The Evolving Clinical Trajectory From a Sliding Hiatus Hernia to Mixed Sliding and Para-Oesophageal Subtype: A Case Report.

We present a compelling case of a patient initially diagnosed with a simple sliding hiatus hernia (HH), which was managed conservatively through optimised medical therapy. Over the span of a few years, she developed new symptoms which included epigastric discomfort and pain, prompting further clinical review and imaging investigation. These revealed the progression of her HH from a simple form to a more complex rolling or para-oesophageal type. This outcome highlights the importance of recognising a potential for progression during the clinical assessment of patients with a history of reflux symptoms and the onset of new epigastric discomfort or pain. Understanding this continuum of HHs is essential for physicians as management plans may need to switch from a conservative to a more invasive approach.

Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection.

BACKGROUND: Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis. AIMS: To define stool BA dynamics in patients with primary CDI and to explore signatures predicting recurrence METHODS: Weekly stool samples were collected from patients with primary CDI from the last day of anti-CDI therapy until recurrence or, otherwise, through 8 weeks post-completion. Ultra-high performance liquid chromatography-mass spectrometry was used to profile BAs. Stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence. RESULTS: Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post-antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post-treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non-relapsing patients (ß = 0.056; likelihood ratio test p = 0.018). A joint longitudinal-survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post-CDI treatment. CONCLUSIONS: Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.

Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility.

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr.

The role of bile acids and their TGR5 receptor in irritable bowel syndrome and diarrhoea.

This commentary looks at recent findings relating to bile acids in patients with irritable bowel syndrome with diarrhoea (IBS-D). Bile acid diarrhoea is recognised to be a frequent, treatable cause of chronic diarrhoea, with a clinical picture which overlaps IBS-D. In the study - by Wei and colleagues, a large proportion of IBS-D patients were shown to have increased faecal bile acids, and an increase in primary bile acids, reflecting changes in bacterial metabolism. Expression of the colonic membrane bile acid receptor, TGR5, was associated with faecal bile acids and the severity of symptoms.

A practical approach to the patient with chronic diarrhoea.

Chronic diarrhoea is common, occurring as the first presentation of several diagnoses, or as a prolonged disorder where stool frequency, urgency and incontinence have major impacts on quality of life. Good history taking is necessary, with different causes to be considered: onset and duration of symptoms, previous treatments, co-existing conditions, travel and drug use may all be relevant. Tests include blood and faecal screening. Exclusion of inflammatory bowel disease and colorectal neoplasia is important and may require colonoscopy. Coeliac disease, microscopic colitis and bile acid diarrhoea are all common conditions which should not be missed, as specific therapy is available for each of these. Functional bowel disorders with diarrhoea are prevalent, overlapping with other more treatable conditions. Dietetic assessment and advice are helpful. Awareness of high FODMAP foods, with identification of individual sensitivities, is often beneficial.

[Bile acid diarrhea, stepchild of chronic diarrhea - prevalence, diagnosis and treatment. Update 2021]. / Chologene Diarrhö, Stiefkind der chronischen Diarrhö ­ Prävalenz, Diagnostik und Therapie. Update 2021.

Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.

Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Making the Diagnosis of Bile Acid Diarrhea.

Bile acid diarrhea is a frequent, treatable cause of functional diarrhea but is difficult to diagnose when the nuclear medicine seleno-taurohomocholic acid test is unavailable. An alternative approach is testing blood for the bile acid precursor, 7α-OH-4-cholesten-3-one, which is raised with increased bile acid synthesis. A recent article has defined measurements that have high negative and positive predictive values, further exploring how they can be improved by incorporating measures such as age, stool number, fibroblast growth factor 19, or plasma sulfated bile acids. Other articles have looked at the percentage of fecal primary bile acids. Together, they promise better use of diagnostic biomarkers for this condition.

The pathophysiology of bile acid diarrhoea: differences in the colonic microbiome, metabolome and bile acids.

