key: cord-0790803-n2i16sro
authors: Wauters, Lucas; Dickman, Ram; Drug, Vasile; Mulak, Agata; Serra, Jordi; Enck, Paul; Tack, Jan; Accarino, Anna; Barbara, Giovanni; Bor, Serhat; Coffin, Benoit; Corsetti, Maura; De Schepper, Heiko; Dumitrascu, Dan; Farmer, Adam; Gourcerol, Guillaume; Hauser, Goran; Hausken, Trygve; Karamanolis, George; Keszthelyi, Daniel; Malagelada, Carolin; Milosavljevic, Tomislav; Muris, Jean; O’Morain, Colm; Papathanasopoulos, Athanassos; Pohl, Daniel; Rumyantseva, Diana; Sarnelli, Giovanni; Savarino, Edoardo; Schol, Jolien; Sheptulin, Arkady; Smet, Annemieke; Stengel, Andreas; Storonova, Olga; Storr, Martin; Törnblom, Hans; Vanuytsel, Tim; Velosa, Monica; Waluga, Marek; Zarate, Natalia; Zerbib, Frank
title: United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia
date: 2021-05-03
journal: United European Gastroenterol J
DOI: 10.1002/ueg2.12061
sha: 0fb5c0dd90fe1e59ca216e55209c733ba7857ba8
doc_id: 790803
cord_uid: n2i16sro

BACKGROUND: Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. METHODS: A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements. RESULTS: The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long‐term prognosis and life expectancy are favorable. CONCLUSIONS AND INFERENCES: A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD.

Functional dyspepsia (FD), defined by the presence of recurrent or chronic epigastric symptoms in the absence of organic disease likely to explain them, is one of the most common conditions seen in clinical practice. 1, 2 In spite of its prevalence, FD is associated with major uncertainties, as definitions and the symptom spectrum of FD have evolved over time, 3 the differential diagnosis is very broad, 1 the optimal diagnostic work-up has not been defined, 4, 5 and there is a lack of available treatments with established efficacy. 6, 7 The aim of this project was to develop a European consensus on the definition, pathophysiological concepts, diagnosis, management, and prognosis of FD. The results of this consensus can offer the clinician guidance in diagnosing and managing FD patients to optimize clinical outcomes.

(ESNM) initiated a Delphi process, funded by United European Gastroenterology, to develop consensus statements on different aspects of FD in collaboration with other European societies. The Delphi approach, which combines the principles of evidence-based medicine, supported by systematic literature reviews and a voting process, aims at determining consensus for complex problems in medicine for which evidence from controlled trials is lacking. 8 The principal steps in the process were (1) When 80% of the Consensus Group agreed (A+ or A) with a statement, this was defined as consensus. The strength of evidence for each statement was scored using the GRADE system (Table 2 ). 9 After the final voting round (summarized in Table 3 The Rome IV criteria stress that heartburn is not a dyspeptic symptom but may often coexist with FD and that the presence of heartburn should not lead to the exclusion of FD as diagnosis. 1, 3 Overall, one-third of FD patients also experience typical symptoms of gastroesophageal reflux disease (GERD). 13 It seems that, in cases of overlap between FD and GERD, FD is often underestimated, favoring the diagnosis of GERD. 14 The substantial overlap of core symptoms of GERD and FD persists, regardless of the use of objective tools or evidence from upper endoscopies or esophageal pH studies. 12, 14 Thus, separating out GERD and FD based on questionnaires and history taking alone can be quite difficult, if not impossible. 13, 15 In addition, non-acid-related conditions such as functional heartburn frequently overlap with FD. 13, 16 Irritable bowel syndrome (IBS) is another symptomatic condition which frequently overlaps with FD. 17 The high rate of overlap between FD and conditions like IBS or GERD may be explained by common etiological risk factors (e.g., acute infectious gastroenteritis, psychological disturbances) and pathophysiological mechanisms (e.g., visceral hypersensitivity, altered motility, etc.). 13, [15] [16] [17] Severity and impact of symptoms are higher in those with overlapping conditions. 40 Over time, several subdivisions of the dyspeptic symptom pattern have also been proposed. 1, 3, 10 STATEMENT NOT ENDORSED, overall agreement 37%: A+

