Sevelamer-Induced Gastrointestinal Disease in 12 Patients with End-Stage Renal Disease: A Case Series.

INTRODUCTION: Isolated case reports and case series have linked the use of sevelamer to severe gastrointestinal (GI) inflammation and perforation among patients with end-stage renal disease. METHODS: In this study, we identified 12 cases of biopsy-proven sevelamer-induced gastrointestinal disease from a large urban community hospital over the course of 5 years. We described baseline characteristics, sites and types of injury, histological findings, timing and dosing of sevelamer initiation compared with symptom onset, and in a smaller subset, endoscopic resolution post drug cessation. We also reviewed preexisting conditions to identify trends in populations at risk. RESULTS: Several of the patients reviewed had preexisting conditions of decreased motility and/or impaired mucosal integrity. The presentation of disease was broad and included both upper-GI and lower-GI pathologies and in varying severity. DISCUSSION: There is a broad phenotypic range of sevelamer-induced gastrointestinal disease. As this becomes a more frequently recognized pathology, clinicians should be aware of how it may present and which populations may be more susceptible.

Neurogastroenterology and Motility Disorders of the Gastrointestinal Tract in Cystic Fibrosis.

PURPOSE OF REVIEW: To discuss all the various motility disorders impacting people with Cystic Fibrosis (PwCF) and provide diagnostic and management approaches from a group of pediatric and adult CF and motility experts and physiologists with experience in the management of this disease. RECENT FINDINGS: Gastrointestinal (GI) symptoms coexist with pulmonary symptoms in PwCF regardless of age and sex. The GI manifestations include gastroesophageal reflux disease, esophageal dysmotility gastroparesis, small bowel dysmotility, small intestinal bacterial overgrowth syndrome, distal idiopathic obstruction syndrome, constipation, and pelvic floor disorders. They are quite debilitating, limiting the patients' quality of life and affecting their nutrition and ability to socialize. This genetic disorder affects many organ systems and is chronic, potentially impacting fertility and future family planning, requiring a multidisciplinary approach. Our review discusses the treatments of motility disorders in CF, their prevalence and pathophysiology. We have provided a framework for clinicians who care for these patients that can help to guide their clinical management.

AGA Clinical Practice Update on Evaluation and Management of Belching, Abdominal Bloating, and Distention: Expert Review.

DESCRIPTION: Belching, bloating, and abdominal distention are all highly prevalent gastrointestinal symptoms and account for some of the most common reasons for patient visits to outpatient gastroenterology practices. These symptoms are often debilitating, affecting patients' quality of life, and contributing to work absenteeism. Belching and bloating differ in their pathophysiology, diagnosis, and management, and there is limited evidence available for their various treatments. Therefore, the purpose of this American Gastroenterological Association (AGA) Clinical Practice Update is to provide best practice advice based on both controlled trials and observational data for clinicians covering clinical features, diagnostics, and management considerations that include dietary, gut-directed behavioral, and drug therapies. METHODS: This Expert Review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature based on clinical trials, the more robust observational studies, and from expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Clinical history and physical examination findings and impedance pH monitoring can help to differentiate between gastric and supragastric belching. BEST PRACTICE ADVICE 2: Treatment options for supragastric belching may include brain-gut behavioral therapies, either separately or in combination, such as cognitive behavioral therapy, diaphragmatic breathing, speech therapy, and central neuromodulators. BEST PRACTICE ADVICE 3: Rome IV criteria should be used to diagnose primary abdominal bloating and distention. BEST PRACTICE ADVICE 4: Carbohydrate enzyme deficiencies may be ruled out with dietary restriction and/or breath testing. In a small subset of at-risk patients, small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth. BEST PRACTICE ADVICE 5: Serologic testing may rule out celiac disease in patients with bloating and, if serologies are positive, a small bowel biopsy should be done to confirm the diagnosis. A gastroenterology dietitian should be part of the multidisciplinary approach to care for patients with celiac disease and nonceliac gluten sensitivity. BEST PRACTICE ADVICE 6: Abdominal imaging and upper endoscopy should be ordered in patients with alarm features, recent worsening symptoms, or an abnormal physical examination only. BEST PRACTICE ADVICE 7: Gastric emptying studies should not be ordered routinely for bloating and distention, but may be considered if nausea and vomiting are present. Whole gut motility and radiopaque transit studies should not be ordered unless other additional and treatment-refractory lower gastrointestinal symptoms exist to warrant testing for neuromyopathic disorders. BEST PRACTICE ADVICE 8: In patients with abdominal bloating and distention thought to be related to constipation or difficult evacuation, anorectal physiology testing is suggested to rule out a pelvic floor disorder. BEST PRACTICE ADVICE 9: When dietary modifications are needed (eg, low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet), a gastroenterology dietitian should preferably monitor treatment. BEST PRACTICE ADVICE 10: Probiotics should not be used to treat abdominal bloating and distention. BEST PRACTICE ADVICE 11: Biofeedback therapy may be effective for bloating and distention when a pelvic floor disorder is identified. BEST PRACTICE ADVICE 12: Central neuromodulators (eg, antidepressants) are used to treat bloating and abdominal distention by reducing visceral hypersensitivity, raising sensation threshold, and improving psychological comorbidities. BEST PRACTICE ADVICE 13: Medications used to treat constipation should be considered for treating bloating if constipation symptoms are present. BEST PRACTICE ADVICE 14: Psychological therapies, such as hypnotherapy, cognitive behavioral therapy, and other brain-gut behavior therapies may be used to treat patients with bloating and distention. BEST PRACTICE 15: Diaphragmatic breathing and central neuromodulators are used to treat abdominophrenic dyssynergia.

Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia.

BACKGROUND & AIMS: Practice guidelines promote a routine noninvasive, non-endoscopic initial approach to investigating dyspepsia without alarm features in young patients, yet many patients undergo prompt upper endoscopy. We aimed to assess tradeoffs among costs, patient satisfaction, and clinical outcomes to inform discrepancy between guidelines and practice. METHODS: We constructed a decision-analytic model and performed cost-effectiveness/cost-satisfaction analysis over a 1-year time horizon on patients with uninvestigated dyspepsia without alarm features referred to gastroenterology. A RAND/UCLA expert panel informed model design. Four competing diagnostic/management strategies were evaluated: prompt endoscopy, testing for Helicobacter pylori and eradicating if present (test-and-treat), testing for H pylori and performing endoscopy if present (test-and-scope), and empiric acid suppression. Outcomes were derived from systematic reviews of clinical trials. Costs were informed by prospective observational cohort studies and national commercial/federal cost databases. Health gains were represented using quality-adjusted life years. RESULTS: From the patient perspective, costs and outcomes were similar for all strategies (maximum out-of-pocket difference of $30 and <0.01 quality-adjusted life years gained/year regardless of strategy). Prompt endoscopy maximized cost-satisfaction and health system reimbursement. Test-and-scope maximized cost-effectiveness from insurer and patient perspectives. Results remained robust on multiple one-way sensitivity analyses on model inputs and across most willingness-to-pay thresholds. CONCLUSIONS: Noninvasive management strategies appear to result in inferior cost-effectiveness and patient satisfaction outcomes compared with strategies promoting up-front endoscopy. Therefore, additional studies are needed to evaluate the drivers of patient satisfaction to facilitate inclusion in value-based healthcare transformation efforts.

Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators.

INTRODUCTION: The success of highly effective modulator therapy (HEMT) has led to consideration of simpler regimens for people with CF (PwCF) with opportunities to modify burdensome regimens. Despite the intuitive appeal of discontinuing chronic therapies no longer necessary, this process should be pursued systematically to ensure safety, adherence, and validate patient-centered preferences. We designed a questionnaire to determine the state of use of acid-suppressive medications (ASM) and pancreatic enzyme therapy (PERT), current self-withdrawal and provider-directed withdrawal practices, and interest in a standardized withdrawal study. METHODS: In collaboration with CF Foundation (CFF), a questionnaire was developed and distributed to members of Community Voice (CV, comprised of PwCF and their loved ones), and CF providers regarding the need to study simplifying the gastrointestinal (GI) regimen for PwCF on HEMT. RESULTS: Approximately 20-40% of CV or CF providers have decreased or stopped ASM for those on HEMT. For PERT, CV and CF providers have decreased dose (34%-48% and approximately 25%, respectively) more often than having stopped it altogether (13%-24% and 3%-12%, respectively). Cumulatively, there is interest in pursuing research in this area (86% CV and 89% CF providers) and willingness to enroll in such a study (80% CV and 89% CF providers). CONCLUSION: Systematically studying the withdrawal of common GI medications, ASM and PERT, is important to CV and CF providers. Decreases in dosing and withdrawal are already taking place without evidence to support this practice. This questionnaire is the first step in designing a GI medication simplification study in PwCF on HEMT.

Multicenter prospective study showing a high gastrointestinal symptom burden in cystic fibrosis.

BACKGROUND AND AIMS: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF). METHODS: Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models. RESULTS: Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus <18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47). CONCLUSION: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions. CLINICALTRIALS: GOV: NCT03801993.

