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Vol.17 No.6
November, 2023
Frequency : Bimonthly
pISSN 1976-2283
eISSN 2005-1212 
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
| Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
| Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
| Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
| Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
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Michael Camilleri
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, MN, USA
Correspondence to: Michael Camilleri, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, 200 First St. S.W., Charl-ton Bldg., Rm. 8-110, Rochester, MN 55905, USA Tel: +1-507-266-2305, E-mail: camilleri.michael@mayo.edu
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2015;9(3):332-339. https://doi.org/10.5009/gnl14397
Published online May 15, 2015, Published date May 31, 2015
Copyright © Gut and Liver.
Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Keywords: Malabsorption, FGF-19, FXR, C4, CYP7A1, Klotho β
Bile acids (BAs) are detergent molecules1 that are synthesized in the liver and are responsible for solubilization of fatty acids and monoglycerides (the lipolysis products of triglycerides), facilitating digestion and lipid absorption in the small intestine. The different BA molecules are differentiated by hydroxylation and conjugation. Chenodeoxycholic acid (CDCA) and cholic acid (CA) are primary BAs synthesized from cholesterol and conjugated with taurine or glycine in the liver; in the colon, bacteria deconjugate and dehydroxylate the BAs to form, respectively, lithocholic acid and deoxycholic acid (DCA).2
Taurine or glycine conjugation of the BAs permits the ionization of BAs which increases their solubility and their impermeability to cell membranes, allowing BAs to reach the critical micellar concentration for spontaneous formation of micelles. In the micelles, the polar BAs surround the insoluble, hydrophobic fatty acids and monoglycerides and present the hydrophobic fat molecules to the enterocyte brush border membrane of the small intestine for digestion and absorption.
The apical Na+-dependent bile salt transporter (ASBT) (also called ileal BA transporter or SLC10A2 [solute carrier family 10, member two]) is responsible for the active reuptake of BAs in the terminal ileum. This reabsorbs approximately 95% of BAs in the terminal ileum and results in a functional enterohepatic circulation of BA,3 transporting the BAs back to the liver. Several molecular mechanisms are involved in the enterohepatic circulation: farnesoid X receptor (FXR) is expressed in ileal enterocytes and hepatocytes; BAs are agonists of the FXR; sensing of the enterocyte BA pool by FXR affects the liver by way of the endocrine factor, fibroblast growth factor 19 (FGF-19); FGF-19 is released from enterocytes into the portal circulation and activates FGF receptor 4 (FGF-R4) in hepatocytes in a process that involves interaction with klothoβ on the hepatocyte membrane, resulting in downregulation of cholesterol 7α-hydroxylase (CYP7A1) and therefore inhibition of the BA synthesis. Cholerheic or BA diarrhea is thought to result predominantly from the interruption of the enterohepatic circulation.3
The causes of BA diarrhea (BAD) are based on the original classification of BA malabsorption (BAM):
A fourth category of BAD may result from excessive hepatic BA synthesis; for example, the oral hypoglycemic drug, metformin, is associated with increased hepatic BA synthesis.4–6
Recent literature has identified several novel potential mechanisms in the development of idiopathic BAD (Fig. 1).7
FGF-19 produced in the ileum in response to BA absorption regulates hepatic BA synthesis.8 In a landmark article, Walters
Genetic mutations in the apical sodium-bile acid transporter (ASBT) are extremely rare.12,13 In addition, defective BA uptake into ileal mucosal biopsies was excluded by Bajor
Accelerated small bowel transit bypassing active BA transport in the ileum has been hypothesized as a cause of BAM in idiopathic15 and postradiation cases.16,17 While this is theoretically possible, it seems unlikely given the ASBT’s affinity for BA, and it is unclear whether the accelerated small bowel transit is a cause or an effect of the BAM.
