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Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum., Competing Interests: Competing interests: NT: Consultancy: Allergan, IM Health Sciences, Takeda, Theravance, Danone, Sanofi. JT: Consultancy: AlfaWassermann, Allergan, Danone, Shire, Takeda, Theravance, Tsumura and Zeria Pharmaceuticals; Speaker fees: Abbott, Allergan, Shire, Takeda and Zeria Pharmaceuticals. TV: Speaker fees: Abbott. Research Grant: Danone., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: MMW: grant/research support: Prometheus Laboratories Inc (Irritable bowel syndrome (IBS Diagnostic), Commonwealth Diagnostics International (Biomarkers for FGIDs). SK: grant/research support: Cancer Institute NSW (Career Development Fellowship), National Health and Medical Research Council (Project Grant APP1128487) Commonwealth Diagnostics International (Biomarkers for FGIDs), Syntrix Biosystems (contract research, drug delivery). NJT: grant/research support: Rome Foundation; Abbott Pharmaceuticals; Datapharm; Pfizer; Salix (Irritable bowel syndrome); Prometheus Laboratories Inc (Irritable bowel syndrome (IBS Diagnostic)); Commonwealth Diagnostics International (Biomarkers for FGIDs); Janssen (Constipation). Consultant/Advisory Boards: Adelphi Values (Functional dyspepsia (patient-reported outcome measures)); GI therapies (Chronic constipation (Rhythm IC)); Allergens PLC; Napo Pharmaceutical; Outpost Medicine; Samsung Bioepis; Yuhan (IBS); Synergy (IBS); Theravance (Gastroparesis); IM Health Sciences (dyspepsia). Patent Holder: Biomarkers of irritable bowel syndrome, Licensing Questionnaires (Mayo Clinic Talley Bowel Disease Questionnaire, Mayo Dysphagia Questionnaire); Nestec European Patent (Application No. 12735358.9); Singapore ‘Provisional’ Patent (NTU Ref: TD/129/17 ‘Microbiota Modulation of BDNF Tissue Repair Pathway’).

Background and Objective: Whether there is distinct pathogenesis in subgroups of functional dyspepsia (FD), the postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) remains controversial. We aimed to identify the risk factors of FD and its subgroups in the Chinese population., Methods: Patients with dyspepsia and healthy subjects who underwent gastric cancer screening were enrolled in this multicentre study from 2010 to 2012. All patients were evaluated by questionnaire, oesophagoduodenoscopy, histological examination and Helicobacter pylori tests. Subgroups of FD were classified according to the Rome III criteria. Psychiatric stress was assessed by the short form Brief Symptom Rating Scale. CagA and VacA genotypes were determined by PCR., Results: Of 2378 patients screened for eligibility, 771 and 491 fulfilled the diagnostic criteria of uninvestigated dyspepsia and FD, respectively. 298 (60.7%) and 353 (71.9%) individuals were diagnosed with EPS and PDS, respectively, whereas 169 (34.4%) had the overlap syndrome. As compared with 1031 healthy controls, PDS and EPS shared some common risk factors, including younger age (OR 0.95; 99.5% CI 0.93 to 0.98), non-steroidal anti-inflammatory drugs (OR 6.60; 99.5% CI 3.13 to 13.90), anxiety (OR 3.41; 99.5% CI 2.01 to 5.77) and concomitant IBS (OR 6.89; 99.5% CI 3.41 to 13.94). By contrast, H. pylori (OR 1.86; 99.5% CI 1.01 to 3.45), unmarried status (OR 4.22; 99.5% CI 2.02 to 8.81), sleep disturbance (OR 2.56; 99.5% CI 1.29 to 5.07) and depression (OR 2.34; 99.5% CI 1.04 to 5.36) were associated with PDS. Moderate to severe antral atrophy and CagA positive strains were also more prevalent in PDS., Conclusions: Different risk factors exist among FD subgroups based on the Rome III criteria, indicating distinct aetiopathogenesis of the subdivisions that may necessitate different therapeutic strategies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Approximately 30% of patients with gastro-oesophageal reflux disease (GORD) do not achieve adequate symptom control with proton pump inhibitors (PPIs). The aim of this study was to determine whether any symptom profile or reflux pattern was associated with refractoriness to PPI therapy., Design: Patients with typical GORD symptoms (heartburn and/or regurgitation) were included and had 24 h pH-impedance monitoring off therapy. Patients were considered to be responders if they had fewer than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for at least 4 weeks. Both clinical and reflux parameters were taken into account for multivariate analysis (logistic regression)., Results: One hundred patients were included (median age 50 years, 42 male), 43 responders and 57 non-responders. Overall, multivariate analysis showed that the factors associated with the absence of response were absence of oesophagitis (p=0.050), body mass index (BMI) ≤25 kg/m(2) (p=0.002) and functional dyspepsia (FD) (p=0.001). In patients who reported symptoms during the recording (n=85), the factors associated with PPI failure were BMI ≤25 kg/m(2) (p=0.004), FD (p=0.009) and irritable bowel syndrome (p=0.045). In patients with documented GORD (n=67), the factors associated with PPI failure were absence of oesophagitis (p=0.040), FD (p=0.003), irritable bowel syndrome (p=0.012) and BMI ≤25 kg/m(2) (p=0.029)., Conclusion: No reflux pattern demonstrated by 24 h pH-impedance monitoring is associated with response to PPIs in patients with GORD symptoms. In contrast, absence of oesophagitis, presence of functional digestive disorders and BMI ≤25 kg/m(2) are strongly associated with PPI failure.

