Position paper on transanal irrigation in chronic non-organic constipation.

The practice of recto-colonic water irrigation to treat constipation has been used since ancient times with different, uncontrolled, and variably performing methods which have been considered interchangeably all alike. The use of better-performing devices with a standardized methodology is relatively recent, and the term Trans Anal Irrigation (TAI) defines a methodology performed with devices able to control the timing, volume, and pressure of the water introduced into the rectum and colon utilizing a catheter or a cone through the anus. Such practice has been implemented with favorable responses in patients with refractory chronic constipation secondary to neurological diseases. However, since the role of Trans Anal Irrigation as a therapeutic aid in chronic functional constipation and functional evacuation disorders is not yet fully clarified and standardized, a group of clinical investigators with recognized expertise in these clinical conditions intends to clarify the elements that characterize a TAI procedure that can benefit patients with functional constipation and functional defecation disorders defined according to the lastly updated Rome Diagnostic Criteria. Finally, the paper deals with adherence and practical implementation of TAI.

Pelvic floor rehabilitation for defecation disorders.

Pelvic floor rehabilitation is frequently recommended for defecation disorders, in both constipation and fecal incontinence. However, the lack of patient selection, together with the variety of rehabilitation methods and protocols, often jeopardize the results of this approach, causing difficulty in evaluating outcomes and addressing proper management, and above all, in obtaining scientific evidence for the efficacy of these methods for specific indications. The authors represent different gastroenterological and surgical scientific societies in Italy, and their aim was to identify the indications and agree on treatment protocols for pelvic floor rehabilitation of patients with defecation disorders. This was achieved by means of a modified Delphi method, utilizing a working team (10 members) which developed the statements and a consensus group (15 members, different from the previous ones) which voted twice also suggesting modifications of the statements.

Anal function after endoluminal locoregional resection by transanal endoscopic microsurgery and radiotherapy for rectal cancer.

AIM: In patients with rectal cancer, surgery and chemoradiotherapy may affect anal sphincter function. Few studies have evaluated anorectal function after neoadjuvant chemoradiotherapy (n-CRT) and/or transanal endoscopic microsurgery (TEM). The aim of this study was to evaluate the effects of n-CRT and TEM on anorectal function. METHOD: Thirty-seven patients with rectal cancer underwent anorectal manometry and Wexner scoring for faecal incontinence at baseline, after n-CRT (cT2-T3N0 cancer) and at 4 and 12 months after surgery. Water-perfused manometry measured anal tone at rest and during squeezing, rectal sensitivity and compliance. Twenty-seven and 10 patients, respectively, underwent TEM without (Group A) or with n-CRT (Group B). RESULTS: In Group A, anal resting pressure decreased from 68 ± 23 to 54 ± 26 mmHg at 4 months (P = 0.04) and improved 12 months after surgery (60 ± 30 mmHg). The Wexner score showed a significant increase in gas incontinence (59%), soiling (44%) and urgency (37%) rates at 4 months, followed by clinical improvement at 1 year (41%, 26% and 18%, respectively). In group B, anal resting pressure decreased from 65 ± 23 to 50 ± 18 mmHg at 4 months but remained stable at 12 months (44 ± 11 mmHg, P = 0.02 vs preoperative values - no significant difference compared with evaluation at 4 months). Gas incontinence, soiling and urgency were observed in 50%, 50%, 25% and in 38%, 12% and 12% of cases, respectively, 4 and 12 months after treatment. CONCLUSION: TEM does not significantly affect anal function. Instead, n-CRT does affect anal function but without causing major anal incontinence.

Rome IV. Gallbladder and Sphincter of Oddi Disorders.

The concept that motor disorders of the gallbladder, cystic duct and sphincter of Oddi can cause painful syndromes is attractive and popular, at least in the USA. However, the results of commonly performed ablative treatments (cholecystectomy and sphincterotomy) are not uniformly good. The predictive value of tests that are often used to diagnose dysfunction (dynamic gallbladder scintigraphy and sphincter manometry) is controversial. Evaluation and management of these patients is made difficult by the fluctuating symptoms and the placebo effect of invasive interventions. A recent stringent study has shown that sphincterotomy is no better than sham treatment in patients with post-cholecystectomy pain and little or no objective abnormalities on investigation, so that the old concept of sphincter of Oddi dysfunction (SOD) type III is discarded. ERCP approaches are no longer appropriate in that context. There is a pressing need for similar prospective studies to provide better guidance for clinicians dealing with these patients. We need to clarify the indications for cholecystectomy in patients with Functional Gallbladder Disorder (FGBD) and the relevance of sphincter dysfunction in patients with some evidence for biliary obstruction (previously SOD type II, now called "Functional Biliary Sphincter Disorder - FBSD") and with idiopathic acute recurrent pancreatitis.

