Abstract
Background
Increased fecal bile acid excretion (IBAX) occurs in a third of patients with functional diarrhea.
Aims
To assess the prevalence of IBAX in benign inflammatory intestinal and colonic diseases presenting with chronic diarrhea.
Methods
All patients with known inflammatory diseases or resections who underwent 48 h fecal fat and BA testing for chronic diarrhea at a single center were included. Quiescent disease was based on clinical evaluation and serum, endoscopic and imaging studies. IBAX was defined by: > 2337 μmol total BA/48 h; or primary fecal BAs > 10%; or > 4% primary BA plus > 1000 μmol total BA /48 h. Demographics, fecal weight, fecal fat, stool frequency and consistency were collected. Nonparametric statistical analyses were used for group comparisons.
Results
Sixty patients had celiac disease (51 quiescent, 9 active), 66 microscopic colitis (MC: 34 collagenous, 32 lymphocytic), 18 ulcerative colitis (UC), and 47 Crohn’s disease (CD). Overall, fecal fat, 48 h stool weight, frequency and consistency were not different among subgroups except for inflammatory bowel disease (IBD) based on disease location. Almost 50% patients with celiac disease and MC had IBAX, with a greater proportion with increased primary fecal BA. Among UC patients, rates of IBAX were higher with pancolonic disease. A high proportion of patients with ileal resection or CD affecting ileum or colon had IBAX. IBAX was present even with quiescent inflammation in UC or CD.
Conclusions
A significant subset of patients with MC, quiescent celiac disease and IBD had increased fecal BA excretion, a potential additional therapeutic target for persistent diarrhea.
Keywords: Microscopic, Collagenous, Lymphocytic, Crohn’s, Ulcerative, Celiac, Colitis
Introduction
Bile acids are central signals in enterohepatic communication. High concentrations of bile acids delivered to the colon result in bile acid diarrhea, most frequently due to ileal disease or resection. In a classical paper, Fromm and Malavolti identified three types of bile acid malabsorption (BAM): type 1 BAM includes ileal disease such as Crohn’s disease, resection, and radiation ileitis; type 2 BAM is “idiopathic” and manifests clinically as functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D); and type 3 BAM is malabsorption of bile acids secondary to diseases such as chronic pancreatitis, cholecystectomy and celiac disease [1].
There is increased fecal bile acid excretion in 25–33% of patients with chronic functional diarrhea [2], that is, in type 2 BAM. It has been proposed that bile acid diarrhea (BAD) plays a role in microscopic colitis, and was identified in up to 43% of Spanish patients [3]. Several papers have identified ileal atrophy in association with microscopic colitis, as reviewed elsewhere [4]. Serum bile acid abnormalities have been described in pediatric [5] and adult celiac disease [6], but there was no evidence of increased fecal bile acid excretion based on a study of 37 consecutive patients before and during a gluten-free diet [7].
Our aim was to assess the prevalence of increased fecal bile acid excretion in benign inflammatory intestinal and colonic disease states presenting with chronic diarrhea and to appraise any differences in fecal bile acid excretion between active and quiescent inflammatory diseases. The diseases of interest were: celiac disease, microscopic colitis, and inflammatory bowel diseases (ulcerative colitis and Crohn’s disease).
Methods
Selection of Patients and Medical Records Review
All patients were sequentially evaluated at a single secondary and tertiary care center, and had presented with clinical features consistent with chronic diarrhea and completed 48-h fecal fat and bile acid testing as part of the diagnostic work-up per physician’s discretion.
All patients were diagnosed with celiac disease, microscopic colitis, or inflammatory bowel disease based on current gold standard diagnostic testing and were on appropriate treatment before inclusion in the study and, yet, they presented with persistent diarrhea despite treatment of the underlying inflammatory disorder. All patients were diagnosed with inflammatory disease and on appropriate treatment before inclusion in the study. Quiescent disease was based on clinical evaluation and serum, endoscopic and imaging studies. Specifically, quiescent celiac disease was based on normal tissue transglutaminase and small bowel biopsy. Quiescent inflammatory bowel disease was based on endoscopic remission confirmed on biopsies. Patients who underwent colectomy for ulcerative colitis were assessed in a different group for both location of disease and disease activity.
