SeHCAT<10%)
o 7 studies (618 patients) indicated that 26% (CI: 23–30) patients had mild (SeHCAT <15%) bile acid malabsorption
o No data on the diagnostic accuracy of specific symptoms and risk factors. The estimated prevalence is equal to the pretest probability of BAM in patients
with IBS-D, but it is not known if this prevalence is statistically higher that the prevalence of BAM in other conditions presenting with chronic diarrhea, such
as functional diarrhea. Therefore, these results cannot help us decide if IBS-D is a risk factor for BAM among patients with chronic diarrhea.
• Lacy Gastro 2016 (Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393-1407. e5): Narrative review, classifying and describing
functional bowel disorders. In the IBS-D chapter, it states that BAM may be the cause of persistent, watery diarrhea in some patients; in the Functional Diarrhea
8
chapter it states that BAM is an often-overlooked diagnosis in patients with longstanding diarrhea. However, there are no detailed data to allow us to quantify the
diagnostic accuracy of “symptom presentation and risk factors” for the diagnosis of BAD.
• Peleman CGH 2017 (Peleman C, Camilleri M, Busciglio I, et al. Colonic transit and bile acid synthesis or excretion in patients with irritable bowel syndrome-diarrhea
without bile acid malabsorption. Clin Gastroenterol Hepatol 2017;15:720-727 e1): elaborate study that in the absence of overt BAM, the total, primary, and secretory
BAs in stool contribute to the acceleration of colonic transit and fecal weight in the diarrhea of patients with IBS-D.
• Camilleri NGM 2014 (Camilleri M, Shin A, Busciglio I, et al. Validating biomarkers of treatable mechanisms in irritable bowel syndrome. Neurogastroenterol Motil
2014;26:1677-85): Assessed potential biomarkers for IBS-D and IBS-C. Found that IBS-D patients had higher total fecal bile acid secretion and evidence of increased BA
synthesis (C4 and FGF19) compared to healthy volunteers (who did not have diarrhea). Does not answer this PICO question.
• Shin CGH 2013 (Shin A, Camilleri M, Vijayvargiya P, et al. Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with
irritable bowel syndrome. Clin Gastroenterol Hepatol 2013;11:1270-1275 e1): Assessed the association between individual unconjugated BAs and stool characteristics
in patients with IBS. Does not answer this PICO question.
• Thomas Gut 2003 (Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic diarrhoea, 2nd edition. Gut 2003;52 Suppl 5:v1-15): BSG CPG for the
investigation of chronic diarrhea. It highlights the risk factors for BAM among patients with chronic diarrhea: “Patients with Crohn’s disease or other terminal ileal
abnormality or resection are particularly at risk of BAM, but the condition has also been well documented following cholecystectomy, post-infectious diarrhoea, and in
idiopathic diarrhoea.” It did not provide qualitative data that would allow us calculate the diagnostic accuracy of specific symptoms and risk factors
Evidence to Decision framework (diagnostic question)

PICO 1: In patients with chronic non-bloody diarrhea, should risk factors (history of terminal ileal resection, cholecystectomy, or
radiotherapy) be used as the initial assessment to identify patients with possible bile acid diarrhea (BAD)?
JUDGEMENT
How accurate is the test?

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know
How substantial are the desirable anticipated effects?

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know
9
How substantial are the undesirable anticipated effects?
○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know
What is the overall certainty of the evidence of test accuracy?

○ Very low
○ Low
CERTAINTY OF THE EVIDENCE
○ Moderate
OF TEST ACCURACY
○ High
○ No included studies
What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or
burden of the test?
○ Very low
CERTAINTY OF THE EVIDENCE ○ Low
OF TEST'S EFFECTS ○ Moderate
○ High
What is the overall certainty of the evidence of effects of the management that is guided by the test results?
○ Very low
○ Low
○ Moderate
OF MANAGEMENT'S EFFECTS
○ High
How certain is the link between test results and management decisions?
○ Very low
○ Low
○ Moderate
OF TEST RESULT/MANAGEMENT
○ High
What is the overall certainty of the evidence of effects of the test?

○ Very low
CERTAINTY OF EFFECTS ○ Low
○ Moderate
○ High
10
Is there important uncertainty about or variability in how much people value the main outcomes?
○ Important uncertainty or variability
VALUES ○ Possibly important uncertainty or variability
○ Probably no important uncertainty or variability
○ No important uncertainty or variability
Does the balance between desirable and undesirable effects favor the intervention or the comparison?
○ Favors the comparison
○ Probably favors the comparison
○ Does not favor either the intervention or the comparison
BALANCE OF EFFECTS ○ Probably favors the intervention
○ Favors the intervention
○ Varies
○ Don't know
How large are the resource requirements (costs)?

○ Large costs
○ Moderate costs
○ Negligible costs and savings
RESOURCES REQUIRED ○ Moderate savings
○ Large savings
○ Varies
○ Don't know
What is the certainty of the evidence of resource requirements (costs)?

○ Very low
○ Low
CERTAINTY OF EVIDENCE OF
○ Moderate
REQUIRED RESOURCES
○ High
Does the cost-effectiveness of the intervention favor the intervention or the comparison?
COST EFFECTIVENESS ○ Probably favors the intervention
○ Varies
ACCEPTABILITY Is the intervention acceptable to key stakeholders?
11
○ No
○ Probably no
○ Probably yes
○ Yes
○ Varies
○ Don't know
Is the intervention feasible to implement?

○ No
○ Probably no
○ Probably yes
FEASIBILITY
○ Yes
○ Varies
○ Don't know

PICO 2: In patients with chronic non-bloody diarrhea, should risk factors should symptom presentation be used as the initial assessment to
identify patients with possible bile acid diarrhea (BAD)?
JUDGEMENT

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

UNDESIRABLE EFFECTS ○ Large
○ Moderate
12
○ Small
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
OF TEST ACCURACY
○ High
burden of the test?
○ Very low
○ High
○ Very low
○ Low
○ Moderate
○ High
○ Very low
○ Low
○ Moderate
○ High

○ Very low
○ Low
CERTAINTY OF EFFECTS ○ Moderate
○ High
VALUES Is there important uncertainty about or variability in how much people value the main outcomes?
13
○ Possibly important uncertainty or variability
○ Varies
○ Don't know

○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
REQUIRED RESOURCES
○ High
○ Varies
Is the intervention acceptable to key stakeholders?

○ No
ACCEPTABILITY
○ Probably no
○ Probably yes
14
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
FEASIBILITY
○ Yes
○ Varies
○ Don't know
References for PICO 1 & 2

1. Bannaga A, Kelman L, O'Connor M, et al. How bad is bile acid diarrhoea: an online survey of patient-reported symptoms and outcomes.
BMJ Open Gastroenterol 2017;4:e000116.
2. Gracie DJ, Kane JS, Mumtaz S, et al. Prevalence of, and predictors of, bile acid malabsorption in outpatients with chronic diarrhea.
Neurogastroenterol Motil 2012;24:983-e538.
3. Borghede MK, Schlutter JM, Agnholt JS, et al. Bile acid malabsorption investigated by selenium-75-homocholic acid taurine ((75)SeHCAT)
scans: causes and treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-
40.
4. Ung KA, Kilander AF, Lindgren A, et al. Impact of bile acid malabsorption on steatorrhoea and symptoms in patients with chronic
diarrhoea. Eur J Gastroenterol Hepatol 2000;12:541-7.
5. Kurien M, Evans KE, Leeds JS, et al. Bile acid malabsorption: an under-investigated differential diagnosis in patients presenting with
diarrhea predominant irritable bowel syndrome type symptoms. Scand J Gastroenterol 2011;46:818-22.
6. Fernandez-Banares F, Esteve M, Salas A, et al. Systematic evaluation of the causes of chronic watery diarrhea with functional
characteristics. Am J Gastroenterol 2007;102:2520-8.
7. Galatola G, Ferraris R, Pellerito R, et al. The prevalence of bile acid malabsorption in irritable bowel syndrome and the effect of
cholestyramine: An uncontrolled open multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7.
8. Aziz I, Mumtaz S, Bholah H, et al. High prevalence of idiopathic bile acid diarrhea among patients with diarrhea-predominant irritable
bowel syndrome based on Rome III criteria. Clin Gastroenterol Hepatol 2015;13:1650-5 e2.
9. Stotzer PO, Abrahamsson H, Bajor A, et al. Are the definitions for chronic diarrhoea adequate? Evaluation of two different definitions in
patients with chronic diarrhoea. United European Gastroenterol J 2015;3:381-6.
10. Williams AJ, Merrick MV, Eastwood MA. Idiopathic bile acid malabsorption--a review of clinical presentation, diagnosis, and response to
treatment. Gut 1991;32:1004-6.
15
PICO I (no vote): In patients with chronic diarrhea, should we use the absence of inflammatory markers or prior surgery to identify patients
with possible primary bile acid diarrhea (Type II BAD)?
A. Diagnostic test accuracy (DTA) studies that assessed what is the diagnostic accuracy of “absence of inflammatory markers or prior
surgery” for the diagnosis of primary BAD, among patients with chronic diarrhea - compared to a reference standard (positive SeHCAT,
with/without positive response to BAS treatment)
B. RCTs that randomized patients to one strategy (considering “absence of inflammatory markers or prior surgery”) vs. another strategy
(not considering “absence of inflammatory markers or prior surgery”) and then treated the patients according to the resulting diagnoses
and captured clinical outcomes.
There was only one study tagged to this PICO: Gothe JCC 2014. However, this was a pediatric study and the committee had a priori decided to
exclude pediatric studies. Even if we had not decided to exclude pediatric studies, this study would not provide results relevant to this PICO: the
study population was patients with IBD (not patients with chronic diarrhea).
Therefore, we were not able to find any evidence in favor or against this PICO.
The quality of evidence could not be assessed.
• Balance between benefits and harms:

• Patient values and preferences:
• Cost

PICO I (no vote): In a patient with chronic diarrhea, should we use the absence of inflammatory markers or prior surgery to identify patients
with primary bile acid diarrhea (Type II BAD)?
The EtD framework was not completed, there was no vote, and no recommendation statement was developed because “prior surgery” is
included in PICO 1, and no data were found regarding the use of inflammatory markers to identify patients with possible BAD.
16
References for PICO I
Not applicable
PICO II (no vote): In patients with chronic diarrhea, should we use appropriate risk factors (e.g. ileal disease/disorders, post-surgical
syndromes, enteropathies), to identify patients with likely bile acid diarrhea
A. Diagnostic test accuracy (DTA) studies that assessed what is the diagnostic accuracy of “appropriate risk factors (e.g. ileal
disease/disorders, post-surgical syndromes, enteropathies)” for the diagnosis (as a triage test) of BAD, among patients with chronic
diarrhea – compared to a reference standard (positive SeHCAT, with/without positive response to BAS treatment)
B. RCTs that randomized patients to one strategy (considering “appropriate risk factors”) vs. another strategy (not considering “appropriate
risk factors”) and then treated the patients according to the resulting diagnoses and captured clinical outcomes.
22 supportive studies have been tagged. The studies that reported the prevalence of positive SeHCAT in at least 10 patients with a specific risk
factor were the following:
• Ludgate CR 1985:1 26 patients with post-irradiation chronic diarrhea (81% positive SeHCAT)
• Murray SJG 2017:2 retrospective observational study of 387 consecutive patients undergoing SeHCAT. Binary logistic regression was used to
define which variables were statistically significant predictors of a positive SeHCAT.
• Gracie NM 20123 (UK): Retrospective cohort study of 373 patients with chronic diarrhea
o Overall: 50.9% had BAM
o Previous cholecystectomy: 68.4% had BAM OR 2.51; 99% CI 1.10–5.77
o TI resection or right hemicolectomy: 89.1% had BAM
17
− TI resection or right hemicolectomy for Crohn’s disease: OR 12.4; 99% CI 2.42–63.8
− TI resection or right hemicolectomy for other reasons: OR 7.94; 99% CI 1.02– 61.6
o Patients with no risk factors for a positive SeHCAT scan, other than chronic diarrhea: 37.5% had BAM
• Smith JRCPL 20004 (UK):
o 37 patients with Crohn’s with ileal resection in remission (97% SeHCAT positive)
o 44 patients with Crohn’s unoperated, in remission (54% SeHCAT positive
o Vagotomy and pyloroplasty, with/without cholecystectomy (58% SeHCAT positive)
• Valdes Olmos EJNM 19915 (Netherlands):
All 39 patients had a history of abdominal irradiation for malignancies of the cervix, endometrium, ovary, rectum or bladder. At the time
of the investigation patients complained of diarrhoea, pain or both.
o in 22 cases no ileal resection had been performed (group A): SeHCAT positive 36.4%
o In 17 patients a ileal resection had been performed because of obstructing radiation damage to the terminal ileum (group B): SeHCAT
positive 88.2%
The assessment of the quality of evidence is similar to the assessment done for the one of the two underlying sub-questions for PICO 1
(regarding risk factors):
Overall
Other Quality of
evidence
TI resection, TI disease or cholecystectomy as risk factors for BAM among patients with chronic diarrhea
Multiple
a ⊕⊝⊝⊝ ⊕⊝⊝⊝
observational Serious Not serious Not serious Not serious None VERY LOW VERY LOW
studies
a. All studies are at either high or unclear risk of bias
Therefore, overall, there is VERY LOW quality evidence (rated down due to risk of bias), that is supporting the use of appropriate risk factors (e.g.
ileal disease/disorders, post-surgical syndromes, enteropathies), to identify patients with likely bile acid malabsorption
18
• Balance between benefits and harms:

• Patient values and preferences:
• Cost

PICO II (no vote): In patients with chronic diarrhea, should we use appropriate risk factors (e.g. ileal disease/disorders, post-surgical
syndromes, enteropathies), to identify patients with likely bile acid diarhea
The EtD framework was not completed, there was no vote, and no additional recommendation statement was developed because “risk factors”
are included in PICO 2.
References for PICO II

Not applicable
Role of laboratory tests in the diagnosis of BAD
PICO 3: In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use SeHCAT testing to identify patients with
BAD?
Evidence for this PICO can be derived from three types of studies:
A. Diagnostic test accuracy (DTA) studies that assessed what is the diagnostic accuracy of SeHCAT testing for the diagnosis of BAD, among
patients with chronic diarrhea - compared to a reference standard (measurement of fecal bile acids)
B. DTA studies that assessed what is the diagnostic/prognostic accuracy of SeHCAT testing for predicting “symptomatic response to BAS
treatment”, among patients with chronic diarrhea compared to the reference standard which is a symptomatic response to BAS regardless of
the result of SeHCAT (in such studies, all patients undergo SeHCAT testing and all patients receive BAS treatment -regardless of the result of
SeHCAT)
19
C. RCTs that randomized patients to one strategy (SeHCAT) vs. another strategy (no SeHCAT, or use of another test) and then treated the
patients according to the resulting diagnoses and captured clinical outcomes.
Contributing to GRADE assessment
Riemsma HTA 2013:6 This is a rigorous and detailed HTA (UK) report: a SR and CE analysis on SeHCAT for the investigation of BAM and
measurement of BA pool loss. This HTA has searched for all three study designs mentioned above, using a very rigorous literature search.
• The HTA conclusions: “The results of our systematic review suggest that the accuracy of the SeHCAT test in predicting either BAM or response
to treatment, and the clinical effectiveness of BAS for the treatment of chronic diarrhoea caused by BAM, are uncertain. Additionally, the
results of our economic evaluation showed that for both populations studied, the lifetime perspective gave different results for different
scenarios meaning that all strategies may potentially be the most cost-effective. Therefore, the implications for service provision of SeHCAT
are equally uncertain. The main reason for this uncertainty is the lack of good-quality evidence.”
• The HTA project decided to focus on two populations with chronic diarrhea: IBS-D and Crohn’s disease (without TI resection).
• They did not identify any RCTs (“type C” studies)
• They did not find any (“type A”) DTA studies that assessed the diagnostic accuracy of SeHCAT testing for the diagnosis of BAD compared to a
gold standard: “None of the studies evaluated in this report, including the studies described in the literature as accuracy studies, was included
in this review as diagnostic test accuracy (DTA) studies, because they either do not use an acceptable reference standard or they include a
population not in line with the scope (i.e. healthy volunteers or people with ileal resection)”
o We independently confirmed this: there are no studies that attempted to measure the diagnostic accuracy of SeHCAT among patients
with chronic diarrhea, using a reference standard, and avoiding the case-control design:
− Even the two Sciarretta studies7, 8 (mentioned below) that were the only two studies that allowed calculation of the diagnostic
accuracy of SeHCAT for predicting response to BAST, were actually designed as case-control studies that assessed the ability of
SeHCAT to discriminate between cases and controls. The DTA calculations that the HTA project did, were post-hoc calculations using
other secondary results that these studies reported.
− We also assessed older studies that have been classically cited as the DTA studies that validated the diagnostic accuracy of SeHCAT,
and we found that none of these studies actually provides true DTA results:
• Boyd JNM 1981 (Boyd GS, Merrick MV, Monks R, Thomas IL. Se-75-labeled bile acid analogs, new radiopharmaceuticals for investigating the
enterohepatic circulation. J Nucl Med 1981;22:720-5): animal (rabbit) study
• Thaysen Gut 1982 (Thaysen EH, Orholm M, Arnfred J, Carl J, Rddbro P. Assessment of ileal function by abdominal counting of the retention of a gamma
emitting bile acid analogue. Gut 1982;23:862-5: The reference standard was clinical features and 14C-cholylglycine breath test.
• Blankestein van M, van den Berg JWO, Delhez H. The use of 75SeHCAT for testing ileal function. Proceedings of the 3rd World Congress of Nuclear
Medicine and Biology, Paris, 1982:2434-6: the proceedings could not be assessed
20
• Nyhlin Gastro 1983 (Nyhlin H, Merrick MV, Eastwood MA, Brydon WG. Evaluation of ileal function using 23-selena-25-homotaurocholate, a rlabeled
conjugated bile acid. Gastroenterology 1983;84:63-8): Used a case-control design (patients with disease of the small intestine, colon, or ileocecal region
vs. healthy controls), i.e. the reference standard was the initial classification as case or control (this study assessed the ability of SeHCAT to
discriminate cases vs. controls). Also measured total fecal and primary bile acids and found a “significant relationship” with SeHCAT results, but,
again, this was a case-control study.
• Fagan Digestion 1983 (Fagan EA, Chadwick VS, Baird McL. SeHCAT absorption: a simple test of ileal dysfunction. Digestion 1983;26:159-85): Used a case-
control design (patients with IBD vs. healthy controls), i.e. the reference standard was the initial classification as case or control (this study assessed
the ability of SeHCAT to discriminate IBD patients vs. controls). SeHCAT was also compared with tests of vitamin B12 absorption (Schilling test and
whole body retention) and the cholylglycine-1-14C breath test and faecal isotope excretion, but, again, this was a case-control study.
• The HTA report concluded that there is no feasible gold standard for the diagnosis of BAM, so as to compare it with SeHCAT: “there is no
direct comparator for SeHCAT. Current diagnostic options include analysis of a patient’s history, investigations to exclude ‘red flag’ symptoms
and a variety of other diagnostic tests such as blood tests and lactose tolerance tests. Trial of treatment and measurement of faecal bile acids
are two methods used, with mixed results, to diagnose BAM. They are, however, not widely used in current practice.”
• The HTA project did not identify any (“type B”) DTA studies that assessed the diagnostic accuracy of SeHCAT testing for the predicting
response to BAS, in patients with CD without resection.
• The HTA project only found 3 (“type B”) DTA studies that assessed the diagnostic accuracy of SeHCAT testing for the predicting response to
BAS, in patients with IBS-D (Sciarretta Gastro 1986;7 Sciarretta Gut 1987;8 Merrick BMJ 19859). They did not proceed to a meta-analysis:
“Meta-analysis of test accuracy studies was considered inappropriate, owing to the small number of studies with varying diagnostic
thresholds and between-study heterogeneity in other study design categories (principal diagnosis, treatment dose, definition of response,
follow-up period and SeHCAT administration)”
o However, we are very confident that Merrick BMJ 19859 was included in the HTA report by mistake: there are no diagnostic accuracy
data for the IBS-D group. Therefore, there are only 2 studies providing DTA evidence for IBS-D patients: Sciarretta Gastro 1986;7
Sciarretta Gut 1987:8 see QUADAS-II risk of bias assessments and comments below