Introduction: The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology., Methods: (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied., Results: (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p<0.001) and supine (R=0.40, p<0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p<0.001; expiration: R=0.78, p<0.001) and inspiratory GOPG (R=0.50, p<0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=-0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP., Conclusion: The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.

Objectives: In most patients undergoing endoscopy for upper gastrointestinal (GI) symptoms in the Western world, no macroscopic abnormality or evidence of Helicobacter pylori infection is identified. Following this negative investigation, proton pump inhibitor (PPI) therapy is usually prescribed. The aim of this study was to assess the value of such treatment compared with placebo and to identify predictors of response., Design: Prospective parallel randomised study., Setting: Dyspepsia Research Clinic., Participant: 105 patients (49 men, median age 44 years, IQR 22) with normal endoscopy and H pylori negative with ongoing upper GI symptoms following 2-week run-in period. Intervention Full demographic symptom severity and characteristics were assessed and 24 h oesophageal pH metry and oesophageal manometry were performed prior to randomisation to 2 weeks of treatment with lansoprazole 30 mg/day or placebo (2:1), with reassessment of symptom severity during the second week of treatment., Primary Outcome: 50% reduction in Glasgow Dyspepsia Severity Score (GDSS)., Results: According to intention to treat analysis, the response was 35.7% for the active group and 5.7% for the placebo group (p < 0001). The only non-invasive independent predictor of response to PPI in multivariable analysis was the patient's body mass index (BMI) (p = 0.003). The association of BMI with response to PPI was apparent across the full range of quartiles (p values for trend=0.01). BMI had a similar predictive value to either 24 h oesophageal pH metry or manometry. Predominant symptom and symptom subgroups were unhelpful in predicting the response to PPI. Including all pretreatment assessments, only BMI (p < 0.05) and lower oesophageal sphincter pressure (p < 0.05) were independent predictors of response., Conclusion: The response to PPI therapy is likely to be related to underlying acid reflux. The strong predictive value of BMI is probably due to its association with underlying reflux disease and the fact that it is a more objective and reproducible measure than symptom characteristics. It is recommended that BMI should be measured in patients with upper GI symptoms. Trial Registration Number ISRCTN 32863375.

Objective: Patients with dyspepsia with alarm features are suspected of having upper gastrointestinal (GI) malignancy; however, the true value of alarm features in predicting an underlying malignancy for patients with dyspepsia with high background prevalence of Helicobacter pylori infection and upper GI malignancy is uncertain. The aim of the present study was to determine the diagnostic accuracy of alarm features in predicting upper GI malignancy by reviewing an endoscopic database consisting of >100,000 Chinese patients., Methods: A retrospective analysis of prospectively collected data was conducted in a single tertiary medical centre. Consecutive patients who underwent oesophagogastroduodenoscopy (OGD) for dyspepsia in 1996-2006 were enrolled. The data including gender, age, symptoms, and endoscopic and pathological findings were analysed. The main outcome measure was the diagnostic accuracy of individual alarm feature., Results: 102,665 patients were included in the final analysis. Among all the 4362 patients with malignancy, 52% (2258/4362) had alarm features. Among 15 235 patients who had alarm features, 2258 (14.8%) were found to have upper GI malignancy. The pooled sensitivity and specificity of the alarm features were 13.4% and 96.6%, respectively. Only the feature of dysphagia in patients between 36 and 74 years old had a positive likelihood ratio (PLR) >10 for malignancy prediction, while all other alarm features in other age groups had a PLR <10., Conclusions: For uninvestigated Chinese patients with dyspepsia with high background prevalence of H pylori infection and upper GI malignancy, alarm features and age, except for dysphagia in patients between 36 and 74 years old, had limited predictive value for a potential malignancy; therefore, prompt endoscopy may be recommended for these patients. However, less invasive, inexpensive screening methods with high diagnostic yield are still needed to reduce unnecessary endoscopy workload.