Approximately 10% of the adult population fulfills symptombased Rome IV criteria for (uninvestigated) FD, and its prevalence appears to disappear with increasing age. 2, 19 In several studies, the peak incidence of FD seems to occur in the forties or fifties age segment. [19] [20] [21] [22] A recent metA−analysis including 55 studies revealed a slightly higher pooled prevalence of dyspepsia in women compared with men. 19 The Rome Global Epidemiology Study, which used the most uniform criteria and approach, showed a significantly higher prevalence of (uninvestigated) Rome IV FD in women compared to men. 2

Grade of Evidence References Acute gastroenteritis is associated with an increased risk of FD, with an estimated mean prevalence of 9.6% in adults. 23 Among pathogens suggested to be associated with post-infectious FD (PI-FD) are Norovirus, Giardia lamblia, Salmonella spp., Escherichia coli O157, and Campylobacter spp. [24] [25] [26] H. pylori does not seem to be a cause of PI-FD. 23, 27 Nonsteroidal anti-inflammatory drug (NSAID) use has been identified as a risk factor for dyspepsia in two population-based studies. 28, 29 It has been suggested that the development of dyspeptic symptoms during treatment with NSAIDs could be linked to alterations in gastric mechanosensory function. 30 However, NSAID intake appears to be most relevant to uninvestigated dyspepsia. 31 Population-and endoscopy-based studies suggested an association between smoking and FD. 20, [49] [50] [51] In contrast, other populationbased studies failed to find an association after adjustment for confounders such as age, gender, and drugs. 52 Several cross-sectional studies have shown that FD frequently coexists with anxiety and depression and that the severity of symptoms correlates with scores on psychopathology questionnaires. [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] Furthermore, psychosocial factors, such as depression, history of childhood abuse, and somatization, have shown to contribute to symptom severity more than the degree of gastric sensorimotor dysfunction. 38 Weight loss occurs in a large subset of subjects with dyspeptic symptoms and is closely associated with symptoms of early satiation as well as epigastric pain, both at the population level and in tertiary care patients. 63 -315 those with lower scores, indicating that psychosocial factors also influence healthcare-seeking behavior. 36, 71 A longitudinal study also found that anxiety or depression precedes dyspepsia among consulters in a larger proportion than in non-consulters, confirming that basal psychosocial comorbidity is associated with healthcare seeking. 71 Consultation rates for dyspepsia vary widely between countries and regions, suggesting that access to the healthcare system may influence healthcare-seeking behavior. 70 However, differences in healthcare-consulting behavior are also modulated by socioeconomic status. Several studies have shown that low socioeconomic status is associated with higher consultation rates for dyspepsia. 68 have shown that food is a major trigger for FD symptoms. 57, 73, 74 Whether alterations in content or timing of meals in FD contributes to this triggering effect has been evaluated in only a few studies. A number of studies reported intake of a lower number of meals in FD patients compared to controls, in some cases with a tendency for more snacks between meals. [75] [76] [77] In terms of macronutrient intake, reduced fat intake has been reported in FD, 77 but also reduced carbohydrate has been reported in a mixed FD/IBS population. 78 Hypersensitivity to gastric distention has been reported in 34%-65% of FD patients by several studies, 64,100-106 without difference between Rome III subgroups, 91 and postprandial sensitivity to gastric distention was even greater than fasting sensitivity. 107 Hypersensitivity to gastric distention was associated with a higher prevalence of postprandial pain, belching, and weight loss, 64 116, 117 Although gastric acid secretion is reported as normal, 118 FD patients displayed increased spontaneous duodenal acid exposure during the daytime and the late postprandial phase with higher symptom severity in patients with high duodenal acid exposure. 119 However, the correlation between acid exposure and symptom severity was weak, and the increased duodenal acid exposure could be, at least in part, attributable to delayed duodenal acid clearance as FD patients display decreased duodenal motor activity in response to acid perfusion. 119, 120 A number of studies suggest the implication of gut hormones in the pathophysiology of FD, but the studies are small and findings are heterogeneous. 121 Early studies focused on cholecystokinin (CCK), as a subset of FD patients had elevated plasma levels, intravenous administration of CCK worsened dyspeptic symptoms, and the selective CCKA antagonist dexloxiglumide reduced symptoms during gastric distention and duodenal lipid infusion. [122] [123] [124] In PDS, ghrelin plasma levels were reported to be reduced. 125 The vagus nerve is also a major contributor to control upper gastrointestinal motility. 133 An early study in seven FD patients, using an insulin hypoglycemia test and plasma levels of pancreatic polypeptide, suggested a disturbed efferent vagal function. 134 The gastric response to sham feeding, a marker for vagal activity, was lower in PDS compared to controls. 135 Conversely, sham feeding was reported to improve the suppressed response to a liquid nutrient meal in FD. 136 Slow deep breathing, which is thought to activate the vagus nerve, was associated with improvement of nutrient volume tolerance and quality of life in FD. 137 Using spectral analysis of cardiac R-R intervals to evaluate vagal tone, Guo et al. showed a decreased vagal tone that was associated with delayed gastric emptying. 138 Taken together, a number of observations suggest decreased vagal activity in FD, but the studies all occurred in laboratory settings in small groups of patients.

