The 50 most-cited articles in The American Journal of Gastroenterology, 2020

OBJECTIVE: Since the outbreak of Coronavirus Disease 2019 (COVID-19) in December 2019, various digestive symptoms have been frequently reported in patients infected with the virus. In this study, we aimed to further investigate the prevalence and outcomes of COVID-19 patients with digestive symptoms. METHODS: In this descriptive, cross-sectional, multicenter study, we enrolled confirmed patients with COVID-19 who presented to 3 hospitals from January 18, 2020, to February 28, 2020. All patients were confirmed by real-time polymerase chain reaction and were analyzed for clinical characteristics, laboratory data, and treatment. Data were followed up until March 18, 2020. RESULTS: In the present study, 204 patients with COVID-19 and full laboratory, imaging, and historical data were analyzed. The average age was 52.9 years (SD ± 16), including 107 men and 97 women. Although most patients presented to the hospital with fever or respiratory symptoms, we found that 103 patients (50.5%) reported a digestive symptom, including lack of appetite (81 [78.6%] cases), diarrhea (35 [34%] cases),…

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…

OBJECTIVES: Coronavirus disease 2019 (COVID-19) most commonly presents with respiratory symptoms, including cough, shortness of breath, and sore throat. However, digestive symptoms also occur in patients with COVID-19 and are often described in outpatients with less severe disease. In this study, we sought to describe the clinical characteristics of COVID-19 patients with digestive symptoms and mild disease severity. METHODS: We identified COVID-19 patients with mild disease and one or more digestive symptoms (diarrhea, nausea, and vomiting), with or without respiratory symptoms, and compared them with a group presenting solely with respiratory symptoms. We followed up patients clinically until they tested negative for COVID-19 on at least 2 sequential respiratory tract specimens collected ≥24 hours apart. We then compared the clinical features between those with digestive symptoms and those with respiratory symptoms. RESULTS: There were 206 patients with low severity COVID-19, including 48 presenting with a digestive symptom alone, 69 with both digestive and respiratory symptoms,…

Achalasia is an esophageal motility disorder characterized by aberrant peristalsis and insufficient relaxation of the lower esophageal sphincter. Patients most commonly present with dysphagia to solids and liquids, regurgitation, and occasional chest pain with or without weight loss. High-resolution manometry has identified 3 subtypes of achalasia distinguished by pressurization and contraction patterns. Endoscopic findings of retained saliva with puckering of the gastroesophageal junction or esophagram findings of a dilated esophagus with bird beaking are important diagnostic clues. In this American College of Gastroenterology guideline, we used the Grading of Recommendations Assessment, Development and Evaluation process to provide clinical guidance on how best to diagnose and treat patients with achalasia.

Small intestinal bacterial overgrowth is defined as the presence of excessive numbers of bacteria in the small bowel, causing gastrointestinal symptoms. This guideline statement evaluates criteria for diagnosis, defines the optimal methods for diagnostic testing, and summarizes treatment options for small intestinal bacterial overgrowth. This guideline provides an evidence-based evaluation of the literature through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the available evidence was not appropriate for a formal GRADE recommendation, key concepts were developed using expert consensus.

OBJECTIVES: To conduct a systematic review and meta-analysis that defines the worldwide incidence of celiac disease (CD) and examines temporal trends. METHODS: MEDLINE and EMBASE were searched for population-based studies reporting the incidence of CD in the overall population, children, or adults. No limits were placed on year or language of publication. Studies solely examining at-risk populations (e.g., patients with type 1 diabetes) were excluded. Random-effects models were performed to meta-analyze sex- and age-specific incidence in the 21st century. Temporal trend analyses assessed the average annual percent change in CD incidence over time. RESULTS: Of 11,189 citations, 86 eligible studies were identified for inclusion, of which 50 were deemed suitable for analyses. In the 21st century, the pooled female incidence of CD was 17.4 (95% confidence interval [CI]: 13.7, 21.1) (I = 99.5%) per 100,000 person-years, compared with 7.8 (95% CI: 6.3, 9.2) (I = 98.6%) in males. Child-specific incidence was 21.3 per 100,000 person-years (95% CI: 15.9, 26.7) (I = 99.7%) compared with 12.9…

