Impact of Bile Acid Diarrhea in Patients with Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life

Abstract

Background:

Bile acid diarrhea (BAD) affects about a quarter of patients with irritable bowel syndrome with diarrhea (IBS-D).

Aim:

To compare the demographics, bowel and somatic symptoms, and quality of life (QOL) of patients with IBS-D with or without BAD.

Methods:

On one occasion, patients with IBS-D (positive for Rome III criteria) completed the following questionnaires: bowel disease questionnaire, Hospital Anxiety and Depression (HAD) Inventory, general QOL (SCL-90), and IBS-specific QOL (IBS-QOL). Fasting serum C4 >52.5 ng/mL was used as a biomarker for BAD. Statistical analysis included multiple variable logistic model to identify strong predictors of BAD in IBS-D.

Results:

Among 219 patients (79% female) with IBS-D, 44 had BAD; the BAD group were significantly older and had higher body mass index (BMI) than those without BAD. Patients with BAD had more severe bowel dysfunction and impact on IBS-QOL (need of toilet proximity) compared to IBS-D without BAD. Patients with BAD were more likely than other IBS-D groups to receive antidiarrheals, bile acid binders, and antacid secretory agents. Severity of diarrhea and need of toilet proximity were predictors of BAD in IBS-D (P<0.01). Patients with BAD were more likely to have depression score >8 on the HAD inventory.

Conclusion:

There is greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared to IBS-D without BAD. Screening for BAD in IBS-D is especially relevant with more severe and frequent diarrhea along with urgency.

Graphical Abstract

INTRODUCTION

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting up to 10% of the general population.¹ The diagnosis is based on clinical criteria, as IBS is defined as recurrent abdominal pain related to defecation and change in frequency or form of stool. IBS is subclassified into IBS: with constipation (IBS-C), with diarrhea (IBS-D), with mixed stool pattern, or unclassified.² Up to 31.5% of people with IBS have IBS-D.³

IBS is associated with several predisposing factors such as antecedent infections, genetic predisposition, and psychological factors. Important gut factors include neuromuscular dysfunction, visceral hypersensitivity, increased permeability, dysbiosis, and bile acid-induced diarrhea (BAD) reflecting overall gut-brain axis dysfunction.^{4, 5} IBS is associated with co-morbidities in the form of other functional and somatic disorders such as fibromyalgia, chronic fatigue syndrome, chronic pelvic pain, as well as psychiatric disorders such as major depressive disorder, anxiety, and somatization.⁶ Consequently, IBS is associated with decreased work productivity, decreased quality of life (QOL), and high health and financial burden.⁷

Although there is increased appreciation of the role of BAD in the development of chronic diarrhea, notably IBS-D, with evidence of 25-50% of patients in different series showing evidence of BAD,^8-11 the impact of BAD on symptoms and quality of life in patients presenting with IBS-D is unknown. Bile acids are amphipathic molecules that mediate lipid digestion and absorption. After being synthesized in the liver, the primary bile acids (cholic acid and chenodeoxycholic acid) are conjugated to taurine and glycine and secreted in bile. Around 95% of these primary bile acids are reabsorbed via the apical Na⁺-dependent bile acid transporter in the terminal ileum and reach the liver via the portal circulation, thereby constituting the enterohepatic circulation. The remaining bile acids are deconjugated and dehydroxylated by colonic bacteria, forming predominantly deoxycholic acid and lithocholic acid and these are subsequently excreted in the feces.

In idiopathic BAD unassociated with intestinal mucosal diseases or ileal resection, as occurs in patients with IBS-D, there is evidence of decreased synthesis of fibroblast growth factor-19 (FGF-19), which is a hormone in the portal circulation that downregulates the hepatocyte synthesis of bile acids.^12-14 Hence, deficiency of FGF-19 is associated with increased bile acid synthesis, which can be assessed indirectly by measuring the level of a bile acid synthesis intermediate, 7α-hydroxy-4-cholesten-3-one (7αC4). Increased synthesis leads to a higher proportion of bile acids reaching the colon, resulting in increased mucosal permeability, increased colonic motility and water secretion contributing to BAD.¹⁵

Given that the impact of BAD on the symptoms and quality of life in patients presenting with IBS-D is unknown, our hypothesis was that patients with IBS-D with or without BAD have similar demographics, bowel and somatic symptoms, and quality of life. Our aim was to compare the demographics, bowel and somatic symptoms, and quality of life of patients with IBS-D with or without BAD.

