Randomised controlled trial of mesalazine in IBS.

OBJECTIVE: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER: ClincialTrials.gov number, NCT00626288.

Confirmatory factor analysis of the Patient Assessment of Constipation-Symptoms (PAC-SYM) among patients with chronic constipation.

BACKGROUND AND AIM: PAC-SYM is widely adopted to asses constipation severity. However, it has been validated in a small sample, few items have been included based on expert opinion and not on empirical grounds, and its factor structure has never been replicated. We aimed at evaluating the psychometric properties of PAC-SYM in patients with chronic constipation. METHODS: We enrolled 2,203 outpatients with chronic constipation in two waves. We used wave I sample to test the psychometric properties of the PAC-SYM and wave II sample to cross-validate its factor structure, to assess criterion validity, responsiveness to clinical change, and its minimal clinically important difference. RESULTS: Only a minority of patients reported any rectal tearing (38 %). Deletion of such item leads to a 11-item version (M:PAC-SYM). The remaining items in the rectal domain were moderately correlated with the stool domain. Exploratory factor analysis and confirmatory factor analysis revealed a bifactor structure with two subscales (stool and abdominal symptoms) and a general severity factor. The M:PAC-SYM demonstrated excellent reliability, moderate correlation with SF-12 and treatment satisfaction (r = 0.28-0.45), discrimination across Rome III criteria for functional constipation and abdominal pain, and responsiveness to clinical change (ß = -0.49; ω (2) = 0.25). M:PAC-SYM minimal clinically important difference was 0.24. CONCLUSION: Our analysis shows that the rectal domain may not represent a relevant cluster of symptoms for patients with chronic constipation. We developed a modified version of the PAC-SYM which might better represent symptom severity of most patients seeking care in gastroenterology referral centers.

Chronic intestinal pseudo-obstruction in adults: A practical guide to identify patient subgroups that are suitable for more specific treatments.

Chronic intestinal pseudo-obstruction is a rare and heterogeneous syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine with air/fluid levels in the absence of any mechanical occlusive lesion. Several diseases may be associated with chronic intestinal pseudo-obstruction and in these cases, the prognosis and treatment are related to the underlying disease. Also, in its "primary or idiopathic" form, two subgroups of patients should be determined as they require a more specific therapeutic approach: patients whose chronic intestinal pseudo-obstruction is due to sporadic autoimmune/inflammatory mechanisms and patients whose neuromuscular changes are genetically determined. In a context of a widely heterogeneous adult population presenting chronic intestinal pseudo-obstruction, this review aims to summarize a practical diagnostic workup for identifying definite subgroups of patients who might benefit from more specific treatments, based on the etiology of their underlying condition.

Duodenojejunal inflammation causing chronic vomiting in adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease with a broad spectrum of clinical manifestations including fever, skin rash, arthralgia and neutrophilic leucocytosis. Small bowel inflammation in AOSD has been reported in association with Crohn's disease, coeliac disease and chronic intestinal pseudo-obstruction. We have here reported the first-time case of AOSD with small bowel involvement, presenting with chronic vomiting. Fluorodeoxyglucose total-body positron emission tomography/CT showed high uptake of the duodenum and first jejunal loop. Faecal calprotectin increased. Duodenal histology revealed neutrophilic infiltrate among duodenal enterocytes and severe chronic lymphoplasmacellular infiltrate of the lamina propria. Vomiting disappeared when duodenojejunal inflammation was controlled by immunomodulatory treatments for AOSD, suggesting a possible causal relation between duodenojejunal inflammation and the symptom.

Intestinal pseudo-obstruction caused by Giardia lamblia infection.