Chronic pancreatitis (CP) is historically defined as an irreversible inflammatory condition of the pancreas leading to varying degrees of exocrine and endocrine dysfunction. Recently however, the paradigm for the diagnosis has changed in that it breaks with the traditional clinicopathologic-based definition of disease, focusing instead on diagnosing the underlying pathologic process early in the disease course and managing the syndrome more holistically to change the natural course of disease and minimize adverse disease effects. Currently, the most accepted mechanistically derived definition of CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress. The most common symptom of CP is abdominal pain, with other symptoms such as exocrine pancreatic insufficiency and diabetes developing at highly variable rates. CP is most commonly caused by toxins such as alcohol or tobacco use, genetic polymorphisms, and recurrent attacks of acute…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome. The gut microbiome plays a role in metabolism and maintaining gut barrier integrity. Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD. Fecal microbiota transplantation (FMT) can be used to alter the gut microbiome. It was hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability. METHODS: Twenty-one patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum. IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test. Additional markers of metabolic…

Colonoscopy is performed routinely for colorectal cancer (CRC) screening, follow-up of other abnormal screening tests, workup of signs and symptoms of gastrointestinal disease, and surveillance after CRC and polyp removal. Post procedure, colonoscopists are expected to provide follow-up recommendations to patients and referring physicians. Recommendations for follow-up after normal colonoscopy among individuals age-eligible for screening, and post-polypectomy among all individuals with polyps are among the most common clinical scenarios requiring guidance.1 Risk of metachronous advanced neoplasia is associated with findings on prior colonoscopy. After high-quality colonoscopy, patients with no neoplasia detected are at the lowest risk, and those with polyps are risk-stratified based on the histology, number, location, and size of polyps detected. Since the release of the last US Multi-Society Task Force (Task Force) recommendations for post-colonoscopy follow-up and polyp surveillance in 2012,2 a number of articles have been published on risk of CRC based on colonoscopy findings and…

Colonoscopy with polypectomy reduces the incidence of and mortality from colorectal cancer (CRC).1,2 It is the cornerstone of effective prevention.3 The National Polyp Study showed that removal of adenomas during colonoscopy is associated with a reduction in CRC mortality by up to 50% relative to population controls.1,2 The lifetime risk to develop CRC in the United States is approximately 4.3%, with 90% of cases occurring after the age of 50 years.4 The recent reductions in CRC incidence and mortality have been largely attributed to the widespread uptake of CRC screening with polypectomy.5 The techniques and outcomes of polyp removal using colonoscopy, however, had historically remained understudied and thus, practice widely varied. Reports have shown that residual tissue after polypectomy that is judged to be “complete” by the endoscopist is common, ranging from 6.5% to 22.7%.6 The significant variation in incomplete resection rates among endoscopists has highlighted the dependence of polypectomy effectiveness on operator technique. A pooled analysis from 8 surveillance studies…

INTRODUCTION: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. METHODS: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH. RESULTS: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences…

INTRODUCTION: The aim of this study was to provide the most comprehensive and up-to-date evidence on the association between cigarette smoking and colorectal cancer (CRC) risk. METHODS: We conducted a systematic review and meta-analysis of epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. We calculated relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with a focus on molecular subtypes of CRC. RESULTS: The meta-analysis summarizes the evidence from 188 original studies. Compared with never smokers, the pooled RR for CRC was 1.14 (95% confidence interval [CI] 1.10-1.18) for current smokers and 1.17 (95% CI 1.15-1.20) for former smokers. CRC risk increased linearly with smoking intensity and duration. Former smokers who had quit smoking for more than 25 years had significantly decreased risk of CRC compared with current smokers. Smoking was strongly associated with the risk of CRC, characterized by high CpG island methylator phenotype (RR 1.42; 95% CI…

Disorders of the mesenteric, portal, and hepatic veins and mesenteric and hepatic arteries have important clinical consequences and may lead to acute liver failure, chronic liver disease, noncirrhotic portal hypertension, cirrhosis, and hepatocellular carcinoma. Although literature in the field of vascular liver disorders is scant, these disorders are common in clinical practice, and general practitioners, gastroenterologists, and hepatologists may benefit from expert guidance and recommendations for management of these conditions. These guidelines represent the official practice recommendations of the American College of Gastroenterology. Key concept statements based on author expert opinion and review of literature and specific recommendations based on PICO/GRADE analysis have been developed to aid in the management of vascular liver disorders. These recommendations and guidelines should be tailored to individual patients and circumstances in routine clinical practice.