Background: Gastric sensorimotor dysfunction, psychosocial factors and somatisation are all implicated in symptom generation in functional dyspepsia (FD)., Aim: To determine the relative contribution of each of these factors to overall dyspeptic symptom severity and weight loss in FD., Methods: In 201 consecutive tertiary care patients with FD (mean age 40.1 (SD 12.6) years), gastric sensorimotor function was studied using barostat (sensitivity, compliance and accommodation). Psychosocial factors (depression and anxiety disorders, positive and negative affect, perceived stress, alexithymia and history of abuse), somatisation and co-morbid irritable bowel syndrome (IBS) and chronic fatigue symptoms were assessed using self-report questionnaires. Variables were correlated with dyspepsia symptom severity (DSS) and weight loss. Hierarchical multiple linear regression was used to identify determinants of DSS and weight loss., Results: Multiple linear regression identified the following determinants of DSS: gastric sensitivity (beta = 0.77, p = 0.25), depression (beta = 0.12, p = 0.06) and somatisation (beta = 0.48, p<0.0001) (controlling for age and occupation, R(2) = 0.29, p<0.0001). The effect of depression on DSS is partially mediated by somatisation. Gastric sensitivity (beta = 2.87, p = 0.08), history of childhood sexual abuse (beta = 9.37, p = 0.0006), depression (beta = 0.19, p = 0.24) and somatisation (beta = 0.67, p = 0.01) are independent determinants of weight loss (controlling for gender and occupation, R(2) = 0.42, p<0.0001). The effect of depression on weight loss is fully mediated by somatisation., Conclusion: Symptom severity and weight loss in FD are determined by psychosocial factors (depression, abuse history) and somatisation, and only to a lesser extent by gastric sensorimotor function. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients.

Objective: To compare a Helicobacter pylori "test and treat" strategy with prompt endoscopy in young Asians with dyspepsia., Methods: A randomised, prospective study was carried out on uninvestigated dyspeptics aged <45 years in a single (academic) primary care centre. Patients were randomised to either a [(13)C]urea breath test (UBT) or prompt endoscopy (oesophagogastroduodenoscopy (OGD) and followed-up for 12 months., Results: 432 patients (mean (SD) age 30 (8) years, male 46%, ethnicity: Malays 33.3%, Chinese 30.6%, Indians 34.7%) were randomised to UBT (n = 222) or OGD (n = 210). 387 (89.6%) patients completed the study. At 12 months, there was no difference in symptom change (measured by the Leeds Dyspepsia Questionnaire) between the two groups, but more patients were very satisfied (40.0% vs 21.6%, p<0.0001) in the OGD group. More additional endoscopy was performed in the UBT group (25 vs 10, p = 0.03), but medication consumption was higher in the OGD group (proton pump inhibitor 3.6 (8.8) vs 2.0 (7.5) weeks, p<0.001; H2 receptor antagonist 5.3 (9.7) vs 3.9 (9.2) weeks, p = 0.017; prokinetics 1.4 (4.7) vs 0.4 (2.5) weeks, p<0.001) and no differences in medical consultation were noted. The median cost of the initial prompt endoscopy approach at 12 months was significantly higher than a "test and treat" strategy (US$179.05 vs US$87.10, p<0.0001)., Conclusion: A H. pylori "test and treat" strategy is more cost-effective but less satisfying than prompt endoscopy in the management of young Asian patients with uncomplicated dyspepsia.

Background: Eosinophilic oesophagitis may be increasing but the prevalence in the general population remains unknown. Our aim was to assess this and the presence of eosinophils in the distal oesophageal epithelium in the community., Methods: Oesophagogastroduodenoscopy was performed in a random sample (n = 1000) of the adult Swedish population (mean age 54 years, 49% men). Oesophageal biopsy samples were obtained from 2 cm above, and at, the Z-line. Any eosinophil infiltration of the epithelium was defined as "eosinophils present". Definite eosinophilic oesophagitis was defined as > or =20, probable as 15-19, and possible as 5-14 eosinophils/high-power field (HPF, at magnification x 40) in oesophageal biopsy specimens., Results: Eosinophils were present in 48 subjects (4.8%, 95% CI 3.5 to 6.1%, mean age 54 years, 63% men), in 54% without troublesome reflux symptoms. Definite eosinophilic oesophagitis was present in four subjects (0.4%, 95% CI 0.01 to 0.8%, mean age 51 years, 75% men) and probable eosinophilic oesophagitis in seven subjects (0.7%, 95% CI 0.2 to 1.2%, mean age 58 years, 43% men). Erosive oesophagitis (OR = 2.99, 95% CI 1.58 to 5.66) and absence of dyspepsia (OR = 0.23, 95% CI 0.07 to 0.75) and Helicobacter pylori infection (OR = 0.41, 95% CI 0.19 to 0.92) were independent predictors for "eosinophils present". Definite eosinophilic oesophagitis was associated with dysphagia (2/66 vs 2/926, p = 0.025), and probable eosinophilic oesophagitis with narrowing of the oesophageal lumen (2/15 vs 5/978, p = 0.005)., Conclusions: Oesophageal eosinophils were present in nearly 5% of the general population; approximately 1% had definite or probable eosinophilic oesophagitis. Oesophageal eosinophils may be a manifestation of reflux disease in adults, but the condition is as likely to be asymptomatic and go unrecognised.