The role of these genetic variants is based on significant associations of SNP rs17618244 in the
TGR5, or GPBAR1, is a member of the G protein-coupled receptor superfamily that functions as a cell surface receptor for BA,20 including colonic epithelial cells,21 regulating basal and cholinergic-induced secretion in rat colon22 and colonic transit.23 We have recently shown that genetic variation in
BA chemistry determines effects on colonic mucosa; in general, the surface active properties that lead to increased colonic mucosal permeability and electrolyte and water secretion are associated with two hydroxyl groups at the 3,7 (CDCA) or 3,12 (DCA) positions in the α-configuration. BAs regulate many cell types in the gut wall and beyond by activating nuclear and plasma membrane receptors. Of these, the G protein-coupled receptor, TGR5, has emerged as a key mediator of the nongenomic actions of BAs. TGR5 is a cell-surface receptor that couples to Gαs, formation of cAMP, activation of protein kinase A and extracellular signal-regulated kinases, and inhibition of inflammatory signaling pathways.25
The mechanisms of diarrhea include increased mucosal permeability;26 water secretion through activation of CFTR via adenylate cyclase27,28 and inhibition of apical Cl/OH exchange;29 lubrication by increased mucus secretion (a direct effect on goblet cells);30,31 and acceleration of colonic motility, likely via TGR5 stimulation of myenteric ganglionic neurons.23 BAs induce colonic high amplitude propagated contractions.32
Type 1 BAD is caused by ileal disease or resection, typically due to Crohn’s disease or radiation ileitis. The classical papers of Hofmann and Poley
Type 2 BAD is currently considered diarrhea without morphological abnormalities. Several studies have documented BAM in one-third to one-half of patients with chronic diarrhea or IBS-D, as summarized in a systematic review.
It has been estimated that 1% of the population of Western countries suffers from BAD.
The colonic microbiome is responsible for the dehydroxylation of cholic and chenodeoxycholic acids to the secondary BAs, deoxycholic and lithocholic acids. Gut microbiota also regulate expression of fibroblast growth factor 15 in the mouse ileum and cholesterol CYP7A1 in the liver by FXR-dependent mechanisms.40 The microbiome influences the generation of BAs and other organic acids in the murine colon.41 In humans, BA pool size and composition appear to be major regulators of microbiome structure, which, in turn, appears to be an important regulator of BA pool size and composition.42 Ongoing research seeks to unravel the contributions of the microbiome and BA composition to diverse conditions including colorectal cancer,43 inflammatory bowel disease,44 and irritable bowel syndrome.45
Several studies have now reported the profile of fecal BAs in patients with IBS-D. Duboc
14C-glycocholate breath and stool test, 75selenium homotauro-cholic acid test (SeHCAT), 7α-hydroxy-4-cholesten-3-one (C4), and fecal BAs are direct measurements of BAs or surrogates for the rate of hepatic synthesis of BAs, which is proportional to BAM.
The 14C-glycocholate (14C-BA) breath and stool test is based on the principles
The 75SeHCAT utilizes a synthetic 75selenium homotaurocholic BA that is resistant to bacterial degradation
Serum 7 α-hydroxy-4-cholesten-3-one (C4) measures BA synthesis, 90% of which is regulated by the rate-limiting enzyme, cholesterol CYP7A1. C4 is a downstream product of CY-P7A1. Serum C4 is a simple blood test, but it requires standardized specimen collection time because of diurnal variability.
Fecal measurements to quantify total and individual fecal BAs are technically cumbersome and not widely available.
An enzymatic 3α-steroid dehydrogenase assay indirectly measures fecal BA. 3α-Steroid dehydrogenase is used to oxidize deconjugated BAs and produces NADH, which is then measured biochemically. This method requires proper stereotactic alignment of enzyme and substrate and with a variety of conjugations (sulfonation, glucuronidation) of BAs while they are in the small intestine. This method would lack precision if it was used to measure concentrations of BAs in small bowel fluid or ileostomy effluent. In addition, because it does not assess BAs with hydroxyl groups in the β-configuration, it tends to underestimate total BAs.
Serum FGF-19 is a useful screening test for BAD,
Urine 2-propanol and acetamide
Cholestyramine and colestipol are generally considered first-line treatment for BAD; however, poor palatability results in low patient compliance.60 Several open label studies have recently demonstrated efficacy of these BA sequestrants in patients with IBS-D, especially those with evidence of BAM.61,62 For example, colestipol treatment improved IBS symptoms (IBS severity scoring system 220±109 vs 277±106; p<0.01), and 15 of 27 patients also fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5 to 8), suggesting benefit both in bowel symptoms and global symptoms.