Esophageal symptoms are common and may indicate the presence of gastroesophageal reflux disease (GERD), structural processes, motor dysfunction, behavioral conditions, or functional disorders. Esophageal physiologic tests are often performed when initial endoscopic evaluation is unrevealing, especially when symptoms persist despite empiric management. Commonly used esophageal physiologic tests include esophageal manometry, ambulatory reflux monitoring, and barium esophagram. Functional lumen imaging probe (FLIP) has recently been approved for the evaluation of esophageal pressure and dimensions using volumetric distension of a catheter-mounted balloon and as an adjunctive test for the evaluation of symptoms suggestive of motor dysfunction. Targeted utilization of esophageal physiologic tests can lead to definitive diagnosis of esophageal disorders but can also help rule out organic disorders while making a diagnosis of functional esophageal disorders. Esophageal physiologic tests can evaluate obstructive symptoms (dysphagia and regurgitation), typical and atypical GERD symptoms, and…

Various lifestyle factors including physical activity and obesity, stress, sleep, and smoking may modify the risk of developing inflammatory bowel diseases (IBDs). In patients with established IBD, these lifestyle factors may significantly impact the natural history and clinical outcomes. Recreational exercise decreases the risk of flare and fatigue in patients with IBD. In contrast, obesity increases the risk of relapse and is associated with higher anxiety, depression, fatigue, and pain and higher health care utilization. Obesity also modifies pharmacokinetics of biologic agents unfavorably and is associated with a higher risk of treatment failure. Sleep disturbance is highly prevalent in patients with IBD, independent of disease activity, and increases the risk of relapse and chronic fatigue. Similarly, stress, particularly perceived stress rather than major life events, may trigger symptomatic flare in patients with IBD, although its impact on inflammation is unclear. Cigarette smoking is associated with unfavorable outcomes including the risk of corticosteroid dependence,…

INTRODUCTION: We conducted a systematic review and meta-analysis to compare the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) and controls. METHODS: Electronic databases were searched up to December 2018 for studies reporting SIBO prevalence in patients with IBS. Prevalence rates, odds ratios (ORs), and 95% confidence intervals (CIs) of SIBO in patients with IBS and controls were calculated. RESULTS: We included 25 studies with 3,192 patients with IBS and 3,320 controls. SIBO prevalence in patients with IBS was significantly increased compared with controls (OR = 3.7, 95% CI 2.3-6.0). In studies using only healthy controls, the OR for SIBO in patients with IBS was 4.9 (95% CI 2.8-8.6). With breath testing, SIBO prevalence in patients with IBS was 35.5% (95% CI 33.6-37.4) vs 29.7% (95% CI 27.6-31.8) in controls. Culture-based studies yielded a SIBO prevalence of 13.9% (95% CI 11.5-16.4) in patients with IBS and 5.0% (95% CI 3.9-6.2) in controls with a cutoff value of 10 colony-forming units per milliliter vs 33.5% (95% CI…

Chronic hepatitis B virus (HBV) infection represents a major global health problem, affecting an estimated 257-291 million persons worldwide and is associated with substantial morbidity and mortality because of clinical complications, such as liver cirrhosis and hepatocellular carcinoma. Despite existing resources for vaccination, screening, and treatment, the burden of chronic HBV remains significant within the United States (US). Both the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) have articulated formal hepatitis elimination plans, although an updated assessment of the epidemiology and prevalence of chronic HBV is needed to inform these initiatives. The Chronic Liver Disease Foundation (CLDF), a nonprofit 501(c)(3) educational organization dedicated to raising awareness of liver disease, partnered with a panel of leading US hepatologists to conduct an updated literature review to develop a contemporary HBV prevalence range estimate. Panel members researched and evaluated the peer-reviewed literature on HBV prevalence and, in May 2019,…

The outbreak of novel coronavirus pneumonia in 2019 (Coronavirus disease 2019 [COVID-19]) is now threatening global public health. Although COVID-19 is principally defined by its respiratory symptoms, it is now clear that the virus can also affect the digestive system. In this review, we elaborate on the close relationship between COVID-19 and the digestive system, focusing on both the clinical findings and potential underlying mechanisms of COVID-19 gastrointestinal pathogenesis.