Background: Numerous studies examining the prevalence and natural history of dyspepsia in the general population have been conducted. However, few have reported the effect of quality of life on the development of dyspepsia. A 10-year longitudinal follow-up study examining the effect of quality of life on subsequent dyspepsia was performed., Methods: Individuals originally enrolled in a population-screening programme for Helicobacter pylori were contacted through a validated postal dyspepsia questionnaire. Baseline demographic data, quality of life at original study entry, and dyspepsia and irritable bowel syndrome (IBS) symptom data were already on file. Consent to examine primary-care records was sought, and data regarding non-steroidal anti-inflammatory drugs (NSAID) and aspirin use were obtained from these., Results: Of 8407 individuals originally involved, 3912 (46.5%) provided symptom data at baseline and 10-year follow-up. Of 2550 (65%) individuals asymptomatic at study entry, 717 (28%) developed new-onset dyspepsia at 10 years, an incidence of 2.8% per year. After multivariate logistic regression, lower quality of life at study entry (OR 2.63; 99% CI 1.86 to 3.71), higher body mass index (OR per unit 1.05; 99% CI 1.02 to 1.08), presence of IBS at study entry (OR 3.1; 99% CI 1.51 to 6.37) and use of NSAIDs and/or aspirin (OR 1.32; 99% CI 0.99 to 1.75) were significant risk factors for new-onset dyspepsia., Conclusions: The incidence of new-onset dyspepsia was almost 3% per year. Low quality of life at baseline exerted a strong effect on the likelihood of developing dyspepsia at 10 years.

The accommodation reflex is an important mechanism of normal gastric physiology. In functional dyspepsia, impairment of accommodation has been found in 40% of cases, but it has been described in several other upper gastrointestinal disorders, such as diabetic gastropathy and postfundoplication syndrome. This review focuses on the pathways involved in the normal accommodation reflex, the relevance of impaired gastric accommodation as a cause of morbidity and the methods used to assess gastric accommodation in humans. The available medical and therapeutic strategies based on the actual knowledge of the physiology and pharmacology of the accommodation reflex are outlined, with a focus on the role of nitrergic neurones and serotonergic receptors.

Background and Aims: Patients with functional dyspepsia who have hypersensitivity to gastric distension have more prevalent pain, suggesting the presence of hyperalgesia. It is unclear whether this reflects activation of pain specific afferent pathways or multimodal afferent pathways that also mediate non-painful sensations. In the former case, hyperalgesia should occur when intensity of non-painful sensations is still low. The aim of the study was to analyse whether the symptom profile during gastric dissentions in functional dyspepsia patients with hyperalgesia reflects sensitisation of pain specific or multimodal pathways., Methods: Forty eight consecutive dyspeptic patients (35 female) underwent gastric sensitivity testing with a barostat balloon using a double random staircase protocol. At the end of every distending step, patients scored perception of upper abdominal sensations on a graphic 0-6 rating scale and completed visual analogue scales (VAS 0-100 mm) for pain, nausea, satiety, and fullness. The end point was a rating scale of 5 or more., Results: Hypersensitivity was present in 20 patients (40%); gastric compliance did not differ between normo- and hypersensitive patients. At maximal distension (score 5 or more), hypersensitive patients had significantly lower distending pressures and intra-balloon volumes, but similar VAS scores for pain, nausea, satiety, and fullness compared with normosensitive patients. In both normosensitive and hypersensitive patients, elevation of pain VAS scores with increasing distending pressures paralleled the elevation in VAS scores for nausea, satiety, and fullness., Conclusions: Hypersensitive dyspeptic patients reach the same intensity of painful and non-painful sensations as normosensitive patients but at lower distending pressures. Hyperalgesia occurs in hypersensitive dyspeptic patients at distending pressures that also induce intense non-painful sensations. These findings argue against isolated upregulation of pain specific afferents in functional dyspepsia patients with visceral hypersensitivity.

Aims: (i) To determine the value of individual alarm features for predicting cancer in subjects referred to a rapid access upper gastrointestinal cancer service; and (ii) to develop a clinical prediction model for cancer and to prospectively validate this model in a further patient cohort., Methods: Patient demographics, referral indications, and subsequent diagnosis were recorded prospectively. Logistic regression analyses were employed to determine the predictive value of individual alarm features in an evaluation cohort of 1852 consecutive cases. The potential impact of applying a modified set of referral criteria was then examined in a validation cohort of 1785 patients., Results: Evaluation cohort: mean age was 59 years; cancer prevalence 3.8%; and serious benign pathology 12.8%. Dysphagia (odds ratio (OR) 3.1), weight loss (OR 2.6), and age >55 years (OR 9.5) were found to be significant predictive factors for cancer but the value of other accepted alarm features was more limited. In particular, uncomplicated dyspepsia in those over 55 years was a negative predictive factor for cancer within this high risk cohort (OR 0.1). Validation cohort: the clinical prediction model would have selected 92% of cancer patients for fast track investigation while reducing the "two week rule" workload by 572 cases (31%)., Conclusions: Fast track endoscopy in subjects fulfilling current criteria for suspected upper gastrointestinal malignancy results in a significant yield of cancer ( approximately 4%) and serious benign diseases such as peptic ulceration, strictures, and severe oesophagitis (13%). However, the predictive value of individual features for cancer varies widely. Uncomplicated dyspepsia in older subjects was a poor predictor of cancer. Application of narrower referral criteria for accessing fast track services may reduce pressures while retaining high sensitivity for cancer.