Alternatives are being tested, even though there are no large clinical trials specifically for the indication of BAD. Thus, patients may prefer colesevelam at a dose of up to 1.875 g, twice a day. In a pharmacodynamics study of 24 unselected patients with IBS-D,63 emptying of the ascending colon took an average of 4 hours longer in patients given colesevelam (1.875 g, twice a day) compared with placebo, treatment effect was significantly associated with baseline serum C4 levels, and colesevelam caused greater ease of stool passage and somewhat firmer stool consistency. In an unpublished open-label study (Camilleri 2014, unpublished) of the same dose of colesevelam in 12 IBS-D patients with elevated fecal BA excretion, we have also shown that colesevelam sequestered BAs and resulted in significantly firmer stool consistency.
FGF-19 production is stimulated by the FXR agonist, obeticholic acid,64 which may potentially reverse the FGF-19 deficiency postulated in BAM that leads to excessive hepatocyte BA synthesis. This treatment has been associated with improved stool frequency and consistency in a preliminary study of patients with BAD.65 Another FXR agonist, GW4064, attenuated Cl− secretory responses to both Ca2+ and cAMP-dependent agonists, and may be efficacious in the treatment of BAD through antisecretory actions on the colonic epithelium.66
The pioneering work conducted 40 years ago by giants in this field (Drs. Alan Hofmann, Donald Small, Hans Fromm, and Vinton Chadwick) is finally going to have an impact beyond the patients with ileal resection or ileal Crohn’s disease. BA diarrhea is finally appreciated as a significant cause of functional, otherwise unexplained, chronic diarrhea in about one-third of such patients. The availability of simple diagnostic stool tests (fecal BA excretion performed at the time of fecal fat measurement) and, even more applicable, serum or urine tests will enhance the ability of physicians to diagnose this eminently treatable disorder.
In the future, BA sequestration with tablet formulations that are associated with higher compliance or Farnesoid X receptor agonists will impact the care of patients and likely reduce overall healthcare costs by reducing the need for expensive tests like colonoscopy and biopsies or treatments like biologic agents in patients with Crohn’s disease.
Fig. 1.Mechanisms of bile acid (BA)-related bowel dysfunction in irritable bowel syndrome with diarrhea (IBS-D) or idiopathic BA diarrhea (Adapted from Camilleri M. J Physiol 2014;592(Pt 14):2967–2980).7 Enterohepatic circulation of bile acids: Ileal enterocytes absorb bile acid through a receptor-mediated process (ileal bile acid transporter [IBAT]). Intracellular bile acids activate the farnesoid-γ receptor to increase fibroblast growth factor 19 (FGF-19) synthesis. FGF-19 in the portal circulation downregulates hepatocyte bile acid synthesis. Disorders of FGF-19 synthesis by ileal enterocytes or genetic variations of FGFR4 or β-klotho lead to excess bile acid concentration in the colon, resulting in activation of the G protein-coupled bile acid receptor 1 (GPBAR1, or TGR5) with enteroendocrine cell stimulation (e.g., release of 5-hydroxytryptamine) and stimulation of colonic motility with acceleration of colonic transit, activation of visceral sensation and fluid secretion (through increased intracellular cAMP, increased mucosal permeability or chloride ion secretion). Genetic variation in GPBAR1 (Diagnostic Tests for Bile Acid Malabsorption and Their Pros and Cons
| BAM diagnosis | Advantages | Disadvantages |
|---|---|---|
| Therapeutic trial with BA sequestrant | Clinically applicable, widely used | Not definitive diagnosis of BAM; nonspecific amelioration of diarrhea due to other causes; poor compliance with some BA sequestrants |
| 14C glycocholate | May identify small bowel bacterial overgrowth | Radiation exposure, β emission, long t1/2 Varying normal values Positive breath excretion at 2–4 hr does not differentiate BAM from small bowel bacterial overgrowth Laborious test method (stool collection) |
| 75SeHCAT | γ Emission, short t1/2, with decreased radiation to extra-abdominal organs | Not available in United States |
| Well-defined normal values; level of isotope retention predicts response to BA sequestrant | Radiation exposure | |
| Simple test method: 2 patient visits | ||
| Serum C4 | No radiation | Fasting sample, diurnal variation |
| Normal values reported in adults | Requires further validation | |
| Not dependent on age, gender or cholesterol | False-positive in liver disease, treatment with statins and altered circadian rhythm | |
| Simple blood test: 1 patient visit | ||
| Serum FGF-19 | No radiation; commercial ELISA assay | Moderate sensitivity and specificity; requires further validation |
| Fecal BA | No radiation | Variable daily fecal BA excretion, requires at least 48 hr sample collection |
| Measures total and individual BAs | Cumbersome method (stool collection) | |
| Urine 2-propanol and acetamide | No radiation; urine sample | Special technology required: Field Asymmetric Ion Mobility Spectrometer; requires replication and validation |
Updated from Vijayvargiya P, et al. Clin Gastroenterol Hepatol 2013;11:1232–1239.47
BAM, bile acid malabsorption; BA, bile acid; 75SeHCAT, 75selenium homotaurocholic acid test; FGF-19, fibroblast growth factor 19; ELISA, enzyme-linked immunosorbent assay.