INTRODUCTION: Proton pump inhibitors (PPIs) increase the risk for enteric infections that is likely related to PPI-induced hypochlorhydria. Although the impact of acid suppression on severe acute respiratory syndrome coronavirus 2 is unknown thus far, previous data revealed that pH ≤3 impairs the infectivity of the similar severe acute respiratory syndrome coronavirus 1. Thus, we aimed to determine whether use of PPIs increases the odds for acquiring coronavirus disease 2019 (COVID-19) among community-dwelling Americans. METHODS: From May 3 to June 24, 2020, we performed an online survey described to participating adults as a "national health survey." A multivariable logistic regression was performed on reporting a positive COVID-19 test to adjust for a wide range of confounding factors and to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Of 53,130 participants, 3,386 (6.4%) reported a positive COVID-19 test. In regression analysis, individuals using PPIs up to once daily (aOR 2.15; 95% CI, 1.90-2.44) or twice daily (aOR 3.67; 95% CI, 2.93-4.60)…

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of…

Carvalho, Alexandre MD, MPH1; Alqusairi, Rana MD1; Adams, Anna DO1; Paul, Michelle BS2; Kothari, Neelay MD1,3; Peters, Stevany MD1,4; DeBenedet, Anthony T. MD, MSc1,4 Author Information

INTRODUCTION: The value of hepatocellular carcinoma (HCC) surveillance is defined by the balance of benefits, i.e., early tumor detection, and potential harms, related to false positive and indeterminate results. Although physical harms can be observed in 15%-20% of patients with cirrhosis undergoing HCC surveillance, previous cost-effectiveness analyses have not incorporated costs of harms. We aimed to evaluate the cost-effectiveness of HCC surveillance including both benefits and harms. DESIGN: We constructed a Markov model to compare surveillance strategies of ultrasound (US) alone, US and alpha fetoprotein (AFP), and no surveillance in 1 million simulated patients with compensated cirrhosis. Harms included imaging and biopsy in patients undergoing surveillance for HCC. Model inputs were based on literature review, and costs were derived from the Medicare fee schedule, with all costs inflated to 2018 dollars. The primary outcome was the incremental cost-effectiveness ratio per incremental quality-adjusted life-year. RESULTS: In the base case analysis, US with AFP was the dominant…

The functional lumen imaging probe (FLIP) measures luminal dimensions using impedance planimetry, performed most often during sedated upper endoscopy. Mechanical properties of the esophageal wall and opening dynamics of the esophagogastric junction (EGJ) can be objectively evaluated in esophageal motor disorders, eosinophilic esophagitis, esophageal strictures, during esophageal surgery and in postsurgical symptomatic states. Distensibility index, the ratio of EGJ cross sectional area to intraballoon pressure, is the most useful FLIP metric. Secondary peristalsis from balloon distension can be displayed topographically as repetitive anterograde or retrograde contractile activity in the esophageal body, similar to high-resolution manometry. Real-time interpretation and postprocessing of FLIP metadata can complement the identification of esophageal outflow obstruction and achalasia, especially when findings are inconclusive from alternate esophageal tests in symptomatic patients. FLIP can complement the diagnosis of achalasia when manometry and barium studies are inconclusive or…

Chen, Lijuan PhD; Lou, Jianghua MD; Bai, Yan MD; Wang, Meiyun PhD, MD Author Information

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

INTRODUCTION: The use of statins in nonalcoholic fatty liver disease (NAFLD) may reduce cardiovascular morbidity, although their effect on NAFLD itself is not well known. We aimed to investigate the role of statins on the development of de novo NAFLD and progression of significant liver fibrosis. METHODS: This study included 11,593,409 subjects from the National Health Information Database of the Republic of Korea entered in 2010 and followed up until 2016. NAFLD was diagnosed by calculating fatty liver index (FLI), and significant liver fibrosis was evaluated using the BARD score. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection. RESULTS: Among 5,339,901 subjects that had a FLI < 30 and included in the non-NAFLD cohort, 164,856 subjects eventually had NAFLD developed. The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65-0.67) and was independent of associated diabetes mellitus (DM) (with DM: AOR 0.44; 95%…