Demographics, fecal weight, fecal fat, stool frequency and consistency were collected from the medical records. Patients were placed on appropriate treatment options per the discretion of their primary gastroenterologist. Response to therapy was determined based on physician or patient reported improvement in diarrhea found in the medical record. Length of follow-up varied per patient and was between two months and two years.
Measurement of Fecal Fat and Bile Acids
Patients completed a four-day, 100-g fat diet, with a 48-h stool collection for total and individual fecal bile acids. Using HPLC/tandem mass spectrometry, we have adapted a method used with serum samples for fecal bile acid measurement [8]. The method for stool processing, homogenization, methanol extraction, and purification on C18 column prior to HPLC/MS measurement is detailed elsewhere [9]. Increased fecal bile acid excretion was defined as: elevated total fecal bile acids (> 2,337 μmol total bile acids/48 h) or elevated primary fecal bile acids (> 10% primary bile acids or > 4% primary bile acids + > 1,000 μmol total bile acids/48 h). Concentration of primary bile acids was calculated. Previous studies have demonstrated that chenodeoxycholic acid ≥ 2.5 μmol/mL in the right colon is sufficient to induce colonic secretion [10, 11]. As 50% of bile acids are passively absorbed within the colon, a concentration of primary bile acids ≥ 1.25 μmol/mL excreted in the stool is sufficient to induce diarrhea [12].
Data and Statistical Analysis
Data were represented as median [interquartile range (IQR)]. Non-parametric Wilcoxon rank sum and Kruskal Wallis were used for comparisons between groups.
Results
Patients, Demographics, and Fecal Data
There were 60 patients with diarrhea associated with celiac disease (51 quiescent disease, 9 active disease), 66 with microscopic colitis (34 collagenous colitis, 32 lymphocytic colitis), 18 ulcerative colitis, and 47 Crohn’s disease. Demographic data are available in Tables 1 and 2. The average stool frequency and form confirmed significant diarrhea in all the groups of patients. Overall, fecal fat, 48-h fecal weight, stool frequency and consistency were no different among the subgroups of patients with diarrhea except for inflammatory bowel disease based on the location of disease (Tables 1, 2, 3).
Table 1.
Demographic and stool data for celiac disease and microscopic colitis
| Celiac disease | Microscopic colitis | |||||
|---|---|---|---|---|---|---|
| Quiescent | Active | P | Collagenous | Lymphocytic | P | |
| N | 51 | 9 | 34 | 32 | ||
| Sex (M/F) | 10/41 | 3/6 | 0.4 | 7/27 | 3/29 | 0.2 |
| Age (years) | 53 (37–64) | 36 (23–50) | 0.03 | 66 (54–72) | 58 (45–69) | 0.2 |
| BMI (kg/m2) | 23 (21–29) | 22(19–32.8) | 0.8 | 25 (20–29) | 23.3 (20.5–30) | 0.8 |
| Cholecystectomy | 24% (12/51) | 22% (2/9) | 0.9 | 18% (6/31) | 28% (9/32) | 0.3 |
| Fecal fat (g) | 7 (3.5–13) | 9.5 (4.3–12.3) | 0.8 | 8 (5–10) | 7 (4–10) | 0.7 |
| 48 h fecal wt (g) | 421(267–748) | 577 (458–812) | 0.2 | 645 (409–941) | 546 (447–838) | 0.5 |
| BM/day | 5 (3–6) | 5.8 (2.6–7.9) | 0.6 | 7 (4.5–10) | 6.5 (5–10) | 0.8 |