A woman in her 40s presented with malaise, nausea, reduced appetite, abdominal distention, loose stools and weight loss. Symptoms had started 6 months earlier and worsened in the last 2 weeks. CT enterography showed hypotonic dilated small bowel loops in absence of any mechanical obstruction. Endoscopic examinations including capsule endoscopy did not reveal any obstructing lesion, but a delayed small bowel transit time of the capsule. Duodenal histology revealed Marsh 3a villous atrophy. Secondary causes of intestinal pseudo-obstruction and villous atrophy were investigated. Giardia lamblia trophozoites were found in the stools and in the duodenal biopsies. The patient's symptoms quickly resolved after metronidazole treatment with complete normalisation of duodenal histology.

Functional gastrointestinal and somatoform symptoms five months after SARS-CoV-2 infection: A controlled cohort study.

BACKGROUND: Gastrointestinal infections represent a risk factor for functional gastrointestinal and somatoform extraintestinal disorders. We investigated the prevalence and relative risk (RR) of gastrointestinal and somatoform symptoms 5 months after SARS-CoV-2 infection compared with a control cohort. METHODS: One hundred and sixty-four SARS-CoV-2 infected patients and 183 controls responded to an online questionnaire about symptoms and signs during the acute phase of the infection and after 4.8 ± 0.3 months. Presence and severity of gastrointestinal symptoms, somatization, anxiety, and depression were recorded with standardized questionnaires. Stool form and presence of irritable bowel syndrome (IBS) were also recorded. Any association between exposure to infection and symptoms was evaluated by calculating crude and adjusted RR values and score differences with 95% confidence intervals (CI). KEY RESULTS: Fever, dyspnea, loss of smell/taste/weight, diarrhea, myalgia, arthralgia, and asthenia were reported by more than 40% of patients during the acute phase. Compared with controls, adjusted RRs for loose stools, chronic fatigue, and somatization were increased after infection: 1.88 (95% CI 0.99-3.54), 2.24 (95% CI 1.48-3.37), and 3.62 (95% CI 1.01-6.23), respectively. Gastrointestinal sequelae were greater in patients with diarrhea during the acute phase. CONCLUSIONS & INFERENCES: Mild gastroenterological symptoms persist 5 months after SARS-CoV-2 infection, in particular in patients reporting diarrhea in the acute phase. Infected patients are at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somatoform disorders may have a common biological origin.

Review of the indications, methods, and clinical utility of anorectal manometry and the rectal balloon expulsion test.

BACKGROUND: Anorectal manometry (ARM) comprehensively assesses anorectal sensorimotor functions. PURPOSE: This review examines the indications, techniques, interpretation, strengths, and weaknesses of high-resolution ARM (HR-ARM), 3-dimensional high-resolution anorectal manometry (3D-HR-ARM), and portable ARM, and other assessments (i.e., rectal sensation and rectal balloon expulsion test) that are performed alongside manometry. It is based on a literature search of articles related to ARM in adults. HR-ARM and 3D-HR-ARM are useful for diagnosing defecatory disorders (DD), to identify anorectal sensorimotor dysfunction and guide management in patients with fecal incontinence (FI), constipation, megacolon, and megarectum; and to screen for anorectal structural (e.g., rectal intussusception) abnormalities. The rectal balloon expulsion test is a useful, low-cost, radiation-free, outpatient assessment tool for impaired evacuation that is performed and interpreted in conjunction with ARM. The anorectal function tests should be interpreted with reference to age- and sex-matched normal values, clinical features, and results of other tests. A larger database of technique-specific normal values and newer paradigms of analyzing anorectal pressure profiles will increase the precision and diagnostic utility of HR-ARM for identifying abnormal mechanisms of defecation and continence.

European guideline on indications, performance, and clinical impact of hydrogen and methane breath tests in adult and pediatric patients: European Association for Gastroenterology, Endoscopy and Nutrition, European Society of Neurogastroenterology and Motility, and European Society for Paediatric Gastroenterology Hepatology and Nutrition consensus.