Gut Liver 2015; 9(3): 332-339
Published online May 31, 2015 https://doi.org/10.5009/gnl14397
Copyright © Gut and Liver.
Michael Camilleri
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, MN, USA
Correspondence to: Michael Camilleri, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, 200 First St. S.W., Charl-ton Bldg., Rm. 8-110, Rochester, MN 55905, USA Tel: +1-507-266-2305, E-mail: camilleri.michael@mayo.edu
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.
Keywords: Malabsorption, FGF-19, FXR, C4, CYP7A1, Klotho &beta,
Bile acids (BAs) are detergent molecules1 that are synthesized in the liver and are responsible for solubilization of fatty acids and monoglycerides (the lipolysis products of triglycerides), facilitating digestion and lipid absorption in the small intestine. The different BA molecules are differentiated by hydroxylation and conjugation. Chenodeoxycholic acid (CDCA) and cholic acid (CA) are primary BAs synthesized from cholesterol and conjugated with taurine or glycine in the liver; in the colon, bacteria deconjugate and dehydroxylate the BAs to form, respectively, lithocholic acid and deoxycholic acid (DCA).2
Taurine or glycine conjugation of the BAs permits the ionization of BAs which increases their solubility and their impermeability to cell membranes, allowing BAs to reach the critical micellar concentration for spontaneous formation of micelles. In the micelles, the polar BAs surround the insoluble, hydrophobic fatty acids and monoglycerides and present the hydrophobic fat molecules to the enterocyte brush border membrane of the small intestine for digestion and absorption.
The apical Na+-dependent bile salt transporter (ASBT) (also called ileal BA transporter or SLC10A2 [solute carrier family 10, member two]) is responsible for the active reuptake of BAs in the terminal ileum. This reabsorbs approximately 95% of BAs in the terminal ileum and results in a functional enterohepatic circulation of BA,3 transporting the BAs back to the liver. Several molecular mechanisms are involved in the enterohepatic circulation: farnesoid X receptor (FXR) is expressed in ileal enterocytes and hepatocytes; BAs are agonists of the FXR; sensing of the enterocyte BA pool by FXR affects the liver by way of the endocrine factor, fibroblast growth factor 19 (FGF-19); FGF-19 is released from enterocytes into the portal circulation and activates FGF receptor 4 (FGF-R4) in hepatocytes in a process that involves interaction with klothoβ on the hepatocyte membrane, resulting in downregulation of cholesterol 7α-hydroxylase (CYP7A1) and therefore inhibition of the BA synthesis. Cholerheic or BA diarrhea is thought to result predominantly from the interruption of the enterohepatic circulation.3
The causes of BA diarrhea (BAD) are based on the original classification of BA malabsorption (BAM):
A fourth category of BAD may result from excessive hepatic BA synthesis; for example, the oral hypoglycemic drug, metformin, is associated with increased hepatic BA synthesis.4–6
Recent literature has identified several novel potential mechanisms in the development of idiopathic BAD (Fig. 1).7
FGF-19 produced in the ileum in response to BA absorption regulates hepatic BA synthesis.8 In a landmark article, Walters
Genetic mutations in the apical sodium-bile acid transporter (ASBT) are extremely rare.12,13 In addition, defective BA uptake into ileal mucosal biopsies was excluded by Bajor
Accelerated small bowel transit bypassing active BA transport in the ileum has been hypothesized as a cause of BAM in idiopathic15 and postradiation cases.16,17 While this is theoretically possible, it seems unlikely given the ASBT’s affinity for BA, and it is unclear whether the accelerated small bowel transit is a cause or an effect of the BAM.