A cross-cultural investigation of attachment style, catastrophizing, negative pain beliefs, and symptom severity in irritable bowel syndrome.

BACKGROUND: Little information exists regarding whether psychosocial variables in irritable bowel syndrome (IBS) vary by geographic location. Adult attachment is an important psychological concept rooted in childhood relationship experience that has not been previously studied in IBS. Catastrophizing and negative pain beliefs have been described in IBS and may be affected by attachment. AIMS: In this cross-cultural study, we determined: (i) whether attachment differs between IBS patients and controls, (ii) whether geographic location has a significant effect on attachment style, catastrophizing and negative pain beliefs, and (iii) how all three variables correlate with IBS symptom severity. METHODS: 463 IBS patients, with moderate to severe symptom scores, and 192 healthy controls completed validated questionnaires about attachment, catastrophizing, negative pain beliefs and IBS-SSS in nine locations, USA (New York, Los Angeles), Mexico, Italy (Rome, Bari), Romania, Iran, India, and China. KEY RESULTS: Attachment anxiety and avoidance scores were significantly higher in IBS patients than in controls (p < 0.001). This was particularly true for the fearful-avoidant attachment category, especially in China and Romania. Path analysis showed that attachment anxiety and avoidance had indirect effects on IBS-SSS through catastrophizing (p < 0.0001) and negative pain beliefs (p = 0.005). All three psychosocial measures varied significantly depending on location. CONCLUSIONS & INFERENCES: In the IBS population studied, attachment style was significantly different in IBS compared to a control population. Geographic differences in attachment, catastrophizing and negative pain beliefs were documented and their correlation with symptom severity and thus, research of psychosocial variables in IBS should take into account the location of the population studied.

A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of long-term treatment with prucalopride.

BACKGROUND: Randomized trials have confirmed the efficacy of prucalopride for the treatment of chronic constipation up to 12 weeks. This study aimed to assess the efficacy of prucalopride over a 24-week period (ClinicalTrials.gov: NCT01424228). METHODS: Adults with chronic constipation and ≤2 spontaneous complete bowel movements (SCBMs)/week were randomized to receive prucalopride 2 mg or placebo daily for 24 weeks. The primary endpoint was the proportion of patients achieving a mean of ≥3 SCBMs/week over the treatment period, assessed using daily e-diaries. Secondary outcomes and safety parameters were assessed throughout the study. KEY RESULTS: Overall, 361 patients were randomized and received prucalopride or placebo. Baseline characteristics were similar in the prucalopride (N = 181) and placebo (N = 180) groups. Mean age was 48.9 years (standard deviation, 16.0) and most patients were women. The proportion of participants achieving the primary endpoint was not statistically different between the prucalopride and placebo groups (25.1% vs 20.7%; p = 0.367). There was also no statistically significant difference between groups over the first 12-week period (prucalopride, 25.1%; placebo, 20.1%; p = 0.341). There were no statistically significant differences between groups for most secondary endpoints. No new safety concerns were identified. CONCLUSIONS & INFERENCES: This trial did not show statistically significant improvements in primary or secondary outcomes with prucalopride compared with placebo over 24 or 12 weeks. This is in contrast to the results of four previous 12-week trials, which demonstrated prucalopride to be significantly more effective than placebo. An extensive evaluation did not provide an explanation for the null efficacy results of this study.

Conducting multinational, cross-cultural research in the functional gastrointestinal disorders: issues and recommendations. A Rome Foundation working team report.

BACKGROUND: Cross-cultural, multinational research can advance the field of functional gastrointestinal disorders (FGIDs). Cross-cultural comparative research can make a significant contribution in areas such as epidemiology, genetics, psychosocial modulators, symptom reporting and interpretation, extra-intestinal co-morbidity, diagnosis and treatment, determinants of disease severity, health care utilisation, and health-related quality of life, all issues that can be affected by geographical region, culture, ethnicity and race. AIMS: To identify methodological challenges for cross-cultural, multinational research, and suggest possible solutions. METHODS: This report, which summarises the full report of a working team established by the Rome Foundation that is available on the Internet, reflects an effort by an international committee of FGID clinicians and researchers. It is based on comprehensive literature reviews and expert opinion. RESULTS: Cross-cultural, multinational research is important and feasible, but has barriers to successful implementation. This report contains recommendations for future research relating to study design, subject recruitment, availability of appropriate study instruments, translation and validation of study instruments, documenting confounders, statistical analyses and reporting of results. CONCLUSIONS: Advances in study design and methodology, as well as cross-cultural research competence, have not matched technological advancements. The development of multinational research networks and cross-cultural research collaboration is still in its early stages. This report is intended to be aspirational rather than prescriptive, so we present recommendations, not guidelines. We aim to raise awareness of these issues and to pose higher standards, but not to discourage investigators from doing what is feasible in any particular setting.