Bile acid diarrhoea (BAD) is a common disorder resulting from increased loss of bile acids (BAs), overlapping irritable bowel syndrome with diarrhoea (IBS-D). The gut microbiota metabolises primary BAs to secondary BAs, with differing impacts on metabolism and homeostasis. The aim of this study was to profile the microbiome, metabolic products and bile acids in BAD. Patients with BAD diagnosed by SeHCAT testing, were compared with other IBS-D patients, and healthy controls. Faecal 16S ribosomal RNA gene analysis was undertaken. Faecal short chain fatty acid (SCFA) and urinary volatile organic compounds (VOCs) were measured. BAs were quantified in serum and faeces. Faecal bacterial diversity was significantly reduced in patients with BAD. Several taxa were enriched compared to IBS-D. SCFA amounts differed in BAD, controls and IBS-D, with significantly more propionate in BAD. Separation of VOC profiles was evident, but the greatest discrimination was between IBS-D and controls. Unconjugated and primary BA in serum and faeces were significantly higher in BAD. The faecal percentage primary BA was inversely related to SeHCAT. BAD produces dysbiosis, with metabolite differences, including VOC, SCFA and primary BAs when compared to IBS-D. These findings provide new mechanistic insights into the pathophysiology of BAD.

Diagnosis and management of bile acid diarrhoea: a survey of UK expert opinion and practice.

OBJECTIVE: Bile acid diarrhoea (BAD), which includes bile acid malabsorption, causes a variety of digestive symptoms. Diagnostic rates and management vary considerably. We conducted a survey of current practice to review expert opinion and provide guidance on diagnosis and management. DESIGN/METHOD: An online survey was conducted of clinical members of the UK Bile Acid Related Diarrhoea Network, who had all published research on BAD (n=21). Most were National Health Service consultants who had diagnosed over 50 patients with the condition. RESULTS: The preferred terminology was to use BAD, with primary and secondary to classify causes. A wide range of presenting symptoms and associated conditions were recognised. SeHCAT (tauroselcholic acid) was the preferred diagnostic test, and 50% of respondents thought general practitioners should have access to this. Patients who met the Rome IV diagnostic criteria for functional diarrhoea, irritable bowel syndrome (IBS) with predominant diarrhoea or postcholecystectomy diarrhoea were usually investigated by SeHCAT, which was used sometimes in other types of IBS. Treatment with a bile acid sequestrant was offered to patients with low SeHCAT values, with expected response rates >70% in the most severe. Colestyramine was the usual sequestrant, starting between 2 g and 8 g daily; colesevelam was an alternative. In patients who had an incomplete response, increasing the dose, changing to an alternative sequestrant, use of loperamide and a low fat diet were suggested. Recommendations for follow-up and to improve the overall patient experience were made. CONCLUSION: This expert survey indicates current best practice in the diagnosis and management of BAD.

Tests that now deserve to be more widely adopted in IBD clinical practice.

Inflammatory bowel diseases are chronic relapsing immune-mediated diseases of the intestinal tract with multifaceted manifestations and treatment related morbidity. Faecal and blood tests, radiological, endoscopic and histologic investigations are now widely used for managing both ulcerative colitis and Crohn's disease. Over the years, a number of new investigations have been proposed but not widely adopted yet. Patients with Crohn's disease may have multiple causes of diarrhoea, not always attributable to disease exacerbation, but sometimes linked to bile acid malabsorption; we have a reliable serum test, C4, that allows us to recognize and treat this cause of diarrhoea efficaciously and not empirically, but it is not available or used widely. There is genetic inter-individual variability in drug responses, in terms of both efficacy and toxicity, leading to high rates of therapeutic failure. Patients treated with thiopurine or, more rarely, 5-aminosalicylic acid may suffer from unpredictable and serious adverse events, some of these with pathogenesis related to genetic variants: myelosuppression, acute pancreatitis and nephrotoxicity. The identification of pre-treatment genetic tests can optimize therapeutic choice and avoid adverse events. With regard to biological drugs, patients can experience primary non-response or loss of response due to induction of immune responses to the drugs affecting drug efficacy and determining hypersensitivity reactions. We have specifically reviewed a number of investigations, whose use is currently limited, and highlighted four tests that deserve to be more widely incorporated in clinical practice as these could improve medical decision-making and patient outcomes.

Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.

BACKGROUND: In primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired. AIMS: To evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non-bile acid FXR agonist, in patients with primary bile acid diarrhoea. METHODS: In this double-blind, multicentre, randomised, cross-over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit. RESULTS: Twenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post-dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half-emptying time (P = 0.036). CONCLUSIONS: Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea. ClinicalTrials.gov number: NCT02713243.

Ursodeoxycholic acid enriches intestinal bile salt hydrolase-expressing Bacteroidetes in cholestatic pregnancy.

Ursodeoxycholic acid (UDCA) treatment can reduce itch and lower endogenous serum bile acids in intrahepatic cholestasis of pregnancy (ICP). We sought to determine how it could influence the gut environment in ICP to alter enterohepatic signalling. The gut microbiota and bile acid content were determined in faeces from 35 pregnant women (14 with uncomplicated pregnancies and 21 with ICP, 17 receiving UDCA). Faecal bile salt hydrolase activity was measured using a precipitation assay. Serum fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) concentrations were measured following a standardised diet for 21 hours. Women with a high ratio of Bacteroidetes to Firmicutes were more likely to be treated with UDCA (Fisher's exact test p = 0.0178) than those with a lower ratio. Bile salt hydrolase activity was reduced in women with low Bacteroidetes:Firmicutes. Women taking UDCA had higher faecal lithocholic acid (p < 0.0001), with more unconjugated bile acids than women with untreated ICP or uncomplicated pregnancy. UDCA-treatment increased serum FGF19, and reduced C4 (reflecting lower bile acid synthesis). During ICP, UDCA treatment can be associated with enrichment of the gut microbiota with Bacteroidetes. These demonstrate high bile salt hydrolase activity, which deconjugates bile acids enabling secondary modification to FXR agonists, enhancing enterohepatic feedback via FGF19.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

BACKGROUND AND 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 antidiarrheal 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.

A Pilot Integrative Analysis of Colonic Gene Expression, Gut Microbiota, and Immune Infiltration in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile Acid Pathways.

BACKGROUND: Although a majority of patients with PSC have colitis [PSC-IBD; primary sclerosing cholangitis-inflammatory bowel disease], this is phenotypically different from ulcerative colitis [UC]. We sought to define further the pathophysiological differences between PSC-IBD and UC, by applying a comparative and integrative approach to colonic gene expression, gut microbiota and immune infiltration data. METHODS: Colonic biopsies were collected from patients with PSC-IBD [n = 10], UC [n = 10], and healthy controls [HC; n = 10]. Shotgun RNA-sequencing for differentially expressed colonic mucosal genes [DEGs], 16S rRNA analysis for microbial profiling, and immunophenotyping were performed followed by multi-omic integration. RESULTS: The colonic transcriptome differed significantly between groups [p = 0.01]. Colonic transcriptomes from HC were different from both UC [1343 DEGs] and PSC-IBD [4312 DEGs]. Of these genes, only 939 had shared differential gene expression in both UC and PSC-IBD compared with HC. Imputed pathways were predominantly associated with upregulation of immune response and microbial defense in both disease cohorts compared with HC. There were 1692 DEGs between PSC-IBD and UC. Bile acid signalling pathways were upregulated in PSC-IBD compared with UC [p = 0.02]. Microbiota profiles were different between the three groups [p = 0.01]; with inferred function in PSC-IBD also being consistent with dysregulation of bile acid metabolism. Th17 cells and IL17-producing CD4 cells were increased in both PSC-IBD and UC when compared with HC [p < 0.05]. Multi-omic integration revealed networks involved in bile acid homeostasis and cancer regulation in PSC-IBD. CONCLUSIONS: Colonic transcriptomic and microbiota analysis in PSC-IBD point toward dysregulation of colonic bile acid homeostasis compared with UC. This highlights important mechanisms and suggests the possibility of novel approaches in treating PSC-IBD.

Canadian Association of Gastroenterology Clinical Practice Guideline on the Management of Bile Acid Diarrhea.

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 antidiarrheal 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.