The role of these genetic variants is based on significant associations of SNP rs17618244 in the
TGR5, or GPBAR1, is a member of the G protein-coupled receptor superfamily that functions as a cell surface receptor for BA,20 including colonic epithelial cells,21 regulating basal and cholinergic-induced secretion in rat colon22 and colonic transit.23 We have recently shown that genetic variation in
BA chemistry determines effects on colonic mucosa; in general, the surface active properties that lead to increased colonic mucosal permeability and electrolyte and water secretion are associated with two hydroxyl groups at the 3,7 (CDCA) or 3,12 (DCA) positions in the α-configuration. BAs regulate many cell types in the gut wall and beyond by activating nuclear and plasma membrane receptors. Of these, the G protein-coupled receptor, TGR5, has emerged as a key mediator of the nongenomic actions of BAs. TGR5 is a cell-surface receptor that couples to Gαs, formation of cAMP, activation of protein kinase A and extracellular signal-regulated kinases, and inhibition of inflammatory signaling pathways.25
The mechanisms of diarrhea include increased mucosal permeability;26 water secretion through activation of CFTR via adenylate cyclase27,28 and inhibition of apical Cl/OH exchange;29 lubrication by increased mucus secretion (a direct effect on goblet cells);30,31 and acceleration of colonic motility, likely via TGR5 stimulation of myenteric ganglionic neurons.23 BAs induce colonic high amplitude propagated contractions.32
Type 1 BAD is caused by ileal disease or resection, typically due to Crohn’s disease or radiation ileitis. The classical papers of Hofmann and Poley
Type 2 BAD is currently considered diarrhea without morphological abnormalities. Several studies have documented BAM in one-third to one-half of patients with chronic diarrhea or IBS-D, as summarized in a systematic review.
It has been estimated that 1% of the population of Western countries suffers from BAD.
The colonic microbiome is responsible for the dehydroxylation of cholic and chenodeoxycholic acids to the secondary BAs, deoxycholic and lithocholic acids. Gut microbiota also regulate expression of fibroblast growth factor 15 in the mouse ileum and cholesterol CYP7A1 in the liver by FXR-dependent mechanisms.40 The microbiome influences the generation of BAs and other organic acids in the murine colon.41 In humans, BA pool size and composition appear to be major regulators of microbiome structure, which, in turn, appears to be an important regulator of BA pool size and composition.42 Ongoing research seeks to unravel the contributions of the microbiome and BA composition to diverse conditions including colorectal cancer,43 inflammatory bowel disease,44 and irritable bowel syndrome.45
Several studies have now reported the profile of fecal BAs in patients with IBS-D. Duboc
14C-glycocholate breath and stool test, 75selenium homotauro-cholic acid test (SeHCAT), 7α-hydroxy-4-cholesten-3-one (C4), and fecal BAs are direct measurements of BAs or surrogates for the rate of hepatic synthesis of BAs, which is proportional to BAM.
The 14C-glycocholate (14C-BA) breath and stool test is based on the principles
The 75SeHCAT utilizes a synthetic 75selenium homotaurocholic BA that is resistant to bacterial degradation
Serum 7 α-hydroxy-4-cholesten-3-one (C4) measures BA synthesis, 90% of which is regulated by the rate-limiting enzyme, cholesterol CYP7A1. C4 is a downstream product of CY-P7A1. Serum C4 is a simple blood test, but it requires standardized specimen collection time because of diurnal variability.
Fecal measurements to quantify total and individual fecal BAs are technically cumbersome and not widely available.
An enzymatic 3α-steroid dehydrogenase assay indirectly measures fecal BA. 3α-Steroid dehydrogenase is used to oxidize deconjugated BAs and produces NADH, which is then measured biochemically. This method requires proper stereotactic alignment of enzyme and substrate and with a variety of conjugations (sulfonation, glucuronidation) of BAs while they are in the small intestine. This method would lack precision if it was used to measure concentrations of BAs in small bowel fluid or ileostomy effluent. In addition, because it does not assess BAs with hydroxyl groups in the β-configuration, it tends to underestimate total BAs.