METHODS

Participants, Regulatory Approval, and Design

Data reported here were obtained from participants with Rome III positive criteria¹⁶ for IBS-D who were recruited to the Mayo Clinic Institutional Review Board approved protocol (IRB #16-001445). Participants signed informed consent for use of their electronic medical records for research. The observational study used standard validated questionnaires and biochemical measurements. Details regarding patient selection and recruitment are included in the Supplemental Materials.

Demographics

Demographic information regarding participants’ age, gender, BMI, race, ethnicity, history of cholecystectomy, and numbers and types of medications taken was retrieved from the electronic medical records.

Questionnaires

The Hospital Anxiety and Depression (HAD) Questionnaire

Participants answered 14 questions, 7 related to anxiety symptoms and 7 related to depression symptoms. Each question was scored from 0 to 3. The sum of the scores for the 7 anxiety-related questions and the 7 depression-related questions was computed. A cut-off score of 8 on each for the subscales was considered consistent with anxiety or depression.^{17, 18}

Validated Bowel Disease Questionnaire

Participants answered 110 questions about their bowel symptoms and the impact on their activities. The questionnaire also included 16 questions related to somatic symptoms. These somatic symptom questions were in the “how often” and “how bothersome” format and were scored on a scale from 0 (not a problem) to 4 (occurs daily or extremely bothersome when occurs). ¹⁹

General Quality of Life: Symptom Checklist-90 (SCL-90) Questionnaire

Participants answered 90 questions, scored from 0 to 4. These 90 questions explored 9 different dimensions (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychotic). A global severity index (mean score of the 90 questions), a positive symptom distress index (mean score for questions with score >0), and a positive symptoms total (number of questions where score was >0) were computed. The mean score for each of the dimensions was also computed.²⁰

Irritable Bowel Syndrome Specific Quality of Life (IBS-QOL) Questionnaire

Participants answered 34 questions about their quality of life, scored from 1 to 5. These questions belonged to 8 different domains (dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual, and relationship).²¹ Using a transformation formula, the scores were transformed into a 0-100 scale. This formula was used to compute the scaled scores of the 8 different domains.²²

Criteria for Identification of BAD

Identification of BAD was based on established biochemical diagnostic criteria, that is, fasting (before 9:00 a.m. because of diurnal variation) serum 7αC4 >52.5ng/mL.²³

Statistical Analysis

The associations between nominal category questionnaire responses as well as history of cholecystectomy and BAD status were assessed using a chi-square test. The associations for continuous baseline characteristics of age, BMI, and SCL-90 subscales were assessed using a two-sample t-test. A nonparametric Wilcoxon rank sum test was used to examine the bowel functions and IBS quality of life category questions.

A multiple variable logistic regression model was used to examine six a priori identified questions for association with BAD status. These six questions pertaining to the last year for each participant were: use of antidiarrheals, stools loose or watery, experienced an urgent need to open your bowels that made you rush to the toilet, worrying about losing control of bowel, number of bowel movements per week, and importance of being near a bathroom. A parsimonious model was fit using backward selection to identify the final model, retaining for variables with p<0.05. The alpha-level was set at 0.05 for statistical significance. SAS version 9,4 was used in all analyses.

RESULTS

Demographics

Our study included 219 patients with IBS-D; among these 44 had BAD. Of our total population, 79% were females. Patients with IBS-D with BAD were significantly older and had higher BMI than those without BAD. Patients with BAD had a significantly higher proportion of cholecystectomy compared to those without BAD. We found no significant differences for sex (Table 1), race, or ethnicity (not shown).

Table 1.