A four-country comparison of healthcare systems, implementation of diagnostic criteria, and treatment availability for functional gastrointestinal disorders: a report of the Rome Foundation Working Team on cross-cultural, multinational research.

BACKGROUND: Variations in healthcare provision around the world may impact how patients with functional gastrointestinal disorder (FGIDs) are investigated, diagnosed, and treated. However, these differences have not been reviewed. PURPOSES: The Multinational Working Team of the Rome Foundation, established to make recommendations on the conduct of multinational, cross-cultural research in FGIDs, identified seven key issues that are analyzed herein: (i) coverage afforded by different healthcare systems/providers; (ii) level of the healthcare system where patients with FGIDs are treated; (iii) extent/types of diagnostic procedures typically undertaken to diagnose FGIDs; (iv) physicians' familiarity with and implementation of the Rome diagnostic criteria in clinical practice; (v) range of medications approved for FGIDs and approval process for new agents; (vi) costs involved in treating FGIDs; and (vii) prevalence and role of complementary/alternative medicine (CAM) for FGIDs. Because it was not feasible to survey all countries around the world, we compared a selected number of countries based on their geographical and ethno-cultural diversity. Thus, we included Italy and South Korea as representative of nations with broad-based coverage of healthcare in the population and India and Mexico as newly industrialized countries where there may be limited provision of healthcare for substantial segments of the population. In light of the paucity of formal publications on these issues, we included additional sources from the medical literature as well as perspectives provided by local experts and the media. Finally, we provide future directions on healthcare issues that should be taken into account and implemented when conducting cross-cultural and multinational research in FGIDs.

Patient with chest pain refractory to proton pump inhibitor: report of a case of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is the most common form of gastrointestinal disorders associated with eosinophilia. Typically, an inappropriate accumulation of eosinophils is found in the esophageal mucosa. EoE can be well managed and treated with several options that include an elimination diet, drug therapy (oral and topical steroids) and esophageal dilatations. We herein, report a case of a 49-year-old male affected by EoE associated to chest pain, treated with proton pump inhibitor without clinical response. The patient suffered from long lasting postprandial fullness and gastroesophageal reflux disease-like symptoms. He had a history of episodic asthmatic attacks and allergic rhinitis but had not dysphagia or food impaction. The patient recovered completely after an adequate treatment.

Contribution of intestinal smooth muscle to Crohn's disease fibrogenesis.

Mesenchymal cells transdifferentiation and extracellular matrix deposition are involved in the fibrotic process of Crohn's disease (CD). Mesenchymal smooth muscle cells (SMCs) de-differentiation, driven by Platelet-derived growth factor (PDGF) that counteracts Transforming growth factor (TGF-ß) has been studied in vascular muscle. The role of SMCs in intestinal fibrogenesis is still not clearly elucidated. Aim of the study was to evaluate the possible myogenic contribution to CD fibrotic process through the comparative analysis of histological, morphometric and molecular alterations occurring in human smooth muscle. Full thickness specimens were obtained from CD (non-involved and stenotic tracts) and healthy (control) ileum. Tissues were processed for histological and immunohistochemical (IHC) analyses and SMCs were isolated from the muscularis propria for morphofunctional and molecular (qPCR) analyses. CD stenotic ileum showed a significant increased thickness of all layers compared to CD non-involved and control ileum. IHC revealed an overexpression of α-smooth muscle actin and collagens I-III throughout all intestinal layers only in stenotic tracts. The two growth factors, PDGF and TGF-ß, showed a progressive increase in expression in the muscle layer from CD non-involved to stenotic tracts. Freshly isolated SMCs presented alterations in CD non-involved tracts that progressively increased in the stenotic tracts consisting in a statistical increase in mRNA encoding for PDGF-ß and collagen III, paralleled to a decrease in TGF-ß and Tribbles-like protein-3 mRNA, and altered morphofunctional parameters consisting in progressive decreases in cell length and contraction to acetylcholine. These findings indicate that intrinsic myogenic alterations occur in CD ileum, that they likely precede stricture formation, and might represent suitable new targets for anti-fibrotic interventions.

Age-dependent association of idiopathic achalasia with vasoactive intestinal peptide receptor 1 gene.