| Stool BSFS (range 1–7-point scale) | 6(5.4–7) | 5.5 (5–6) | 0.1 | 6 (6–7) | 6.5 (6–7) | 0.3 |
| % primary BA | 3.7 (1–25) | 14.5 (1.6–70) | 0.1 | 5.6 (1.1–21.7) | 4.9 (1.2–27) | 0.9 |
| Total fecal BA μmol/48 h | 767 (288–1758) | 882 (355–2363) | 0.7 | 727 (450–1889) | 1131 (446–2091) | 0.5 |
| Primary BA (μmol/mL) | 0.04 (0.02–0.8) | 0.06 (0.02–2.4) | 0.7 | 0.05 (0.02–0.3) | 0.07 (0.02–0.8) | 0.5 |
| Primary BA ≥ 1.25 μmol/mL (%) | 20% (10/51) | 33% (3/9) | 0.3 | 9% (3/34) | 19% (6/32) | 0.24 |
| ↑ Primary IBAX | 25% (13/51) | 33% (3/9) | 0.9 | 35% (12/34) | 31% (10/32) | 0.9 |
| ↑ Total IBAX | 22% (11/51) | 22% (2/9) | 0.9 | 18% (6/34) | 19% (6/32) | 0.9 |
| ↑ BA (primary or total IBAX) | 47% (24/51) | 56% (5/9) | 0.9 | 53% (18/34) | 50% (16/32) | 0.9 |
M, male; F, female; Wt, weight; BM, bowel movement; BSFS, Bristol Stool Form Scale;BA, bile acid; IBAX, increased bile acid excretion
Celiac disease was subdivided into quiescent and active disease from serum and endoscopic evaluation. Microscopic colitis was subdivided into collagenous and lymphocytic colitis based on pathology specimens. Data show median (IQR); ↑ = increased; the row showing ↑ BA (primary or total IBAX) reflects data in the two preceding rows
Table 2.
Demographics and stool data for ulcerative colitis
| Ulcerative colitis | ||||||||
|---|---|---|---|---|---|---|---|---|
| Left sided | Pancolonic | Pouch | P | Active disease | Inactive disease | Pouch | P | |
| N | 7 | 6 | 5 | 0.7 | 8 | 5 | 5 | |
| Sex (M/F) | 2/5 | 2/4 | 2/3 | 0.7 | 3/5 | 1/4 | 2/3 | 0.7 |
| Age (years) | 40 (29–80) | 64.5 (19–68) | 66(48–70) | 0.7 | 49 (21.5–65) | 64 (34–79) | 66(48–70) | 0.4 |
| BMI (kg/m2) | 22(21–27) | 22(19–24) | 26 (25–29) | 0.04 | 22 (19–26) | 21.6 (20–25) | 26 (25–29) | 0.1 |
| Cholecystectomy | 29% (2/7) | 33% (2/6) | 0% (0/5) | 0.2 | 38% (3/8) | 20% (1/5) | 0% (0/5) | 0.2 |
| Fecal fat (g) | 8 (5–10) | 14 (7–31) | 11 (6–15) | 0.3 | 10 (4–13) | 10 (6–31) | 11 (6–15) | 0.8 |
| 48 h fecal weight (g) | 452 (350–565) | 766(517–1241) | 1251 (516–2103) | 0.06 | 602 (398–774) | 452 (370–829) | 1251 (516–2103) | 0.3 |
| # BM/day | 4.5(3.5–5) | 11 (8–15) | 11.5 (6–16) | 0.08 | 5 (3.8–11.3) | 4.5 (3.6–12.5) | 11.5 (6–16) | 0.3 |
| Stool BSFS (range 1–7) | 5.5 (4.8–7) | 7 (6–7) | 7 (7–7) | 0.3 | 7 (5.5–7) | 6 (4.5–6.5) | 7 (7–7) | 0.3 |
| % primary BA | 2.5 (0.8–9) | 34 (4–99) | 95 (78–99) | 0.02 | 7.1 (2.3 – 46.6) | 2.8(0.3–85.2) | 95 (78–99) | 0.04 |
| Total fecal BA μmol/48 h | 761 (426–1908) | 669 (91–3237) | 3863 (2471–4329) | 0.04 | 859 (371–1801) | 630 (222–4658) | 3863 (2471–4329) | 0.09 |
| Primary BA (μmol/mL) | 0.03 (0.01–0.6) | 0.4 (0.01–2.6) | 2.7 (1.7–6.2) | 0.03 | 0.05 (0.02–0.7) | 0.03 (0.01–4.5) | 2.7 (1.7–6.2) | 0.03 |
| Primary BA ≥ 1.25 μmol/mL (%) | 14% (1/7) | 17% (1/6) | 80% (4/5) | 0.03 | 0% (0/8) | 40% (2/5) | 80% (4/5) | 0.03 |
| ↑ Primary IBAX | 14% (1/7) | 50% (3/6) | 20% (1/5) | 0.04 | 38% (3/8) | 20% (1/5) | 20% (1/5) | 0.5 |
| ↑ Total IBAX | 14% (1/7) | 17% (1/6) | 80% (4/5) | 0.04 | 13% (1/8) | 20% (1/5) | 80% (4/5) | 0.7 |
| ↑ BA (primary or total IBAX) | 29% (2/7) | 67% (4/6) | 100% (5/5) | 0.04 | 50% (4/8) | 40% (2/5) | 100% (5/5) | 0.1 |