Demographics of patients with IBS-D with and without BAD

Data median (IQR) or N (%)	IBS-D BAD	IBS-D without BAD	P-value
Number of patients	44	173
Demographics
Age, years, mean (SD)	46.3 (14.3)	39.8 (14.0)	0.006
Gender, M/F %	15.9% / 84.1%	22.3% / 77.7%	0.353
BMI, kg/m2, mean (SD)	33.3 (7.3)	29.2 (6.9)	<0.001
Cholecystectomy	16 (36)	20 (11)	<0.001
Gastrointestinal medications used
Total number of patients	4.3 (2.3)	3.9 (2.3)	0.604
Antidiarrheals	15 (34.1%)	31 (17.9%)	0.019
Bile acid binders	5 (11.4%)	2 (1.2%)	0.004
Laxative	1 (2.3%)	1 (0.6%)	0.365
Antacid secretory agents	15 (34.1%)	33 (19.1%)	0.032
Central neuromodulators used
Antidepressants *	16 (36.4%)	68 (39.3%)	0.721
TCA	1 (2.3%)	5 (2.9%)	1.0
SSRI	14 (31.8%)	53 (30.6%)	0.880
SNRI	2 (4.5%)	7 (4.0%)	0.880
Dopaminergic/noradrenergic reuptake inhibitors	4 (9.1%)	10 (5.8%)	0.490
Alpha-2 adrenergic antagonists	0 (0.0%)	1(0.6%)	1.0
Dopamine agonist	3 (6.8%)	1 (0.6%)	0.027
Opioid agonist	1 (2.3%)	1 (0.6%)	0.365
Other medications
Eye lubricant	5 (11.4%)	3 (1.7%)	0.010

^*Patients taking any kind of antidepressants are counted in this category. Patients taking more than one type of antidepressants are counted once.

Medication Use

There was no significant difference in the median number of medications used between the two groups (Table 1). However, the use of antidiarrheal medications was significantly higher among BAD subjects compared to IBS-D without BAD. The use of fiber was comparable, with no statistically significant differences between groups (data not shown). There was a higher prevalence of using antacid secretory agents [H2 receptor antagonists and proton pump inhibitors (p=0.0321)] and bile acid binders (p=0.0043) in the BAD group compared to the group of IBS-D without BAD.

No significant differences were found between both groups in the use of central neuromodulators. Moreover, no significant differences were found between both groups when the use of antidepressant was stratified by class of antidepressant. Dopamine agonist medication use in the BAD group was higher than in the group of IBS-D without BAD (3 in BAD group and 1 in IBS-D without BAD, p=0.0270); the indication for these dopamine agonists was restless legs syndrome. There was a significant difference in the use of eye lubricants between BAD and non-BAD groups (5 in BAD group and 4 in IBS-D without BAD).

Symptoms

Gastrointestinal and somatic symptoms

Patients with BAD were more likely to report more frequent, urgent, and watery bowel movements when compared to IBS-D without BAD. As for the severity of straining, patients with IBS-D with BAD reported significantly lower prevalence of straining and seeing mucus in stool with bowel movements in the last year than those with IBS-D without BAD (Table 2).

Table 2.

Bowel functions

Data show N (%)	IBS-D BAD	IBS-D without BAD	P-value
Number of patients	44	160
Bowel function
Stools loose or watery in last year: Sometimes	5 (12.2%)	29 (19.5%)	0.002
Often	11 (26.8%)	74 (49.7%)
Usually	25 (61.0%)	46 (30.9%)
Experienced an urgent need to open your bowels that made you rush to the toilet in the last year               Sometimes	8 (19.5%)	53 (35.6%)	0.002
Often	19 (46.3%)	76 (51.0%)
Usually	14 (34.1%)	18 (12.1%)
Mucus in stools in the last year	8 (25.0%)	61 (46.9%)	0.029
# of bowel movements/week   17-21	11 (26.8%)	20 (13.4%)	0.001
22-26	6 (14.6%)	19 (12.8%)
>26	9 (22.0%)	16 (10.7%)
Severity of straining with BM  Never	18 (43.9%)	35 (23.6%)	0.049
Very mild	9 (22.0%)	38 (25.7%)
Mild	4 (9.8%)	29 (19.6%)
Moderate	7 (17.1%)	40 (27.0%)
Severe	2 (4.9%)	5 (3.4%)
Very Severe	1 (2.4%)	1 (0.7%)

No significant differences were found between the two groups in their experiences of somatic symptoms, and frequency or intensity of bowel movements. Those in the IBS-D with BAD group were more likely to smoke cigarettes, which was defined as at least 1 cigarette per day for at least 30 days, when compared to IBS-D without BAD.

Quality of Life

General QOL based on SCL-90

No significant differences were found in the global severity index, positive symptoms distress index, and total positive symptoms between the two groups. Similarly, there were no significant differences between the mean scores on each of the 9 dimensions between the two groups (Table 3).

Table 3. General QOL based on SCL-90 dimensions.

Data show mean (SD).