The main factors involved in the pathophysiology of fat induced dyspepsia were investigated by reviewing a series of controlled double blind randomised studies which sought to determine the role of nutrient fat and the postprandial release of cholecystokinin (CCK) in the development of dyspeptic symptoms in healthy volunteers and in patients with functional dyspepsia. The studies showed that during distension of the stomach, lipids are a major trigger of dyspeptic symptoms such as nausea, bloating, pain, and fullness, and that they modulate upper gastrointestinal sensations and symptoms in a dose related fashion. CCK is a major mediator of the sensitisation of gastric perception by lipids in patients with functional dyspepsia as the CCK-A receptor antagonist dexloxiglumide markedly diminishes this effect. The studies provide important insights into the mechanisms underlying gastrointestinal perception in response to fat and the role of CCK in patients with functional dyspepsia.

Functional dyspepsia is a symptom complex characterised by postprandial upper abdominal discomfort or pain, early satiety, nausea, vomiting, abdominal distension, bloating, and anorexia in the absence of organic disease. Gastrointestinal motor abnormalities, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. This perspective has now replaced the earlier view that the condition was the result of a sole motor or sensory disorder of the stomach. Future therapeutic strategies should be aimed at reducing nociception as well as enhancing the accommodation response.

Dyspepsia is a common clinical condition, and its diagnostic evaluation and treatment result in the expenditure of enormous healthcare resources each year. Studies indicate that the omeprazole test is the most sensitive and cost effective test for diagnosing gastro-oesophageal reflux disease (GORD) in patients with extra-oesophageal or more "classic" symptoms suggestive of GORD. Studies also indicate that a therapeutic trial of omeprazole in patients with dyspepsia results in greater symptom improvement and lower costs than treatment with less potent acid suppression.

The annual prevalence of dyspepsia in Western countries is approximately 25%, and the condition accounts for 2-5% of all primary care consultations, yet optimal management remains a subject of considerable debate. Some of the outstanding issues and considerations in the management of dyspepsia are discussed, providing an overview of current thinking and recommendations on patient management by primary care physicians and specialists.

Up to 40% of individuals complain of dyspepsia but only 25% of these present to their general practitioner. If symptoms have been present for a relatively short period the majority can be managed by reassurance and symptomatic treatment. Those with a longer history require empirical treatment with more powerful medication, endoscopy, testing for Helicobacter pylori, or a combination of these approaches. There is some debate about whether the treatment of Helicobacter pylori infection is an appropriate strategy for patients with dyspepsia. It is the general practitioner who determines how the uninvestigated patient with dyspepsia will be managed because those referred to hospital usually undergo endoscopy at an early stage.

Endoscopy is recommended as the first investigation in the work up of a patient with dyspeptic symptoms and is essential in the classification of the patient's condition as organic or functional dyspepsia. Although the correlation between mucosal alterations and symptom pattern is difficult, endoscopy will remain the initial investigation of choice for clinically relevant abnormalities that need proper detection and biopsy.

Introduction: Erythromycin, a motilin agonist, is a potent prokinetic. ABT-229 is a specific motilin agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying., Methods: Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C(13) octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit., Results: The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline -169, -101, -155, -143, and -138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms., Conclusions: The motilin agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying.

Introduction: Symptoms of dyspepsia are common but most patients do not have major upper gastrointestinal pathology. Endoscopy is recommended for dyspeptic patients over the age of 45, or those with certain "alarm" symptoms. We have evaluated the effectiveness of age and "alarm" symptoms for predicting major endoscopic findings in six practising endoscopy centres., Methods: Clinical variables of consecutive patients with dyspepsia symptoms undergoing upper endoscopy examinations were recorded using a common endoscopy database. Patients who had no previous upper endoscopy or barium radiography were included. Stepwise multivariate logistic regression was used to identify predictors of endoscopic findings. The accuracy of these for predicting endoscopic findings was evaluated with receiver operating characteristic analysis. The sensitivity and specificity of age thresholds from 30 to 70 years were evaluated., Results: Major pathology (tumour, ulcer, or stricture) was found at endoscopy in 787/3815 (21%) patients with dyspepsia. Age, male sex, bleeding, and anaemia were found to be significant but weak independent predictors of endoscopic findings. A multivariate prediction rule based on these factors had poor predictive accuracy (c statistic=0.62). Using a simplified prediction rule of age > or =45 years or the presence of any "alarm" symptom, sensitivity was 87% and specificity was 26%. Increasing or decreasing the age cut off did not significantly improve the predictive accuracy., Conclusions: Age and the presence of "alarm" symptoms are not effective predictors of endoscopic findings among patients with dyspepsia. Better clinical prediction strategies are needed to identify patients with significant upper gastrointestinal pathology.