Note: the risk of bias assessment refers to the data extracted on DTA of SeHCAT for predicting response to BAST (if we attempt to assess the studies for the DTA of SeHCAT for
diagnosing “BAD”, then the risk of bias is substantially higher)
Study Patient selection Index test (here: Reference standard Flow and Comments
SeHCAT) (here: response to BAST) timing
Sciarretta Unclear if the The threshold The reference standard OK (Italy): Prospective study of SeHCAT and results on response to BAST (all patients
Gastro 19867 enrolled patients was not pre- results (response to received BAST regardless of the results of SeHCAT test). The study included four
were consecutive specified BAST) were not groups of patients:
interpreted without (a) healthy controls
knowledge of the results (b) patients with resected pathological distal ileum
of the index test (SeHCAT (c) patients with intestinal pathology, but normal distal ileum
results) (d) patients with diarrhoea, but no evidence of intestinal or extraintestinal
pathology
21
The dose and duration of Data were extracted for group D (n= 13)
BAST and the definition
of response are unclear Applicability concerns
• indirectness of population: 3/13 (23%) of patients in group D (“chronic
unexplained diarrhea”) had cholecystectomy (in 2 of these, diarrhea
started after the cholecystectomy)
• Indirectness of Index Test: 3rd day SeHCAT retention values were used
Sciarretta Gut Unclear if the OK The reference standard OK (Italy): Prospective study of SeHCAT and results on response to BAST (all patients
8
1987 enrolled patients results (response to received BAST regardless of the results of SeHCAT test). The study included 46
were consecutive. BAST) were not patients (38 with IBS-D and 8 with cholecystectomy). No separate results for IBS-D.
interpreted without
Unclear if the knowledge of the results Applicability concerns
study population of the index test (SeHCAT • indirectness of population: 8/46 (17%) of patients had cholecystectomy
partially overlaps results) (no separate results for the IBS-D patients)
with the patients • (moderate) Indirectness of Index Test: 7th day SeHCAT retention value
used in Sciarretta of < 8% was used as cut-off point
Gastro 19867 (for
sure they used the
same controls for
both studies)
The calculated sensitivity and specificity of SeHCAT for predicting response to BAST (copy-pasted from the HTA report – deleted Merrick 19859)6
22
Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and
cost-effectiveness analysis. Health Technol Assess 2013;17:1-236.
Added post hoc in response to peer-reviewers’ comments:
• Downstream clinical consequences of FP results: patients with diarrhea without BAD will be erroneously be diagnosed as having BAD
and will be treated with BAST, thus delaying the true diagnosis and using a costly treatment, that will be unlikely to be effective and has
common, although usually non-serious, adverse effects
• Downstream clinical consequences of FN results: patients with BAD will be erroneously diagnosed as not having BAD and will be denied
BAST, and will continue suffering from diarrhea while undergoing unnecessary additional investigations and treatments.
Figure showing the confidence intervals for sensitivity and specificity of SeHCAT for predicting response to BAST (copy-pasted from the HTA
report – Merrick 19859 should be ignored; also there is a typo in the legend of X-axis: it should read “1-specificity”6
23
Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and
cost-effectiveness analysis. Health Technol Assess 2013;17:1-236.
Our assessment of the quality of evidence:
Overall
Other Quality of
evidence
Two DTA studies
(Sciarretta Gastro ⊕⊝⊝⊝ ⊕⊝⊝⊝
7 Serious a Not serious Serious b Very serious c None VERY LOW VERY LOW
1986; Sciarretta
Gut 19878)
a. High risk of bias for Index test and Reference standard (see QUADAS-2 table)
b. indirectness of population and index test (see applicability concerns in QUADAS-2 table)
24
c. The lower limits of the confidence intervals for sensitivity and specificity cross the threshold for clinically useful diagnostic tests; very small sample sizes (13 and 46 patients; there might
even be overall among the populations of the two studies)
In conclusion, the only diagnostic accuracy results for SeHCAT, are derived from two studies conducted by one group of investigators. There is
serious risk of bias, serious indirectness and very serious imprecision. There is VERY LOW quality evidence, which seems to be inefficient to
support or refute the clinical utility of SeHCAT in patients with IBS-D. There is no evidence on the diagnostic accuracy of SeHCAT for patients
with Crohn’s disease without TI resection
• Balance between benefits and harms: The harms of using SeHCAT should be considered
o Radiation risks (for the patients (esp. the gallbladder), the personnel and the environment)
o Inconvenience, anxiety while awaiting to have the test, delay in initiating BAST
o Not trying BAST in false negative results
• Patient values and preferences
• Cost and recourse requirements
for this PICO
Sciarretta IJG 1988 (Sciarretta G, Furno A, Fagioli G, et al. The SeHCAT test: a new radioisotopic diagnostic tool for bile acid malabsorption. Ital J Gastroenterol 1988;20:83-87):
Review article (no access to the full-text pdf)
Merrick BMJ 1985 (Merrick MV, Eastwood MA, Ford MJ. Is bile acid malabsorption underdiagnosed? An evaluation of accuracy of diagnosis by measurement of SeHCAT
retention. Br Med J (Clin Res Ed) 1985;290:665-8) (UK): compared the diagnostic yield of SeHCAT in normal controls and in various groups of patients with chronic diarrhea
(small bowel resection, PUD surgery, IBS, etc.). The positivity rate was high in these patients, but there were no results on the diagnostic accuracy of SeHCAT for BAD, because
there is no comparison with a gold standard).
Some (not very detailed) results on clinical response to cholestyramine are available, but only for those who tested positive for the SeHCAT (most, but not all responded). There
are no results on the response to cholestyramine for the patients with negative SeHCAT, therefore we cannot calculate the diagnostic accuracy of SeHCAT for response to
cholestyramine response either. NOTE: The UK HTA report (Riemsma HTA 2013) concluded that this study reported the efficacy of cholestyramine treatment in the IBS-D
patients who had negative SeHCAT, but we are confident that this is a mistake: such results are not reported anywhere in the paper.
Slattery APT 2015 (Slattery SA, Niaz O, Aziz Q, et al. Systematic review with meta-analysis: the prevalence of bile acid malabsorption in the irritable bowel syndrome with
diarrhoea. Aliment Pharmacol Ther 2015;42:3-11): SRMA that assessed the diagnostic yield of SeHCAT in IBS-D. No results on diagnostic accuracy.
Wedlake APT 2009 (Wedlake L, A'Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients
with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30:707-17): SRMA that assessed the diagnostic yield of SeHCAT in IBS-D. No results on
diagnostic accuracy. It found a “dose-response relationship according to severity of malabsorption to treatment with a bile acid binder: response to colestyramine occurred in
25
96% of patients with <5% retention, 80% at <10% retention and 70% at <15% retention” but the studies were not blinded and there were no results for patients with negative
SeHCAT (retention > 15%)
Pattni BMB 2009 (Pattni S, Walters JR. Recent advances in the understanding of bile acid malabsorption. Br Med Bull 2009;92:79-93): Narrative review of the pathophysiology of
idiopathic BAM. No specific data or references to studies with data on the diagnostic accuracy of SeHCAT.
Murray SJG 2017 (Murray IA, Murray LK, Woolson KL, et al. Incidence and predictive factors for positive (75)SeHCAT test: improving the diagnosis of bile acid diarrhoea. Scand J
Gastroenterol 2017;52:698-703) (UK): retrospective observational study of 387 consecutive patients undergoing SeHCAT. There were no significant differences in the response
rates to cholestyramine treatment according to the severity of the SeHCAT results: response 66.7% (mild), 78.6% (moderate), and 75.9% (severe BAD). The response rate of
those with normal SeHCAT was not mentioned.
Summers BMJOG 2016 (Summers JA, Peacock J, Coker B, et al. Multicentre prospective survey of SeHCAT provision and practice in the UK. BMJ Open Gastroenterol
2016;3:e000091) (UK): prospective multicentre observational study of 1036 patients undergoing SeHCAT. No diagnostic accuracy data. Follow up information (with info
regarding treatment with BAS and response) was reported for only 340 out of 1036 patients.
Orekoya CM 2015 (Orekoya O, McLaughlin J, Leitao E, et al. Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. Clin Med (Lond)
2015;15:252-7) (UK): retrospective observational study of 264 consecutive patients undergoing SeHCAT. “Response to BAS therapies decreased with reduced severity of BAM,
although not reaching statistical significance”. No diagnostic accuracy data.
Vijayvargiya CGH 2013 (Vijayvargiya P, Camilleri M, Shin A, et al. Methods for diagnosis of bile acid malabsorption in clinical practice. Clin Gastroenterol Hepatol 2013;11:1232-
9): narrative review of methods for diagnosis of bile acid malabsorption in clinical practice. For the diagnostic accuracy of SeHCAT, the results from Sciarretta Gastro 1986 are
used (we have assessed the original study separately)
Smith NMC 2013 (Smith MJ, Perkins AC. A survey of the clinical use of SeHCAT in the UK. Nucl Med Commun 2013;34:306-13) (UK): survey of the clinical use of SeHCAT in the
UK. No original diagnostic accuracy data.
Borghede EJIM 2011 (Borghede MK, Schlutter JM, Agnholt JS, et al. Bile acid malabsorption investigated by selenium-75-homocholic acid taurine ((75)SeHCAT) scans: causes and
treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-40) (Denmark): Retrospective cohort study of 289 patients
with chronic watery diarrhea undergoing SeHCAT scan. No diagnostic accuracy data.
Seetharam SJG 2011 (Seetharam P, Rodrigues G. Short bowel syndrome: a review of management options. Saudi J Gastroenterol 2011;17:229-35): Narrative review of the
management options for sort bowel syndrome.
Bajor DDS 2008 (Bajor A, Kilander A, Sjovall H, et al. The bile acid turnover rate assessed with the (75)SeHCAT test is stable in chronic diarrhoea but slightly decreased in healthy
subjects after a long period of time. Dig Dis Sci 2008;53:2935-40) (Sweden): Assessment of repeat SeHCAT tests in patients with diarrhea (median interval 44 months) and in
healthy volunteers (interval 16 years). No diagnostic accuracy data.

PICO 3: In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use SeHCAT testing to identify patients with
BAD?
JUDGEMENT

TEST ACCURACY ○ Very inaccurate
○ Inaccurate
26
○ Accurate
○ Very accurate
○ Varies
○ Don't know

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
OF TEST ACCURACY
○ High
burden of the test?
○ Very low
○ High
○ Very low
OF MANAGEMENT'S EFFECTS ○ Moderate
○ High
27
○ Very low
○ Low
○ Moderate
○ High

○ Very low
○ Low
○ High
○ Varies
○ Don't know

○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

CERTAINTY OF EVIDENCE OF ○ Very low
REQUIRED RESOURCES ○ Low
○ Moderate
28
○ High
○ Varies

○ No
○ Probably no
○ Probably yes
ACCEPTABILITY
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
FEASIBILITY
○ Yes
○ Varies
○ Don't know
References for PICO 3

1. Ludgate SM, Merrick MV. The pathogenesis of post-irradiation chronic diarrhoea: measurement of SeHCAT and B12 absorption for
differential diagnosis determines treatment. Clin Radiol 1985;36:275-8.
2. Murray IA, Murray LK, Woolson KL, et al. Incidence and predictive factors for positive (75)SeHCAT test: improving the diagnosis of bile
acid diarrhoea. Scand J Gastroenterol 2017;52:698-703.
3. Gracie DJ, Kane JS, Mumtaz S, et al. Prevalence of, and predictors of, bile acid malabsorption in outpatients with chronic diarrhea.
Neurogastroenterol Motil 2012;24:983-e538.
4. Smith MJ, Cherian P, Raju GS, et al. Bile acid malabsorption in persistent diarrhoea. J R Coll Physicians Lond 2000;34:448-51.
29
5. Valdes Olmos R, den Hartog Jager F, Hoefnagel C, et al. Imaging and retention measurements of selenium 75 homocholic acid
conjugated with taurine, and the carbon 14 glycochol breath test to document ileal dysfunction due to late radiation damage. Eur J Nucl
Med 1991;18:124-8.
6. Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and
measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis. Health Technol Assess 2013;17:1-236.
7. Sciarretta G, Vicini G, Fagioli G, et al. Use of 23-selena-25-homocholyltaurine to detect bile acid malabsorption in patients with illeal
dysfunction or diarrhea. Gastroenterology 1986;91:1-9.
8. Sciarretta G, Fagioli G, Furno A, et al. 75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its
correlation with small bowel transit. Gut 1987;28:970-5.
9. Merrick MV, Eastwood MA, Ford MJ. Is bile acid malabsorption underdiagnosed? An evaluation of accuracy of diagnosis by
measurement of SeHCAT retention. Br Med J (Clin Res Ed) 1985;290:665-8.
PICO 4: In patients with small intestinal Crohn's disease without objective evidence of inflammation who have persistent diarrhea, should we
use SeHCAT testing?
In patients with small intestinal Crohn's disease without objective evidence of inflammation who have persistent diarrhea, we suggest SeHCAT testing.
The underlying questions:
• In patients with small intestinal Crohn's disease and persistent diarrhea despite adequate IBD therapy, what is the diagnostic accuracy
of SeHCAT testing (compared to a reference standard) for
o (a) diagnosing BAD and
o (b) for predicting response to BAST?
• In patients with small intestinal Crohn's disease and persistent diarrhea despite adequate IBD therapy, does the use of SeHCAT testing
improve clinical outcomes (compared to not using SeHCAT testing)
None of the 7 tagged papers provide any information related to the above questions. The UK HTA report (Riemsma HTA 2013)1 has very
rigorously searched for evidence for these questions, and concluded that there is no relevant study (see comments for PICO #4)
An observational cohort study (Smith. JRCPL 2000)2 appeared relevant, but on close inspection does not provide direct qualitative data for this
PICO. This study included patients with diarrhea and underlying GI diseases (Crohn’s disease with ileal resection, unoperated Crohn’s disease;
30
post-vagotomy and pyloroplasty +/- cholecystectomy). There were 44 patients with unoperated Crohn’s disease in clinical remission (other than
diarrhea) and with normal hematology, plasma viscosity and CRP. SeHCAT testing was abnormal (<10% retention) in 24/44 (54%). Of the 24 with
positive SeHCAT, 20 received treatment: Initial treatment was convectional (prednisolone +/- 5 ASA) with BAST used when conventional
treatment failed: 11 responded to prednisolone +/- 5 ASA, 8 responded to BAST and 1 failed both treatments. The duration of the treatments
was not stated. The outcome assessment was not described. It is unclear why some patients positive SeHCAT did not receive treatment and
what the outcome was. It is unclear if patients with negative SeHCAT received treatment and what the outcome was.