Idiopathic achalasia is a rare disorder of the oesophagus of unknown aetio-pathogenesis characterized by a myenteric inflammation, aperistalsis and insufficient lower oesophageal sphincter relaxation. Vasoactive intestinal peptide (VIP), present in the myenteric plexus, is involved in smooth muscle relaxation and acts as an anti-inflammatory cytokine. The human VIP receptor 1 gene (VIPR1) is highly polymorphic and may play a role in idiopathic achalasia. One hundred and four consecutive patients and 300 random controls from the same geographic area were typed for five SNPs mapping in the VIPR1 gene. Patients with idiopathic achalasia show a significant difference in allele, genotype and phenotype distribution of SNP rs437876 mapping in intron 4. This association, however, was almost entirely due to the group of patients with late disease onset (P = 0.0005). These results strongly suggest that idiopathic achalasia is a heterogeneous disease with a different aetiology in cases with early or late disease onset.

Gallstones, cholecystectomy and irritable bowel syndrome (IBS) MICOL population-based study.

BACKGROUND: Subjects with irritable bowel syndrome may undergo an excess of cholecystectomy. It is not known, however, whether the cholecystectomy rate parallels an increased risk of gallstones. AIM: Aim was to assess the prevalence and the incidence of gallstones and cholecystectomy in subjects with irritable bowel syndrome symptoms. SUBJECTS AND METHODS: In this population-based study, 29,139 subjects (63.2% of 46,139 randomly selected subjects, age 30-69 years) underwent a physical examination, an interview on gastrointestinal symptoms and an upper abdominal ultrasonography. An identical survey was carried out 7.8+/-1.0 (M+/-S.D.) years later on 8460 gallstone-free subjects at the first survey. Prevalence and incidence of gallstones and cholecystectomy were assessed in subjects with (1) irritable bowel syndrome; (2) abdominal pain and normal bowel; (3) altered bowel and no abdominal pain and (4) asymptomatic controls; univariate and multivariate regression logistic models were used for statistical analysis. RESULTS: Prevalence odds of gallstones and cholecystectomy were significantly higher in irritable bowel syndrome and abdominal pain and normal bowel than in controls. Irritable bowel syndrome and abdominal pain and normal bowel subjects were more aware of gallstones than controls (p<0.001), and the prevalence of gallstones in irritable bowel syndrome subjects unaware of their gallbladder status was not significantly different from the controls. The incidence of gallstone disease in irritable bowel syndrome, abdominal pain and normal bowel, and altered bowel and no abdominal pain subjects did not differ from the controls. The incidence of cholecystectomy was higher in irritable bowel syndrome and abdominal pain and normal bowel groups than in controls and altered bowel and no abdominal pain group. CONCLUSIONS: Irritable bowel syndrome subjects have an increased risk of cholecystectomy that is not due to an increased risk of gallstones, but rather to abdominal pain, awareness of having gallstones, and inappropriate surgical indications.

Chronic constipation in hemiplegic patients.

AIM: To assess the prevalence of bowel dysfunction in hemiplegic patients, and its relationship with the site of neurological lesion, physical immobilization and pharmacotherapy. METHODS: Ninety consecutive hemiplegic patients and 81 consecutive orthopedic patients were investigated during physical motor rehabilitation in the same period, in the same center and on the same diet. All subjects were interviewed >= 3 mo after injury using a questionnaire inquiring about bowel habits before injury and at the time of the interview. Patients' mobility was evaluated by the Adapted Patient Evaluation Conference System. Drugs considered for the analysis were nitrates, angiogenic converting enzyme (ACE) inhibitors, calcium antagonists, anticoagulants, antithrombotics, antidepressants, anti-epileptics. RESULTS: Mobility scores were similar in the two groups. De novo constipation (OR = 5.36) was a frequent outcome of the neurological accident. Hemiplegics showed an increased risk of straining at stool (OR: 4.33), reduced call to evacuate (OR: 4.13), sensation of incomplete evacuation (OR: 3.69), use of laxatives (OR: 3.75). Logistic regression model showed that constipation was significantly and independently associated with hemiplegia. A positive association was found between constipation and use of nitrates and antithrombotics in both groups. Constipation was not related to the site of brain injury. CONCLUSION: Chronic constipation is a possible outcome of cerebrovascular accidents occurring in 30% of neurologically stabilized hemiplegic patients. Its onset after a cerebrovascular accident appears to be independent from the injured brain hemisphere, and unrelated to physical inactivity. Pharmacological treatment with nitrates and antithrombotics may represent an independent risk factor for developing chronic constipation.

Relationship between gastrointestinal and extra-gastrointestinal symptoms and delayed gastric emptying in functional dyspeptic patients.