As mentioned above, there is an association of anxiety with FD, and anxiety may precede FD. Moreover, FD is associated with altered brain processing of gastrointestinal (GI) stimuli, altered central nervous system connectivity, and structure and altered expression of neurotransmitter pathways. [139] [140] [141] [142] [143] However, a causal relation between anxiety and FD has not been established. As mentioned above, depression is also associated with FD, but also in this case, there is a lack of evidence for a causal relation.

Numerous studies have shown that FD patients report more symptoms or earlier symptoms following gastroduodenal stimulation with either balloon, liquid volume, or food compared to healthy controls. A systematic review evaluated studies on central processing of signals from the gastroduodenal region in FD patients and controls, mostly by balloon distention of the stomach, using PET or fMRI technology. 144 The results show that FD is associated with functional abnormalities in sensory and pain modulation, emotion, saliency, and homeostatic processing regions, suggesting that disordered central processing of incoming signals from the gastroduodenal region is indeed a relevant pathophysiological mechanism at least in a subgroup of FD patients. However, this does not exclude an involvement of peripheral mechanisms as well.

Family studies support a genetic component in FD susceptibility. 145 A mea-analysis of eight studies indicated that the GNβ3

C825T polymorphism is significantly associated with FD, and susceptible to racial variation. 146 However, a meta-analysis based on 12 studies has failed to confirm a significant association. 147 Empiric therapy, either with proton pump inhibitors (PPIs), prokinetics or H. pylori eradication ("test and treat strategy"), is valuable for the management of uninvestigated dyspepsia. When considering the actual diagnosis of FD, endoscopy is mandatory to rule out not only malignancies, but also benign organic disorders which may explain the symptoms such as peptic ulcer (prevalence 8%), esophagitis (20%), or H. pylori-associated gastritis. 6 The cutoff between young and old is now considered to be 60 years in the West, adjusted to additional risk factors and local incidence age of gastric cancer. 150