INTRODUCTION: To compare outcomes in patients hospitalized with coronavirus (COVID-19) receiving famotidine therapy with those not receiving famotidine. METHODS: Retrospective, propensity-matched observational study of consecutive COVID-19-positive patients between February 24, 2020, and May 13, 2020. RESULTS: Of 878 patients in the analysis, 83 (9.5%) received famotidine. In comparison to patients not treated with famotidine, patients treated with famotidine were younger (63.5 ± 15.0 vs 67.5 ± 15.8 years, P = 0.021), but did not differ with respect to baseline demographics or preexisting comorbidities. Use of famotidine was associated with a decreased risk of in-hospital mortality (odds ratio 0.37, 95% confidence interval 0.16-0.86, P = 0.021) and combined death or intubation (odds ratio 0.47, 95% confidence interval 0.23-0.96, P = 0.040). Propensity score matching to adjust for age difference between groups did not alter the effect on either outcome. In addition, patients receiving famotidine displayed lower levels of serum markers for severe disease including lower median peak…

1Division of Hepatology, Northwell Health and Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA; 2Division of Infectious Diseases, Northwell Health and Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA. Correspondence: Praneet Wander, MD. E-mail: [email protected].

INTRODUCTION: Although coronavirus disease (COVID-19) has been associated with gastrointestinal manifestations, its effect on the pancreas remains unclear. We aimed to assess the frequency and characteristics of hyperlipasemia in patients with COVID-19. METHODS: A retrospective cohort study of hospitalized patients across 6 US centers with COVID-19. RESULTS: Of 71 patients, 9 (12.1%) developed hyperlipasemia, with 2 (2.8%) greater than 3 times upper limit of normal. No patient developed acute pancreatitis. Hyperlipasemia was not associated with poor outcomes or symptoms. DISCUSSION: Although a mild elevation in serum lipase was observed in some patients with COVID-19, clinical acute pancreatitis was not seen.

INTRODUCTION: Although current literature has addressed gastrointestinal presentations including nausea, vomiting, diarrhea, abnormal liver chemistries, and hyperlipasemia as possible coronavirus disease 2019 (COVID-19) manifestations, the risk and type of gastrointestinal bleeding (GIB) in this population is not well characterized. METHODS: This is a matched case-control (1:2) study with 41 cases of GIB (31 upper and 10 lower) in patients with COVID-19 and 82 matched controls of patients with COVID-19 without GIB. The primary objective was to characterize bleeding etiologies, and our secondary aim was to discuss outcomes and therapeutic approaches. RESULTS: There was no difference in the presenting symptoms of the cases and controls, and no difference in severity of COVID-19 manifestations (P > 0.05) was observed. Ten (32%) patients with upper GIB underwent esophagogastroduodenoscopy and 5 (50%) patients with lower GIBs underwent flexible sigmoidoscopy or colonoscopy. The most common upper and lower GIB etiologies were gastric or duodenal ulcers (80%) and rectal ulcers related to…

Chronic unexplained gastrointestinal symptoms impact more than 1 in 5 Americans and their families; these disorders include the irritable bowel syndrome (IBS) and functional dyspepsia (FD), currently classified by Rome IV as functional gastrointestinal disorders. By definition, IBS and FD have no established pathology, but emerging evidence suggests this paradigm may need revision. Immune activation and, in subsets, subtle intestinal pathology have been identified in FD (most notably, postprandial distress syndrome) and IBS-diarrhea. A disease model is proposed that accounts for all of the intestinal and extraintestinal symptoms, relationship to food and infection, and the overlap with gastroesophageal reflux disease. It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the intestine with low-grade intestinal inflammation and subsequently neuronal structural and functional alterations, producing regional intestinal hypersensitivity and motor…

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk. METHODS: Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%. RESULTS: The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD…

Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early…

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available…

OBJECTIVES: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period. RESULTS: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45…

Nonalcoholic fatty liver disease (NAFLD) is generally considered a silent and potentially reversible condition. The subtype of NAFLD that can be classified as nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis. Because of the metabolic nature of the pathogenic mechanism underlying NAFLD and NASH, it is often accompanied by common comorbidities such as obesity, insulin resistance, and type 2 diabetes mellitus. The increase in the prevalence of these comorbidities has resulted in a parallel increase in the prevalence of NAFLD and NASH, globally, nationally, and even in children. In recent years, it has been identified that the stage of fibrosis is the most important predictor of liver outcomes; therefore, identifying patients with NAFLD and NASH with more advanced stages of fibrosis can be essential for optimal management. Several noninvasive tools for diagnosing and staging NAFLD and NASH are available, but simple and straightforward recommendations on the use of these tools are not. Recognizing these unmet needs, hepatologists who are members of the…