Background/aims: We aimed to evaluate the role of fat and cholecystokinin (CCK) in the pathophysiology of functional dyspepsia (FD) by investigating symptoms and plasma CCK levels following increasing doses of duodenal lipid during gastric distension, and the effect of CCK-A receptor blockade., Subjects/methods: In study A, six FD patients were studied on three occasions during duodenal infusion of saline or lipid (1.1 (L-1) or 2 kcal/min (L-2)) and proximal gastric distensions. Six healthy subjects were also studied as controls during L-2 only. In study B, the effect of the CCK-A antagonist dexloxiglumide (5 mg/kg/h) on L-2 induced symptoms was studied in 12 FD patients. Changes in gastric volume at minimal distending pressure and plasma CCK (study A) were assessed, gastric distensions were performed using a barostat, and dyspeptic symptoms were monitored., Results: Lipid increased gastric volume compared with saline (DeltaV (ml): saline 15 (20), L-1 122 (42), L-2 114 (28)) in patients and even more so in controls (221 (37); p<0.05). During distensions, symptoms were greater during L-2 than during saline or L-1, and greater in patients than in controls, while gastric compliance was smaller in patients than in controls (p<0.05). Lipid increased plasma CCK levels in patients and controls (p>0.05). Dexloxiglumide abolished the increase in gastric volume (DeltaV (ml): dexloxiglumide 17 (9), placebo 186 (49)) and dyspeptic symptoms (sum of scores: dexloxiglumide 24 (7), placebo 44 (19)) during duodenal lipid infusion. Dexloxiglumide also reduced gastric compliance (ml/mm Hg: dexloxiglumide 51 (7), placebo 72 (11)) and symptoms (sum of scores: dexloxiglumide 101 (17), placebo 154 (21)) during gastric distension., Conclusion: CCK-A receptors are involved in the generation of dyspeptic symptoms by duodenal lipid during gastric distension.

Background: Abnormal visceral mechano-sensory function has been reported in 50% of non-ulcer (functional) dyspepsia patients. However, only a minority of subjects with functional dyspepsia ever seek medical attention. Whether factors promoting health care seeking behaviour explain visceral hypersensitivity is unknown. Decreased rectal thresholds following sigmoid mechanical stimulation have been observed in irritable bowel but this mechanism has not been evaluated in functional dyspepsia., Aims: To compare visceral mechanosensory function in healthy asymptomatic subjects and non-consulters with chronic unexplained dyspepsia., Methods: Forty two volunteers were recruited: 10 had a history of chronic or recurrent upper abdominal pain or discomfort as assessed by a standardised questionnaire, and Helicobacter pylori status was determined (ELISA and (13)C urea breath test). Eight H pylori negative, currently asymptomatic dyspeptic subjects who were non-consulters and eight asymptomatic age and sex matched H pylori negative controls were enrolled. With a barostat bag in the proximal part of the stomach, visceral perception thresholds were determined by random tracking. Thereafter, standardised ramp distensions were performed (2 mm Hg increments, duration of each pressure step 30 seconds, maximum pressure 35 mm Hg (or occurrence of pain)) and tracking of sensory thresholds and ramp distension repeated every 30 minutes for a total of two hours., Results: Overall, thresholds for first perception were significantly lower in dyspeptic subjects compared with asymptomatic controls (12.5 (0.6) mm Hg v 17.5 (1.0) mm Hg; p<0.02). After repeated ramp distensions, thresholds for first perception significantly increased by 3.6 (0.7) mm Hg in healthy subjects compared with 0.1 (1.4) mm Hg in subjects with dyspepsia (p<0.05 dyspeptics v controls)., Conclusions: (1) Repeated mechanical stimulation increases visceral sensory thresholds in asymptomatic subjects while thresholds remain unchanged in dyspeptics. (2) Visceral hyperalgesia occurs in dyspeptic subjects who are not health care seekers.

Background: It has been suggested that endoscopy could be replaced with non-invasive assessment of helicobacter status in the initial work up of young dyspeptic patients without sinister symptoms., Aims: To determine the incidence of gastro-oesophageal malignancy in young dyspeptic patients., Methods: The Alberta Endoscopy Project captured clinical and demographic data on all endoscopies performed from April 1993 to February 1996 at four major adult hospitals in Alberta. The endoscopic and histological diagnosis in a subgroup of patients under 45 years of age without alarm symptoms that had undergone gastroscopy was reviewed. In addition, a random list of 200 patients was generated and their medical records reviewed in order to assess the proportion with symptoms suitable for a non-invasive management strategy., Results: Gastroscopy was performed in 7004 patients under 45 years. In 3634 patients (56% female) alarm type symptoms were absent; 78.9% of patients had symptoms amenable to a non-invasive initial approach, giving a corrected sample size of 2867 patients (correction factor 0.789). Three gastric cancers, one case of moderate dysplasia, 10 biopsy proved cases of Barrett's oesophagus, and 19 oesophageal strictures/rings were detected within this sample. The corrected prevalence of gastric cancer in this select population was 1.05 per thousand patients., Discussion: Endoscopy yielded three gastric cancers in this sample of under 45 year old dyspeptic patients without sinister symptoms. While initial non-invasive screening with one-week triple therapy for helicobacter positive individuals is unlikely to have a detrimental outcome the physician is advised to consider endoscopy in patients with persisting, recurrent, or sinister symptoms.