Disease state was subdivided based on location of disease and activity. The patients listed as “pouch” had all undergone ileal pouch anal anastomosis exclusively for ulcerative colitis. Data show median (IQR); ↑ = increased; the row showing ↑ BA (primary or total IBAX) reflects data in the two preceding rows
M, male; F, female; Wt, weight; BM, bowel movement; BSFS, Bristol Stool Form Scale; BA, bile acid; IBAX, increased bile acid excretion
Table 3.
Demographics and stool data for Crohn’s disease
| Crohn’s disease | |||||||
|---|---|---|---|---|---|---|---|
| Ileal resection | Ileal | Colonic | P | Active disease | Inactive disease | P | |
| N | 30 | 13 | 4 | 15 | 32 | ||
| Sex (M/F) | 17/13 | 3/10 | 1/3 | 0.4 | 7/8 | 10/22 | 0.3 |
| Age (years) | 50.5 (39–62.5) | 46 (23–59) | 51.5 (42–61) | 0.5 | 45 (37–59) | 49 (35–61) | 0.7 |
| BMI (kg/m2) | 25.6 (21 – 34) | 27 (20–34.5) | 20.1 (19–28) | 0.4 | 26 (19–33) | 26 (21–32) | 0.6 |
| Cholecystecomy | 17% (5/30) | 15% (2/13) | 50% (2/4) | 0.3 | 13% (2/15) | 22% (7/32) | 0.5 |
| Fecal fat (g) | 9 (5.3–30) | 5.5 (3.5–11) | 10 (2–51) | 0.2 | 9 (5–30) | 7.5 (4.8–16) | 0.6 |
| 48 h fecal weight (g) | 1011 (203–1348) | 450 (252–672) | 944 (393–1641) | 0.04 | 625 (422–1336) | 753 (464–1277) | 0.6 |
| # BM/day | 7.3 (5.4–10) | 7.5(4–11.5) | 4.3 (3.5–5.8) | 0.1 | 7 (3.5–11.5) | 7 (5–9.5) | 0.8 |
| Stool BSFS (range 1–7) | 6 (6–7) | 6 (6–7) | 5.8 (5–6) | 0.2 | 6.5 (6–7) | 6 (5.9–6.6) | 0.1 |
| % primary BA | 95 (75–99) | 41.1(12–72) | 20.4 (5–81) | < 0.01 | 73 (4–97) | 85 (35–98) | 0.6 |
| Total fecal BA μmol/48 h | 6134 (3307–12,262) | 1640 (788–2631) | 3846 (830–6249) | < 0.01 | 2223 (884–4928) | 5683 (2302–9789) | 0.05 |
| Primary BA (μmol/mL) | 6.1 (2.7 – 7.7) | 2 (0.2 – 3.4) | 1.1 (0.1–2.4) | < 0.01 | 1.8 (0.08–3.7) | 5.1 (2.0 – 7.4) | 0.02 |
| Primary BA ≥ 1.25 μmol/mL (%) | 83% (25/30) | 62% (8/13) | 50% (2/4) | 0.2 | 53% (8/15) | 81% (26/32) | 0.09 |
| ↑ Primary IBAX | 13% (4/30) | 54% (7/13) | 0% | < 0.01 | 33% (5/15) | 19% (6/32) | 0.3 |
| ↑ Total IBAX | 83% (25/30) | 23% (3/13) | 75% (3/4) | < 0.01 | 47% (7/15) | 75% (24/32) | 0.06 |
| ↑ BA (primary or total IBAX) | 96% (29/30) | 77% (10/13) | 75% (3/4) | < 0.01 | 80% (12/15) | 94% (30/32) | 0.2 |
Disease state was subdivided based on location of disease and activity. Data show median (IQR); ↑ = increased; the row showing ↑ BA (primary or total IBAX) reflects data in the two preceding rows
M, male; F, female; Wt, weight; BM, bowel movement; BSFS, Bristol Stool Form Scale; BA, bile acid; IBAX, increased bile acid excretion
Bile Acid Excretion
Celiac Disease
The majority of patients had quiescent celiac disease, but had clinically significant diarrhea, similar to those with active celiac disease. The proportion of patients with bile acid diarrhea, approximately 50%, was similar among patients with quiescent and active celiac disease. Among patients with quiescent celiac disease, nine patients had microscopic colitis (one collagenous colitis and eight lymphocytic colitis). Only 56% (5/9) of the patients with concomitant microscopic colitis responded to therapy with budesonide, bismuth or Imodium. Among the patients with concomitant microscopic colitis and celiac disease, 11 patients were initiated on bile acid sequestrants, and 82% (9/11) demonstrated improvement in diarrhea (Table 1).