OBJECTIVES: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs. METHODS: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical…

INTRODUCTION: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort. METHODS: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method. RESULTS: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred…

INTRODUCTION: Endoscopic full-thickness resection (EFTR) is a powerful option for resection of colorectal lesions not amenable to conventional endoscopic resection. The full-thickness resection device (FTRD) allows clip-assisted EFTR with a single-step technique. We report on results of a large nationwide FTRD registry. METHODS: The "German colonic FTRD registry" was created to further assess efficacy and safety of the FTRD System after approval in Europe. Data were analyzed retrospectively. RESULTS: Sixty-five centers contributed 1,178 colorectal FTRD procedures. Indications for EFTR were difficult adenomas (67.1%), early carcinomas (18.4%), subepithelial tumors (6.8%), and diagnostic EFTR (1.3%). Mean lesion size was 15 × 15 mm and most lesions were pretreated endoscopically (54.1%). Technical success was 88.2% and R0 resection was achieved in 80.0%. R0 resection was significantly higher for subepithelial tumor compared with that for other lesions. No difference in R0 resection was found for smaller vs larger lesions or for colonic vs rectal procedures. Adverse events occurred in…

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this…

INTRODUCTION: Acute gastrointestinal (GI) bleed is a common reason for hospitalization with 2%-10% risk of mortality. In this study, we developed a machine learning (ML) model to calculate the risk of mortality in intensive care unit patients admitted for GI bleed and compared it with APACHE IVa risk score. We used explainable ML methods to provide insight into the model's prediction and outcome. METHODS: We analyzed the patient data in the Electronic Intensive Care Unit Collaborative Research Database and extracted data for 5,691 patients (mean age = 67.4 years; 61% men) admitted with GI bleed. The data were used in training a ML model to identify patients who died in the intensive care unit. We compared the predictive performance of the ML model with the APACHE IVa risk score. Performance was measured by area under receiver operating characteristic curve (AUC) analysis. This study also used explainable ML methods to provide insights into the model's outcome or prediction using the SHAP (SHapley Additive exPlanations) method. RESULTS: The ML model performed better than the APACHE…

INTRODUCTION: Conventionally, patients with irritable bowel syndrome (IBS) are subgrouped based on their predominant bowel habit. Given the relevance of psychological comorbidity to IBS symptoms, our aim was to explore an alternative approach to subgrouping by incorporating factors beyond stool form and frequency. METHODS: We collected demographic, symptom, and psychological health data from 1,375 adult subjects in the community who self-identified as having IBS, identifying 2 cohorts meeting either Rome III or Rome IV criteria. In each cohort, we performed latent class analysis, a method of model-based clustering, to identify specific subgroups (clusters). For each cluster, we drew a radar plot and compared these by visual inspection, describing cluster characteristics. RESULTS: In total, 1,080 individuals met the Rome III criteria for IBS, and 811 met the Rome IV criteria. In both cohorts, a 7-cluster model was the optimum solution, and the characteristics of the clusters were almost identical between Rome III and IV. Four clusters were defined by the pattern of gastrointestinal…

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. METHODS: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. RESULTS: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]:…

INTRODUCTION: The low FODMAP diet (LFD) reduces symptoms and bifidobacteria in irritable bowel syndrome (IBS). β-galactooligosaccharides (B-GOS) may reduce the symptoms and increase bifidobacteria in IBS. We investigated whether B-GOS supplementation alongside the LFD improves IBS symptoms while preventing the decline in bifidobacteria. METHODS: We performed a randomized, placebo-controlled, 3-arm trial of 69 Rome III adult patients with IBS from secondary care in the United Kingdom. Patients were randomized to a sham diet with placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.4 g/d B-GOS (LFD/B-GOS) for 4 weeks. Gastrointestinal symptoms, fecal microbiota (fluorescent in situ hybridization and 16S rRNA sequencing), fecal short-chain fatty acids (gas-liquid chromatography) and pH (probe), and urine metabolites (H NMR) were analyzed. RESULTS: At 4 weeks, adequate symptom relief was higher in the LFD/B-GOS group (16/24, 67%) than in the control group (7/23, 30%) (odds ratio 4.6, 95% confidence interval: 1.3-15.6; P = 0.015); Bifidobacterium concentrations…