While widely used in research, the 1991 Rome criteria for the gastroduodenal disorders, especially symptom subgroups in dyspepsia, remain contentious. After a comprehensive literature search, a consensus-based approach was applied, supplemented by input from international experts who reviewed the report. Three functional gastroduodenal disorders are defined. Functional dyspepsia is persistent or recurrent pain or discomfort centered in the upper abdomen; evidence of organic disease likely to explain the symptoms is absent, including at upper endoscopy. Discomfort refers to a subjective, negative feeling that may be characterized by or associated with a number of non-painful symptoms including upper abdominal fullness, early satiety, bloating, or nausea. A dyspepsia subgroup classification is proposed for research purposes, based on the predominant (most bothersome) symptom: (a) ulcer-like dyspepsia when pain (from mild to severe) is the predominant symptom, and (b) dysmotility-like dyspepsia when discomfort (not pain) is the predominant symptom. This classification is supported by recent evidence suggesting that predominant symptoms, but not symptom clusters, identify subgroups with distinct underlying pathophysiological disturbances and responses to treatment. Aerophagia is an unusual complaint characterized by air swallowing that is objectively observed and troublesome repetitive belching. Functional vomiting refers to frequent episodes of recurrent vomiting that is not self-induced nor medication induced, and occurs in the absence of eating disorders, major psychiatric diseases, abnormalities in the gut or central nervous system, or metabolic diseases that can explain the symptom. The current classification requires careful validation but the criteria should be of value in future research.

Background: Dyspepsia is prevalent in about 30% of the general population in Europe, but only 25% of people with complaints consult their general practitioner., Aims: To study the relation between the severity of dyspeptic complaints and the health status of patients presenting to the general practitioner; and the relation with patient characteristics, Helicobacter pylori infection, and psychological distress., Methods: A cross sectional, general practice based survey of 360 unselected primary care dyspeptic patients from 92 general practices in The Netherlands was conducted. Symptom severity was measured using a validated symptom score, H pylori using a whole blood test, and psychological distress using the GHQ-12 test. Functional health status was assessed using the COOP/Wonca charts., Results: Symptoms lasting more than three months and presence of relevant psychological distress were both associated with higher levels of dyspepsia. H pylori infection, frequency of symptoms, and age had no influence on dyspepsia severity. Severity of dyspepsia and psychological distress, but not H pylori infection or duration of symptoms, affected health status univariately. Dyspepsia correlated with general health, daily activities, and social activities. In logistic modelling, health status was far better predicted by psychological distress than by dyspepsia severity., Conclusion: The relation between dyspeptic symptom severity and health status is limited. H pylori infection relates neither to functional health status, nor to intensity of dyspepsia. Psychological distress is a major determinant of impaired health of dyspeptic patients in general practice and may be the clue to improvement of health status in many dyspeptic patients.

Aims: To test the hypothesis that gastric cancer presenting with uncomplicated dyspepsia is rare below the age of 55., Patients and Methods: The area studied was the postcode defined catchment area of a district general hospital (Gloucestershire Royal) serving a population of 280,500. An open access endoscopy service has been available in this district for more than 17 years. All cases of gastric cancer during a seven year period (1986-92) were drawn from the local pathology database. The database of the neighbouring hospital and the South West Cancer Registry were searched for missed cases from the postcoded area. Hospital and general practitioner records were retrospectively reviewed with respect to duration of symptoms, and previous consultation and investigation for dyspepsia; and alarming symptoms and signs suggestive of underlying malignancy (unexplained recent weight loss, dysphagia, haematemesis or melaena, anaemia, previous gastric surgery, palpable mass, and perforation)., Results: Twenty five of 319 cases of gastric cancer detected during the seven year period were aged less than 55. Twenty four of these 25 patients presented with one or more suspicious symptoms or signs. Only one patient (4%) aged less than 55 presented with uncomplicated dyspepsia. In two patients there was a delay in diagnosis of more than six months after first presenting to the general practitioner. Both these patients had significant symptoms at presentation., Conclusion: Gastric cancer is rare below the of 55 (7.8% of all cases) and, even in the presence of established open access endoscopy, presents with suspicious symptoms or signs in 96% of cases. The age limit for screening uncomplicated dyspepsia can be raised safely to 55.