Serum FGF-19 is a useful screening test for BAD,
Urine 2-propanol and acetamide
Cholestyramine and colestipol are generally considered first-line treatment for BAD; however, poor palatability results in low patient compliance.60 Several open label studies have recently demonstrated efficacy of these BA sequestrants in patients with IBS-D, especially those with evidence of BAM.61,62 For example, colestipol treatment improved IBS symptoms (IBS severity scoring system 220±109 vs 277±106; p<0.01), and 15 of 27 patients also fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5 to 8), suggesting benefit both in bowel symptoms and global symptoms.
Alternatives are being tested, even though there are no large clinical trials specifically for the indication of BAD. Thus, patients may prefer colesevelam at a dose of up to 1.875 g, twice a day. In a pharmacodynamics study of 24 unselected patients with IBS-D,63 emptying of the ascending colon took an average of 4 hours longer in patients given colesevelam (1.875 g, twice a day) compared with placebo, treatment effect was significantly associated with baseline serum C4 levels, and colesevelam caused greater ease of stool passage and somewhat firmer stool consistency. In an unpublished open-label study (Camilleri 2014, unpublished) of the same dose of colesevelam in 12 IBS-D patients with elevated fecal BA excretion, we have also shown that colesevelam sequestered BAs and resulted in significantly firmer stool consistency.
FGF-19 production is stimulated by the FXR agonist, obeticholic acid,64 which may potentially reverse the FGF-19 deficiency postulated in BAM that leads to excessive hepatocyte BA synthesis. This treatment has been associated with improved stool frequency and consistency in a preliminary study of patients with BAD.65 Another FXR agonist, GW4064, attenuated Cl− secretory responses to both Ca2+ and cAMP-dependent agonists, and may be efficacious in the treatment of BAD through antisecretory actions on the colonic epithelium.66
The pioneering work conducted 40 years ago by giants in this field (Drs. Alan Hofmann, Donald Small, Hans Fromm, and Vinton Chadwick) is finally going to have an impact beyond the patients with ileal resection or ileal Crohn’s disease. BA diarrhea is finally appreciated as a significant cause of functional, otherwise unexplained, chronic diarrhea in about one-third of such patients. The availability of simple diagnostic stool tests (fecal BA excretion performed at the time of fecal fat measurement) and, even more applicable, serum or urine tests will enhance the ability of physicians to diagnose this eminently treatable disorder.
In the future, BA sequestration with tablet formulations that are associated with higher compliance or Farnesoid X receptor agonists will impact the care of patients and likely reduce overall healthcare costs by reducing the need for expensive tests like colonoscopy and biopsies or treatments like biologic agents in patients with Crohn’s disease.
Table 1 Diagnostic Tests for Bile Acid Malabsorption and Their Pros and Cons
| BAM diagnosis | Advantages | Disadvantages |
|---|---|---|
| Therapeutic trial with BA sequestrant | Clinically applicable, widely used | Not definitive diagnosis of BAM; nonspecific amelioration of diarrhea due to other causes; poor compliance with some BA sequestrants |
| 14C glycocholate | May identify small bowel bacterial overgrowth | Radiation exposure, β emission, long t1/2 |
| 75SeHCAT | γ Emission, short t1/2, with decreased radiation to extra-abdominal organs | Not available in United States |
| Well-defined normal values; level of isotope retention predicts response to BA sequestrant | Radiation exposure | |
| Simple test method: 2 patient visits | ||
| Serum C4 | No radiation | Fasting sample, diurnal variation |
| Normal values reported in adults | Requires further validation | |
| Not dependent on age, gender or cholesterol | False-positive in liver disease, treatment with statins and altered circadian rhythm | |
| Simple blood test: 1 patient visit | ||
| Serum FGF-19 | No radiation; commercial ELISA assay | Moderate sensitivity and specificity; requires further validation |
| Fecal BA | No radiation | Variable daily fecal BA excretion, requires at least 48 hr sample collection |
| Measures total and individual BAs | Cumbersome method (stool collection) | |
| Urine 2-propanol and acetamide | No radiation; urine sample | Special technology required: Field Asymmetric Ion Mobility Spectrometer; requires replication and validation |
Updated from Vijayvargiya P, et al. Clin Gastroenterol Hepatol 2013;11:1232–1239.47
BAM, bile acid malabsorption; BA, bile acid; 75SeHCAT, 75selenium homotaurocholic acid test; FGF-19, fibroblast growth factor 19; ELISA, enzyme-linked immunosorbent assay.
pISSN 1976-2283
eISSN 2005-1212
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
| Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
| Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
| Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
| Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