AIM: Delayed gastric emptying and an enlarged fasting gastric antrum are common findings in functional dyspepsia but their relationship with gastrointestinal (GI), and the frequently associated extra-GI symptoms remains unclear. This study evaluated the relationship between GI and extra-GI symptoms, fasting antral volume and delayed gastric emptying in functional dyspepsia. METHODS: In 108 functional dyspeptic patients antral volume and gastric emptying were assessed with ultrasonography (US). Symptoms were assessed with standardized questionnaire. The association of symptoms and fasting antral volume with delayed gastric emptying was estimated with logistic regression analysis. RESULTS: Delayed gastric emptying was detected in 39.8% of the patients. Postprandial drowsiness (AOR 11.25; 95%CI 2.75-45.93), nausea (AOR 3.51; 95%CI 1.19-10.32), fasting antral volume (AOR 1.93; 95%CI 1.22-3.05), were significantly associated with delayed gastric emptying. Symptoms, mainly the extra-GI ones as postprandial drowsiness and nausea, combined with fasting antral volume predicted the modality of gastric emptying with a sensitivity and specificity of 78%. CONCLUSION: In functional dyspeptic patients, (1) an analysis of fasting antral volume and of symptoms can offer valuable indication on the modality of gastric emptying, and (2) it seems appropriate to inquire on postprandial drowsiness that showed the best correlation with delayed gastric emptying.

Sphincter of Oddi dysfunction.

Biliary-like pain alone, or associated with a transient increase in liver or pancreatic enzyme, may be the clinical manifestations of sphincter of Oddi dysfunction. Since it is not always possible to dissociate functional conditions from subtle structural changes, the term sphincter of Oddi dysfunction is used to define motility abnormalities caused by 'sphincter of Oddi stenosis' and 'sphincter of Oddi dyskinesia'. Both sphincter of Oddi stenosis and sphincter of Oddi dyskinesia may account for obstruction to flow through the sphincter of Oddi and may thus induce retention of bile in the biliary tree and pancreatic juice in the pancreatic duct. Most of the clinical information concerning sphincter of Oddi dysfunction refers to post-cholecystectomy patients who have been arbitrarily classified according to clinical presentation, laboratory results and endoscopic retrograde cholangiopancreatography findings in: (a) biliary type I, (b) biliary type II, and (c) biliary type III. Prevalence of biliary-type of pain has been reported to vary from 1 to 1.5% in unselected postcholecystectomy people, to 14% in a selected group of patients complaining of postcholecystectomy symptoms. The frequency of sphincter of Oddi dysfunction, as shown by manometry, differs in the different clinical subgroups: 65-95% in biliary group I, mainly due to sphincter of Oddi stenosis; 50-63% in biliary type II, and 12-28% in biliary type III. In patients with idiopathic recurrent pancreatitis, sphincter of Oddi dysfunction varies from 39 to 90%. Diagnostic work-up of postcholecystectomy patients for suspected sphincter of Oddi dysfunction includes liver biochemistry and pancreatic enzymes, plus negative findings of structural abnormalities. Usually, this would include transabdominal ultrasound and endoscopic retrograde cholangiopancreatography. Depending on the available resources, endoscopic ultrasound and magnetic resonance cholangiography may precede endoscopic retrograde cholangiopancreatography in specific clinical conditions. Quantitative evaluation of bile transit from the hepatic hilum to the duodenum at choledochoscintigraphy appears valuable in the decision to undertake sphincter of Oddi manometry or to treat. Sphincterotomy is the standard treatment for sphincter of Oddi dysfunction. In biliary type I patients, the indication for endoscopic sphincterotomy is straightforward without the need of any additional investigation. Slow bile transit in biliary type II is an indication to undergo endoscopic sphincterotomy without sphincter of Oddi manometry. Slow bile transit in biliary type III patients is an indication to perform sphincter of Oddi manometry. Diagnostic work-up of patients with gallbladder in situ is part of the same diagnostic algorithm that has initially excluded the presence of a gallbladder dysfunction.

Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome.

Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations. This consensus report highlights the following points. (a) A 4-week period is considered to be adequate to assess drug efficacy for the control of symptoms. (b) For the cyclic and non-life-threatening nature of the disease, a long-term study of 4-6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients. (c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow-up period prolonged for a sufficient time (4-8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post-treatment benefit. (d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on-demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome. (e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome. (f) The main efficacy outcome of the treatment should be based on one primary end-point. (g) The primary efficacy end-point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms. (h) A 50% improvement in the primary efficacy end-point seems to be a reasonable definition of a responder.