Overall, there is a lack of data on cost-benefit utility of laboratory testing in patients presenting with dyspeptic symptoms. A study from India found that apart from warning signs, blood tests for hemoglobin and albumin could discriminate functional from organic disease when placed in a risk model, 152 In population-based symptom analyses, dyspeptic symptoms were shown to group around clusters, representing EPS and PDS. 3, 156 The literature is divided on the usefulness of distinguishing PDS and EPS for patient management. When the Rome III subdivision is used, a major overlap is found between both, which is largely corrected with the Rome IV subdivision as a good separation between both subtypes is now found both in epidemiological studies and in clinical practice. 3, 11, 40, [156] [157] [158] While some studies report different treatment responses, 159,160 others do not. 161, 162 To date, no fully published study has evaluated differential pathophysiological mechanisms or treatment outcomes according to the Rome IV subdivision. 163, 164 Kraag et al. performed a meta-analysis of 21 controlled studies on the association between gallstones and dyspeptic symptoms and found no reasonable association between gallstones and "classical" dyspeptic symptoms other than upper abdominal pain. 165 In a systematic review of 24 publications, biliary colic was the only single symptom associated with gallstones. 166 Hence, guidelines do not recommend upper abdominal ultrasound for exclusion of biliary pathology in the diagnosis of FD. 1, 150 The prevalence of delayed gastric emptying in FD ranges between 20% and 50%, but its association with symptoms and response to therapy has shown inconsistent results. 1, 91, 167, 168 The American

College of Gastroenterology and Canadian Association of Gastroenterology, as well as the Rome IV consensus did not recommend the use of gastric emptying testing in the diagnosis or management of FD. 1, 150 Abnormal esophageal acid exposure on pH monitoring can be found in 20%-30% of patients presenting with dyspeptic symptoms without heartburn as a predominant symptom, and in up to 50% in the subgroup of patients with epigastric burning. 13 181 There were no differences between low-and high-dose PPI, type of PPI, and H. pylori status. 150, 181, 182 In a metaanalysis of two studies including 740 FD patients, directly comparing PPI and histamine-2 receptor antagonists, there was no difference between both treatments. 181 However, both studies are older, possibly including GERD patients, and one is only available in abstract form. 183, 184 In areas of low (<20%) prevalence of H. pylori, a course of PPI has been suggested as the preferred first-line option before a test-and-treat approach. 185 The Rome IV consensus stated that PPIs are ineffective in relieving PDS symptoms, based on older data. 1 Two Japanese studies that investigated the effect of PPI in the 320 -UNITED EUROPEAN GASTROENTEROLOGY JOURNAL Rome III/IV subgroups found no significant difference between subgroups. 177, 186 The ACG/CAG guidelines, based on an updated metaanalysis, propose PPI as first-line therapy, irrespective of the Rome IV subgroups. 150 A recent meta-analysis of 29 studies involving 10,044 patients with FD demonstrated a significant effect of prokinetics in reducing dyspeptic symptoms (RR of ongoing dyspeptic symptoms 0.81; 95%

CI [0. 74-.89] ) with an NNT of 7. 187 However, the studies showed significant heterogeneity and the funnel plot was asymmetrical, suggesting publication bias. Moreover, 12 studies involved cisapride, which has been withdrawn from the market because of cardiac adverse events. 188 When cisapride was removed from the metaanalysis, the overall effect was still significant, but the NNT increased to 12. 187 The rationale for prokinetic therapy in FD is the presence of motor abnormalities such as delayed gastric emptying, especially in PDS, but in a large study, similar prevalence of gastric motor abnormalities was found in PDS, EPS, and the overlap group. 91 Itopride is a combined D2 antagonist and acetylcholinesterase inhibitor and is available in Asia and several countries in Eastern Europe.

