Systematic review with meta-analysis: prompt endoscopy as the initial management strategy for uninvestigated dyspepsia in Asia.

BACKGROUND: Prompt endoscopy should be considered as an initial strategy for uninvestigated dyspepsia in the background of high prevalence of Helicobacter pylori infection and malignancy. However, with changes of disease patterns and dyspepsia definition, the prevalence of organic lesions at endoscopy in dyspepsia patients and the predictive values of alarm features and age for in malignancy remain unclear in Asian population. AIMS: To evaluate the appropriateness of prompt endoscopy as an initial dyspepsia management strategy, we investigated the organic lesion detection rates in Asian dyspepsia patients as well as the diagnostic accuracies of alarm features and age thresholds for malignancy. METHODS: Literature was retrieved from MEDLINE, PubMed, Embase, Cochrane Library and CINAHL Plus. The prevalence rates of organic lesions and young cancer patients among dyspeptic patients and the sensitivities, specificities, likelihood ratios and diagnostic odds ratio (DOR) of alarm features and ages were estimated. The summary receiver operating characteristic curve was constructed and the area under the curve (AUC) calculated. Subgroup, sensitivity and meta-regression analyses were performed. RESULTS: Of the 18 included studies, 15 reported organic lesion detection rates, and six and five analysed the predictive values of alarm features and ages respectively. The overall malignancy detection rate was 1.3% (95% CI: 0.80-2.10). Among cancer patients, 17.8% (95% CI: 10.90-29.00) were younger than 45 years and 3.0% (95% CI: 2.50-3.50) were younger than 35 years. The diagnostic accuracy of alarm features for predicting malignancy was moderate (DOR: 4.87, 95% CI: 2.72-8.71; AUC = 0.74). The diagnostic accuracy at age >35 years (DOR: 9.41, 95% CI: 7.89-11.21; AUC = 0.82) was better than that at age >45 years (DOR: 3.50, 95% CI: 2.32-5.27; AUC = 0.70). CONCLUSIONS: The malignancy detection rate and proportion of young cancer patients were high among Asian dyspepsia patients. Alarm features and age were of limited value for predicting malignancy, and prompt endoscopy should be considered as the initial strategy for dyspepsia in Asian populations. The optimal age threshold for endoscopy screening in Asia might be 35 years.

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.

Systematic review: worldwide variation in the frequency of coeliac disease and changes over time.

BACKGROUND: Coeliac disease (CD), originally thought to be largely confined to Northern Europe and Australasia and uncommon in North America and the Middle East, is now recognised to be equally common in all these countries. It is still thought to be rare in the Orient and Sub-Saharan Africa. AIM: To assess geographical differences and time trends in the frequency of CD. METHODS: Medline and Embase searches were conducted on 10 November 2012, from 1946 and 1980 respectively, using the key words: coeliac disease or celiac disease + prevalence or incidence or frequency. RESULTS: There were significant intra- and inter-country differences in the prevalence and incidence of CD. Only 24 ethnic Chinese and Japanese patients have been reported in the English literature. Of CD-associated HLA DQ antigens, DQ2 occurs in 5-10% of Chinese and sub-Saharan Africans, compared to 5-20% in Western Europe. DQ8 occurs in 5-10% of English, Tunisians and Iranians, but in <5% of Eastern Europeans, Americans and Asians. The prevalence and incidence of both clinically and serologically diagnosed CD increased in recent years. These geographical and temporal differences seem genuine, although variable indices of suspicion and availability of diagnostic facilities are confounding factors. CONCLUSIONS: Coeliac disease is increasing in frequency, with significant geographical differences. Although few cases have been described to date in the Orient and Sub-Saharan Africa, there is a significant prevalence of HLA DQ2 and wheat consumption is of the same order as that in Western Europe. CD may therefore become more common in the future in these countries.

Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study.