Note: the risk of bias assessment refers to the data extracted on DTA of SeHCAT for predicting response to BAST (if we attempt to assess the studies for the DTA of
SeHCAT for diagnosing “BAD”, then the risk of bias is substantially higher)
Study Patient Index test (here: Reference standard Flow and timing Comments
selection SeHCAT) (here: response to BAST)
Smith 20002 Unclear if the OK Response to BAST was reported only Results have not It is impossible to calculate diagnostic accuracy or the effects of the
enrolled for 20/24 positive SeHCAT. No been reported management that is guided by the test results, without knowledge of
patients were outcomes for those with negative for all patients results in the control group (those with negative SeHCAT).
consecutive SeHCAT
Applicability concerns
The reference standard results • indirectness of intervention/reference standard: patients
(response to BAST) were not were treated with conventional treatment first
interpreted without knowledge of the
results of the index test (SeHCAT
results)
The dose and duration of BAST and

the definition of response are unclear
Quality of evidence:
Overall
Other Quality of
evidence
1 DTA study Very ⊕⊝⊝⊝ ⊕⊝⊝⊝
Not serious Not serious b Very serious c None
(Smith 20002) serious a VERY LOW VERY LOW
a. High risk of bias for Reference standard and flow (see QUADAS-2 table)
b. There is moderate indirectness of intervention/reference standard (see applicability concerns in QUADAS-2 table)
c. Very small sample size
31
There is VERY LOW-quality evidence in support of this PICO.
• Balance between benefits and harms when using vs. not using SeHCAT in this situation
• Cost and recourse utilization

PICO 4: In patients with small intestinal Crohn's disease without objective evidence of inflammation and persistent diarrhea, should we use
SeHCAT testing?
JUDGEMENT

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know
32
○ Very low
○ Low
○ Moderate
OF TEST ACCURACY
○ High
burden of the test?
○ Very low
○ High
○ Very low
○ Low
○ Moderate
○ High
○ Very low
○ Low
○ Moderate
○ High

○ Very low
○ Low
○ High
BALANCE OF EFFECTS Does the balance between desirable and undesirable effects favor the intervention or the comparison?
33
○ Probably favors the intervention
○ Varies
○ Don't know

○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
REQUIRED RESOURCES
○ High
○ Varies

○ No
○ Probably no
○ Probably yes
ACCEPTABILITY
○ Yes
○ Varies
○ Don't know
FEASIBILITY Is the intervention feasible to implement?
34
○ No
○ Probably no
○ Probably yes
○ Yes
○ Varies
○ Don't know

PICO A (no recommendation): In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use a FGF-19 assay to
identify possible BAD?
• In patients with chronic diarrhea and clinical features suggestive of BAD, what is the diagnostic accuracy of C4 and FGF assays compared
to a reference standard for
o (a) diagnosing BAD and
o (b) for predicting response to BAST?
• In patients with chronic diarrhea and clinical features suggestive of BAD, does the use of C4 and FGF assays improve clinical outcomes
(compared to not using C4 and FGF assays)
Supporting evidence
Important note about the reference standard: SeHCAT has been formally assessed for a previous PICO for this guideline and it was concluded
that there is very low quality of evidence for the diagnostic accuracy of SeHCAT (derived from only 2 studies conducted by one group of
investigators, with serious risk of bias, serious indirectness and very serious imprecision). Therefore, unless we have high quality of evidence for
35
an almost perfect diagnostic accuracy for SeHCAT, it cannot be considered reference standard in studies that aim to measure the diagnostic
accuracy of other tests (such as C4 and FGF assays). The following studies compared C4 and/or FGF against SeHCAT as reference standard:
1
Johnston AJG 2016 (UK): exhaustive study of possible pathophysiology mechanisms for low serum FGF19 in patients with primary BAD. Did not compare with a gold standard
other than SeHCAT
2
Borup JGH 2015 (Denmark): Assessed if single postprandial sampling of FGF19 has greater discriminative value than fasting FGF19 for detection of BAD among patients with
diarrhea. Did not compare with a gold standard other than SeHCAT
3
Pattni APT 2013 (UK): compared prospectively SeHCAT and FGF19 in patients with chronic diarrhoea of unknown aetiology. No gold standard other than SeHCAT. Limited
(retrospective data, most patients missing) report of response to BAST, but only for the SeHACT positive group.
4
Sauter DDS 1999 (Germany): compared prospectively SeHCAT and C4 in patients with chronic diarrhea. No gold standard other than SeHCAT.
5
Farkkila CS 1996 (Finland): case-control design DTA: patients with CD who had TI resections vs. healthy controls. Compared various plasma cholesterol precursors with SeHCAT
and with fecal bile acids (but did not describe the methods). Unable to estimate diagnostic accuracy for patients with chronic diarrhea of unknown etiology
Brydon EJGH 19966 (UK): assessed the association between C4 and SeHCAT in a group of patients with chronic diarrhea (IBS-D and various diseases). Reported response rates to
BAST, but only for SeHACT positive patients. No gold standard other than SeHCAT.
7
Eusufzai Gut 1993 (Sweden): assessed the association between C4 and SeHCAT in a group of patients with chronic diarrhea (most had various organic diseases). No gold
standard other than SeHCAT.
Overall, the above studies showed good correlation between C4 and SeHCAT and between FGF and SeHCAT. After a discussion at the face-to-
face meeting, it was agreed to include these studies is the Evidence Tables, acknowledging that the true diagnostic accuracy cannot be estimated
and that the quality of evidence from such studies will be very low.
Among the identified papers, only one study (Vijayvargiya APT 20178) provides evidence on DTA outcomes for this PICO compared to a reference
standard that directly measures bile acid malabsorption (28 h fecal BA). No study has reported clinical outcomes from the use vs. not use of
these assays.
The Risk of Bias assessment and the QoE assessment are identical for both C4 and FGF19:
Study Patient Index test Reference standard Flow and Comments
selection (here: C4 or (here: 28 h fecal timing
FGF19) bile acids)
Vijayvargiya Unclear if the Unclear if the Unclear if the Unclear if (US): DTA study on patients with IBS-D (some have had cholecystectomy) who underwent
APT 20178 enrolled index test results reference standard there was measurement of C4 and FGF19.
patients were (C4 or FGF19) results (28 h fecal there an For a proportion of the patients (30 patients), older (measured probably 5 years previously)
consecutive or were interpreted BA) were appropriate values of 28 h fecal bile acids were available and these were used as gold standard for BAD.
random. without interpreted without interval These 30 patients had C4 and FGF19 measured both at the time of the study and 5 years earlier.
knowledge of the knowledge of the between the Unclear if the new or the old measurements (for C4 and FGF19) were used for the calculation of
results of the results of the index index test DTA compared to the old fecal BA measurements
reference test (C4 or FGF19) and • When patients with cholecystectomy were excluded, serum C4 showed 40% sensitivity, 85%
standard (28 h reference specificity, 40% PPV and 85% NPV to diagnose BAD.
36
fecal BA) standard • For FGF19, exclusion of patients with prior cholecystectomy resulted in 20% sensitivity, 75%
specificity, 17% PPV and 79% NPV to diagnose BAD.
Note: the assay and method of measurement of fecal BA is not described in detail in this paper.
The reference is a paper on an assay for measurement of BA in plasma, not feces (Tagliacozzi et
al. Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray
tandem mass spectrometry: a simple and rapid one-step method. Clin Chem Lab Med.
2003;41:1633-1641). However, we are aware that this group has successfully adapted a method
used with serum samples to measure fecal total and individual BAs (Shin CGH 2013).
Applicability concerns: no concerns (provided that we use the results produced after the
exclusion of patients with prior cholecystectomy)
Overall
Other Quality of
evidence
1 DTA study
Moderately ⊕⊝⊝⊝ ⊕⊝⊝⊝
(Vijayvargiya APT 2017) Not serious Not serious Very serious b None
serious a VERY LOW VERY LOW
N < 30
Multiple DTA studies
⊕⊝⊝⊝ ⊕⊝⊝⊝
that used SeHCAT as Very serious d Not serious Serious Not serious None VERY LOW VERY LOW
reference standard c
a. Unclear risk of bias for all domains (see QUADAS-2 table)
b. The lower limits of the confidence intervals for sensitivity and specificity cross the threshold for clinically useful diagnostic tests *; small sample sizes (30 patients in the initial analysis; final
analysis had even less patients after excluding those with previous cholecystectomy
c. Pattni APT 2013, Johnston AJG 2016; Borup JGH 2015; Sauter DDS 1999; Farkkila CS 1996; Brydon EJGH 1996; Eusufzai Gut 1993
d. Downrated by two levels due to very low quality of evidence on the diagnostic accuracy of SeHCAT (used as reference standard here)
*The paper does not report 95% CIs for the DTA results. We cannot calculate the CIs for the final results (excluding prior cholecystectomy) because the 2x2 raw data are not shown. However, we are
able to do so for the initial results (see our table below), and this showed that the 95% CI were very wide (about 20 decimal points lower than the point estimate; see results for sensitivity and
specificity highlighted in the red box in the second table below). The 95% CIs for the final results will be slightly wider because the sample size becomes smaller.
37
8
Results as reported in Vijayvargiya APT 2017
Vijayvargiya P, Camilleri M, Carlson P, et al. Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea
in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ther 2017;46:581-588.
38
Our calculation of the 95% CIs for the DTA results for C4:
39
Therefore, there is VERY LOW quality evidence regarding the use of C4 or FGF assays in this population (patients with chronic diarrhea and
clinical features suggestive of BAD).
• Balance between benefits and harms when using vs. not using C4/ FGF19 in this situation
• Cost and recourse utilization
for this PICO
Valentin Gut 2016 (Valentin N, Camilleri M, Altayar O, et al. Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-
analysis. Gut 2016;65:1951-1959): SRMA of the diagnostic yield of SeHCAT, C4 and FGF19 in patients with functional bowel disorder with diarrhea (due to lack of gold standard
no diagnostic accuracy results could be calculated)
Prost CMS 2017 (Prost J-C, Brunner F, Bovet C, et al. A UHPLC–MS/MS method for the quantification of 7α-hydroxy-4-cholesten-3-one to assist in diagnosis of bile acid
malabsorption. Clin Mass Spectrometry 2017;3:1-6): description of a new method (ultra high-performance liquid chromatography–tandem mass spectrometry) to measure C4 in
human serum. Did not compare with a gold standard.
Walters NRGH 2014 (Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2014;11:426-34): Narrative
review. No data on diagnostic accuracy of C4 or FGF19, through comparison with a gold standard other than SeHCAT
9): narrative review of methods for diagnosis of bile acid malabsorption in clinical practice, including C4. No DTA results, other than via comparison with SeHCAT.
Pattni CTG 2012 (Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 and 7alpha-hydroxy-4-cholesten-3-one in the diagnosis of patients with possible bile acid
diarrhea. Clin Transl Gastroenterol 2012;3:e18) (UK): compared C4 and FGF19 in patients with chronic diarrhea. No gold standard was used.
Brydon CGH 2011 (Brydon WG, Culbert P, Kingstone K, et al. An evaluation of the use of serum 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption
causing watery diarrhea. Can J Gastroenterol 2011;25:319-23) (UK): assessed C4 in patients with chronic diarrhea. No gold standard was used. This study was discussed at the
face-to-face meeting because it appeared relevant initially, but on close inspection, it was confirmed that the reference standard was not adequately valid. The reference
standard was the “final diagnosis [that] was determined based on medical history and investigations, serum levels of 7HCO [C4] and response to cholestyramine”. There is
serious incorporation bias (index test being part of the reference standard) and differential verification bias (patients who had negative C4 test were not assessed for BAD with
the “reference standard”). Therefore there are no data on false negatives and true negatives, therefore diagnostic accuracy cannot be possibly calculated (it is unclear how the
ROC curves shown in the paper were produced)
40
Camilleri NGM 2009 (Camilleri M, Nadeau A, Tremaine WJ, et al. Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid
malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil 2009;21:734-e43) (US):
described the development of a serum 7aC4 assay, normal values, and compared results from healthy controls, patients with ileal CD or resection, and patients with IBS-D or IBS-
C. No diagnostic accuracy data (no gold standard was used)

JUDGEMENT

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know

○ Very low
OF TEST ACCURACY ○ Moderate
○ High
41
burden of the test?
○ Very low
○ High
○ Very low
○ Low
○ Moderate
○ High
○ Very low
○ Low
○ Moderate
○ High

○ Very low
○ Low
○ High
BALANCE OF EFFECTS ○ Does not favor either the intervention or the comparison
42
○ Varies
○ Don't know

○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
REQUIRED RESOURCES
○ High
○ Varies

○ No
○ Probably no
○ Probably yes
ACCEPTABILITY
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
FEASIBILITY ○ Probably yes
○ Yes
○ Varies
43
○ Don't know

PICO A (no recommendation): In patients with chronic diarrhea including IBS-D and functional diarrhea, should we use a FGF-19 assay to
identify possible BAD?
JUDGEMENT

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know

○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
OF TEST ACCURACY
○ High
CERTAINTY OF THE EVIDENCE What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or
44
OF TEST'S EFFECTS burden of the test?
○ Very low
○ Low
○ Moderate
○ High
○ Very low
○ Low
○ Moderate
○ High
○ Very low
○ Low
○ Moderate
○ High

○ Very low
○ Low
○ High
○ Varies
○ Don't know
45
○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
REQUIRED RESOURCES
○ High
○ Varies

○ No
○ Probably no
○ Probably yes
ACCEPTABILITY
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
FEASIBILITY
○ Yes
○ Varies
○ Don't know
46
References
References for PICO 5 & PICO A
1. Johnston IM, Nolan JD, Pattni SS, et al. Characterizing factors associated with differences in FGF19 blood levels and synthesis in patients
with primary bile acid diarrhea. Am J Gastroenterol 2016;111:423-32.
2. Borup C, Syversen C, Bouchelouche P, et al. Diagnosis of bile acid diarrhoea by fasting and postprandial measurements of fibroblast
growth factor 19. Eur J Gastroenterol Hepatol 2015;27:1399-402.
3. Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19
serum assay and SeHCAT retention. Aliment Pharmacol Ther 2013;38:967-76.
4. Sauter GH, Munzing W, von Ritter C, et al. Bile acid malabsorption as a cause of chronic diarrhea: diagnostic value of 7alpha-hydroxy-4-
cholesten-3-one in serum. Dig Dis Sci 1999;44:14-9.
5. Farkkila MA, Kairemo KJ, Taavitsainen MJ, et al. Plasma lathosterol as a screening test for bile acid malabsorption due to ileal resection:
correlation with 75SeHCAT test and faecal bile acid excretion. Clin Sci (Lond) 1996;90:315-9.
6. Brydon WG, Nyhlin H, Eastwood MA, et al. Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole
body retention in the assessment of bile acid induced diarrhoea. Eur J Gastroenterol Hepatol 1996;8:117-23.
7. Eusufzai S, Axelson M, Angelin B, et al. Serum 7 alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid
malabsorption in patients with diarrhoea: correlation to SeHCAT test. Gut 1993;34:698-701.
8. Vijayvargiya P, Camilleri M, Carlson P, et al. Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis
of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ther 2017;46:581-588.
Role of BAST in the diagnosis of BAD
A. In patients with suspected BAD, what is the diagnostic accuracy of BAST (compared to a reference standard- which has to be better than
SeHCAT) for diagnosing BAD
B. In patients with suspected BAD, does the use of BAST improve clinical outcomes (compared to using one of the tests for BAD (SeHCAT,
C4, FGF19))
Four papers have been tagged to this PICO. None provides evidence for underlying question A.
47
One paper provides evidence for underlying question B:
• Riemsma HTA 20131: This is a rigorous UK HTA project, presented in detail under PICO 4. One of the questions that the UK HTA project
has assessed is in fact assessed is almost the inverse of our “underlying question B”: in patients with IBS-D or Crohn’s without resection,
does the use of SeHCAT improve clinical outcomes and is it cost-effective compared to using BAST (without SeHCAT)?
• There were no primary studies that assessed such outcomes, however the HTA team conducted a cost-effectiveness analysis: the
conclusion was that “considerable decision uncertainty exists and that no firm conclusions can be formulated about which strategy is
optimal”
Therefore, there are no comparative or diagnostic primary studies addressing the underlying questions.
Through a CE analysis, there is VERY LOW quality of evidence for uncertainty regarding the optimal strategy.
Other Quality of Overall quality of

Studies Risk of bias Inconsistency Indirectness Imprecision
considerations Evidence evidence
1 CE study (Riemsma ⊕⊝⊝⊝ ⊕⊝⊝⊝

Serious a Serious b Serious c Not serious None
HTA 2013)1 VERY LOW VERY LOW
a. High risk of bias of the studies that informed the CE analysis (see QUADAS-2 table for PICO 4)
b. Various scenarios in the CE analysis showed widely differing and/or opposite results
c. No direct studies have been identified; the CE analysis can only provide indirect evidence.

JUDGEMENT

○ Very inaccurate
○ Inaccurate
○ Accurate
TEST ACCURACY
○ Very accurate
○ Varies
○ Don't know
48
○ Trivial
○ Small
○ Moderate
DESIRABLE EFFECTS
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
UNDESIRABLE EFFECTS
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
OF TEST ACCURACY
○ High
burden of the test?
○ Very low
○ High
○ Very low
○ Low
○ Moderate
○ High
CERTAINTY OF THE EVIDENCE ○ Very low
OF TEST RESULT/MANAGEMENT ○ Low
○ Moderate
49
○ High

○ Very low
○ Low
○ High
○ Varies
○ Don't know

○ Large costs
○ Moderate costs
○ Large savings
○ Varies
○ Don't know

○ Very low
○ Low
○ Moderate
REQUIRED RESOURCES
○ High
COST EFFECTIVENESS Does the cost-effectiveness of the intervention favor the intervention or the comparison?
50
○ Varies

○ No
○ Probably no
○ Probably yes
ACCEPTABILITY
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
FEASIBILITY
○ Yes
○ Varies
○ Don't know

Role of BAST in the induction treatment of BAD
PICO 7: In patients with Type 1 or Type 3 BAD, should we use treatments for remediable causes (e.g. Crohn’s, microscopic colitis, SIBO) in
addition to treatment for BAD for induction of clinical response?
51
Cohort studies
Similar for Outcome detection Free of other
Study Follow-up complete Comments
prognostic factors similar bias
• Open label, non-randomized cohort study (Group 1: CD with ileal resection, in

remission; Group 2: CD, unoperated, in remission; Group 3: vagotomy and
No pyloroplasty +/- choly; Group 4: IBS-D. All tested for BAM with 7d SeHCAT (<
“successful response No 10%).
Smith 20001 was whether “Treatment and F/U • BAM found in a significant proportion of patients n = 75 (97% vs. 54% vs. 58%
(n=56, excluding Unlikely patients felt there information available No vs. 33%).
IBS-D) had been a marked in 96/140 patients • Treated with conventional therapy first n = 56 (prednisolone +/- ASAs, anti-
improvement in the with BAM” diarrheal) and if no response -> BAS.
QoL” - subjective • A significant proportion of patients responded to conventional treatment
(32% vs 55% vs 18% vs 15%) and to BAS (60% vs. 40% vs. 64% vs. 70%). Did
not subgroup response based on SeHCAT result (BAM + vs. BAM -)
GRADE report
Quality Assessment Summary of Findings
No of patients Effect
Quality Overall
Risk of Other Efficacy of “Conventional Relative Absolute
Studies Inconsistency Indirectness Imprecision of quality of
bias considerations treatment” before BAST (95% CI) (95% CI)
Evidence evidence
Efficacy (Clinical response felt by patients)
1 Observational
study ⊕⊝⊝⊝ ⊕⊝⊝⊝ 21 / 56
Seriousa Not serious Seriousb Seriousc None VERY LOW VERY LOW
NA NA
(Cohort Study) (37.5%)
n = 56
a. High risk for selection bias, incomplete follow-up, and outcome detection bias.
b. Not a direct comparison of treatment for “remediable causes” vs. BAST.
c. Small sample size and low event rates.