Microscopic Colitis
There were no significant differences identified in any of the measurements of bowel function or stool content between collagenous and microscopic colitis. Similar to celiac disease, increased fecal bile acid excretion was found in approximately 50% of patients with microscopic colitis. In both microscopic colitis and celiac disease, the identification of excess increased fecal bile acid excretion was based on increased total fecal bile acids in about 20% and on increased primary fecal bile acids in about 33% (Table 1).
Sixty-two percent (28/45) of patients with follow-up data had improvement in diarrhea after initiation of budesonide. Of the 38% of patients (17/45) that did not improve with standard treatment for microscopic colitis, six patients had bile acid diarrhea, and 33% (2/6) demonstrated improvement in diarrhea after initiation of bile acid sequestrant.
Ulcerative Colitis
Among patients with ulcerative colitis, increased fecal bile acid excretion levels were higher in patients with pancolonic disease compared to patients with left-sided ulcerative colitis and were observed even in those whose colitis was in complete remission. Patients who had undergone ileal pouch-anal anastomosis for ulcerative colitis had the highest levels of total and primary fecal bile acids among the groups with ulcerative colitis studied. Of the eight patients with an intact colon, four patients were on aminosalicylates, two on budesonide, and two on tumor necrosis factor inhibitor (infliximab). Four patients had previously undergone cholecystectomy, but only one was diagnosed with bile acid diarrhea (Table 2).
Crohn’s Disease
As expected, a high proportion of patients with ileal resection had bile acid diarrhea, and the total fecal bile acid excretion levels were highest among the patients with Crohn’s disease. The high total fecal bile acids was in the same range as observed in patients with ileal pouches; however, the former had median 20% primary bile acids, whereas the pouch patients had 95% primary bile acids in stool. Overall, 24 patients were initiated on tumor necrosis factor inhibitors, three on aminosalicylates, four on methotrexate, eight on chronic corticosteroid therapy, seven on vedolizumab, and one on ustekinumab.
Approximately 75% of patients with Crohn’s disease affecting the ileum or colon had increased fecal bile acid excretion, even in patients with quiescent disease. It is important to note that ileal disease without resection was associated with higher primary fecal bile acids compared to those with ileal resection; however, the latter had higher total fecal bile acids compared to those with ileal disease. Of the four patients with exclusively colonic Crohn’s disease and diarrhea, three had elevated total and primary fecal bile acids, but none had > 10% primary bile acids in stools (Table 3).