BACKGROUND: Melatonin is involved in the regulation of gastrointestinal motility and sensation. AIM: To determine the potential therapeutic effects of melatonin in irritable bowel syndrome (IBS). METHOD: Seventeen female patients satisfying the Rome II criteria for IBS were randomized to receive either melatonin 3 mg nocte or identically appearing placebo 1 nocte for 8 weeks, followed by a 4-week washout period and placebo or melatonin in the reverse order for another 8 weeks. Three validated questionnaires - the GI symptom, the sleep questionnaires and the Hospital Anxiety and Depression Scale - were used to assess symptom severity and to compute the IBS, sleep and anxiety/depression scores, respectively. RESULTS: Improvements in mean IBS scores were significantly greater after treatment with melatonin (3.9 +/- 2.6) than with placebo (1.3 +/- 4.0, P = 0.037). Percent response rate, defined as percentage of subjects achieving mild-to-excellent improvement in IBS symptoms, was also greater in the melatonin-treated arm (88% vs. 47%, P = 0.04). The changes in mean sleep, anxiety, and depression scores were similar with either melatonin or placebo treatment. CONCLUSIONS: Melatonin is a promising therapeutic agent for IBS. Its therapeutic effect is independent of its effects on sleep, anxiety or depression.

Melatonin attenuates stress-induced defecation: lesson from a rat model of stress-induced gut dysfunction.

Melatonin is known to alleviate stress and modulate gut motility. We investigated the modulating effects of melatonin on stress-induced gut dysfunction. One hundred Wistar rats were randomly assigned to five equal groups, receiving intraperitoneal injections of 0, 1, 10, 100 or 1000 microg kg(-1) melatonin, respectively. Fifteen minutes later, each group was divided again into four subgroups receiving no treatment, 0.25 mg luzindole (a non-selective melatonin receptor antagonist) intraperitoneally, wrap-restraint stress, and 10 mg kg(-1) serotonin intraperitoneally, respectively. Two hours later, serum serotonin, corticotropin-releasing factor (CRF) and melatonin levels, and faecal output were recorded. Results showed that intraperitoneal melatonin increased faecal output, but this effect was abolished by luzindole. In wrap-restraint group, prior intraperitoneal melatonin at doses of 100 or 1000 microg kg(-1) significantly inhibited stress-induced defecation. This effect was associated with corresponding reductions in serum serotonin and CRF concentrations. In serotonin-treated group, serotonin-induced defecation was also inhibited by melatonin. In conclusion, melatonin exhibited an excitatory effect on bowel output in rats placed under resting state, while attenuated defecation in those subjected to wrap-restraint stress or serotonin treatment. The inhibitory effects of melatonin on stress-induced defecation may stem from its antagonistic effect on stress-induced enhancement of serotonin and CRF secretion.

Empirical treatment for the management of patients presenting with uninvestigated reflux symptoms: a prospective study in an Asian primary care population.

BACKGROUND: Data on Asian patients who present with reflux symptoms to their primary care physicians are limited. AIM: To determine whether empirical therapy without endoscopy is appropriate for patients who present to their primary care physicians with uninvestigated reflux symptoms without alarm symptoms. METHOD: Forty-seven patients presenting with uninvestigated, dominant reflux symptoms but without alarm features to their primary care physicians underwent endoscopy within 2 weeks of referral. Their endoscopic findings were compared with those of 162 primary care patients presenting with uninvestigated dominant dyspepsia. All patients, except those with ulcers, were treated with esomeprazole 20 mg b.d. for 2 weeks. Their treatment response was assessed at 2 weeks using a symptom score. RESULTS: Among patients with dominant reflux symptoms, 14 (30%) had erosive oesophagitis. No other clinically significant endoscopic findings were detected among them. In contrast, erosive oesophagitis and peptic ulcer were found in 13 (8%, P < 0.001 vs. reflux group), and 12 (7%, P = 0.06 vs. reflux group), respectively, of patients with dominant dyspepsia. Thirty-seven of forty-five (82%) of those with dominant reflux symptoms and 109 of 139 (78%; P = N.S. vs. reflux group) of those with dominant dyspepsia reported > or = 50% resolution of symptoms after esomeprazole treatment. CONCLUSIONS: Empirical proton pump inhibitor without endoscopy is reasonable for uninvestigated patients who present to primary care physicians with dominant reflux symptoms.