There are no RCTs or observational studies that directly compared treatment for remediable causes vs. BAST in patients with Type 1
or Type 3 BAD.
One observational cohort study (Smith 20001) included 75 patients with BAD (diagnosed by 7d SeHCAT) and underlying GI diseases
(unoperated and operated Crohn’s disease with ileal resection; post-vagotomy and pyloroplasty +/- cholecystectomy). Only 56
patients were treated. Patients were first treated with “conventional treatment” including prednisolone +/- 5 ASA in Crohn’s and
anti-diarrheals in the others) before BAST was used. A proportion of patients (37.5%) responded to conventional treatment (32%
52
Crohn’s with ileal resection, 55% Crohn’s with no resection, 18% post-vagotomy and pyloroplasty). When conventional treatment
failed, BAST was successful in achieving symptom control in a significant proportion (55.3% of 56) of patients (60% Crohn’s with ileal
resection, 40% Crohn’s with no resection, 64% post vagotomy and pyloroplasty). However, there was no control group or blinding of
interventions, and the outcome was highly subjective with unclear duration of follow-up. The evidence was downgraded for risk of
bias, imprecision and indirectness (not a direct comparison between treatments for remediable causes vs. BAST).
Overall, there is VERY LOW quality evidence supporting the treatment of remediable causes (e.g. Crohn’s disease, vagotomy) prior
to the use of BAST in patients with Type I and III BAD. We found no evidence for other conditions (e.g. SIBO). The decisions to treat
remediable causes first as opposed to using BAST first may be dependent on the underlying disease.
Balance between benefits and harms: treatment of remediable causes of diarrhea (e.g. Crohn’s, SIBO) as opposed to BAST may
achieve better control of symptoms and stop disease progression. Depending on the conditions, the treatment for remediable
causes may also carry more risks or side effects than BAST treatment (e.g. steroids, immunosuppressives, biologics). The
investigations for remediable causes may also be invasive and costly (e.g. colonoscopy).
Patient values and preferences: it is uncertain how patients value side effects or risks of medications that are used to treat the
remediable causes (e.g. immunosuppressive / biologics for Crohn’s disease, antibiotics for SIBO) as opposed to BAST.
Cost: depending on the remediable conditions, treatment cost may be higher (or lower) than with BAST. However, this may be offset
by downstream savings through more effective control of symptoms and disease?
for this PICO
Chande CDBSR 2008 (Chande N, McDonald JW, Macdonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev 2008:CD003575): SR of 10 RCTs
comparing various therapies to either placebo or active comparator in patients with collagenous or microscopic colitis. Most trials did not specify if patients also had BAD. 1 RCT
(Munck 2003) excluded patients with BAD.
Gupta SCC 2015 (Gupta A, Muls AC, Lalji A, et al. Outcomes from treating bile acid malabsorption using a multidisciplinary approach. Support Care Cancer 2015;23:2881-90):
retrospective cohort study of patients with BAD (based on 7-day SeCHAT scan < 20%) post-cancer treatment (GI, GU, gyne, heme, etc). 90/143 patients with BAD also had other
major GI diagnoses (SIBO, pancreatic insufficiency, lactose intolerance, IBD). Followed algorithm to manage BAD (low fat diet, Colesevelam). Did not report whether patients
were treated for their other major GI diagnoses / “remediable causes”.
Vitek IBD 2013 (Vitek L. Bile acid malabsorption in inflammatory bowel disease. Inflamm Bowel Dis 2015;21:476-83): review article on BAM in IBD
Jahnel DMD 2014 (Jahnel J, Fickert P, Hauer AC, et al. Inflammatory bowel disease alters intestinal bile acid transporter expression. Drug Metab Dispos 2014;42:1423-31): ex vivo
study of mucosal biopsy specimens from IBD patients assessed for mRNA expression of intestinal BA transporters, BA detoxifying systems, and nuclear receptors that regulate
BA transport and detoxification. BA handling in IBD is altered.
53
Baert ACB 2004 (Baert D, Coppens M, Burvenich P, et al. Chronic diarrhoea in non collagenous microscopic colitis: therapeutic effect of cholestyramine. Acta Clin Belg
2004;59:258-62): case series of 20 patients with microscopic colitis treated with cholestyramine. Did not specify if patients also had BAD.
Nyhlin Gut 1994 (Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption in Crohn's disease and indications for its assessment using SeHCAT. Gut 1994;35:90-3): case
series of 51 patients with CD who had failed to respond to conventional treatment tested for BAM with SeHCAT. A small subgroup of patients was given cholestyramine with
good response (19/22).
Evidence to Decision framework (management question)

PICO 7: In patients with Type 1 or Type 3 BAD, should we use treatments for remediable causes (e.g. Crohn’s, microscopic colitis, SIBO) in
addition to treatment for BAD for induction of clinical response?
Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know
What is the overall certainty of the evidence of effects?

○ Very low
○ Low
Certainty of evidence ○ Moderate
○ High
Values ○ Possibly important uncertainty or variability
54
Balance of effects ○ Probably favors the intervention
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

RCTs
55
Adequate Incomplete Free of
Allocation Free of
Study sequence Blinding outcome data selective Comments
concealment other bias
generation addressed reporting
• 26 patients with chronic functional watery diarrhea or IBS-D (SeHCAT 7-d
retention < 20%) randomized to cholestyramine 4g bid vs. hydroxypropyl
cellulose x 8 wks.
• Clinical remission: < 3 BMs/d x 1 wk before visit (< 1 watery stool/d). No
difference in clinical remission (53.8% vs. 38.4%; P = 0.43; ITT). Higher mean
Fernandez- % decrease in watery stool number with cholestyramine (-92.4+/- 3.5% vs. -
OK OK OK OK OK OK
Banares 20151 75.8+/-7.1%; P = 0.048).
• No difference in adverse events
• Presence of BAM (SeHCAT < 10%) was not a prerequisite for inclusion (77%
vs. 54%).
• Hydroxypropyl cellulose may be an active drug (bulking effect) – no placebo
group for comparison.
SR of Observational Studies
Similar for
Outcome Follow-up Free of other
Study prognostic Comments
detection similar complete bias
factors
• SR of 23 cohort studies (n = 801) of BAM patients treated with cholestyramine.

Wilcox 20142 No • Treatment success in 67% of patients with < 5% retention, 73% of patients with < 8 -11.7%
(included High risk for retention, 59% of patients with < 15% retention on SeHCAT
studies in No No Unclear performance • 11% patients found cholestyramine intolerable due to unpalatability or side effects
Wedlake bias, selection • Variation in diagnostic testing used for BAM and cut-off value, treatment dose and timing of
3
2009 ) bias etc administration, and definition of clinical response
• No quality assessment of included studies
No • SR of 15 cohort studies (n = 268) patients with I-BAM from IBS-D treated with cholestyramine
Outcomes were • Response in 96% with < 5% retention, 80% with < 10% retention and 70% with < 15% retention on
No
not standardized SeCHAT
High risk for
Wedlake
No
– objective and
Unclear performance • No report of adverse effects
20093 subjective • Variation in cut-off values for SeHCAT, treatment dose and timing of administration, and definition of
bias, selection
reports of response
bias etc
symptomatic • No quality assessment of included studies
improvement
Cohort Studies
Similar for Outcome detection Follow-up

Study Free of other bias Comments
prognostic factors similar complete
56
• Retrospective cohort study (107/207 patients diagnosed with Type 1 – 3
BAD with 10% SeHCAT and started on BAS, only 58 were contactable and
No had f/u data (median f/u was 6.8 yrs)
54% of BAD No • Only 38% of patients were still on BAS during f/u (cholestyramine /
patients who High risk for colestipol / colesevelam) with decreased median bowel freq (6 vs 3). Did
Lin 20164 No OK were started on selection bias, not provide subgroup data on cholestyramine vs. other BAST.
BAS were performance bias, • Assumed 17 patients who stayed on cholestyramine were responders
contactable and etc • Unclear if cholestyramine were used as first line / second line treatments
agreed to f/u • 28% used alternative tx (loperamide, diet, octreotide) had decreased
median bowel freq (7.5 vs. 3)
• 34% d/c tx (poor tolerability of BAS) had no change in stool freq (6 vs. 5)
• Retrospective cohort study of 92 patients with BAM (SeHCAT < 15%)
treated with BAS with f/u data available
No
No • Subjective improvement in frequency, consistency, QOL
High risk for
Subjective report of • Cholestyramine as 1st line (49/87, 56%) had successful response
Orekoya 20155 selection bias,
No symptom No • Only 45% of cholestyramine non-responders were offered colesevelam as
(not tagged) outcome detection
improvement or 2nd line treatment. Colesevelam as 1st line (2/5, 40%) had successful
bias, performance
improved QoL response, as 2nd line (7/15, 47%) had successful response
bias etc
• 20% of patients had Intolerance to cholestyramine
• No patient reported intolerance to colesevelam
GRADE report
Summary of Findings
Quality Assessment
Overall
Other Quality of Relative Absolute
Studies Risk of bias Inconsistency Indirectness Imprecision quality of Cholestyramine Comparator
considerations Evidence (95% CI) (95% CI)
evidence
Efficacy (subjective / objective clinical response – highly variable definitions among studies)
5/13
335 more
(38.5%)
RR 1.87 per 1000
1 RCT Very b ⊕⊝⊝⊝ 7/13 Hydroxypropyl
Not serious Not serious Serious None (0.39 to (from 235
n = 26 seriousa VERY LOW (53.8%) cellulose
8.89) fewer to
(possible
1000 more)
active drug)
⊕⊝⊝⊝
Variation in VERY LOW 559 / 801
diagnostic
1 SR of (69.8%)
testing used
Observational range: 63 to
for BAD and
Studies ⊕⊝⊝⊝ 100%
Seriousc Not serious Seriousd Seriouse cut-off values, VERY LOW
NA NA NA
(Cohort Cholestyramine
treatment
studies) as first-line
dose and
n = 801 treatment in all
timing of
studies
administration,
57
and definition
of clinical
response
(subjective /
objective)
49 / 87
1 Cohort (56.3%)
⊕⊝⊝⊝
study Seriousf Not serious Seriousg Seriouse None VERY LOW Cholestyramine NA NA NA
n = 87 as first-line
treatment
Safety (Adverse events)
0 fewer per
2/ 13 2 / 13 1000 (from
1 RCT Very ⊕⊝⊝⊝ 1.00 (0.12
Not serious Not serious a Seriousb None VERY LOW (15.4%) (15.4%) 135 fewer
n = 26 serious to 8.42)
drug-related drug-related to 1000
more)
11%
1 SRs of Range: 0% to
Observational 46%
Studies c d e ⊕⊝⊝⊝ Cholestyramine
Serious Not serious Serious Serious None VERY LOW NA NA NA
(Cohort intolerable due
studies) to
n = 801 unpalatability
or side effects
a. Not a direct comparison of treatment for cholestyramine vs. other BAST. The comparator was hydroxypropyl cellulose (possible active drug). All patients had SeHCAT 7-d retention < 20%,
but not all patients had BAD (SeHCAT 7-d retention < 10%).
b. Small sample size and low event rates. Optimal information size not met.
c. High risk for selection bias, incomplete follow-up, performance bias, and outcome detection bias. Lack of reporting of adverse effects in many studies.
d. Not a direct comparison of treatment for cholestyramine vs. other BAST. All studies used cholestyramine as first-line treatment. A few studies other BAST as second line treatments.
e. Small sample size and low event rates.
Overall QoE for PICO 8 & 9:

Efficacy:
There are no RCTs comparing cholestyramine vs. other BAST in patients with BAD.
1 RCT included patients with chronic watery diarrhea / IBS-D with 7d SeHCAT < 20% (69% had SeHCAT < 10%), compared
cholestyramine vs. hydroxypropyl cellulose which may be an active drug, and showed no difference in clinical remission (a mean of 3
or fewer stools per day during the week before visit with less than 1 watery stool per day). However, there was a significant
reduction in daily watery stool number with cholestyramine than with hydroxypropyl cellulose. The evidence was downgraded for
imprecision and indirectness (as not a direct comparison for cholestyramine vs. other BAST). Also, not all patients had BAD (SeHCAT
7-day < 10%).
58
There are 1 SRs of observational cohort studies and 1 cohort study published after the SR. Cholestyramine was used as first line
therapy in all studies, other BASTs were offered as second line therapy in a few studies. Among these cohort studies, there was large
variation in study designs, patient populations, inclusion / exclusion criteria, diagnostic testing used for BAD and cut-off values,
treatment dose and timing of administration, and definition of clinical response. Overall, about 70% of patients responded to
cholestyramine as first line treatment (range 63 – 100%). The evidence was downgraded for risk of bias, imprecision, and
indirectness (not a direct comparison of treatment for cholestyramine vs. other BAST).
Overall, there is VERY LOW quality evidence supporting the use of cholestyramine over no treatment in patients with BAD. There is,
however, no direct evidence that cholestyramine is more effective than other BAST.
Safety:
1 RCT found that the rate of drug-related adverse events did not differ between cholestyramine and hydroxypropyl cellulose. In 1 SR
of observational cohort studies, there was lack of reporting of adverse effects in most studies. Overall, 11% of patients found
cholestyramine intolerable due to unpalatability or side effects. The reported rates of adverse events range from 0 to 46% with
no control group for comparison. It is also uncertain whether these adverse events were drug related. There is no direct evidence
that Cholestyramine is associated with more side effects than other BAST.
Adverse events of BAST in non-GI conditions:

In a large RCT of pravastatin vs. pravastatin + cholestyramine6 in patients at increased risk for cardiovascular disease (dyslipidemia
and/or additional risk factors), the rates of GI adverse events were significantly higher with the addition of cholestyramine (269/492,
54.7% cholestyramine + pravastatin vs. 172/1049, 16.4% pravastatin), mainly constipation. The compliance rates were also
significantly lower with the addition of cholestyramine (261/492, 53% vs. 812/1049, 77%).
In a Cochrane SR7 of 6 RCTs (n = 1450 participants) in patients with T2DM and dyslipidemia comparing colesevelam vs. placebo (+/-
antidiabetic agents), the rates of adverse events were similar in both the colesevelam and placebo groups (RR 1.06, 95% CI 0.97-
1.15), and most AEs were minor. Colesevelam was well tolerated. The most common drug-related AEs with colesevelam were
gastrointestinal in nature (mainly constipation, dyspepsia and nausea) and were mild in nature.
Balance between benefits and harms: In the SR of cohort studies, the overall response rate was 69.8% (range 63 – 100%). The
safety of short term use of cholestyramine has also been demonstrated in a RCT and observational studies with minor AEs (bloating
59
and pain, dyspepsia, nausea and vomiting, flatulence, borborygmi, distension, constipation and diarrhea) and unpalatability. Of the
23 cohort studies in 1 SR (Wilcox 20142), 30% reported treatment failure with first line cholestyramine therapy and did not continue
with treatment due to ineffectiveness / side effects / unpalatability (11% found cholestyramine intolerable due to unpalatability or
side effects, 16% found therapy ineffective, 0.12% was noncompliant with treatment regime, 2% unclear reasons).
Patient values and preferences: unknown if patient values more the reduction in diarrhea vs. side effects / unpalatability of
Cholestyramine. Also, Cholestyramine administered as granules and powders, less convenient, and less palatable? Need to time with
administration of other medications.
Cost: lower cost compared to other BASTs
Data from Canadian Drug Expert Committee (CDEC 2012 Common Drug Review):
Cholestyramine - $1.32 to 7.90; 4g to 24g
Colesevelam - $4.40 to $7.70; 2.5g to 4.5g
Colestipol - $0.91 to $5.46; 5 g to 30g
Uncertainty regarding the dose equivalence of colesevelam vs. cholestyramine and colestipol.
for this PICO
Mottacki APT 2016 (Mottacki N, Simren M, Bajor A. Review article: bile acid diarrhoea - pathogenesis, diagnosis and management. Aliment Pharmacol Ther 2016;43:884-898):
Review article.
Barkun CJG 2013 (Barkun AN, Love J, Gould M, et al. Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment. Can J Gastroenterol 2013;27:653-9): Review
article.
treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-40): Retrospective cohort study included in the SR by
Wilcox 2014.
Fernandez-Banares AJG 2007 (Fernandez-Banares F, Esteve M, Salas A, et al. Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics. Am J
Gastroenterol 2007;102:2520-8): Prospective cohort study included in the SR by Wilcox 2014.
Westergaard CTOG 2007 (Westergaard H. Bile acid malabsorption. Curr Treat Options Gastroenterol 2007;10:28-33): Review article.
Wildt SJG 2003 (Wildt S, Norby Rasmussen S, Lysgard Madsen J, et al. Bile acid malabsorption in patients with chronic diarrhoea: clinical value of SeHCAT test. Scand J
Gastroenterol 2003;38:826-30): Retrospective cohort study included in the SR by Wilcox 2014.
Sinha APT 1998 (Sinha L, Liston R, Testa HJ, et al. Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. Aliment
Pharmacol Ther 1998;12:839-44): Prospective cohort study included in the SR by Wilcox 2014.
Niaz JRCPL 1997 (Niaz SK, Sandrasegaran K, Renny FH, et al. Postinfective diarrhoea and bile acid malabsorption. J R Coll Physicians Lond 1997;31:53-6): Retrospective cohort
study included in the SR by Wilcox 2014.
60
Rudberg AR 1996 (Rudberg U, Nylander B. Radiological bile acid absorption test 75SeHCAT in patients with diarrhoea of unknown cause. Acta Radiol 1996;37:672-5): Prospective
cohort study included in the SR by Wilcox 2014.
Luman EJGH 1995 (Luman W, Williams AJ, Merrick MV, et al. Idiopathic bile acid malabsorption: long-term outcome. Eur J Gastroenterol Hepatol 1995;7:641-5): Case series of 23
patients with IBAM who all responded to bile acid chelator (cholestyramine / aluminum hydroxide) follow-up data.
Eusufzai Gut 1993 (Eusufzai S, Axelson M, Angelin B, et al. Serum 7 alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid malabsorption in patients with
diarrhoea: correlation to SeHCAT test. Gut 1993;34:698-701): Prospective cohort study included in the SR by Wilcox 2014.
Ford PM 1992 (Ford GA, Preece JD, Davies IH, et al. Use of the SeHCAT test in the investigation of diarrhoea. Postgrad Med J 1992;68:272-6): Retrospective cohort study included
in the SR by Wilcox 2014.
Galatola EJGH 1992 (Galatola G, Ferraris R, Pellerito R, et al. The prevalence of bile acid malabsorption in irritable bowel syndrome and the effect of cholestyramine: An
uncontrolled open multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7): Prospective cohort study included in the SR by Wilcox 2014.

Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
61
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

Judgement

○ Trivial
Desirable Effects ○ Small
○ Moderate
○ Large
62
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

Feasibility
○ No
63
○ Probably no
○ Probably yes
○ Yes
○ Varies
○ Don't know
References for PICO 8 & 9

1. Fernandez-Banares F, Rosinach M, Piqueras M, et al. Randomised clinical trial: colestyramine vs. hydroxypropyl cellulose in patients with
functional chronic watery diarrhoea. Aliment Pharmacol Ther 2015;41:1132-40.
2. Wilcox C, Turner J, Green J. Systematic review: the management of chronic diarrhoea due to bile acid malabsorption. Aliment Pharmacol
Ther 2014;39:923-39.
3. Wedlake L, A'Hern R, Russell D, et al. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT
scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009;30:707-17.
4. Lin S, Sanders DS, Gleeson JT, et al. Long-term outcomes in patients diagnosed with bile-acid diarrhoea. Eur J Gastroenterol Hepatol
2016;28:240-5.
5. Orekoya O, McLaughlin J, Leitao E, et al. Quantifying bile acid malabsorption helps predict response and tailor sequestrant therapy. Clin
Med (Lond) 2015;15:252-7.
6. Eriksson M, Hadell K, Holme I, et al. Compliance with and efficacy of treatment with pravastatin and cholestyramine: a randomized study
on lipid-lowering in primary care. J Intern Med 1998;243:373-80.
7. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus. Cochrane Database Syst Rev 2012;12:CD009361.
PICO 10: In patients with BAD who are unable to tolerate cholestyramine, should an alternate BAST be used for induction of clinical
response?
RCTs
Allocation
Study sequence Blinding outcome data selective Free of other bias Comments
concealment
Inflammatory • 26 patients with CD in remission with BAM (cholestenone >
Beigel 20141 OK OK OK OK OK disease cannot be 50ng/mL) randomized to COV 3 x 2 tablets 625mg (3750mg) vs.
completely placebo x 4 wks
64
excluded as • Primary endpt (proportion of pts with > 30% reduction of liquid
remission was stools /d) 69.7% vs. 27.3% (ns ITT, 0.036 PP).
based on CRP < 1 • Secondary endpts: significant reduction of liquid stools and
and CDAI < 150. improvement of stool consistency with COV
• No difference in mild AEs (constipation, bloating and nausea)
• 24 patients with IBS-D randomized to COV 1.875g bid vs. placebo x
12-14 d. Only 4/24 patients had BAM by serum C4. Excluded
Odunsi- • COV had no effect on # of BM/d, but trend to improve stool
Shiyanbade OK Unclear OK OK OK OK consistency (P = 0.12) and ease stool passage (P= 0.048). Did not
20102 subgroup data based on BAM + /-
• No difference in mild AEs (headache, nausea, flatulence, green
colored stools, cramps)
Similar for Outcome
Follow-up Free of other
Study prognostic detection Comments
complete bias
factors similar
• SR of 1 cohort study (Ung 2000) of 12 patients with BAM treated with cholestyraine as 1st line, and due
to poor taste, one patient switched to colestipol with improvement in diarrhea < 1 week that was
maintained after 2 mos
No • SR of 1 RCT and 4 cohort studies (n = 90) treated with Colesevelam.
High risk for • RCT (Odunsi-Shiyanbade 20102) of COV vs. placebo (n = 24): COV -> greater ease of stool passage
performance (p=0.048) and firmer stool consistency (ns).
bias, selection • 3 retrospective cohort studies used COV as 2nd line: 36/63, 57% found tx effective.
Wilcox 20143 No No No
• 1 retrospective cohort study (Wedlake 2009 ) on cancer patients with BAM (SeHCAT < 10%), COV
4
bias, recall bias,
ascertainment as 1st line: 13/15, 87% effective; COV as 2nd line: 17/30, 57% effective.
bias, co- • 19% found tx ineffective, 9% found tx intolerable due to unpalatability or side effects (bloating,
interventions etc constipation, flatulence, N/V)
• Variation in diagnostic testing used for BAM and cut-off value, treatment dose and timing of
administration, and definition of clinical response
Cohort Studies
Similar for Outcome
Follow-up
Study prognostic detection Free of other bias Comments
complete
factors similar
No • Prospective cohort study of 12 patients with IBS-D and “evidence of increased BA synthesis / fecal
High risk for excretion” treated with colesevelam 1875 mg bid x 10 d
Camilleri selection bias, • Colesevelam resulted in significant decrease in the average score of stool consistency from 4.8+/-0.3
Unclear OK OK
20155 performance bias, to 4.4 +/-0.3 (Bristol Stool Form) and numerical reductions in # of BMs (ns). No dichotomous
outcome outcome
detection bias etc • No report of side effects
No No • Retrospective cohort study (107/207 patients diagnosed with Type 1 – 3 BAD with 10% SeHCAT and
Lin 20166 No OK
54% of BAD High risk for started on BAS, only 58 were contactable and had f/u data (median f/u was 6.8 yrs)
65
patients who selection bias, • Only 38% of patients were still on BAS during f/u (17 cholestyramine / 4 colestipol / 1 colesevelam)
were started performance bias, with decreased median bowel freq (6 vs 3). Did not provide subgroup data on cholestyramine vs.
on BAS were etc other BAST
contactable • 28% used alternative tx (loperamide, diet, octreotide) had decreased median bowel freq (7.5 vs. 3)
and agreed to • 34% d/c tx (poor tolerability) had no change in stool freq (6 vs. 5)
f/u
• Retrospective cohort study of 92 patients with BAM (SeHCAT < 15%) treated with BAS with f/u data
No No
available
Subjective High risk for
• Subjective improvement in frequency, consistency, QOL
report of selection bias,
Orekoya • Cholestyramine as 1st line (49/87, 56%) had successful response
No symptom No outcome
20157 • Only 45% of cholestyramine non-responders were offered colesevelam as 2nd line treatment.
improvement detection bias,
Colesevelam as 1st line (2/5, 40%) had successful response, as 2nd line (7/15, 47%) had successful
or improved performance bias
response
QoL etc
• No patient reported colesevelam intolerance.
GRADE report
Summary of findings
Quality Assessment
Overall
Risk of Other Quality of Alternative Relative Absolute
Studies Inconsistency Indirectness Imprecision quality of Comparator
bias considerations Evidence BAST (95% CI) (95% CI)
evidence
Efficacy (subjective / objective clinical response – highly variable definitions among studies)
1000 more
Diagnostic 10/15
per 1000
tests used for (66.7%) 3/11 RR 6.67
1 RCT Not ⊕⊕⊝⊝ (from 65
Not serious Seriousa Seriousb BAD LOW Colesevelam as (27.3%) (1.24 to
n = 26 serious more to
(cholestenone first-line Placebo 35.71)
1000
> 50ng/mL) treatment
more)
Variation in
diagnostic
36 / 63
testing used
(57%)
1 SR of for BAD and
⊕⊕⊝⊝ range 42 –
Observational cut-off values, LOW 100%
Studies (4 treatment ⊕⊝⊝⊝
Seriousc Not serious Not serious Seriousd VERY LOW
Colesevelam as NA NA NA
Cohort dose and
second-line
studies) timing of
treatment after
n = 63 administration,
failure of
and definition
Cholestyramine
of clinical
response
1 Cohort Variation in 7/15
⊕⊝⊝⊝
Study Seriousc Not serious Not serious Seriousd diagnostic VERY LOW (46.7%) NA NA NA
n = 15 testing used Colesevelam as
66
for BAD and second-line
cut-off values, treatment after
treatment failure of
dose and Cholestyramine
timing of
administration,
and definition
of clinical
response
Safety (Adverse events)
62 more
per 1000
RR 1.17
1 RCT Not ⊕⊕⊝⊝ 6 / 15 4 / 11 (from 280
Not serious Seriousa Seriousb None LOW (0.34 to
(n = 26) serious (40.0%) (36.4%) fewer to
5.81)
1000
more)
8/90
1 SR of (9%)
Observational Colesevelam
c d ⊕⊝⊝⊝
Studies Serious Not serious Not serious Serious None VERY LOW intolerable due NA NA NA
(Cohort) to
n = 90 unpalatability
or side effects
a. Alternative BAST was used as first line therapy, and not in patients who were unable to tolerate cholestyramine. 1 RCT (Beigel 2014) may have included patients with active Crohn’s disease.
c. High risk for selection bias, incomplete follow-up, recall bias, and outcome detection bias.
d. Small sample size and low event rates.

Efficacy:
There are no RCTs comparing alternative BASTS to other treatments / placebo in patients with BAD who are unable to tolerate
cholestyramine.
1 RCT (Beigel 20141) assessed Colesevelam as first line treatment vs. placebo in patients with BAD (cholestenone > 50ng/mL) and
Crohn’s disease in remission, and found colesevelam to be more effective than placebo. The study may have included patients with
active Crohn’s as remission was defined as CDAI < 150 points and CRP < 1mg/dL. Clinical response was defined as proportion of pts
with > 30% reduction of liquid stools /d (RR 6.67, 95% CI 1.24 to 35.71). 1 RCT (Odunsi-Shiyanbade 20102) was excluded as the
majority of patients 20/24 (83%) did not have BAD (Serum 7αC4 < 61ng/mL), and the results were not reported based on BAD +/-.
The evidence was downgraded for imprecision and indirectness (alternative BAST was used as first line therapy).
67
There is 1 SR of 4 observational cohort studies and 1 cohort study published after the SR. colesevelam was used as second-line
therapy after failing cholestyramine. Among these cohort studies, there was large variation in study designs, patient populations,
inclusion / exclusion criteria, diagnostic testing used for BAD and cut-off values, treatment dose and timing of administration, and
definition of clinical response. Overall, about 57% of patients responded to colesevelam as second line treatment (range 42 – 100%).
However, with no control group, we cannot exclude a higher likelihood of placebo response, as there may be great expectation
associated with second line colesevelam. The evidence was downgraded for risk of bias and imprecision.
Overall, there is LOW quality evidence supporting the use of colesevelam over no treatment in patients with BAD who are unable to
tolerate Cholestyramine.
For colestipol, there is very limited evidence of its use as second-line treatment after failing cholestyramine. 1 cohort study (Ung
2000) of 12 patients with BAD and collageneous colitis treated with cholestyramine as 1st line, and due to poor taste, 1 patient
switched to colestipol with improvement in diarrhea < 1 week that was maintained after 2 months.
Safety:
1 RCT found that the rate of drug-related adverse events did not differ between colesevelam vs. placebo. All drug-related adverse
events were mild (constipation). In 1 SR of observational cohort studies (Wilcox 20143), 19% patients found colesevelam ineffective;
9% found therapy intolerable due to unpalatability or side effects; 3% felt the treatment regime was too difficult to follow. Side
effects included bloating, constipation, flatulence, nausea and vomiting. There is no direct evidence that colesevelam is associated
with more/ less side effects than cholestyramine or other BAST.
Adverse events of BAST in non-GI conditions:

In a large RCT of pravastatin vs. pravastatin + cholestyramine8 in patients at increased risk for cardiovascular disease (dyslipidemia
and/or additional risk factors), the rates of GI adverse events were significantly higher with the addition of cholestyramine (269/492,
54.7% cholestyramine + pravastatin vs. 172/1049, 16.4% pravastatin), mainly constipation. The compliance rates were also
significantly lower with the addition of cholestyramine (261/492, 53% vs. 812/1049, 77%).
In a Cochrane SR9 of 6 RCTs (n = 1450 participants) in patients with T2DM and dyslipidemia comparing colesevelam vs. placebo (+/-
antidiabetic agents), the rates of adverse events were similar in both the colesevelam and placebo groups (RR 1.06, 95% CI 0.97-
1.15), and most AEs were minor. Colesevelam was well tolerated. The most common drug-related AEs with colesevelam were
gastrointestinal in nature (mainly constipation, dyspepsia and nausea) and were mild in nature.
68
Balance between benefits and risks: In the SR of cohort studies, the overall response rate of colesevelam as a second-line
treatment was 57% (range 42 – 100%). The safety of short term use of alternative BASTS (Colesevelam) has been demonstrated in
RCTs with minor AEs (bloating, nausea, and constipation). Of the 4 cohort studies in 1 SR, 9% found colesevelam intolerable due to
unpalatability or side effects, 19% found therapy ineffective. No significant AEs was found in RCTs.
Patient values and preferences: Administered more easily (tablet rather than granules and powders) and more convenient than
cholestyramine. Apparent lack of effect on the bioavailability of co-administered drugs based on pharmacokinetics study (see PICO
17). May increase compliance, particularly in patients who require the use of multiple medications.
Cost: higher cost with colesevelam compared to cholestyramine (7x). Lower cost with Colestipol compared to cholestyramine.
Data from Canadian Drug Expert Committee (CDEC 2012 Common Drug Review):
Cholestyramine - $1.32 to 7.90; 4g to 24g
Colesevelam - $4.40 to $7.70; 2.5g to 4.5g (most studies used close to 4g dose)
Colestipol - $0.91 to $5.46; 5 g to 30g
Uncertainty regarding the dose equivalence of colesevelam vs. cholestyramine and colestipol.
for this PICO
Wedlake Clin Ther 2009 (Wedlake L, Thomas K, Lalji A, et al. Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a
retrospective chart review and patient questionnaire. Clin Ther 2009;31:2549-58): Retrospective cohort study included in the SR by Wilcox 2014.
Review article.
Camilleri Gut Liver 2015 (Camilleri M. Bile acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver 2015;9:332-9). Review article.
Camilleri ERGH 2014 (Camilleri M. Advances in understanding of bile acid diarrhea. Expert Rev Gastroenterol Hepatol 2014;8:49-61): Review article.
Arnold AJSP 2014 (Arnold MA, Swanson BJ, Crowder CD, et al. Colesevelam and colestipol: novel medication resins in the gastrointestinal tract. Am J Surg Pathol 2014;38:1530-
7): BAS resins (morphologic description of colesevelam, colestipol and cholestyramine) in biopsy specimens.
Tziomalos CPD 2013 (Tziomalos K, Karagiannis A, Mikhailidis DP, et al. Colesevelam: a new and improved bile acid sequestrant? Curr Pharm Des 2013;19:3115-23): Review article
on Colesevelam in cardiovascular prevention strategies.
article.
69
PICO 10: In patients with BAD who are unable to tolerate cholestyramine, should an alternate BAST be used for induction of clinical
response?
Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
Balance of effects
○ Varies
70
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

1. Beigel F, Teich N, Howaldt S, et al. Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's
disease: a randomized, double-blind, placebo-controlled study. J Crohns Colitis 2014;8:1471-9.
2. Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, et al. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on
intestinal transit and bowel function. Clin Gastroenterol Hepatol 2010;8:159-65.
Ther 2014;39:923-39.
4. Wedlake L, Thomas K, Lalji A, et al. Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients
with cancer: a retrospective chart review and patient questionnaire. Clin Ther 2009;31:2549-58.
5. Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable
bowel syndrome. Aliment Pharmacol Ther 2015;41:438-48.
6. Lin S, Sanders DS, Gleeson JT, et al. Long-term outcomes in patients diagnosed with bile-acid diarrhoea. Eur J Gastroenterol Hepatol
2016;28:240-5.
Med (Lond) 2015;15:252-7.
8. Eriksson M, Hadell K, Holme I, et al. Compliance with and efficacy of treatment with pravastatin and cholestyramine: a randomized study
on lipid-lowering in primary care. J Intern Med 1998;243:373-80.
9. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus. Cochrane Database Syst Rev 2012;12:CD009361.
71
PICO 11: In patients with BAD receiving empiric BAST, should gradual daily dose titration vs. no titration be used to minimize side effects?
Similar for Outcome

Follow-up Free of other
Study prognostic detection Comments
complete bias
factors similar
• SR of 23 cohort studies (n = 801) of BAM patients treated with cholestyramine, 1 RCT and 4 cohort studies of
colesevelam, 1 cohort study (1 patient) switched to colestipol after failing cholestyramine.
No
• Treatment dose and timing of administration not standardized and were highly variable among studies.
High risk for
Wilcox • Cholestyramine: generally started at low dose 2-4 g/d and titrated to response (no mention of dose
No No Unclear performance
20141 titration in some studies)
bias, selection
• Colesevelam / colestipol: no mention of dose titration
bias etc
• 11% patients found cholestyramine intolerable due to unpalatability or side effects
• 9% patients found colesevelam intolerable due to unpalatability or side effects
Cohort Studies
Similar for
factors
• Retrospective cohort study of 92 patients with BAM (SeHCAT < 15%) treated with BAS with f/u
data available
No
• Subjective improvement in frequency, consistency, QOL
No High risk for
• Cholestyramine: practice varied, but generally prescribed low dose (2-4 g/d) and titrated dose
Subjective report selection bias,
Orekoya based on response (max 4-24g/d)
No of symptom No outcome
20152 • Cholestyramine as 1st line (49/87, 56%) had successful response. 20% of patients had
improvement or detection bias,
Intolerance to cholestyramine
improved QoL performance
bias etc • Only 45% of cholestyramine non-responders were offered colesevelam as 2nd line treatment.
Colesevelam as 1st line (2/5, 40%) had successful response, as 2nd line (7/15, 47%) had successful
response. No patient reported colesevelam intolerance.
GRADE report
Quality Assessment
72
Risk of
Studies Inconsistency Indirectness Imprecision Other considerations Quality of Evidence Overall quality of evidence
bias
Safety
Variation in diagnostic testing
1 SR of
used for BAD and cut-off values,
Observational
treatment dose and timing of ⊕⊝⊝⊝
Studies (Cohort) Seriousa Not serious Not serious Seriousb VERY LOW
administration, definition of
n = 1241 ⊕⊝⊝⊝
clinical response, and assessment VERY LOW
of adverse events
Dose and timing of
1 Cohort Study
administration, as well as ⊕⊝⊝⊝
n = 92 Seriousa Not serious Not serious Seriousb VERY LOW
practice of titration highly
variable (not standardized)
a. High risk for selection bias, incomplete follow-up, performance bias, and outcome detection bias.
b. Small sample size and low event rates.