SCL-90
Dimension on SCL-90	IBS-D BAD	IBS-D without BAD	P-value
Number of patients	44	161
Somatization	0.5(0.5)	0.4(0.4)	0.185
Compulsive	0.5(0.5)	0.4(0.4)	0.682
Sensitivity	0.4(0.7)	0.3(0.5)	0.628
Depression	0.5(0.5)	0.4(0.5)	0.778
Anxiety	0.3(0.5)	0.2(0.3)	0.468
Hostility	0.3(0.4)	0.3(0.4)	0.831
Phobic	0.2(0.4)	0.1(0.3)	0.676
Paranoid	0.2(0.5)	0.1(0.3)	0.246
Psychoticism	0.1(0.2)	0.1(0.2)	0.980

IBS-QOL

Significant differences between the two groups were found concerning the importance of being in proximity to a toilet, the worry about losing control of bowels (both more prevalent in BAD group), and the fear of not being able to have a bowel movement (less likely to be present in the BAD group) (Table 4). Out of the 8 subscales (see Methods), only interference with activity was significantly different between the two groups (p=0.0375): BAD patients 39.3 (IQR 23.3-60.7) compared to 33 (IQR 17.9-50) for IBS-D without BAD, based on a scale of 0-100.

Table 4.

IBS Quality of Life

Data show N (%)	IBS-D BAD (N=44)	IBS-D without BAD (N=161)	P-value
It is important to be near a toilet because of my bowel problems.			0.0105
Not at all	0 (0.0%)	12 (7.7%)
Slightly	9 (20.9%)	44 (28.4%)
Moderately	9 (20.9%)	38 (24.5%)
Quite a bit	9 (20.9%)	31 (20.0%)
Extremely	15 (34.9%)	30 (19.4%)
I worry about losing control of my bowels.			0.0029
Not at all	8 (18.6%)	41 (26.5%)
Slightly	10 (23.3%)	57 (36.8%)
Moderately	5 (11.6%)	32 (20.6%)
Quite a bit	11 (25.6%)	15 (9.7%)
A great deal	9 (20.9%)	10 (6.5%)
I fear that I won't be able to have a bowel movement.			0.0457
Missing	1	6
Not at all	39 (90.7%)	120 (77.4%)
Slightly	4 (9.3%)	24 (15.5%)
Moderately	0 (0.0%)	7 (4.5%)
Quite a bit	0 (0.0%)	1 (0.6%)
A great deal	0 (0.0%)	2 (1.3%)

Hospital Anxiety and Depression HAD scale

The questionnaire was completed by 206 patients. There were no significant differences between the two groups regarding total anxiety score, total depression score, and total (anxiety plus depression) score. When a cut-off of 8 was used for the depression subscore, 9.1% of patients with BAD were positive compared to only 1.9% of patients without BAD (p=0.0188).

Multiple Variable Logistic Model for Prediction of BAD Status

A final parsimonious model examining use of antidiarrheal medications, frequency of bowel movements, frequency of loose bowel movements, urgency, importance of being near a bathroom, and worrying about losing control of bowel identified two variables: frequency of bowel movements (OR=1.35; 95% CI 1.08-1.68) and worrying about losing control of bowel (OR=1.42; 95% CI 1.08-1.868). The area under the ROC curve for this final model was 0.69, 95% CI 0.59-0.78.

DISCUSSION

In this study, we have shown that patients with IBS-D with or without BAD differ in their BMI, medication use, symptoms, and quality of life parameters. Patients with BAD were older, were more likely to have undergone cholecystectomy, and had higher BMI compared to patients without BAD. The higher BMI has been previously reported in prior studies of BAD. ^{24, 25}

Patients with BAD were found to take significantly more antacids compared to patients without BAD, consistent with the high prevalence of gastroesophageal reflux disease among patients with IBS, and the fact that up to 44% of patients with IBS receive PPI therapy.^{26, 27} It is conceivable that bacterial overgrowth in the small intestine (SIBO) associated with PPI use may increase deconjugation of bile acids and decrease their reabsorption^{28, 29} and further studies would be required to explore this hypothesis.

In our study, a greater proportion of the BAD group was receiving bile acid binders. Medical records review of the 5 patients with BAD taking bile acid binders showed that in 4, the indication was diagnosis of BAD prior to their enrollment in this study, and the fifth patient was treated for post-cholecystectomy diarrhea.