Irritable bowel syndrome in developing countries--a disorder of civilization or colonization?

While irritable bowel syndrome (IBS) is common in the West, early studies suggest that the prevalence is low in developing countries. However, recent studies point to increasing prevalence in newly developed Asian economies. The presentation appears to differ from the West, with a lack of female predominance, a greater frequency of upper abdominal pain and defecatory symptoms perceived as being less bothersome. This difference, together with the preoccupation with organic disease, could explain why we may be missing IBS in Asia and also why excess surgery has been observed in some Asian countries. While a recent study from China, consistent with western studies, support an important role for infection and inflammation, early studies from India reporting no association between amoebic infection and IBS appear to dispute this observation. To reconcile these seemingly contradictory observations, an hygiene hypothesis model is proposed. Exposure to a variety of microorganisms early in life could result in the colonization of the intestine with microflora that can respond more efficiently to an episode of gastroenteritis. Together with the changes with evolution of Asian economies such as westernization of the diet and increased psychosocial stress, it is proposed that loss of this internal protective effect, could give rise to a more uniform worldwide prevalence of IBS.

Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study.

BACKGROUND AND AIMS: Melatonin, a sleep promoting agent, is involved in the regulation of gastrointestinal motility and sensation. We aimed to determine if melatonin was effective in improving bowel symptoms and sleep disturbances in irritable bowel syndrome (IBS) patients with sleep disturbance. METHODS: Forty IBS patients (aged 20-64 years; 24 female) with sleep disturbances were randomly assigned to receive either melatonin 3 mg (n = 20) or matching placebo (n = 20) at bedtime for two weeks. Immediately before and after the treatment, subjects completed bowel, sleep, and psychological questionnaires, and underwent rectal manometry and overnight polysomnography. RESULTS: Compared with placebo, melatonin taken for two weeks significantly decreased mean abdominal pain score (2.35 v 0.70; p<0.001) and increased mean rectal pain threshold (8.9 v -1.2 mm Hg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not significantly differ after treatment in both groups. Data from sleep questionnaires and polysomnography showed that the two week course of melatonin did not influence sleep parameters, including total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stages 1-4, rapid eye movement (REM) sleep, and REM onset latency. CONCLUSIONS: Administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles.

An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome.

BACKGROUND: Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western populations. However, little information is available regarding the use of tegaserod in the Asia-Pacific population. AIMS: To evaluate the efficacy, safety, and tolerability of tegaserod versus placebo in patients with IBS from the Asia-Pacific region. PATIENTS: A total of 520 patients from the Asia-Pacific region with IBS, excluding those with diarrhoea predominant IBS. METHODS: Patients were randomised to receive either tegaserod 6 mg twice daily (n=259) or placebo (n=261) for a 12 week treatment period. The primary efficacy variable (over weeks 1-4) was the response to the question: "Over the past week do you consider that you have had satisfactory relief from your IBS symptoms?" Secondary efficacy variables assessed overall satisfactory relief over 12 weeks and individual symptoms of IBS. RESULTS: The mean proportion of patients with overall satisfactory relief was greater in the tegaserod group than in the placebo group over weeks 1-4 (56% v 35%, respectively; p<0.0001) and weeks 1-12 (62% v 44%, respectively; p<0.0001). A clinically relevant effect was observed as early as week 1 and was maintained throughout the treatment period. Reductions in the number of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements, and hard/lumpy stools were greater in the tegaserod group compared with the placebo group. Headache was the most commonly reported adverse event (12.0% tegaserod v 11.1% placebo). Diarrhoea led to discontinuation in 2.3% of tegaserod patients. Serious adverse events were infrequent (1.5% tegaserod v 3.4% placebo). CONCLUSIONS: Tegaserod 6 mg twice daily is an effective, safe, and well tolerated treatment for patients in the Asia-Pacific region suffering from IBS and whose main bowel symptom is not diarrhoea.

Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome.