There are no RCTs or observational studies that have directly compared dose titration vs. no dose titration of BAST in patients with
BAD.
In general, most cohort studies reported gradual dose titration for cholestyramine to clinical response. There was, however, no
mention of dose titration of colesevelam or colestipol. For any medication that alleviates symptoms but does not alter the natural
history of the disease, it is intuitive to gradually titrate the medication to minimize symptoms / side effects. This is particularly
relevant with BAST due to the high frequency of side effects and intolerance. It is conceivable that gradual dose titration may reduce
the risks of side effects, increase compliance, and potentially less costly. Does the panel believe that in patients with BAD, gradual
dose titration to minimize symptoms represents good practice? If so, this statement can be considered a good practice statement.
This statement can be considered an ungraded good practice statement. The unstated alternative of no dose titration when starting
patients on BAST be absurd given the side effects and poor tolerability of BAST.
Checklist for good practice statements:

1. Is the statement clear and actionable?
2. Is the message really necessary in regard to actual health care practice?
73
3. After consideration of all relevant outcomes and potential downstream consequences, will implementing the good practice
statement result in large net positive consequences? Need to consider benefits are large and harm very small; certainty of
benefits and harms are great; the values and preferences are clear; the intervention is cost saving; and the intervention is
clearly acceptable, feasible, and promotes equity.
4. Is collecting and summarizing the evidence a poor use of a guideline panel’s limited time and energy?
5. Is there a well-documented clear and explicit rationale connecting the indirect evidence?
for this PICO
Camilleri APT 2015 (Camilleri M, Acosta A, Busciglio I, et al. Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome.
Aliment Pharmacol Ther 2015;41:438-48): Cohort study of colesevelam in 12 patients with IBS-D. No titration of dose. All took 1875mg BID x 10 days.
Review article.
Gastroenterol 2007;102:2520-8): Prospective cohort study included in the SR by Wilcox 2014. Starting Cholestyramine 8g/d, titrated to clinical response (range 2 – 12 g/d).
Gastroenterol 2003;38:826-30): Retrospective cohort study included in the SR by Wilcox 2014.
Rossel SJG 1999 (Rossel P, Sortsoe Jensen H, Qvist P, et al. Prognosis of adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol 1999;34:587-90): Retrospective
cohort study of patients with IBAM treated with cholestyramine. No mention of how the drug was dosed / titrated.
in the SR by Wilcox 2014.
Sciarretta AJG 1992 (Sciarretta G, Furno A, Mazzoni M, et al. Post-cholecystectomy diarrhea: evidence of bile acid malabsorption assessed by SeHCAT test. Am J Gastroenterol
1992;87:1852-4): Prospective cohort study included in the SR by Wilcox 2014.
uncontrolled open multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7): Prospective cohort study included in the SR by Wilcox 2014.
Williams Gut 1991 (Williams AJ, Merrick MV, Eastwood MA. Idiopathic bile acid malabsorption--a review of clinical presentation, diagnosis, and response to treatment. Gut
1991;32:1004-6): Prospective cohort study included in the SR by Wilcox 2014.

PICO 11: In patients with BAD receiving empiric BAST, should gradual daily dose titration vs. no titration be used to minimize patient-reported
symptoms (interpreted as side effects)?
74
DESIGNATED A GOOD PRACTICE STATEMENT

Ther 2014;39:923-39.
Med (Lond) 2015;15:252-7.
Cohort Studies
Similar for
factors
• Experimental design on patients with ileal resection

• 4 randomized periods: LCT, LCT + cholestyramine, MCT, MCT + cholestyramine
• Measured fecal fat, total fecal BA excretion, stearrohea, diarrhea, fecal lyte
• 3 patients severe steatorrhea (ileal resection >100cm, steatorrhea > 20g/d): cholestyramine leads
Hofmann 19721 High risk for
No OK OK to small decrease in diarrhea with no symptomatic benefit, but increase in steatorrhea causing
(Not tagged) selection bias
significant caloric loss
• 6 patients Mild steatorrhea (ileal resection < 100cm, steatorrhea < 20g/d): Cholestyramine
significantly decreased diarrhea of symptomatic benefit, but increase in steatorrhea with no caloric
significance.
• Fat digestion after two sequential test meals +/- cholestyramine in 8 patients with ileal resection (5
Poley 19762 with “small” resection, BAD and steatorrhea < 20g/d; 3 with “large” resection, fatty acid diarrhea
(Not tagged) High risk for and steatorrhea > 20g/d) and 4 controls
No ok ok
(same patients as selection bias • Cholestyramine decreased the aqueous phase bile acid concentrations in all patients. The degree of
Hofmann 1972) fat maldigestion in patients with small resections (and normal control) became similar to that in
patients with large resections.
GRADE report
Quality Assessment
75
Risk of Other Quality of
Studies Inconsistency Indirectness Imprecision Overall quality of evidence
bias considerations Evidence
Safety
1 Cohort Study
Patients were
n = 3 with ileal
divided into 2 ⊕⊝⊝⊝
resection > ⊕⊝⊝⊝
Seriousa Not serious Not serious Very seriousb groups < 100cm vs. VERY LOW
VERY LOW
100cm,
> 100cm ileal
steatorrhea >
resection.
20g/d
a. High risk for selection bias.
b. Small sample size.

Based on 1 experimental cohort study (3 patients with ileal resection > 100cm), there is VERY LOW quality evidence against the use
of BAST in patients with Crohn’s disease with extensive ileal disease or resection (but not > 50cm). In these 3 patients,
cholestyramine leads to small decrease in diarrhea with no symptomatic benefit, but increase in steatorrhea causing significant
caloric loss.
Balance between benefits and risks: There is no long term study assessing the safety of cholestyramine especially in patients with
extensive ileal resection. Based on the small cohort study with increase in steatorrhea in patients with extensive ileal resection >
100cm, the potential long term effects of this medication could be very harmful.
Patient values and preferences: ?
Cost: ?
for this PICO
Ford PM 1992 (Ford GA, Preece JD, Davies IH, et al. Use of the SeHCAT test in the investigation of diarrhoea. Postgrad Med J 1992;68:272-6): Small cohort study of 28 patients
with Type 1 BAD (7 ileal resection). SeHCAT was < 10% in all patients with ileal resection. All patients were treated with cholestyramine. They all responded to cholestyramine.
Did not specify how much ileum was resected.
Nyhlin Gut 1994 (Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption in Crohn's disease and indications for its assessment using SeHCAT. Gut 1994;35:90-3): Small
cohort study of 53 patients with Crohn’s disease and tested for SeHCAT. Some patients were treated with cholestyramine with relief in symptoms. Did not specify how much
ileum was resected.
76
Worobetz CJGH 1993 (Worobetz L, Wilkinson A, Chmielowiec C, et al. Evaluation of SeHCAT test in determining ileal involvement and dysfunction in Crohn’s disease. Can J
Gastroenterol Hepatol 1993;7:597-601): Small cohort study of 22 patients with Crohn’s limited to small bowel underwent SeHCAT testing (14 had ileal resection). No correlation
between clinical response to cholestyramine vs. length of TI disease / resection (35.3+/-5.4 cm in responder vs. 46.4cm +/-6.1 cm in non-responders) – Most patients had ileal
disease / resection < 50cm.
Valdes Olmos EJGH 1993 (Valdés Olmos RA, Taal BG, Hoefnagel CA, et al. 75SeHCAT in the assessment of improved bile acid absorption in patients with ileal damage by delaying
bowel motility with loperamide. Eur J Gastroenterol Hepatol 1993;5:941-946): Small cohort study (13/19 patients who had ileocolonic resection, all had cancer) ha improvement
/ normalization of SeHCAT retention with loperamide

Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
Values
○ Possibly important uncertainty or variability
77
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

1. Hofmann AF, Poley JR. Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection. I.
Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology
1972;62:918-34.
2. Poley JR, Hofmann AF. Role of fat maldigestion in pathogenesis of steatorrhea in ileal resection. Fat digestion after two sequential test
meals with and without cholestyramine. Gastroenterology 1976;71:38-44.
78
Role of BAST in the maintenance treatment of BAD
Cohort Studies
Similar for
factors
No • Prospective cohort study assessing the prevalence of bile acid malabsorption (7d
High risk for SeHCAT<8%) patients with diarrhea post choly (25/26)
performance / • Cholestyramine was effective 23/26 patients, recurrent diarrhea in 9/23 patients when tx
Sciarretta 19921 No No OK
co-intervention was withdrawn. 14 patients (61%) remained normal and only took the drug occasionally
bias, selection (no demand) in the event of slight diarrhea.
bias, etc
No • Prospective cohort study assessing the prevalence of bile acid malabsorption (7d SeHCAT <
High risk for 11.7%) in patients with IBS-D (56/98, 57%)
performance / • Cholestyramine was effective in 39/42 patients, recurrent diarrhea in 33/35 (94%) patients
Galatola 19922 No No
co-intervention when tx was withdrawn. 2 (6%) patients did not have recurrent diarrhea and stopped tx.
bias, selection
bias, etc
GRADE report
Quality Assessment
Risk of Other Quality of

Studies Inconsistency Indirectness Imprecision Overall quality of evidence
bias considerations Evidence
Safety ⊕⊝⊝⊝
a b ⊕⊝⊝⊝ VERY LOW
2 Cohort Studies Serious Not serious Not serious Serious None VERY LOW
a. High risk for selection bias, performance bias, and outcome detection bias.
b. Small sample size.

There are no RCTs or observational studies that have directly compared regular daily dosing vs. intermittent, on-demand therapy in
patients with BAD who respond to BAST.
79
There are 2 small cohort studies suggesting that in some patients with BAD, their symptoms could be controlled with on-demand
therapy or no therapy at all. In a cohort study (Sciarretta 19921) of patients with BAD post cholecystectomy, recurrent diarrhea
occurred only in 9/23 (39%) of patients when cholestyramine was withdrawn, and 61% remained normal and took the drug on
demand in the event of slight diarrhea. In another small cohort study (Galatola 19922) of patients with BAD and IBS-D, recurrent
diarrhea occurred in 33/35 (94%) of patients when Cholestyramine was withdrawn, only 6% of patients did not have recurrent
diarrhea and stopped treatment. In those with recurrent diarrhea, they were advised to continue treatment at the dose that
controlled their symptoms (unclear if regular daily vs. on demand).
The dose or frequency of BAST required to control symptoms may be dependent on severity of symptoms, underlying cause of BAD,
any other associated GI conditions, concurrent illness (e.g. gastroenteritis, c. diff infection), or concurrent medication use (eg.
medications that cause constipation may reduce the use of cholestyramine and medications that cause diarrhea may increase the
use of cholestyramine).
Overall, there is VERY LOW quality of evidence suggesting that some patients with BAD will need regular daily dosing, while some
may be able to come off therapy or use on-demand therapy to minimize symptoms.
Balance between benefits and risks: Side effects, uncertainty of long term harms with BAST - malabsorption of fat / fat soluble
vitamins, and unpalatability
Patient values and preferences: ? compliance. Patients may use on demand after achieving an initial response to minimize side
effects.
Cost: on-demand therapy is less costly than regular use
for this PICO
Torbicki TDTMV 2015 (Torbicki E, Oh J, Mishra S, et al. Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy. Trop Dis Travel Med
Vaccines 2015;1:1): 2 retrospective cohort studies on cholestyramine were included in this SR. Patients took different doses of cholestyramine and for different lengths of time.
No comparison between daily vs. on demand therapy.
Riemsma HTA 2013 (Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile
acid pool loss: a systematic review and cost-effectiveness analysis. Health Technol Assess 2013;17:1-236): Systematic review and cost effectiveness analysis of SeHCAT for bile
acid malabsorption. Irrelevant to the PICO.
80
Wedlake 2009 (Wedlake L, Thomas K, Lalji A, et al. Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective
chart review and patient questionnaire. Clin Ther 2009;31:2549-58): Retrospective cohort study of colesevelam in patients with bile acid malabsorption and cancer. Did not
assess daily vs. on demand therapy.
Review article.
Camilleri Gut Liver 2015 (Camilleri M. Bile acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver 2015;9:332-9): Review article.
7): Coleveselam and Colestipol resins in the GI tract. Irrelevant to the PICO.
article.
treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-40): Retrospective cohort study of patients with bile acid
malabsorption by SeHCAT and response to Cholestyramine. Did not assess daily vs. on demand therapy.
cohort study of patients with I-BAM and their response to Cholestyramine. Did not assess daily vs. on demand therapy.
Pharmacol Ther 1998;12:839-44): Retrospective cohort study of patients with I-BAM and their response to Cholestyramine. Did not assess daily vs. on demand therapy.
study of patients with PI-IBS and bile acid malabsorption and their response to Cholestyramine. Did not assess daily vs. on demand therapy.
RuDusky Angiol 1997 (RuDusky BM. Cholestyramine therapy for quinidine-induced diarrhea. Case reports. Angiology 1997;48:173-6): Case reports of Cholestyramine therapy for
Quinidine-induced diarrhea. Irrelevant to the PICO.
Luman EJGH 1995 (Luman W, Williams AJ, Merrick MV, et al. Idiopathic bile acid malabsorption: long-term outcome. Eur J Gastroenterol Hepatol 1995;7:641-5): Long term
outcome of I-BAM and response to Cholestyramine. Did not assess daily vs. on demand therapy.
diarrhoea: correlation to SeHCAT test. Gut 1993;34:698-701): Prevalence of bile acid malabsorption in patients with chronic diarrhea and response to cholestyramine. Did not
assess daily vs. on demand therapy.
1991;32:1004-6): Prevalence of bile acid malabsorption in patients with chronic diarrhea and their response to cholestyramine. Did not assess daily vs. on demand therapy.

Judgement
81
○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
○ Varies
○ Don't know

○ No
Acceptability ○ Probably no
○ Probably yes
○ Yes
82
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

1. Sciarretta G, Furno A, Mazzoni M, et al. Post-cholecystectomy diarrhea: evidence of bile acid malabsorption assessed by SeHCAT test.
Am J Gastroenterol 1992;87:1852-4.
2. Galatola G, Ferraris R, Pellerito R, et al. The prevalence of bile acid malabsorption in irritable bowel syndrome and the effect of
cholestyramine: An uncontrolled open multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7.
PICO 14: In patients with BAD who are unable to tolerate BAST, should alternative anti-diarrheal agents vs. no treatment be used for long-
term symptomatic therapy?
RCTs
Allocation Free of
Study sequence Blinding outcome data selective Comments
concealment other bias
• 26 patients with chronic functional watery diarrhea or IBS-D (SeHCAT 7-
d retention < 20%) randomized to cholestyramine 4g bid vs.
hydroxypropyl cellulose x 8 wks.
• Clinical remission: < 3 BMs/d x 1 wk before visit (< 1 watery stool/d). No
Fernandez-
OK OK OK OK OK OK difference in clinical remission (53.8% vs. 38.4%; P = 0.43; ITT). Higher
Banares 20151
mean % decrease in watery stool number with cholestyramine (-
92.4+/- 3.5% vs. -75.8+/-7.1%; P = 0.048).
• No difference in adverse events
• Presence of BAM (SeHCAT < 10%) was not a prerequisite for inclusion
83
(77% vs. 54%).
• Hydroxypropyl cellulose may be an active drug (bulking effect) – no
placebo group for comparison.
• 18 patients with diarrhea caused by chronic radiation enteritis.
• Double-blind randomized cross-over order loperamide (3mg bid) and
placebo x 14 days (washout period of 14 days).
Yeoh 19932 Probably OK Probably OK OK OK OK OK • Mean 7d SeHCAT % 3.3% during placebo phase and 20.5% during
loperamide phase
• Reduced frequency of BMs during loperamide phase (mean BMs/ week
13.5 vs. 19)
Similar for
factors
• 1 prospective cohort study (Smith 2000) assessed “conventional” anti-diarrheal therapies
in 96 patients with BAM (7d SeHCAT < 10%). CD with ileal resection, Unoperated CD,
No No
Vagotomy & pylorplasty +/- choly, IBS-D
Outcome High risk for
3 • Did not specify response to individual medications, stating only that patients received first
Wilcox 2014 No No available in performance
line treatment with codeine, loperamide, or prednisolone (not considered a conventional
96/304 bias, selection
anti-diarrheal agent).
patients bias etc
• Patient’s perception of improvement in symptoms: 28% of patients
• If conventional therapies failed, BAST were used.
Cohort Studies
Similar for
factors
• Prospective cohort study of 19 patients with chronic diarrhea due to ileal irradiation and/or
No
resection.
Selection,
• Measured SeHCAT before and during administration of loperamide
performance
• 7d SeHCAT normalized or improved in 13 patients (7 with resection 20-50cm, 6 no resection)
4
Valdes 1993 No OK OK
bias, co-
with symptomatic relief during loperamide (subjective outcome)
intervention
• 7d SeHCAT remained abnormal in 6 patients (resection > 80cm) during loperamide. 3 patients
bias
with slight relief. (subjective outcome)
GRADE report
Summary of Findings
Quality Assessment
84
Studies Risk of Inconsistency Indirectness Imprecision Other Quality of Overall Alternative Comparator Relative Absolute
bias considerations Evidence quality of anti-diarrheal (95% CI) (95% CI)
evidence agents
Efficacy (subjective / objective clinical response – highly variable definitions among studies) ⊕⊝⊝⊝
VERY LOW
248
fewer
5/13
First line 7/13 per 1000
(38.5%) RR 0.54
1 RCT Not Very treatment with ⊕⊝⊝⊝ (53.8%) (from
Not serious Seriousb Hydroxypropyl (0.11 to
n = 26 serious seriousa hydroxypropyl VERY LOW
Cholestyramine 479
cellulose 2.55)
cellulose fewer to
(possible
835
active drug)
more)
First line
1 RCT Not Very Very ⊕⊝⊝⊝
Not serious treatment with NA NA NA NA
n = 18 serious seriousc seriousd VERY LOW
loperamide
27/96
(28.1%)
1 SR of First line Conventional
Observational treatment with anti-diarrheal
c d e ⊕⊝⊝⊝
Studies (1 Serious Not serious Serious Serious codeine, VERY LOW agents NA NA NA
Cohort study) loperamide, or (codeine,
n = 96 prednisolone loperamide,
or
prednisolone)
13/16 no
resection or
ilea resection
2 Cohort
20-50cm
studies
(81.3%)
n = 37 First line
⊕⊝⊝⊝
(only 1 Cohort Seriousf Not serious Seriousg Seriouse treatment with VERY LOW
NA NA NA
3/6 ileal
study had loperamide
resection >
dichotomous
80cm
outcome)
(50%)
Loperamide
a. Not in patients who are unable to tolerate BAST. All patients had SeHCAT 7-d retention < 20%, but not all patients had BAD (SeHCAT 7-d retention < 10%).
c. High risk for selection bias, incomplete follow-up, and outcome detection bias.
d. Not in patients who are unable to tolerate BAST. Anti-diarrheal agents were used as first-line treatments.
e. Small sample size and low event rates.
f. High risk for selection bias, performance bias, and outcome detection bias.
g. Not in patients who are unable to tolerate BAST.
85
There are no RCTs or observational studies that have systematically assessed the effectiveness of other anti-diarrheal agents in
patients with BAD who are unable to tolerate BAST.
There is 1 RCT (Fernandez-Banares 20151) comparing cholestyramine vs. hydroxypropyl cellulose as first-line treatment in patients
with functional chronic watery diarrhea and bile acid malabsorption (7d SeHCAT < 20%) suggesting that there was no difference
between the 2 medications in clinical remission. Another cross-over RCT patients with chronic diarrhea due to chronic radiation
enteritis ileal irradiation and/or resection compared loperamide and placebo. Both RCTs have indirectness and imprecision. There
are 2 cohort studies assessing Loperamide as first-line treatment in patients with BAD. The effectiveness of loperamide in these
cohort studies is difficult to estimate due to differences in patient populations, study designs, and outcome measurements (mostly
subjective improvement of symptoms). Overall, there is VERY LOW quality evidence supporting the use of alternative anti-diarrheal
agents in patients with BAD who are unable to tolerate BAST.
Balance between benefits and harms: Alternative anti-diarrheal agents (loperamide, diphenoxylate, hydroxypropyl cellulose) are
generally safe agents to use over the long term.
Patient values and preferences: value controlling diarrhea with alternative agents than no treatment
Cost: Inexpensive
for this PICO
Lacy Gastro 2016 (Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393-1407. e5): Review article.
Torbicki TDTMV 2015 (Torbicki E, Oh J, Mishra S, et al. Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy. Trop Dis Travel Med
Vaccines 2015;1:1): Systematic review of interventions for PI-IBS. 2 retrospective studies on cholestyramine. No report on alternative anti-diarrheal agents.
Nee EOP 2015 (Nee J, Zakari M, Lembo AJ. Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome. Expert Opin Pharmacother
2015;16:2781-92): Review article.
Wadhwa CGR 2015 (Wadhwa A, Camilleri M, Grover M. New and investigational agents for irritable bowel syndrome. Curr Gastroenterol Rep 2015;17:46.): Review article.
Camilleri EOP 2013 (Camilleri M. Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome. Expert Opin Pharmacother 2013;14:1151-
60): Review article.
Li BPRCG 2012 (Li Z, Vaziri H. Treatment of chronic diarrhoea. Best Pract Res Clin Gastroenterol 2012;26:677-87): Review article.
Manabe CGR 2010 (Manabe N, Rao AS, Wong BS, et al. Emerging pharmacologic therapies for irritable bowel syndrome. Curr Gastroenterol Rep 2010;12:408-16.): Review
article.
86
Chande CDBSR 2008 (Chande N, McDonald JW, Macdonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev 2008:CD003575): SR of 10 RCTs
comparing various therapies to either placebo or active comparator in patients with collagenous or microscopic colitis. Most trials did not specify if patients also had BAD. 1 RCT
(Munck 2003) excluded patients with BAD.
Shah RGD 2007 (Shah SB, Hanauer SB. Treatment of diarrhea in patients with inflammatory bowel disease: concepts and cautions. Rev Gastroenterol Disord 2007;7 Suppl 3:S3-
10): Review article.
Nyhlin APT 2006 (Nyhlin N, Bohr J, Eriksson S, et al. Systematic review: microscopic colitis. Aliment Pharmacol Ther 2006;23:1525-34): Review article.
Thomas Gut 2003 (Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic diarrhoea, 2nd edition. Gut 2003;52 Suppl 5:v1-15): Guidelines for
investigation of chronic diarrhea.
Review article.
article.