Dyspepsia is common in the general population, and despite a paucity of data, smoking, alcohol, and analgesics are believed to be important risk factors. The role of these environmental factors in subjects with uninvestigated dyspepsia was evaluated in a representative population sample. An age and gender stratified random sample of residents of Olmsted County, Minnesota, aged 20 to 64 years was mailed a valid self report questionnaire; 77% responded (n = 1644). Age and gender adjusted (1990 US white population) prevalence rates for dyspepsia (defined as frequent pain located in the upper abdomen, or nausea in the absence of a history of peptic ulcer disease) were calculated. Logistic regression analysis was used to estimate the association between dyspepsia and potential risk factors. The age and gender adjusted prevalence (per 100) of dyspepsia in the community was 21.8 (95% confidence interval 19.6, 23.9). Dyspepsia was significantly more common in younger subjects and females. Adjusting for age and gender, paracetamol (odds ratio (OR) = 2.2), aspirin (OR = 1.8), and smoking (OR = 1.5), but not alcohol (OR = 0.9), were associated with dyspepsia (all p < 0.05). When non-gastrointestinal somatic complaints were included in the logistic models, however, these environmental factors were no longer significant (OR = 1.3, 1.1, 1.2 and 0.9, respectively). Similar results were obtained when ulcer-like, dysmotility-like, and reflux-like dyspepsia were considered separately. The results were not significantly changed when subjects with a history of ulcer disease were included in the analyses. Smoking, alcohol, and analgesics may not therefore be important risk factors for dyspepsia in the community.

A prospective study of dyspepsia was carried out in a primary referral hospital between 1974-1987 including 1540 patients of whom 1433 were seen as outpatients. The study protocol was agreed in advance and a structured questionnaire was used to elicit relevant clinical information: up to three diagnoses were permitted for each patient. The commonest principal diagnoses were duodenal ulcer (26%), functional dyspepsia (22%), and irritable bowel syndrome (IBS) (15%); alcohol related dyspepsia (4%) was as common as gastric carcinoma or symptomatic gall stones. Multiple diagnoses were common (31% given two diagnoses, and 6% given three) so that in all 2111 diagnoses were given to 1540 patients; the functional disorders (IBS and functional dyspepsia) considered together accounted for 39% of all diagnoses made. Whereas organic conditions were diagnosed by clinicians with confidence (63-98% considered 'certain'), even when given as the principal or first diagnosis IBS was considered 'certain' in only 61% and functional dyspepsia 48%. The demographic symptom data, together with information on tobacco and alcohol use, and work lost are described in detail.

We describe six patients in whom severe dyspeptic symptoms developed after fundoplication. The symptoms began immediately after operation (three patients) or shortly thereafter (three and eight months). There were no other known predisposing factors to gastroparesis. Seven, age-matched, healthy volunteers served as controls. Pressure activity from antrum (two sites), duodenum (two sites), and jejunum (one site) was recorded by a low compliance perfusion system connected to external strain gauge transducers. Activity was recorded for three hours during fasting and for two hours after the ingestion of a solid and a liquid meal. To determine whether an inadvertent vagotomy had been performed, basal acid output and the response to insulin (Hollander's test) were measured on a separate day. Manometric studies revealed postprandial hypomotility in these patients, whereas fasting antral and intestinal activities were normal. Acid output increased in all patients during insulin induced hypoglycaemia. In three patients, an antrectomy was subsequently performed, and they were relieved of their symptoms. We conclude that, after fundoplication, symptoms associated with postprandial antral hypomotility may develop in some patients. The pathophysiologic mechanism is unknown, but a positive acid response to insulin induced hypoglycaemia does not support the occurrence of incidental vagotomy. We do not know the prevalence of this motor abnormality among asymptomatic patients with prior fundoplication. A favourable symptomatic response to antrectomy in several of our patients, however, suggests that the symptoms were related to antral motor dysfunction.

The results of cholecystectomy in terms of symptomatic improvement were prospectively evaluated in 124 unselected gall stone patients interviewed before and two years after elective surgery. Indications for cholecystectomy were biliary pain (n = 65), previous complications of gall stone disease (n = 52), and flatulent dyspepsia (n = 7). At two years 93 patients could be re-evaluated, of whom only 49 (53%) were completely symptom free. Postcholecystectomy symptoms occurring in the remaining 44 patients were mainly flatulent dyspepsia (which had relapsed in 22 of 46 patients who suffered it preoperatively), dull abdominal pain or diarrhoea. Incisional hernia was present in five patients and one had recurrence of pain because of retained common bile duct stones. Symptomatic cures after cholecystectomy decreased with the duration of the preoperative history. The results reconfirm that cholecystectomy eradicates specific symptoms and complications of gall stone disease, but they also show that nearly one half of operated patients are dissatisfied with the procedure because of mild but distressing 'postcholecystectomy' symptoms. These are probably caused by previously undiagnosed functional gut disease associated with, but unrelated to, gall stones. A systemic approach to multisymptomatic patients with gall stones is recommended.

This paper describes the clinical presentation of 360 patients suffering from "dyspepsia" at the time of their initial visit to two hospitals in Yorkshire. Disease categories studied were cholecystitis, duodenal ulcer, gastric ulcer, gastric cancer, and "functional" dyspepsia, with at least 50 patients in each category. The findings of this series are contrasted with "textbook" descriptions of these conditions. Some contrasts are quite surprising-for example, most of the 360 patients claimed that their pain was not aggravated by food. It is suggested that one reason for diagnostic error in this area of medicine is that clinicians have a faulty mental "database" of information with regard to the presentation of the various diseases concerned.