BACKGROUND AND AIMS: Chronic bowel disturbances resembling irritable bowel syndrome (IBS) develop in approximately 25% of patients after an episode of infectious diarrhoea. Although we have previously shown that psychosocial factors operating at the time of, or prior to, the acute illness appear to predict the development of post-infectious IBS (PI-IBS), our finding of an increased inflammatory cell number in the rectum persisting for at least three months after the acute infection suggested that there is also an organic component involved in the development of PI-IBS. To evaluate this further, we measured expressions of interleukin 1beta (IL-1beta) and its receptor antagonist (IL-1ra) in these patients to provide additional evidence that the pathogenesis of PI-IBS is underpinned by an inflammatory process. METHODS: Sequential rectal biopsy samples were prospectively obtained during and three months after acute gastroenteritis, from eight patients who developed post-infectious IBS (INF-IBS) and seven patients who returned to normal bowel habits after acute gastroenteritis (infection controls, INF-CON). Eighteen healthy volunteers who had not suffered from gastroenteritis in the preceding two years served as normal controls (NOR-CON). IL-1beta and IL-1ra gene expressions were assayed by reverse transcriptase-polymerase chain reaction, and their levels of expression were quantitated by optical densitometry after electrophoresis on agarose gel. RESULTS: INF-IBS patients exhibited significantly greater expression of IL-1beta mRNA in rectal biopsies than INF-CON patients both during and three months after acute gastroenteritis. Moreover, IL-1beta mRNA expression had increased in biopsies taken from INF-IBS patients at three months after the acute infection but no consistent change was observed in INF-CON patients. IL-1beta mRNA expression of INF-IBS patients at three months post gastroenteritis was significantly greater than NOR-CON whereas that of INF-CON patients was not significantly different from NOR-CON. Despite these differential changes in IL-1beta mRNA expression, no significant changes were observed in IL-1ra mRNA expression among the three groups. CONCLUSIONS: These findings indicate that those patients who develop IBS post infection exhibit greater IL-1beta mRNA expression, both during and after the infection, compared with individuals who do not develop PI-IBS. We conclude that such patients may be susceptible to inflammatory stimuli, and that inflammation may play a role in the pathogenesis of PI-IBS.

The role of psychological and biological factors in postinfective gut dysfunction.

BACKGROUND: Both psychological and physiological disturbances have been implicated in the aetiopathogenesis of irritable bowel syndrome (IBS). AIMS: To investigate how the psychological factors act, and the involvement of infective and physiological factors. METHODS: Consecutive patients hospitalised for gastroenteritis reported life events for the previous 12 months, and past illness experiences on standardised questionnaires. They also completed psychometric questionnaires for anxiety, neuroticism, somatisation, and hypochondriasis. In some patients, rectal biopsy specimens were obtained during the acute illness and at three months postinfection. RESULTS: Ninety four patients completed all questionnaires: 22 patients were diagnosed with IBS after their gastroenteritis (IBS+), and 72 patients returned to normal bowel habits (IBS-). IBS+ patients reported more life events and had higher hypochondriasis scores than IBS- patients. The predictive value of the life event and hypochondriasis measures was highly significant and independent of anxiety, neuroticism, and somatisation scores, which were also elevated in IBS+ patients. Rectal biopsy specimens from 29 patients showed a chronic inflammatory response in both IBS+ and IBS- patients. Three months later, specimens from IBS+ patients continued to show increased chronic inflammatory cell counts but those from IBS- patients had returned to normal levels. IBS+ and IBS- patients exhibited rectal hypersensitivity and hyper-reactivity and rapid colonic transit compared with normal controls, but there were no significant differences between IBS+ and IBS- patients for these physiological measurements. CONCLUSION: Psychological factors most clearly predict the development of IBS symptoms after gastroenteritis but biological mechanisms also contribute towards the expression of symptoms.

Validation of [13C]urea breath test for Helicobacter pylori using a simple gas chromatograph-mass selective detector.