It is worth noting that there was no difference in the numbers of patients in each group being treated with dietary fiber or with metformin which may cause BAD by inhibiting ileal bile acid reabsorption.^{30, 31} Patients on metformin, were only included if the diarrhea preceded metformin initiation, the dose was stable, and they had not experienced aggravation of the diarrhea by the medication.

We found a smaller number of patients with BAD reported mucus in their stools compared to patients without BAD. This finding was not expected since previous animal studies showed that chenodeoxycholic and deoxycholic acid perfused into the colon increased mucus secretion.^32-35

The observation that patients with BAD took more antidiarrheal medications than patients without BAD is consistent with more frequent bowel movements per week in the BAD group. In fact, among patients with BAD, 63% had more than 17 bowel movements per week, 22% had more than 26 bowel movements per week, 61% reported loose or watery stools more than 75% of the time, and 80.4% of patients with BAD reported urgent need to defecate more than 25% of the time. In fact, 34.1% had urgency to defecate more than 75% of the time.

Conversely, patients with BAD strained less with bowel movements. These findings are consistent with previous studies that reported more severe diarrhea in patients with BAD, based on ⁷⁵SeHCAT retention <10%²⁵, and on an online survey conducted by the Bile Acid Malabsorption (BAM) Support UK Study, which showed that up to 80% reported severe diarrhea and 85% reported urgency.³⁶

Consistent with the significantly worse diarrhea, patients with BAD reported the importance of being near a toilet and the fear of losing control of bowels, which precluded them from engaging in normal daily activities. Other studies have shown that patients with IBS-D had worse disease specific quality of life and more interference with daily activities, especially those that involve getting out of the home and taking place in locations with no proximity to bathrooms when compared to other subtypes of IBS.³⁷ Treatment of BAD with bile acid sequestrants significantly improved work absenteeism.³⁶

BAD also impacts mental health, specifically showing higher prevalence of symptoms suggestive of depression measured by the HAD Scale, but not when assessed by the SCL-90. The divergent result might be due to the small proportion of patients with symptoms consistent with depression even in the BAD group.

The strengths of our study include being the first study that compares the demographics, symptoms, and quality of life of IBS-D patients with and without BAD, and the >200 patients with IBS-D with typical demographic features including female sex, middle age, and active symptoms at the time of study. Our study highlights the importance of screening for BAD among patients with IBS-D, especially in those with greater severity of symptoms such as number of bowel movements, urgency, looser stool consistency, and insecurity associated with needing proximity to a bathroom which interferes with daily activities. Two features (frequency and worrying about losing control of bowel movements) also proved highly relevant on the multiple variable logistic model.

The limitations of our study are that the results are based on validated questionnaires which still constitute a subjective measurement, and the absence of correction for multiple comparisons in the interrogations in the multiple questionnaires. However, in a prior study, we had reported objective evidence consistent with more severe diarrhea in BAD (fecal bile acid excretion >2337μmol/48h) documented by significantly faster colonic transit at 24 and 48 hours as well as higher fecal fat excretion compared to patients with IBS-D with normal fecal bile acid excretion.³⁸ Another limitation of our observational study was the assessment of the population of interest at a single point in time and hence the need for replication of our findings.

We conclude that patients with BAD had higher BMI, took more antidiarrheal agents, and had more severe and frequent diarrhea, as well as urgency. These symptoms interfere with daily activities, and the impact is confirmed on a rigorous regression model. The study adds to the body of evidence, including impact on healthcare utilization,³⁹ that searching for evidence of BAD is relevant in patients with IBS-D especially in those with more severe and frequent diarrhea associated with urgency.

What You Need to Know.

Background:

Bile acid diarrhea (BAD) is identified in approximately a third of patients with irritable bowel syndrome with diarrhea (IBS-D).

This study investigated the impact of BAD by an analysis of bowel and somatic symptoms and quality of life (QOL) of patients with IBS-D with or without BAD.

Findings:

Patients with BAD had more severe bowel dysfunction (number of bowel movements, urgency), impact on IBS-QOL (need of toilet proximity), and depression compared to IBS-D without BAD.

Patients with BAD were more likely to receive antidiarrheal agents, bile acid binders, and anti-hydrogen ion secretion agents.

Implications for patient care:

There is greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared to IBS-D without BAD.

Screening for BAD in IBS-D is especially relevant with more severe and frequent diarrhea along with urgency.