PICO 14: In patients with BAD who are unable to tolerate BAST, should alternative anti-diarrheal agents vs. no treatment be used for long-
term symptomatic therapy?
Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

Certainty of evidence ○ Very low
○ Low
87
○ Moderate
○ High
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know

1. Fernandez-Banares F, Rosinach M, Piqueras M, et al. Randomised clinical trial: colestyramine vs. hydroxypropyl cellulose in patients with
functional chronic watery diarrhoea. Aliment Pharmacol Ther 2015;41:1132-40.
2. Yeoh EK, Horowitz M, Russo A, et al. Gastrointestinal function in chronic radiation enteritis--effects of loperamide-N-oxide. Gut
1993;34:476-82.
88
Ther 2014;39:923-39.
4. Valdés Olmos RA, Taal BG, Hoefnagel CA, et al. 75SeHCAT in the assessment of improved bile acid absorption in patients with ileal
damage by delaying bowel motility with loperamide. Eur J Gastroenterol Hepatol 1993;5:941-946.
PICO 15: In patients with BAD receiving BAST, should maintenance therapy be used at the lowest dose needed to maintain symptom
response vs. no dose titration?
Similar for
Outcome Follow-up
Study prognostic Free of other bias Comments
detection similar complete
factors
No • SR of interventions for PI-IBS.

OK High risk for • ½ retrospective study (menon et al) reported long term outcome of 25 patients with PI-IBS and
Torbicki
No Frequency of No performance bias, bile acid malabsorption (SeHCAT) treated with cholestyramine. 18 had significant decrease in
20151
diarrhea co-interventions, frequency of BM with sustained response for over 1 year. Patients were allowed to titrate their
selection bias etc own dose of cholestyramine, varying between 2- 16g/d
• SR of 23 cohort studies (n = 801) of BAM patients treated with cholestyramine.
• Most studies did not specify duration of treatment. Treatment for 6 – 12 months (Rudberg 1996,
Fernandez-Banares 2007, Ung 2000).
Wilcox No
• Cholestyramine: generally started at low dose 2-4 g/d and titrated to response (no mention of
20142 High risk for
No No Unclear dose titration in some studies)
(not performance bias,
• Colesevelam / Colestipol: no mention of dose titration
tagged) selection bias etc
• Variation in diagnostic testing used for BAM and cut-off value, treatment dose and timing of
administration, and definition of clinical response
GRADE report
There are no RCTs or observational studies that have directly compared dose titration vs. no dose titration of BAST in patients with
BAD.
89
In general, most cohort studies reported gradual dose titration for cholestyramine to clinical response. There was, however, no
mention of dose titration of colesevelam or colestipol. For any medication that alleviates symptoms but does not alter the natural
history of the disease, it is intuitive to gradually titrate the medication to minimize symptoms / side effects. This is particularly
relevant with BAST due to the high frequency of side effects and intolerance. It is conceivable that gradual dose titration may reduce
the risks of side effects, increase compliance, and potentially less costly. Does the panel believe that in patients with BAD, gradual
dose titration to minimize symptoms represents good practice? If so, this statement can be considered a good practice statement.
for this PICO
Beigel JCC 2014 (Beigel F, Teich N, Howaldt S, et al. Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: a randomized,
double-blind, placebo-controlled study. J Crohns Colitis 2014;8:1471-9): RCT of Colesevelam for bile acid malabsorption associated diarrhea in Crohn’s disease. 4-week endpoint.
Not a maintenance trial.
Wong DDS 2012 (Wong BS, Camilleri M, Carlson PJ, et al. Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea. Dig Dis Sci
2012;57:1222-6): Cohort study of the pharmacogenetics of the effects of Colesevelam on colonic transit in IBS-D. Not specifically on patients with BAD.
Islam PG 2012 (Islam RS, DiBaise JK. Bile acids: an underrecognized and underappreciated cause of chronic diarrhea. Pract Gastroenterol 2012;36:32-44): Review article.
Walters ERGH 2010 (Walters JR. Defining primary bile acid diarrhea: making the diagnosis and recognizing the disorder. Expert Rev Gastroenterol Hepatol 2010;4:561-7): Review
article.
Odunsi-Shiyanbade CGH 2010 (Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, et al. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit
and bowel function. Clin Gastroenterol Hepatol 2010;8:159-65): RCT of Colesevelam for 12 – 14 days in patients with IBS-D. Outcomes were colonic transit time, daily bowel
frequency and consistency and permeability. Only 4/24 patients had abnormal 7αC4 levels (BAD). Not a maintenance trial.
Wedlake 2009 (Wedlake L, Thomas K, Lalji A, et al. Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective
chart review and patient questionnaire. Clin Ther 2009;31:2549-58): Retrospective cohort study of patients with cancer and bile acid malabsorption who were prescribed
colesevelam. No mention of dose titration.
DeMeo AJG 1998 (DeMeo M, Kolli S, Keshavarzian A, et al. Beneficial effect of a bile acid resin binder on enteral feeding induced diarrhea. Am J Gastroenterol 1998;93:967-71):
RCT of Colestid on enteral feeding induced diarrhea x 7 days. Not a maintenance trial. No mention of dose titration.
Peleman CGH 2017 (Peleman C, Camilleri M, Busciglio I, et al. Colonic transit and bile acid synthesis or excretion in patients with irritable bowel syndrome-diarrhea without bile
acid malabsorption. Clin Gastroenterol Hepatol 2017;15:720-727 e1): Cohort study assessing colonic transit and bile acid synthesis or excretion in patients with IBS-D without
bile acid malabsorption. BAST was not assessed.
Review article.
Appleby NGM 2014 (Appleby RN, Walters JR. The role of bile acids in functional GI disorders. Neurogastroenterol Motil 2014;26:1057-69): Review article.
90
7): Morphologic description of bile acid sequestrants.
article.
treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-40): Retrospective cohort study of patients with chronic
watery diarrhea and their response to cholestyramine. No mention of duration of treatment or titration of doses.
Baert ACB 2004 (Baert D, Coppens M, Burvenich P, et al. Chronic diarrhoea in non collagenous microscopic colitis: therapeutic effect of cholestyramine. Acta Clin Belg
2004;59:258-62): case series of 20 patients with microscopic colitis treated with cholestyramine. Did not specify if patients also had BAD.
Gastroenterol 2003;38:826-30): Retrospective cohort study of patients with chronic diarrhea and bile acid malabsorption. Response to cholestyramine reported. Dosage was
titrated to response, but unclear duration of cholestyramine.
Ung EJGH 2000 (Ung KA, Kilander AF, Lindgren A, et al. Impact of bile acid malabsorption on steatorrhoea and symptoms in patients with chronic diarrhoea. Eur J Gastroenterol
Hepatol 2000;12:541-7): Prospective cohort study included in Wilcox 2014.
cohort study of patients with IBAM treated with cholestyramine. No mention of how the drug was dosed / titrated.
Pharmacol Ther 1998;12:839-44): Retrospective cohort study included in Wilcox 2014.
study included in Wilcox 2014. Outcome assessed only over 2 weeks.
Luman EJGH 1995 (Luman W, Williams AJ, Merrick MV, et al. Idiopathic bile acid malabsorption: long-term outcome. Eur J Gastroenterol Hepatol 1995;7:641-5): Case series of 23
patients with IBAM who all responded to bile acid chelator (cholestyramine / aluminum hydroxide) follow-up data. No mention of dose titration.
Nyhlin Gut 1994 (Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption in Crohn's disease and indications for its assessment using SeHCAT. Gut 1994;35:90-3): case
series of 51 patients with CD who had failed to respond to conventional treatment tested for BAM with SeHCAT. A small subgroup of patients was given cholestyramine with
good response (19/22). No mention of dose titration.
Sciarretta AJG 1994 (Sciarretta G, Bonazzi L, Monti M, et al. Bile acid malabsorption in AIDS-associated chronic diarrhea: a prospective 1-year study. Am J Gastroenterol
1994;89:379-81). Case control study of patients with AIDS associated chronic diarrhea and AIDS controls for bile acid malabsorption. No mention of BAST.
diarrhoea: correlation to SeHCAT test. Gut 1993;34:698-701): Prospective cohort study included in the SR by Wilcox 2014. Dose was titrated to symptoms. But unclear duration
of treatment.
in the SR by Wilcox 2014. Dose was titrated to symptoms. Duration only 1 month
1992;87:1852-4): Prospective cohort study already included in the SR by Wilcox 2014. Did not mention dose titration.
91
uncontrolled open multicentre study. Eur J Gastroenterol Hepatol 1992;4:533-7): Prospective cohort study included in the SR by Wilcox 2014. Dose titrated to symptoms.
Unclear duration of treatment. Follow-up was 1 – 24 months.
1991;32:1004-6): Prospective cohort study included in the SR by Wilcox 2014. Did not mention dose titration.

PICO 15: In patients with BAD receiving BAST, should maintenance therapy be used at the lowest dose needed to maintain symptom
response vs. no dose titration?

15
1. Torbicki E, Oh J, Mishra S, et al. Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy.
Trop Dis Travel Med Vaccines 2015;1:1.
Ther 2014;39:923-39.
PICO 16: In patients with BAD and recurrent or worsening symptoms despite stable BAST, should diagnostic re-evaluation or dose escalation
be used?
The underlying PICO question is that in patients with BAD and recurrent or worsening symptoms despite stable BAST, what is the
probability / likelihood that another condition is causing the symptoms that warrants re-evaluation? Unfortunately, the tagged
studies did not address this question. Most of the included studies evaluated the diagnostic utility of different tests for BAD and the
response to BAST based on the test results. We found no evidence relevant to this PICO.
The PICO is somewhat vague and/or unclear. First, it is unclear what type of evaluations the patients had prior to the diagnosis of
BAD and how the diagnosis of BAD was made (therapeutic trial with BAST, SeHCAT or other tests). Second, it is also unclear what
type of BAD this question relates to – Type 1/2/3 as the decision to re-evaluate may differ depending on the underlying GI condition.
92
Third, it is unclear what type of re-evaluations the PICO is referring to (repeat SeHCAT test, stool studies, colonoscopy, etc). Fourth,
the severity of symptoms may play a role in the decision making for re-evaluation or dose escalation. We will need to discuss
whether it is worth splitting the PICOs based on Type 1 / 2 / 3.
for this PICO
Scheurlen Dig 1986 (Scheurlen C, Kruis W, Bull U, et al. Comparison of 75SeHCAT retention half-life and fecal content of individual bile acids in patients with chronic diarrheal
disorders. Digestion 1986;35:102-8): Comparison of SeHCAT retention half-life and fecal content of individual bile acids in patients with chronic diarrheal disorders. Irrelevant to
the PICO.
Valentin Gut 2016 (Valentin N, Camilleri M, Altayar O, et al. Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-
analysis. Gut 2016;65:1951-1959): Systematic review of the diagnostic yield of biomarkers of bie acid diarrhea. Irrelevant to the PICO.
Riemsma HTA 2013 (Riemsma R, Al M, Corro Ramos I, et al. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile
acid pool loss: a systematic review and cost-effectiveness analysis. Health Technol Assess 2013;17:1-236): Systematic review and cost-effectiveness analysis of SeHCAT for the
investigation of bile acid malabsorption and measurement of bile acid pool loss. Irrelevant to the PICO.
Wong DDS 2012 (Wong BS, Camilleri M, Carlson PJ, et al. Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea. Dig Dis Sci
2012;57:1222-6): Pharmacogenetics of the effects of Colesevelam on colonic transit in IBS-D. Irrelevant to the PICO.
Walters ERGH 2010 (Walters JR. Defining primary bile acid diarrhea: making the diagnosis and recognizing the disorder. Expert Rev Gastroenterol Hepatol 2010;4:561-7): Review
article.
Odunsi-Shiyanbade CGH 2010 (Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, et al. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit
and bowel function. Clin Gastroenterol Hepatol 2010;8:159-65): Effects of Chenodeoxycholate and a bile acid sequestrant, Colesevelam, on intestinal transit and bowel function.
Irrelevant to the PICO.
Vijayvargiya APT 2017 (Vijayvargiya P, Camilleri M, Carlson P, et al. Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid
diarrhoea in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ther 2017;46:581-588): Performance characteristics of serum C4 and FGF19 in identifying BAD in
patients with IBS-D or functional diarrhea (compared to 48 hour fecal bile acids). Irrelevant to the PICO.
Peleman CGH 2017 (Peleman C, Camilleri M, Busciglio I, et al. Colonic transit and bile acid synthesis or excretion in patients with irritable bowel syndrome-diarrhea without bile
acid malabsorption. Clin Gastroenterol Hepatol 2017;15:720-727 e1): Associations among BA in stool and colonic transit in IBS-D without BAM patients. Irrelevant to the PICO.
Review article.
Johnston AJG 2016 (Johnston IM, Nolan JD, Pattni SS, et al. Characterizing factors associated with differences in FGF19 blood levels and synthesis in patients with primary bile
acid diarrhea. Am J Gastroenterol 2016;111:423-32): Exploratory studies of functional variants in candidate genes for patients with primary bile acid diarrhea. Irrelevant to the
PICO.
93
Gothe JCC 2014 (Gothe F, Beigel F, Rust C, et al. Bile acid malabsorption assessed by 7 alpha-hydroxy-4-cholesten-3-one in pediatric inflammatory bowel disease: correlation to
clinical and laboratory findings. J Crohns Colitis 2014;8:1072-8): Correlation between C4 and symptoms and laboratory findings in pediatric patients with IBD. Irrelevant to the
PICO.
Appleby NGM 2014 (Appleby RN, Walters JR. The role of bile acids in functional GI disorders. Neurogastroenterol Motil 2014;26:1057-69): Review article.
Camilleri NGM 2014 (Camilleri M, Shin A, Busciglio I, et al. Validating biomarkers of treatable mechanisms in irritable bowel syndrome. Neurogastroenterol Motil 2014;26:1677-
85): Associations between biomarkers and colonic transit and fecal bile acids in patients with IBS. Irrelevant to the PICO.
9): Review article.
article.
Pattni APT 2013 (Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and
SeHCAT retention. Aliment Pharmacol Ther 2013;38:967-76): Correlation between FGF19 and C4 values in patients with chronic diarrhea. Irrelevant to the PICO.
Gracie NGM 2012 (Gracie DJ, Kane JS, Mumtaz S, et al. Prevalence of, and predictors of, bile acid malabsorption in outpatients with chronic diarrhea. Neurogastroenterol Motil
2012;24:983-e538): Prevalence of bile acid malabsorption in patients with chronic diarrhea. Irrelevant to the PICO.
Pattni CTG 2012 (Pattni SS, Brydon WG, Dew T, et al. Fibroblast growth factor 19 and 7alpha-hydroxy-4-cholesten-3-one in the diagnosis of patients with possible bile acid
diarrhea. Clin Transl Gastroenterol 2012;3:e18): Fibroblast growth factor 19 and 7 alpha-hydroxy-4-cholesten-3-one in the diagnosis of patients with possible bile acid diarrhea.
treatment responses to cholestyramine in 298 patients with chronic watery diarrhoea. Eur J Intern Med 2011;22:e137-40): Prevalence of bile acid malabsorption in patients with
chronic diarrhea by SeHCAT and response to cholestyramine. Irrelevant to the PICO.
Brydon CGH 2011 (Brydon WG, Culbert P, Kingstone K, et al. An evaluation of the use of serum 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption
causing watery diarrhea. Can J Gastroenterol 2011;25:319-23): Evaluation of 7-alpha-hydroxycholestenone as a diagnostic test of bile acid malabsorption in patients with chronic
diarrhea. Irrelevant to the PICO.
Camilleri NGM 2011 (Camilleri M, Vazquez-Roque MI, Carlson P, et al. Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal
disorders. Neurogastroenterol Motil 2011;23:995-9, e458): Association of genetic variation in TGR5 and small bowel transit and colonic transit in patients with IBS. Irrelevant to
the PICO.
Gastroenterol 2007;102:2520-8): Prevalence of gluten-sensitive enteropathy, bile acid malabsorption, and sugar malabsorption in patients with chronic watery diarrhea.
Montagnani WJG 2006 (Montagnani M, Abrahamsson A, Galman C, et al. Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with
multiple cases of idiopathic bile acid malabsorption. World J Gastroenterol 2006;12:7710-4): Analysis of ileal sodium / bile acid cotransporter and related nuclear receptor genes
in a family with multiple cases if IBAM. Irrelevant to the PICO.
Gastroenterol 2003;38:826-30): Prevalence of bile acid malabsorption in patients with chronic diarrhea and response to cholestyramine. Irrelevant to the PICO.
94
Montagnani SJG 2001 (Montagnani M, Love MW, Rossel P, et al. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset
idiopathic bile acid malabsorption. Scand J Gastroenterol 2001;36:1077-80): Mutations in the ileal sodium bile acid cotransporter gene in patients with IBAM. Irrelevant to the
PICO.
Sauter DDS 1999 (Sauter GH, Munzing W, von Ritter C, et al. Bile acid malabsorption as a cause of chronic diarrhea: diagnostic value of 7alpha-hydroxy-4-cholesten-3-one in
serum. Dig Dis Sci 1999;44:14-9): Diagnostic value of serum HCO for bile acid malabsorption in patients with positive SeHCAT. Irrelevant to the PICO.
Rudberg AR 1996 (Rudberg U, Nylander B. Radiological bile acid absorption test 75SeHCAT in patients with diarrhoea of unknown cause. Acta Radiol 1996;37:672-5): Prevalence
of bile acid malabsorption (SeHCAT) in patients with chronic diarrhea and their response to cholestyramine. Irrelevant to the PICO.
Nyhlin Gut 1994 (Nyhlin H, Merrick MV, Eastwood MA. Bile acid malabsorption in Crohn's disease and indications for its assessment using SeHCAT. Gut 1994;35:90-3):
Prevalence of bile acid malabsorption in Crohn’s disease not responding to conventional treatment. Irrelevant to the PICO.
Valdes Olmos EJGH 1993 (Valdés Olmos RA, Taal BG, Hoefnagel CA, et al. 75SeHCAT in the assessment of improved bile acid absorption in patients with ileal damage by delaying
bowel motility with loperamide. Eur J Gastroenterol Hepatol 1993;5:941-946): Bile acid absorption in patients with ileal damage in response to loperamide. Irrelevant to the
PICO.
Worobetz CJGH 1993 (Worobetz L, Wilkinson A, Chmielowiec C, et al. Evaluation of SeHCAT test in determining ileal involvement and dysfunction in Crohn’s disease. Can J
Gastroenterol Hepatol 1993;7:597-601): Correlation of SeHCAT with Crohn’s disease activity, extent, diarrhea, and response to cholestyramine. Irrelevant to the PICO.
diarrhoea: correlation to SeHCAT test. Gut 1993;34:698-701): Prevalence of bile acid malabsorption in patients with chronic diarrhea and response to cholestyramine. Irrelevant
to the PICO.
Ford PM 1992 (Ford GA, Preece JD, Davies IH, et al. Use of the SeHCAT test in the investigation of diarrhoea. Postgrad Med J 1992;68:272-6): Prevalence of bile acid
malabsorption by SeHCAT test in patients with chronic diarrhea and response to cholestyramine. Irrelevant to the PICO.
1992;87:1852-4): Prevalence of bile acid malabsorption by SeHCAT test in post-cholecystectomy patients and their response to cholestyramine. Irrelevant to the PICO.
Ferraris DDS 1992 (Ferraris R, Galatola G, Barlotta A, et al. Measurement of bile acid half-life using [75Se]HCAT in health and intestinal diseases. Comparison with [75Se]HCAT
abdominal retention methods. Dig Dis Sci 1992;37:225-32): Measurement of bile acid half-life using SeHCAT. Irrelevant to the PICO.
1991;32:1004-6): Prevalence of bile acid malabsorption in patients with chronic diarrhea and their response to cholestyramine. Irrelevant to the PICO.