A phase IIb placebo-controlled trial found significantly more responders to itopride, based on a global efficacy measure. 190 However, no significant improvement over placebo in reduction of FD symptoms was observed in two subsequent Phase III trials. 191 These trials suffered from issues with patients and endpoint selection, 192 but their negative outcome stopped further development of itopride in the West. In a recent controlled trial in Belgium, itopride seemed more effective in Rome IV PDS compared to Rome III PDS. 193 Psychotropic drugs appear to be an effective treatment for FD, as demonstrated by a systematic review and meta-analysis, with an NNT of 6 when data from all studies were pooled (1241 patients, 673 assigned to psychoactive drugs, and 568 to placebo). However, this beneficial effect appeared to be limited to TCAs and antipsychotics. 194 In a randomized placebo-controlled trial including 292 FD patients assigned to either placebo, 50 mg amitriptyline or 10 mg escitalopram for 12 weeks, subjects with "ulcer-like" FD (likely equivalent to EPS) receiving amitriptyline reported more adequate relief of symptoms than those receiving placebo or escitalopram (p = 0.06). 195 There were adverse events in 30% (n = 29) individuals in the amitriptyline arm, leading to discontinuation of treatment in two of them. Those with delayed gastric emptying were less likely to report adequate relief on amitriptyline compared with FD patients with normal emptying, but this was not related to an amitriptyline-induced delay in gastric emptying. 194 Amitriptyline appeared to derive its benefit predominantly through improving abdominal pain, since no change in psychological distress measures nor gastric emptying rates was found. 195, 196 In the subset of pa- The systematic review and meta-analysis on the efficacy of psychotropics in FD included two studies of selective serotonin reuptake inhibitors (sertraline 50 mg o.d. and escitalopram 10 mg o.

d.), containing almost 400 patients, which were negative. 194, 195, 198 Thus, it seems reasonable to assume that these drugs are of no benefit in FD.

A double-blind clinical trial randomly assigned 160 FD patients to 8 weeks of treatment with venlafaxine or placebo. 199 At none of the measurement times there was a statistically significant difference in symptom severity, quality of life or anxiety, and depression scores between venlafaxine and placebo. 199 The dropout rate among venlafaxine-treated patients was high due to side effects. While this single study with venlafaxine in FD was negative, it remains to be elucidated whether certain groups of patients might benefit from treatment with serotonin/noradrenaline reuptake inhibitors with a more potent analgesic effect at lower doses, for example, duloxetine.

In FD, weight loss is normally considered an alarming symptom, but may be present in up to 40% of tertiary care FD patients. 10 found for overall dyspepsia symptom score at week 4 in the mirtazapine group, but not at week 8. Nevertheless, this was associated with significant recovery of weight loss, improvement of quality of life, and visceral specific anxiety score. Another trial treated 60 FD patients with depression and weight loss with either mirtazapine 30 mg daily, paroxetine 20 mg daily or conventional therapy, and showed that mirtazapine did not only alleviate symptoms associated with dyspepsia and depression linked to FD with weight loss, but also significantly increased body weight. 201 In summary, two limited size trials showed the efficacy of mirtazapine in FD, one in patients without and one in patients with coexisting depression.

Tandospirone citrate, a serotonin 1A receptor agonist, was shown to improve abdominal symptom scores in FD patients. 200 However, R-137696, another 5-HT1A agonist, failed to improve symptoms or visceral hypersensitivity in FD patients. 203 In a small cross-over controlled trial, buspirone significantly A single double-blind, placebo-controlled randomized study examined the efficacy of rifaximin in subjects with Rome III criteria defined FD who were H. pylori negative. 211 The authors found that rifaximin was superior to placebo for the relief of global dyspeptic symptoms, postprandial fullness/bloating, and belching. Additional future trials are needed to examine the efficacy of rifaximin in FD and to elucidate the underlying mechanism of action.

In a 2017 review, a total of 12 controlled trials of psychological therapies involving 1563 FD patients were identified. 150 All trials reported a statistically significant benefit of psychological therapies over control, which was most commonly usual management. Information on individual types of psychological therapies is variable. For hypnotherapy in FD, only one small randomized controlled study reported benefit. 212 For CBT, two studies showed positive shortterm effects on FD symptoms. 213, 214 Meta-analyses of numerous low-quality randomized, controlled studies suggest manual and electric acupuncture being effective in the treatment of FD, as shown by improved symptom scores and health-related quality-of-life scores. [215] [216] [217] Effects are most pronounced in sham-controlled trials and less pronounced in trials comparing to prokinetic medication or traditional Chinese medicine.