There was a non-significant increase in elevated total bile acid diarrhea in patients with inactive Crohn’s disease compared to patients with active disease.
Discussion
Our study has shown that, among patients with inflammatory intestinal diseases causing diarrhea, there is evidence of increased fecal total or primary bile acid excretion in at least 50% of patients, and this occurs even in the context of quiescent diseases such as quiescent celiac disease or ulcerative colitis. The findings of increased fecal bile acid excretion in patients with ileal pouch-anal anastomosis or ileal resection or disease are expected, since the ileal pathology interferes with the active re-absorption of bile acids. Moreover, our study confirms prior literature in documenting evidence of bile acid malabsorption in active inflammatory diseases such as microscopic colitis and celiac disease in adults or children [4–6].
However, it is important to note the novel findings in our study. The most important finding is that patients with quiescent celiac disease, patients with both variants of microscopic colitis (collagenous and lymphocytic colitis), and patients with colonic (rather than small bowel) involvement by ulcerative colitis or Crohn’s disease all have evidence of increased fecal bile acid excretion. Elevated fecal concentration of primary bile acids correlated well with increased total fecal bile acid excretion in quiescent inflammatory disease states, increasing the probability that excess colonic bile acids is the cause of diarrhea.
The current studies do not permit an evaluation of ileal mucosal morphology or biopsies to exclude ileal involvement as might occur in patients with colonic Crohn’s disease or patients with ulcerative pancolitis who may have back-wash ileitis. However, irrespective of the mechanism that results in the increased fecal excretion of bile acids, the current data support the need to exclude bile acids as a contributor to the development of chronic diarrhea even in the presence of quiescent inflammatory diseases as illustrated in the case of quiescent celiac disease in the current study. Both human [12] and animal [10] studies have provided evidence of passive absorption of bile acids in the colon, and the presence of inflammation due to microscopic colitis or ulcerative or Crohn’s colitis may conceivably interfere with this passive component of bile acid absorption that is characterized by zero order kinetics, that is, the absorption results from passive, concentration-dependent diffusion. However, this may be a minor factor contributing to the increased concentrations of bile acids in the colon and in stool. It appears more likely that interference of the disease processes with active absorption of bile acids in the ileum is the major contributing factor to the increased bile acid excretion in stool and indeed, involvement of ileal mucosa with atrophy [13–16] in microscopic colitis. In a large series of 1,131 cases in an open-access endoscopy practice, ileoscopy was performed in 508 cases and was abnormal in 26 cases (5%), manifesting as ileitis and/or ulceration in 25 cases and ileal stricture in one case [17].
Ileal involvement in celiac disease, in the absence of ulcerative jejunoileitis, is increasingly recognized on enterography [18, 19] as increased number of folds in the ileum (jejunization of ileum) and reduced number of jejunal folds together with jejunization of ileum (jejunoileal fold pattern reversal). Magnified ileoscopy also demonstrates evidence of ileal atrophy in patients with celiac disease [20]. Terminal ileal biopsies may also reveal classical histological features of celiac disease [21], although that is relatively rare [22].
The patients with ileal pouches had markedly elevated total and predominantly primary fecal bile acids as could be expected; although further evaluation for normal values in asymptomatic pouch patients is required. The literature suggests that fecal bile acids, short-chain fatty acids, and bacteria after ileal pouch-anal anastomosis do not differ in patients with or without pouchitis [23].
At present, the increased bile acid excretion in a 48-h stool sample is the gold standard for diagnosis. However, with the recent development of a serum screening test using either serum 7alpha-C4 or serum FGF-19 and with further validation of the utility of primary fecal bile acid excretion in a random stool sample [24], it may be possible to identify increased bile acid excretion in patients with inflammatory diseases associated with diarrhea and to specifically treat those patients with sequestrants in addition to the anti-inflammatory or dietary approaches. It is conceivable that some patients with inflammatory bowel disease whose inflammation is in remission and who remain symptomatic and are thought to have irritable bowel syndrome may actually have a component of increased bile acid concentrations in the colon and increased fecal BA excretion. This increase in intra-colonic BA may be targeted specifically with a bile acid sequestrant instead of increasing the dose of biological or anti-inflammatory therapy.