PICO 16: In patients with BAD and recurrent or worsening symptoms despite stable BAST, should diagnostic re-evaluation or dose escalation
be used?

16
Not applicable
95
This statement can be considered an ungraded good practice statement. It is generally considered good practice to check for
potential drug interactions when patients are started on new medications. The unstated alternative of not checking for potential
drug interactions is absurd.
BAST is known to bind other medications and this necessitates spaced administration. For example, cholestyramine has been shown
to reduce the bioavailability of fluvastatin, ezetimibe, glipizide, furosemide, hydrochlorothiazide, digoxin and valproic acid when
administered at the same time with the latter. In some pharmacokinetics studies, Colesevelam appears to interact less with some
medications (eg, lovastatin, ezetimibe, fenofibrate, digoxin, warfarin, verapamil, metoprolol, quinidine and valproic acid), but in
other studies, Colesevelam was found to reduce the absorption of other medications (e.g. glyburide, levothyroxine). Would the
panel consider a good practice to always check for medication interactions when patients are started on new medications?
Checklist for good practice statements:

6. Is the statement clear and actionable?
7. Is the message really necessary in regard to actual health care practice?
8. After consideration of all relevant outcomes and potential downstream consequences, will implementing the good practice
statement result in large net positive consequences? Need to consider benefits are large and harm very small; certainty of
benefits and harms are great; the values and preferences are clear; the intervention is cost saving; and the intervention is
clearly acceptable, feasible, and promotes equity.
9. Is collecting and summarizing the evidence a poor use of a guideline panel’s limited time and energy? It is possible to collect
all the case reports of the adverse consequences of not checking for potential drug interactions. We could also collect and
summarize the benefits of checking for potential drug interactions. We can then link the bodies of evidence to make the case
for checking for potential drug interactions. This makes the case for a good practice statement rather than a GRADEd
recommendation as it is poor use of time in collecting and summarizing the relevant evidence.
10. Is there a well-documented clear and explicit rationale connecting the indirect evidence?
• The panel believes that in patients being considered for BAST, a review of concurrent medications to minimize
the potential drug interactions represents good practice?
96
• BAST is known to bind other medications and this necessitates spaced administration. For example,
cholestyramine has been shown to reduce the bioavailability of fluvastatin, ezetimibe, glipizide, furosemide,
hydrochlorothiazide, digoxin and valproic acid when administered at the same time with the latter. In some
pharmacokinetics studies, Colesevelam appears to interact less with some medications (eg, lovastatin,
ezetimibe, fenofibrate, digoxin, warfarin, verapamil, metoprolol, quinidine and valproic acid), but in other
studies, Colesevelam was found to reduce the absorption of other medications (eg, glyburide, levothyroxine).
for this PICO
Donovan JM, Kisicki JC, Stiles MR, Tracewell WG, Burke SK. Effect of colesevelam on lovastatin pharmacokinetics. Ann Pharmacother. 2002;36:392-7.
Jones MR1, Baker BA, Mathew P. Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics. Clin Pharmacokinet. 2004;43:943-50.
Donovan JM, Stypinski D, Stiles MR, Olson TA, Burke SK. Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther.
2000;14:681-90.
Brown KS, Armstrong IC, Wang A, et al. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone,
levothyroxine, and glyburide. J Clin Pharmacol. 2010;50:554-65.
Weitzman SP, Ginsburg KC, Carlson HE. Colesevelam hydrochloride and lanthanum carbonate interfere with the absorption of levothyroxine. Thyroid. 2009;19:77-9.
Brown DD, Juhl RP, Warner SL. Decreased bioavailability of digoxin due to hypocholesterolemic interventions. Circulation. 1978;58:164-72.
Brown DD, Schmid J, Long RA, Hull JH. A steady-state evaluation of the effects of propantheline bromide and cholestyramine on the bioavailability of digoxin when administered
as tablets or capsules. J Clin Pharmacol. 1985;25:360-4.
Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin
Pharmacokinet. 2005;44:467-94. Review.
Malloy MJ, Ravis WR, Pennell AT, Diskin CJ. Effect of cholestyramine resin on single dose valproate pharmacokinetics. Int J Clin Pharmacol Ther. 1996;34:208-11.
Smith HT, Jokubaitis LA, Troendle AJ, Hwang DS, Robinson WT. Pharmacokinetics of fluvastatin and specific drug interactions. Am J Hypertens. 1993;6:375S-382S.
Kivistö KT, Neuvonen PJ. The effect of cholestyramine and activated charcoal on glipizide absorption. Br J Clin Pharmacol. 1990;30:733-6.
Neuvonen PJ, Kivistö K, Hirvisalo EL. Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide. Br J Clin Pharmacol. 1988;25:229-33.
Hunninghake DB, Hibbard DM. Influence of time intervals for cholestyramine dosing on the absorption of hydrochlorothiazide. Clin Pharmacol Ther. 1986;39:329-34.
Hunninghake DB, King S, LaCroix K. The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide. Int J Clin Pharmacol Ther Toxicol. 1982;20:151-4.

97

Not applicable
PICO B (no recommendation): In patients receiving long-term maintenance therapy with BAST, should fat-soluble vitamin levels be measured
at baseline and annually, thereafter?
The literature search failed to identify any relevant article assessing fat-soluble vitamin levels before and after initiation of long-term
maintenance therapy with BAST.
It has been long known that in theory the use of BAST can cause coagulopathy due to reduced absorption of vitamin K, only a few
case reports of coagulopathy and bleeding due to vitamin K deficiency with cholestyramine use have been reported.1-5 In patients
with BAD on long-term maintenance therapy with BAST, the risks for malabsorption of fat-soluble vitamin levels may be even higher.
In a case report (Gross 19701), a woman on chronic cholestyramine therapy for diarrhea due to extensive distal ileal post-radiation
changes (cholerheic enteropathy) developed bleeding with gross hematuria, gastrointestinal bleeding, and hypotension with
prolongation of prothrombin time that was reversed with vitamin K. She had normal prothrombin time before cholestyramine
therapy. “It is likely that despite a reduced enterohepatic circulation before cholestyramine was maintained at a level above the
critical micellar concentration by increased hepatic bile-salt synthesis. Addition of cholestyramine further interfered with the
enterohepatic circulation beyond the compensatory capacity of the liver and probably reduced jejunal bile-salt concentration
critically, resulting in vitamin K malabsorption and hemorrhage secondary to hypoprothrombinemia.”
In one case report (West 19755), long term use of cholestyramine led to reduced absorption of vitamin A and E.
Overall, there is VERY LOW quality evidence supporting the assessment of fat-soluble vitamin levels at baseline and annually,
thereafter, in patients receiving long term therapy with BAST. Panel to provide other applicable evidence during meeting.
98
PICO B (no recommendation): In patients receiving long-term maintenance therapy with BAST, should fat-soluble vitamin levels be measured
at baseline and annually, thereafter?
Judgement

○ Trivial
○ Small
○ Moderate
Desirable Effects
○ Large
○ Varies
○ Don't know

○ Large
○ Moderate
○ Small
Undesirable Effects
○ Trivial
○ Varies
○ Don't know

○ Very low
○ Low
○ High
Balance of effects
○ Varies
99
○ Don't know

○ No
○ Probably no
○ Probably yes
Acceptability
○ Yes
○ Varies
○ Don't know

○ No
○ Probably no
○ Probably yes
Feasibility
○ Yes
○ Varies
○ Don't know
References for PICO B

1. Gross L, Brotman M. Hypoprothrombinemia and hemorrhage associated with cholestyramine therapy. Ann Intern Med 1970;72:95-6.
2. Vroonhof K, van Rijn HJ, van Hattum J. Vitamin K deficiency and bleeding after long-term use of cholestyramine. Neth J Med 2003;61:19-
21.
3. Shojania AM, Grewar D. Hypoprothrombinemic hemorrhage due to cholestyramine therapy. CMAJ 1986;134:609-10.
4. Sadler LC, Lane M, North R. Severe fetal intracranial haemorrhage during treatment with cholestyramine for intrahepatic cholestasis of
pregnancy. Br J Obstet Gynaecol 1995;102:169-70.
5. West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut 1975;16:93-8.
PICO III (no vote): In patients with BAD, should BAST be taken once daily to minimize interaction with other medications?
The literature search failed to identify any relevant article assessing whether BAST should be taken once daily or more than once
daily to minimize interaction with other medications.
100
A paper by Camilleri 20161 reviewed the functions of the stomach and the kinetics of emptying at different food forms or
formulations. He concluded a window of 3 hours would be expected to allow a median of at least 80% of a resin-like or other
medication with particle size < 1mm to empty from the stomach and, hence to avoid potential interactions such as binding within
the stomach. However, there is no clinical study or physiologic study that compared once daily vs. more than once daily
administration in terms of drug interactions. Theoretically, the more frequent the dosing of BAST, the more likely there will be
interactions with other medications and compliance will decrease. It is uncertain whether frequency of dosing has any impact on
efficacy of BAST.
Overall, there is no evidence found to support BAST be taken once daily to minimize interaction with other medications. There is
VERY LOW quality evidence supporting the practice of spacing out timing of BAST from other medications by at least 3 hours. Panel
to provide other applicable evidence during meeting.

PICO III (no vote): In patients with BAD, should BAST be taken once daily to minimize interaction with other medications?
The EtD framework was not completed, there was no vote, and no additional recommendation statement was developed because “drug
interactions” are included in PICO 17.
References for PICO III

1. Camilleri M. Drug-resin drug interactions in patients with delayed gastric emptying: What is optimal time window for drug
administration? Neurogastroenterol Motil 2016;28:1268-71.
PICO IV (no vote): In patients with BAD, should BAST be taken AM (or PM/ HS)?
The literature search failed to identify any relevant article assessing whether BAST should be AM (or PM/HS).
There is no evidence found to support BAST be taken AM (or PM/HS). Panel to provide other applicable evidence during meeting.

PICO IV (no vote): In patients with BAD, should BAST be taken AM (or PM/ HS)?
101
The EtD framework was not completed, there was no vote, and no recommendation statement was developed because there were no data to
inform this issue, which is discussed in terms of future research needs
References for PICO IV

Not applicable
102

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CANADIAN ASSOCIATION OF GASTROENTEROLOGY CLINICAL PRACTICE

Daniel C. Sadowski, Michael Camilleri, William D. Chey, Grigorios I. Leontiadis,

To appear in: Clinical Gastroenterology and Hepatology

© 2019 by the AGA Institute

CANADIAN ASSOCIATION OF GASTROENTEROLOGY CLINICAL PRACTICE

Running title: Management of Bile Acid Diarrhea

Abbreviations used in this paper:

CONSULTING: Allergan (WC), AstraZeneca (MC), Biomerican (WC), Dignify Therapeutics

EDUCATION/RESEARCH GRANT: Allergan (MC), AstraZeneca (MC), Elira (MC), ENYO

Scope and purpose

Sources, literature searches, and systematic reviews (SRs)

Assessment of the certainty (quality) of evidence (CoE)

Role of the funding sources

Key evidence: No published randomized controlled trials (RCTs) were available

Discussion: In patients presenting with non-bloody, chronic diarrhea or IBS-D, rates of

Key evidence: An observational cohort study, included a subgroup of 44 patients with

Key evidence: The majority of published DTAs compared 7 α-hydroxy-4-cholesten-3-

A poor response to a therapeutic trial of BAST could be related to non-compliance and

Induction therapy for BAD

Key evidence: One RCT compared cholestyramine to hydroxypropyl cellulose (HPC).63

There is no direct evidence that colesevelam is associated with a higher or lower

Key evidence: Good practice statement, CoE not assessed.

Maintenance therapy for BAD

Key evidence: Good practice statement, CoE not assessed.

Key evidence: Good practice statement, CoE not assessed.

Key evidence: Good practice statement, CoE not assessed.

acid, and estrogen-containing drugs.3,73,84 Colesevelam has a different structure, which

No recommendation B: In patients receiving long-term maintenance therapy with BAST, the

Canadian Association of Gastroenterology Statement

Table 1: Summary of consensus recommendations for the management of BAD*

Maintenance therapy for BAD (BAST)

Figure 1: Enterohepatic circulation of bile acids

60. Baert D, Coppens M, Burvenich P, et al. Chronic diarrhoea in non collagenous

PICO questions with no recommendations

DTA studies (QUADAS-II risk of bias domains)

QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies- 2) tool

Quality of evidence assessment

There are no diagnostic-strategy RCTs informing this PICO.

Evidence to Decision framework (diagnostic question)

How accurate is the test?

How substantial are the desirable anticipated effects?

What is the overall certainty of the evidence of test accuracy?

What is the overall certainty of the evidence of effects of the test?

How large are the resource requirements (costs)?

What is the certainty of the evidence of resource requirements (costs)?

ACCEPTABILITY Is the intervention acceptable to key stakeholders?

Is the intervention feasible to implement?

Evidence to Decision framework (diagnostic question)

How accurate is the test?

How substantial are the desirable anticipated effects?

How substantial are the undesirable anticipated effects?

What is the overall certainty of the evidence of test accuracy?

What is the overall certainty of the evidence of effects of the test?

How large are the resource requirements (costs)?

What is the certainty of the evidence of resource requirements (costs)?

Is the intervention acceptable to key stakeholders?

Is the intervention feasible to implement?

References for PICO 1 & 2