A recent sham-controlled trial adds that the effect of acupuncture, following 20 treatment sessions in a 4-week episode, is sustained for 24 weeks. 218 Besides the overall small number of patients included and the different acupuncture protocols followed, selection bias, performing bias, reporting bias, attrition bias, and blinding difficulties remain the major concerns when interpreting findings in the metaanalyses.

In a meta-analysis, the quality and effectiveness of mindfulnessbased therapy in FGIDs was evaluated. 219 However, studies evaluating the effectiveness of mindfulness specifically in FD have not been found in the literature.

While severe weight loss may occur in FD patients, especially in those with PDS and food avoidance, few studies have addressed its management. The antidepressant mirtazapine seems to help with weight gain in these patients 200, 201 and to improve FD symptoms, so the conclusion that other clinical management strategies for weight-gain support may also be effective, is plausible but has not been tested. This holds true specifically for enteral and parenteral feeding. In one preliminary report of 19 

Based on the statements that achieved consensus (Table 3) , a number of recommendations for understanding and managing FD can be made, which are summarized in Table 4 . The Delphi process also identified several areas of uncertainty, which require additional evidence or further research. Figure 1 schematically In case of severe weight loss in FD, nutritional support may be needed. 6.27

The long-term prognosis is favorable in the majority of patients with FD, whose life expectancy is similar to that of the general population. healthcare costs, on the ability to work, and on psychosocial well-being.

In terms of pathophysiological mechanisms that are relevant to FD, consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, H.

pylori infection, and altered central processing of incoming signals from the gastroduodenal region. There is no consensus on duodenal mucosal alterations, sensitivity to luminal contents, peptide release, or microbiota. Anxiety is a risk factor for the development of functional dyspepsia; however, anxiety, depression, or stress is not considered a pathophysiological mechanism that underlies FD symptom generation.

There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that patients in primary care with dyspeptic symptoms and no alarm symptoms or risk factors can be managed without endoscopy. There is consensus that endoscopy is mandatory in case of alarm symptoms or risk factors, and that H.

pylori status should be determined at endoscopy or non-invasively in every patient. There is no consensus on the benefit of additional examinations including laboratory testing, abdominal ultrasound, gastric emptying testing, or esophageal pH monitoring.

The biggest area of lack of consensus is the section on treatment approaches for FD. There is an agreement to use to subdivision in PDS and EPS to guide management, but the vast majority of treatment options are not supported for a specific subgroup. There is consensus to eradicate every H. pylori positive FD patient, and PPI therapy is considered an effective therapy for FD, although there is no consensus that it is the preferred initial therapy. There is no consensus on the indication and efficacy of prokinetics or antidepressants, but an almost-agreement (78%) on the use of TCA in EPS. There is also no consensus on the use of other neuromodulators, herbal therapies, acupuncture, or psychological therapies in FD. There is agreement on the use of nutritional support in case of severe weight loss. Finally, there is consensus that the long-term prognosis of FD is favorable and that life expectancy is not shortened in FD.

The areas of uncertainty revealed by this consensus are multiple.

Further unraveling of the FD symptom pattern is useful, and especially the concept of using pictograms deserves additional, preferably multilingual and multicultural studies. These may aid further diagnostic refinement, where the currently only supported tools are endoscopy and H. pylori status assessments, with their limited sensitivity and impact on management and outcome. While there is acceptance of a role for gastric sensorimotor dysfunction in F I G U R E 1 Schematic representation, in an algorithm-like fashion, of the outcome of the consensus on functional dyspepsia management. The blue arrows depict the diagnostic and therapeutic flow of the patient. Green arrows refer to risk or pathophysiological factors. The circles depict the % of agreement, using a green color for ≥80% consensus, light orange for consensus between 70% and 80%, and dark orange for lower levels of consensus 