Our study has limitations since it is based on a tertiary referral population of patients with diarrhea complicating their known inflammatory intestinal or colonic diseases. Thus, it needs to be replicated in an independent cohort of patients, including an assessment of the role of serological (serum C4) and random stool sample measurements of primary bile acid content in the identification of increased bile acid excretion. We perceive that additional investigations are required to determine the underlying etiology of the excess bile acids within the colon in inflammatory disease states, as well as obtaining prospective data on the effects of bile acid sequestrants in patients with increased bile acid excretion and inflammatory diseases.
Our study also has strengths in terms of the numbers of patients evaluated in each of these non-malignant inflammatory diseases, the spectrum of the different diseases included, the comprehensive information regarding the patients in the study, and the use of the gold standard test available for diagnosis of bile acid diarrhea in the United States, that is, total fecal bile acid excretion over 48 h.
We conclude that a significant proportion of patients with celiac disease, microscopic colitis, and inflammatory bowel disease in our tertiary referral cohort had increased fecal bile acid excretion. Further studies of the potential role of bile acid excretion as an additional therapeutic target for persistent diarrhea in inflammatory intestinal diseases are warranted.
Acknowledgments
We thank Mrs. Cindy Stanislav for excellent secretarial assistance
Funding
This work was supported by grant R01-DK115950 from National Institutes of Health to Michael Camilleri.
Conflict of interest
Michael Camilleri has received research grants from Allergan and Novartis to study treatments for bile acid diarrhea (specifically eluxadoline and tropifexor, respectively). The other authors have no conflicts of interest.
Abbreviations
- BA
Bile acid
- CD
Crohn’s disease
- IBAX
Increased bile acid excretion
- IBD
Inflammatory bowel disease
- UC
Ulcerative colitis
Footnotes
Research involving human participants This retrospective review study was approved by the Mayo Clinic Institutional Review Board (IRB #17–009774) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The records of all patients between January 1, 2015 and December 17, 2019 were evaluated.
Informed consent The study was based on the retrospective review of the medical records of patients who had approved use of their medical records for research purposes.
References
- 1.Fromm H, Malavolti M. Bile acid-induced diarrhoea. Clin Gastroenterol. 1986;15:0567–582. [PubMed] [Google Scholar]
- 2.Wedlake L, A’Hern R, Russell D, Thomas K, Walters JRF, Andreyev HJN. 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;30:707–717. [DOI] [PubMed] [Google Scholar]
- 3.Fernandez-Bañares F, Esteve M, Salas A et al. Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea. Dig Dis Sci. 2001;46:2231–2238. 10.1023/A:1011927302076 [DOI] [PubMed] [Google Scholar]
- 4.Pardi DS. Diagnosis and management of microscopic colitis. Am J Gastroenterol. 2017;112:78–85. [DOI] [PubMed] [Google Scholar]
- 5.Ejderhamn J, Samuelson K, Strandvik B. Serum primary bile acids in the course of celiac disease in children. J Pediatr Gastroenterol Nutr. 1992;14:443–449. [DOI] [PubMed] [Google Scholar]
- 6.Spiller RC, Frost PF, Stewart JS, Bloom SR, Silk DB. Delayed postprandial plasma bile acid response in coeliac patients with slow mouth-caecum transit. Clin Sci (Lond). 1987;72:217–223. [DOI] [PubMed] [Google Scholar]
- 7.Vuoristo M, Miettinen TA. The role of fat and bile acid malabsorption in diarrhoea of coeliac disease. Scand J Gastroenterol. 1987;22:289–294. [DOI] [PubMed] [Google Scholar]