INTRODUCTION: Measurement of breath hydrogen (H2 ) and methane (CH4 ) excretion after ingestion of test-carbohydrates is used for different diagnostic purposes. There is a lack of standardization among centers performing these tests and this, together with recent technical developments and evidence from clinical studies, highlight the need for a European guideline. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of H2 -CH4 -breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 44 experts from 18 European countries. Eighty eight statements and recommendations were drafted based on a review of the literature. Consensus (≥80% agreement) was reached for 82. Quality of evidence was evaluated using validated criteria. RESULTS: The guideline incorporates new insights into the role of symptom assessment to diagnose carbohydrate (e.g., lactose) intolerances and recommends that breath tests for carbohydrate malabsorption require additional validated concurrent symptom evaluation to establish carbohydrate intolerance. Regarding the use of breath tests for the evaluation of oro-cecal transit time and suspected small bowel bacterial overgrowth, this guideline highlights confounding factors associated with the interpretation of H2 -CH4 -breath tests in these indications and recommends approaches to mitigate these issues. CONCLUSION: This clinical practice guideline should facilitate pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, it identifies areas of future research needs to clarify diagnostic and therapeutic approaches.

Coordinated Multi-Language Translation of A Validated Symptom Questionnaire for Carbohydrate Intolerances: A Practical Structured Procedure.

BACKGROUND AND AIMS: Validated questionnaires help to minimize diagnostic bias, to standardize symptom assessment and to achieve comparability between studies and centers. In a recent European guideline the adult and the pediatric carbohydrate perception questionnaires (aCPQ and pCPQ), were recommended to be used for the diagnosis of carbohydrate intolerances in adult and pediatric patients. The implementation of this guideline into clinical practice makes availability of validated translations a necessity. METHODS: Clinical experts who recognized the need for these questionnaires to be available in their own language participated in the translation process. The tasks were assigned and a workflow following a predefined procedure based on recommendations of the Rome foundation was developed. The procedure had 5 phases: foundation, nomination, translation, revision, cognitive debriefing. RESULTS: Within eight months the aCPQ was translated into Bulgarian, French, Hungarian, Italian, Polish, Romanian, Russian and Slovenian language and the pCPQ into Dutch, French and Romanian. This expands the population which can be served with the aCPQ from 160 million to over 500 million Europeans. The reach of pCPQ expanded from 92 million to 193 million Europeans. CONCLUSIONS: We report the development and implementation of a centrally organized process of translation of validated questionnaires, following a predefined procedure based on recommendations of the Rome foundation. This structured procedure may aid future efforts to standardize and harmonize the translation of validated questionnaires.

Gastrointestinal symptoms impair quality of life in Italian renal transplant recipients but are under-recognized by physicians.

We assessed patient- and physician-reported prevalence of gastrointestinal symptoms and their impact on quality of life (QOL) in Italian renal transplant recipients with stable graft function. Patients ≥18years with a renal allograft functioning for ≥6months and stable serum creatinine levels of <2.5mg/dl were enrolled. Physicians and patients completed an Italian translation of the Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) questionnaires. The average time since transplantation (n=1130) was 5.9years. Forty-two immunosuppressant drug regimens were reported. The top three regimens (cyclosporine/mycophenolate mofetil/steroids; tacrolimus/mycophenolate mofetil/steroids; cyclosporine/steroids) accounted for approximately 40% of patients. In the physician interview, 39.2% of patients had ≥1 gastrointestinal symptom vs. 88.3% of patients in the self-administered questionnaire. The prevalence of GSRS symptoms was similar for each of the most frequently prescribed immunosuppressant drug regimens. GIQLI total score was significantly poorer in patients with versus those without gastrointestinal symptoms (121.8±17.6 vs. 138.4±3.7; P<0.0001), and there was a strong inverse correlation between GIQLI and patient-reported GSRS scores (Pearson's correlation coefficient -0.816; P<0.0001). Gastrointestinal symptoms are frequent in renal transplant patients, are under-evaluated by physicians and may adversely impact on patient QOL.