Functional gastroduodenal disorders

Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study

Functional dyspepsia−symptoms, definitions and validity of the Rome III criteria

What is the prevalence of clinically significant endoscopic findings in subjects with dyspepsia? Systematic review and meta-analysis

Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis

New developments in the treatment of gastroparesis and functional dyspepsia

Postprandial distress syndrome: stratification and management

Delphi: myths and reality

GRADE guidelines: 3. Rating the quality of evidence

Functional gastroduodenal disorders

Effects of Rome IV definitions of functional dyspepsia subgroups in secondary care

Functional dyspepsia

Gastroesophageal reflux disease-functional dyspepsia overlap: do birds of a feather flock together?

Overdiagnosis of gastro-esophageal reflux disease and underdiagnosis of functional dyspepsia in a USA community

Overlap of functional dyspepsia and GERD−-diagnostic and treatment implications

Gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome: common overlapping gastrointestinal disorders

Systematic review and metA−analysis of the prevalence of irritable bowel syndrome in individuals with dyspepsia

Vandenberghe A. The use of pictograms improves symptom evaluation by patients with functional dyspepsia

Global prevalence of, and risk factors for, uninvestigated dyspepsia: a meta-analysis

Prevalence and impact of upper gastrointestinal symptoms in the Canadian population: findings from the DIGEST study. Domestic/International Gastroenterology Surveillance Study

The link between psychosocial factors and functional dyspepsia: an epidemiological study

Prevalence of non-ulcer dyspepsia in the Japanese population

Systematic review with metA −analysis: post-infectious functional dyspepsia

Postinfectious gastrointestinal disorders following norovirus outbreaks

Increased visceral sensitivity in GiardiA−induced postinfectious irritable bowel syndrome and functional dyspepsia

Prevalence of uninvestigated dyspepsia 8 years after a large waterborne outbreak of bacterial dysentery: a cohort study

Clinical and pathophysiological characteristics of acute-onset functional dyspepsia

The prevalence and risk factors of functional dyspepsia in a multiethnic population in the United States

The proportion of upper gastrointestinal symptoms in the community associated with Helicobacter pylori, lifestyle factors, and nonsteroidal anti-inflammatory drugs. Leeds HELP Study Group

Do changes in visceral sensory function determine the development of dyspepsia during treatment with aspirin?

Epidemiology of functional dyspepsia: a global perspective

Non-enteric infections, antibiotic use, and risk of development of functional gastrointestinal disorders

Functional dyspepsia is associated with sleep disorders

Health-related anxiety and the effect of openaccess endoscopy in US patients with dyspepsia

Dyspepsia is strongly associated with major depression and generalised anxiety disorder -a community study

Anxiety but not depression determines health care-seeking behaviour in Chinese patients with dyspepsia and irritable bowel syndrome: a population-based study

Psychopathology is associated with dyspeptic symptom severity in primary care patients with a new episode of dyspepsia

Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation?

Evidence that independent gut-tobrain and brain-to-gut pathways operate in the irritable bowel syndrome and functional dyspepsia: a 1-year population-based prospective study

Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study

Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study

Anxiety is linked to new-onset dyspepsia in the Swedish population: a 10-year follow-up study

Early life factors initiate a 'vicious circle' of affective and gastrointestinal symptoms: a longitudinal study

Stress profile, coping style, anxiety, depression, and gastric emptying as predictors of functional dyspepsia: a case-control study

Anxiety, personality traits and quality of life in functional dyspepsiA−suffering patients

Acute anxiety and anxiety disorders are associated with impaired gastric accommodation in patients with functional dyspepsia

Anxiety and depression increase in a stepwise manner in parallel with multiple FGIDs and symptom severity and frequency

Longitudinal and cross-sectional factors associated with long-term clinical course in functional dyspepsia: a 5-year follow-up study

Non-ulcer dyspepsia and peptic ulcer: the distribution in a population and their relation to risk factors