- 8.Tagliacozzi D, Mozzi AF, Casetta B 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. [DOI] [PubMed] [Google Scholar]
- 9.Wong BS, Camilleri M, Carlson P et al. Increased bile acid bio-synthesis is associated with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2012;10:e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Camilleri M, Murphy R, Chadwick VS. Dose-related effects of chenodeoxycholic acid in the rabbit colon. Dig Dis Sci. 1980;25:433–438. 10.1007/BF01395507 [DOI] [PubMed] [Google Scholar]
- 11.Camilleri M, Murphy R, Chadwick VS. Pharmacological inhibition of chenodeoxycholate-induced fluid and mucus secretion and mucosal injury in the rabbit colon. Dig Dis Sci. 1982;27:865–869. 10.1007/BF01316567 [DOI] [PubMed] [Google Scholar]
- 12.Mekhjian HS, Phillips SF, Hofmann AF. Colonic absorption of unconjugated bile acids: perfusion studies in man. Dig Dis Sci. 1979;24:545–550. 10.1007/BF01489324 [DOI] [PubMed] [Google Scholar]
- 13.Hamilton I, Sanders S, Hopwood, Bouchier IA. Collagenous colitis associated with small intestinal villous atrophy. Gut 1986;27:1394–1398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hwang WS, Kelly JK, Shaffer EA, Sylwestrowicz T, Klassen J. A novel enteropathy with partial villous atrophy, microscopic colitis and pemphigoid change. J Clin Gastroenterol. 1989;11:216–219. [DOI] [PubMed] [Google Scholar]
- 15.Marteau P, Lavergne-Slove A, Lemann M et al. Primary ileal villous atrophy is often associated with microscopic colitis. Gut 1997;41:561–564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Padmanabhan V, Callas PW, Li SC, Trainer TD. Histopathological features of the terminal ileum in lymphocytic and collagenous colitis: a study of 32 cases and review of literature. Mod Pathol. 2003;16:115–119. [DOI] [PubMed] [Google Scholar]
- 17.Yusoff IF, Ormonde DG, Hoffman NE. Routine colonic mucosal biopsy and ileoscopy increases diagnostic yield in patients undergoing colonoscopy for diarrhea. J Gastroenterol Hepatol. 2002;17:276–280. [DOI] [PubMed] [Google Scholar]
- 18.Tomei E, Semelka RC, Braga L et al. Adult celiac disease: what is the role of MRI? J Magn Reson Imaging 2006;24:625–629. [DOI] [PubMed] [Google Scholar]
- 19.Tomei E, Diacinti D, Stagnitti A et al. MR enterography: relationship between intestinal fold pattern and the clinical presentation of adult celiac disease. J Magn Reson Imaging 2012;36:183–187. [DOI] [PubMed] [Google Scholar]
- 20.Trecca A, Gaj F, Gagliardi G, Calcaterra R, Battista S, Silano M. Role of magnified ileoscopy in the diagnosis of cases of coeliac disease with predominant abdominal symptoms. Scand J Gastroenterol. 2009;44:320–324. [DOI] [PubMed] [Google Scholar]
- 21.Dickey W, Hughes DF. Histology of the terminal ileum in coeliac disease. Scand J Gastroenterol. 2004;39:665–667. [DOI] [PubMed] [Google Scholar]
- 22.Hopper AD, Hurlstone DP, Leeds JS et al. The occurrence of terminal ileal histological abnormalities in patients with coeliac disease. Dig Liver Dis. 2006;38:815–819. [DOI] [PubMed] [Google Scholar]
- 23.Sandborn WJ, Tremaine WJ, Batts KP et al. Fecal bile acids, short-chain fatty acids, and bacteria after ileal pouch-anal anastomosis do not differ in patients with pouchitis. Dig Dis Sci. 1995;40:1474–1483. 10.1007/BF02285195 [DOI] [PubMed] [Google Scholar]
- 24.Vijayvargiya P, Camilleri M, Taylor A, Busciglio I, Loftus EV Jr, Donato L. Brief Communication: Combined fasting serum C4 and primary bile acids from a single stool sample diagnose bile acid diarrhea. Gastroenterology 2020. Jul 6;S0016–5085(20)34914–3. 10.1053/j.gastro.2020.07.001. Online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]