Patient dissatisfaction with medical therapy for chronic constipation or irritable bowel syndrome with constipation: analysis of N-of-1 prospective trials in 81 patients.

BACKGROUND: Patients with chronic constipation (CC) or with irritable bowel syndrome with constipation are often dissatisfied about their medical therapy, but their condition remains poorly defined. AIM: To evaluate the patients' satisfaction rates and which factors predict favourable outcomes through the aggregate analysis of N-of-1 trials. METHODS: Eighty-one outpatients with CC or with irritable bowel syndrome with constipation underwent N-of-1 trials with at least a one-month cycle of effective treatment. Three primary endpoints (satisfaction with therapy, improvement after treatment and an extended satisfaction criterion including both endpoints) were adopted to define satisfaction with therapy. Dyssynergia, resting anal pressure, colonic transit time and somatisation were assessed. The Patient Assessment of Constipation-Symptoms (PAC-SYM) questionnaire and its Modified version (M-PAC-SYM) measured constipation severity. Straining at defecation, stool frequency and form were daily recorded. K statistics for agreement and logistic regression were used at statistical analysis. RESULTS: Satisfaction with therapy was not achieved by 43% of patients, who had a significantly lower Body Mass Index (BMI) and more severe constipation at baseline. Only the change in constipation severity according to M-PAC-SYM remained significantly associated with satisfaction with therapy (OR = 4.3; P < 0.001) at multivariate analysis. CONCLUSIONS: Satisfaction with therapy is often an unmet need for patients with CC or with irritable bowel syndrome with constipation. Lower BMI and more severe constipation are associated with worse outcome. Changes in M-PAC-SYM reflect satisfaction with therapy. ClinicalTrials.gov no. NCT02813616.

Seated anorectal manometry during simulated evacuation: A physiologic exercise or a new clinically useful diagnostic test?

Symptoms such as a feeling of incomplete evacuation, straining, absence of the call to stool, anal blockage, or digitation suggest the presence a functional defecation disorder. As symptoms do not distinguish between patients with and without functional defecation disorder, Rome IV criteria recommend that this disorder is diagnosed when two of three tests are positive: balloon expulsion test (BET), anorectal manometry (ARM), and defecography. However, previous studies have demonstrated that the agreement among these tests is limited. In this issue of Neurogastroenterology and Motility, Sharma et al tested the hypothesis that conducting the ARM in a seated position would increase the diagnostic accuracy of the test in discriminating between patients with normal and prolonged BET. This minireview discusses the current knowledge on the role of the techniques to diagnose defecation disorder and the potential role of the ARM in a seated position.

Neuromuscular alterations in the dilated ileum of an adult patient with segmental lymphangiectasia.

Intestinal lymphangiectasia is a rare condition, which is characterized by the dilation of small bowel lymphatics and presents with signs and symptoms of protein-losing enteropathy. Some patients have complained of occlusive symptoms attributable to the mechanical obstruction caused by the considerable mucosal edema associated with the lymphatic dilation. On the basis of the hypothesis that alterations in the neuromuscular structures controlling clearance function or gut tone may play a role in ileal dilation, we examined the resected ileum of a 48-year-old male patient with segmental lymphangiectasia histologically, immunohistochemically (for S100 protein, PGP 9.5, Bcl-2, neuron-specific enolase, neurofilaments, synaptophysin, and CD117/C-kit), and by means of electron microscopy. Histology showed pseudocystic dilation of the mucosal, submucosal, and muscular lymphatics with fragmentation of the circular and longitudinal muscle layers. Hardly any neural expression of synaptophysin was observed, but the neural structures were otherwise morphologically normal and reacted normally to the other neural markers. This case shows that neuromuscular alterations can be found in the dilated ileum of patients with segmental lymphangiectasia.

Oesophageal motor function in chronic intestinal idiopathic pseudo-obstruction: A study with high-resolution manometry.