A Narrative Review of Irritable Bowel Syndrome with Diarrhea: A Primer for Primary Care Providers.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction, characterized by recurrent abdominal pain in association with more frequent, loose stools. The pathophysiology of irritable bowel syndrome (IBS) includes disordered gut motility, alterations in gut microbiota, neural-hormonal system abnormalities, immune reactivity, and visceral hypersensitivity. Timely diagnosis of IBS-D can be achieved easily using clinical criteria. Formal IBS diagnosis is important for optimizing treatment and patient outcomes and facilitating patient access to appropriate educational resources. Yet, given the symptom overlap with other gastrointestinal conditions, diagnosis of IBS-D often is perceived to be challenging. Treatment of IBS includes both nonpharmacologic and pharmacologic options. Rifaximin, alosetron, and eluxadoline are effective treatments indicated for IBS-D, but have limited availability internationally. Dietary approaches may also be indicated for certain patients with IBS-D. Psychological interventions may be effective in treating abdominal pain alone and global symptoms in IBS. We describe use of these diverse therapies and provide an overview to facilitate the primary care provider's approach to distinguishing IBS-D from other conditions with symptom overlap.

Optimal timing of imaging in gastric emptying scintigraphy for the detection of delayed emptying.

OBJECTIVE: The purpose of this study was to evaluate a standard 4-h imaging protocol for gastric emptying scintigraphy (GES) in detecting delayed gastric emptying (GE). SUBJECTS AND METHODS: Gamma camera imaging was performed in the anterior and posterior views at 0, 0.5, 1, 1.5, 2, 2.5 and 4-h as per established Miami method (MIA) and National Standard Protocol (NSP), in accordance with the consensus guidelines of the ANMS/SNM [SNMMI] Societies. Patients (N=1002) received a standardized solid meal radiolabeled with 1mCi of technetium-99 (99mTc) sulfur colloid. Quantitative analysis was performed using geometric mean calculation of decay-corrected counts at each imaging time point, expressed as percent emptying or retention. RESULTS: In our patient cohort, 21% had delayed GE at 4h, whereas 79% had normal emptying with less than 10% retention at 4h. There was a 25% increase in delayed GE studies at 4h versus 2h. From those patients who had delayed GE at 2h, 30% normalized at 4h, while 10% of patients with normal GE at 2h became delayed at 4h thus indicating that more studies changed from abnormal to normal than from normal to abnormal at 4h. Greater than 90% GE was found in 9% of patients at 2 h and 25% of patients at 2.5h and this persisted at 4h. The study at 2h as compared with 4h, had 56% sensitivity, 95% specificity, 70% PPV and 91% NPV. CONCLUSION: The 4-h imaging was very important in detecting cases that were delayed at 2h but normalized at 4h, and also cases with normal GE at 2h that became abnormal at 4h. These findings support the ANMS/SNM [SNMMI] recommendations. Gastric emptying value ≥90% at 2.5h can be used as threshold in predicting normal GE and the study could be terminated without additional imaging.

Efficacy of Linaclotide in Reducing Abdominal Symptoms of Bloating, Discomfort, and Pain: A Phase 3B Trial Using a Novel Abdominal Scoring System.

INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to linaclotide 290 µg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of linaclotide vs placebo. The mean overall CFB AS reduction for linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (linaclotide = 4.6%, placebo = 1.6%). DISCUSSION: Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.

Functional dyspepsia: A critical appraisal of the European consensus from a global perspective.

The European Society for Neurogastroenterology and Motility's (ESNM) consensus document on functional dyspepsia (FD) has provided a critical review of the evidence for 36 statements highly relevant to the diagnosis and treatment of FD. We provide here our expert opinion on the North American, Australian and Asian assessments of the same topics discussed, and provide evidence where the ESNM consensus may deviate from those in the other continents. New and exciting data about the pathogenesis of FD are emerging including the possible central role of duodenal micro-inflammation (most notably eosinophilic duodenitis and intestinal mast cell disease), but this is a very dynamic field with several gaps remaining in our understanding that are summarized in this review. Identification of non-invasive biomarkers and testing of targeted therapies, including assessing the benefits of multidisciplinary teams in the management of FD, should be future priorities.

Utilization of electronic patient-reported outcome measures in cystic fibrosis research: Application to the GALAXY study.

BACKGROUND: The Food and Drug Administration considers patient-reported outcome measures (PROMs) an essential part of clinical research studies for approval of new drugs and new indications for existing drugs. GALAXY evaluated the feasibility of electronic PROMs (ePROMS) to conduct a comprehensive evaluation of gastrointestinal (GI) symptoms in persons with cystic fibrosis (pwCF). METHODS: Three validated GI ePROMs (PAC-SYM, PAGI-SYM and PAC-QOL) were combined with a Stool-Specific questionnaire to make up the GALAXY ePROMs and administered prospectively across 26 CF centers in the United States. The ePROMs were completed at enrollment visit and then electronically at weeks 1, 2 and 4. PwCF at least 2 years and older were eligible for the study. Reminders were only provided by the mobile application during the study window. RESULTS: There were 402 participants enrolled in GALAXY. Of those, 169 (42%) were under 18 years old and 193 (48%) were female. The proportion of all follow-up weeks with at least 1 ePROM fully completed was 80%, slightly higher in those ≥18 years of age (82.5%) compared to those <18 years of age (76.5%). When assessing the completion for all 4 ePROMs, the percentage was 77.6%, also higher among those ≥18 year of age (81.5% versus 72.2% for < 18 years of age). CONCLUSION: Using ePROMs, our study demonstrated that GI symptoms can be feasibly collected with good reproducibility and with minimal involvement of research coordinator time. This mechanism of symptom collection may provide an efficient tool for future CF trials.