INTRODUCTION: Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines. METHODS: We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models. RESULTS: We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69…

INTRODUCTION: Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. METHODS: This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. RESULTS: Patients with FD had significantly…

OBJECTIVES: Chronic idiopathic constipation (CIC) is characterized by unsatisfactory defecation and difficult or infrequent stools. CIC affects 9%-20% of adults in the United States, and although prevalent, gaps in knowledge remain regarding CIC healthcare seeking and medication use in the community. We recruited a population-based sample to determine the prevalence and predictors of (i) individuals having discussed their constipation symptoms with a healthcare provider and (ii) the use of constipation therapies. METHODS: We recruited a representative sample of Americans aged 18 years or older who had experienced constipation. Those who met the Rome IV criteria for irritable bowel syndrome and opioid-induced constipation were excluded. The survey included questions on constipation severity, healthcare seeking, and the use of constipation medications. We used multivariable regression methods to adjust for confounders. RESULTS: Overall, 4,702 participants had experienced constipation (24.0% met the Rome IV CIC criteria). Among all respondents with previous constipation, 37.6%…

INTRODUCTION: Elevated liver enzyme levels are observed in patients with coronavirus disease 2019 (COVID-19); however, these features have not been characterized. METHODS: Hospitalized patients with COVID-19 in Zhejiang Province, China, from January 17 to February 12, 2020, were enrolled. Liver enzyme level elevation was defined as alanine aminotransferase level >35 U/L for men and 25 U/L for women at admission. Patients with normal alanine aminotransferase levels were included in the control group. Reverse transcription polymerase chain reaction was used to confirm severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and patients symptomatic with SARS-CoV-2 infection were defined as patients with COVID-19. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected and compared. RESULTS: Of 788 patients with COVID-19, 222 (28.2%) patients had elevated liver enzyme levels (median [interquartile range {IQR}] age, 47.0 [35.0-55.0] years; 40.5% women). Being male, overweight, and smoking increased the risk of liver enzyme level…

OBJECTIVES: Symptoms are inconsistently associated with esophageal motor findings on high-resolution manometry (HRM). We aimed to evaluate predictors of dysphagia severity, including esophageal hypervigilance and visceral anxiety, among patients evaluated with HRM. METHODS: Adult patients undergoing HRM at 4 academic medical centers (United States and France) were prospectively evaluated. HRM was completed and analyzed per the Chicago Classification v3.0. Validated symptom scores, including the Brief Esophageal Dysphagia Questionnaire and Esophageal Hypervigilance and Anxiety Scale, were completed at the time of HRM. RESULTS: Two hundred thirty-six patients, aged 18-85 (mean 53) years, 65% female, were included. Approximately 59 (25%) patients had a major motor disorder on HRM: 19 achalasia, 24 esophagogastric junction outflow obstruction, 12 absent contractility, and 4 jackhammer. Approximately 177 (75%) patients did not have a major motor disorder: 71 ineffective esophageal motility and 106 normal motility. Having a major motor disorder was a significant predictor of dysphagia…

INTRODUCTION: Higher levels of thyroid-stimulating hormone (TSH) in the euthyroid state can negatively affect the metabolic health, including nonalcoholic fatty liver disease (NAFLD). We studied the effect of TSH levels in the setting of normal levels of thyroid hormone on all-cause and cause-specific mortality stratified by NAFLD status. METHODS: The National Health and Nutrition Examination Survey (NHANES) III from 1988 to 1994 and NHANES III-linked mortality data through 2015 were used. NAFLD was defined as ultrasonographically diagnosed hepatic steatosis without coexisting liver diseases. Subclinical hypothyroidism was defined as a TSH level over 4.5 mIU/L and "low-normal" thyroid function as higher TSH level (2.5-4.5 mIU/L) within the euthyroid reference range. The Cox proportional hazard model analyzed the all-cause mortality and cause-specific mortality. RESULTS: In a multivariate logistic regression analysis, individuals with low thyroid function demonstrated an association with NAFLD in a dose-dependent manner. During a median follow-up of 23 years, low thyroid function was…