BACKGROUND: Chronic intestinal idiopathic pseudo-obstruction (idiopathic CIPO) is a rare heterogeneous condition for which the different phenotypes are difficult to be established. Oesophageal motility has shown to be impaired in patients with idiopathic CIPO at traditional manometry, whereas no studies have assessed it by high resolution manometry (HRM). AIMS: To evaluate oesophageal motility by HRM in patients with idiopathic CIPO. METHODS: 14 patients with idiopathic CIPO underwent oesophageal HRM. Multiple rapid swallows (MRS) were performed in order to evaluate contraction reserve. The Chicago Classification 3.0 was used to classify the oesophageal motility disorders. RESULTS: One idiopathic CIPO patient had type-II achalasia, one aperistalsis and 12 had minor disorder of peristalsis (11 ineffective oesophageal motility and one fragmented peristalsis). These minor disorders were not significantly different from those of 50 other consecutive patients who underwent HRM for dysphagia or GERD and received the diagnosis of ineffective oesophageal motility. Three of the 12 idiopathic CIPO patients with minor disorder of peristalsis had no contraction reserve after MRS. CONCLUSIONS: HRM is able to identify different grades of oesophageal motor impairment in patients with idiopathic CIPO. Presence of major oesophageal dismotility or absent contraction reserve suggest a more severe and widespread motor disorder.

Ultrasound Elasticity Imaging Predicts Therapeutic Outcomes of Patients With Crohn's Disease Treated With Anti-Tumour Necrosis Factor Antibodies.

BACKGROUND AND AIMS: Ultrasound elasticity imaging is a non-invasive technique developed to evaluate fibrosis. Measuring tissue strain by ultrasound elasticity imaging can reliably detect severe ileal fibrosis in patients with Crohn's disease [CD]. We have hypothesised that a more severe range of fibrosis might influence the therapeutic response to anti-tumour necrosis factor [TNF] treatment. The aim of this study was to assess the ability of ultrasound elasticity imaging to predict the therapeutic outcome for CD patients. METHODS: Consecutive patients with ileal/ileocolonic CD, starting anti-TNF treatment, were enrolled for the study. These patients underwent bowel ultrasound and ultrasound elasticity imaging at baseline and at 14 and 52 weeks after anti-TNF treatment. Bowel wall stiffness was quantified by calculating the strain ratio between the mesenteric tissue and the bowel wall. Strain ratio ≥ 2 was used to identify severe ileal fibrosis. Transmural healing at 14 and 52 weeks was defined as bowel wall thickness ≤ 3 mm. RESULTS: Thirty patients with CD were enrolled. Five patients underwent surgery for bowel obstruction. The frequency of surgeries was significantly greater in patients with a strain ratio ≥ 2 at baseline [p = 0.003]. A significant reduction of the bowel thickness was observed after 14 and 52 weeks of anti-TNF treatment [p < 0.005]. A significant inverse correlation was observed between the strain ratio values at baseline and the thickness variations following anti-TNF therapy [p = 0.007]; 27% of patients achieved transmural healing at 14 weeks. The baseline strain ratio was significantly lower in patients with transmural healing [p < 0.05]. CONCLUSIONS: This study shows that ultrasound elasticity imaging predicts therapeutic outcomes for CD patients treated with anti-TNF.

[Pathogenesis of irritable bowel syndrome: current understanding]. / Sulla patogenesi della sindrome dell'intestino irritabile. Attuali conoscenze.

Irritable bowel syndrome is one of the most frequent functional bowel disorders. The pathogenesis of the condition is not completely understood, but an alteration of the neural circuits that regulate the sensory-motor homeostatic reflex responses to visceral stimuli is involved. The causes of this alteration are unknown and include both genetic and environmental factors, such as a previous gastrointestinal infection. A more precise definition of the pathogenesis of the condition might help to develop more effective treatments to correct the altered sensitive and motor reflex responses in the patients.