OBJECTIVE: Isotope ratio mass spectrometry (IRMS) is the accepted method for accurately measuring the 13CO2:12CO2 ratio in the non-invasive and non-radioactive [13C]urea breath test (13C-UBT) for Helicobactor pylori. The IRMS instrument, an expensive and highly specialized analyser, is rarely available. The objective of this project was to modify and validate the use of a simple bench-top gas chromatograph-mass selective detector (GC-MSD) for 13C-UBT. METHODS: Breath samples from 71 patients were taken at baseline and 30 min after ingestion of 100 mg [13C]urea. The breath samples were analysed using GC-MSD in the selected ion monitoring mode. The reference 13CO2:12CO2 ratio was from NBS19 obtained from the US National Institute of Standards and Technology. 13CO2:12CO2 ratios of the breath samples were determined. Excess delta per thousand (per mil, delta/thousand) of the 30 min sample over the baseline (deltadelta/thousand) of > or = 6deltadelta/thousand was considered H. pylori positive. Results from 13C-UBT and histology determined blind to each other were compared. RESULTS: The coefficient of variation of the reference 13CO2:12CO2 ratio was 0.06%. Using histology as the 'gold standard', the sensitivity (97.9%) and specificity (95.8%) of the GC-MSD 13C-UBT were comparable to those of other methods of H. pylori diagnosis. CONCLUSION: A gas chromatograph coupled to a mass selective detector that is available in many analytical and biomedical laboratories can be used for the 13C-UBT. This method will increase the availability and reduce the cost of this non-invasive, non-radioactive diagnostic test.

Effect of cisapride on functional dyspepsia in patients with and without histological gastritis: a double-blind placebo-controlled trial.

In the present double-blind placebo-controlled study the effect of cisapride on functional dyspepsia was evaluated in patients with and without histological gastritis. Patients with functional dyspepsia and whose symptoms persisted after a 2 week run-in period with antacid treatment were randomized to receive cisapride (10 mg) or matching placebo three times daily for 4 weeks. Symptoms of epigastric pain, bloating, nausea, belching, early satiety and heartburn were graded on a four-point scale based on patients' feedback and diary card recording. A global response was also formulated by the investigators. One hundred and four patients entered the study and 76 completed the trial, comprising 36 patients with histological gastritis and 40 patients without gastritis. Symptom scores in both gastritis and non-gastritis groups were significantly improved by both cisapride and placebo; however, the improvement was not statistically different between the two treatment groups. Cisapride produced a good or better global response in 58% of subjects with histological gastritis and in 53% of subjects without gastritis compared with 47% and 52%, respectively, of patients on placebo; this difference was not statistically significant. Gastric histology did not influence the effect of cisapride on the symptoms of functional dyspepsia.

Psychometric scores and persistence of irritable bowel after infectious diarrhoea.

BACKGROUND: Although previous studies have shown that psychological disturbances are frequently associated with the irritable bowel syndrome (IBS), the relation was not necessarily cause and effect. The development of chronic bowel symptoms resembling IBS after an episode of acute gastroenteritis has allowed us to examine prospectively the role of psychological factors. METHODS: 75 patients with acute gastroenteritis completed a series of psychometric tests soon after admission to hospital. Of these, 22 had persistent symptoms compatible with IBS after the acute illness, and in 20 of these the symptoms were still present at six months. FINDINGS: At the time of their initial illness, patients who subsequently developed IBS symptoms had higher scores for anxiety, depression, somatisation, and neurotic trait than those who returned to normal bowel function. The psychometric scores had not changed when remeasured three months after the acute illness. Lactose malabsorption was not an important factor. INTERPRETATION: These results support the hypothesis that psychological factors are important in IBS.

The effect of polyunsaturated phosphatidyl choline in the treatment of acute viral hepatitis.

BACKGROUND: Polyunsaturated phosphatidyl choline is a preparation often advocated for diseases of the liver. METHODS: In a randomized open controlled trial, a preparation of polyunsaturated phosphatidyl choline, at a dose of 900 mg orally daily, was given to 22 patients with acute viral hepatitis. A control group of 25 patients was not treated. RESULTS: Serial serum bilirubin and alanine amino transferase levels were measured up to 12 weeks. The falls in their levels after 2 and 5 weeks, and the lengths of time to their normalization, were not significantly different in the treated group compared to the control group. CONCLUSION: The results indicated that polyunsaturated phosphatidyl choline had no beneficial effect on the course of acute viral hepatitis.