Designing the GALAXY study: Partnering with the cystic fibrosis community to optimize assessment of gastrointestinal symptoms.

BACKGROUND: Gastrointestinal (GI) involvement among persons with cystic fibrosis (CF) is highly prevalent, representing a significant source of morbidity. Persons with CF have identified GI concerns as a top research priority, yet universal clinical outcome measures capturing many of the GI symptoms experienced in CF are lacking. The GALAXY study was envisioned to address this unmet need. METHODS: The GALAXY study team partnered with Community Voice, a community of patients with CF and their caregivers, to identify the patient reported outcome measures that most accurately reflected their experience with GI symptoms in CF. We also surveyed CF care teams to identify the comfort level of various team members (providers, nurses and dieticians) in managing a variety of GI conditions. RESULTS: Members of Community Voice identified the combination of PAC-SYM, PAGI-SYM, PAC-QOL and the Bristol Stool scale with three additional symptom-specific questions as patient-reported outcome measures that comprehensively captured the CF experience with GI disease. CF care team providers reported a high level of comfort in treating GI conditions including constipation (92%), GERD (93%), and gassiness (77%), however comfort level was limited to only first-line interventions. CONCLUSION: By partnering with persons with CF as well as their caregivers and medical providers, the GALAXY study is designed to uniquely capture the prevalence and severity of GI involvement among persons with CF in a manner that reflects the CF patient experience. The results of GALAXY will inform the development of future interventional trials and serve as a reproducible and objective study endpoint.

WITHDRAWN: In Memoriam: Phillip P. Toskes, MD.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1053/j.gastro.2021.07.041. The duplicate article has therefore been withdrawn.

ACG Clinical Guideline: Management of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.

American Neurogastroenterology and Motility Society Task Force Recommendations for Resumption of Motility Laboratory Operations During the COVID-19 Pandemic.

The American Neurogastroenterology and Motility Society Task Force recommends that gastrointestinal motility procedures should be performed in motility laboratories adhering to the strict recommendations and personal protective equipment (PPE) measures to protect patients, ancillary staff, and motility allied health professionals. When available and within constraints of institutional guidelines, it is preferable for patients scheduled for motility procedures to complete a coronavirus disease 2019 (COVID-19) test within 48 hours before their procedure, similar to the recommendations before endoscopy made by gastroenterology societies. COVID-19 test results must be documented before performing procedures. If procedures are to be performed without a COVID-19 test, full PPE use is recommended, along with all social distancing and infection control measures. Because patients with suspected motility disorders may require multiple procedures, sequential scheduling of procedures should be considered to minimize need for repeat COVID-19 testing. The strategies for and timing of procedure(s) should be adapted, taking into consideration local institutional standards, with the provision for screening without testing in low prevalence areas. If tested positive for COVID-19, subsequent negative testing may be required before scheduling a motility procedure (timing is variable). Specific recommendations for each motility procedure including triaging, indications, PPE use, and alternatives to motility procedures are detailed in the document. These recommendations may evolve as understanding of virus transmission and prevalence of COVID-19 infection in the community changes over the upcoming months.

Epidemiology and Pathophysiology of Gastroparesis.

Gastroparesis is a complex syndrome with symptoms that include nausea, vomiting, and postprandial abdominal pain, and is frequently accompanied by significant delays in gastric emptying. The pathophysiology of diabetic gastroparesis is fairly well understood; however, idiopathic gastroparesis, which accounts for one-third of all cases, may stem from infections, or autoimmune or neurologic disorders, among other causes. To date, few population-based studies have estimated the true prevalence and incidence of gastroparesis. Nonetheless, its prevalence appears to be rising, as does its incidence among minority populations, documented via hospitalizations, which can impose significant economic burdens on patients.

Motility Evaluation in the Patient with Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) suffer frequently from functional bowel diseases (FBD) and motility disorders. Management of FBD and motility disorders in IBD combined with continued treatment of a patient's IBD symptoms will likely lead to better clinical outcomes and improve the patient's quality of life. The goals of this review were to summarize the most recent literature on motility disturbances in patients with IBD and to give a brief overview of the ranges of motility disturbances, from reflux disease to anorectal disorders, and discuss their diagnosis and specific management.