Epidemiology of functional dyspepsia and subgroups in the Italian general population: an endoscopic study

Natural history of functional dyspepsia: a 10-year populationbased study

Smoking, alcohol, and analgesics in dyspepsia and among dyspepsia subgroups: lack of an association in a community

Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study

Prevalence of functional gastrointestinal disorders in Taiwan: questionnaire-based survey for adults based on the Rome III criteria

Functional dyspepsia: the economic impact to patients

Functional dyspepsia impacts absenteeism and direct and indirect costs

Dyspeptic symptoms in the general population: a factor and cluster analysis of symptom groupings

Clinical and epidemiological differences in functional dyspepsia between the East and the West

Helicobacter eradication relief of dyspetic symptoms trial investigators. Influence of organic and functional dyspepsia on work productivity: the HEROES-DIP study

Factors associated with health-related quality of life in patients with functional dyspepsia

Functional dyspepsia impairs quality of life in the adult population

Risk factors for impaired health-related quality of life in functional dyspepsia

Role of impaired gastric accommodation to a meal in functional dyspepsia

Symptoms accosiated with hypersensitivity to gastric distention in functional dyspepsia

Community subgroups in dyspepsia and their association with weight loss

Symptom pattern and pathophysiological correlates of weight loss in tertiary-referred functional dyspepsia

Assessment of meal-induced gastric accommodation by a satiety drinking test in health and in functional dyspepsia

Who consults with dyspepsia? Results from a longitudinal 10-yr follow-up study

Dyspepsia consulters and patterns of management: a population-based study

Factors associated with consulting medical or non-medical practitioners for dyspepsia: an australian population-based study

Mood and anxiety disorders precede development of functional gastrointestinal disorders in patients but not in the population

Systematic review: frequency and reasons for consultation for gastro-oesophageal reflux disease and dyspepsia

A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia

Relationship between symptoms and ingestion of a meal in functional dyspepsia

Food and nutrient intakes and eating patterns in functional and organic dyspepsia

Relationship between symptoms and dietary patterns in patients with functional dyspepsia

Food intolerance, diet composition, and eating patterns in functional dyspepsia patients

Diet and functional gastrointestinal disorders: a population-based case-control study

Food and functional dyspepsia: a systematic review

European Helicobacter and microbiota study group and consensus panel. Management of Helicobacter pylori infection -the Maastricht V/Florence consensus report

Faculty members of Kyoto Global Consensus Conference

Helicobacter Pylori and nonulcer dyspepsia

Abnormal distribution of food during gastric emptying in functional dyspepsia patients

Impaired accommodation of proximal stomach to a meal in functional dyspepsia

Responses to gastric distention in functional dyspepsia

Impaired drinking capacity in patients with functional WAUTERS ET AL

dyspepsia: relationship with proximal stomach function

Gastric accommodation and emptying in evaluation of patients with upper gastrointestinal symptoms

Distension-induced gastric accommodation in functional dyspepsia: effect of autonomic manipulation

The ultrasound meal accommodation test in 509 patients with functional gastrointestinal disorders

Prevalence of gastric motility disorders in patients with functional dyspepsia

Pathophysiological abnormalities in functional dyspepsia subgroups according to the Rome III criteria

Fundal dysaccommodation in functional dyspepsia: heaD−to-head comparison between the barostat and three-dimensional ultrasonographic technique

Dyspeptic symptoms and gastric emptying of solids in patients with functional dyspepsia. Role of Helicobacter pylori infection

Symptom patterns in functional dyspepsia and irritable bowel syndrome: relationship to disturbances in gastric emptying and response to a nutrient challenge in consulters and non-consulters

Gastric emptying, esophageal 24-hour pH and gastric potential difference measurements in non-ulcer dyspepsia

Disturbed soliD−phase gastric emptying in functional dyspepsia: a metA−analysis

Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia

Patterns of symptoms in functional dyspepsia: role of Helicobacter pylori infection and delayed gastric emptying

Symptoms associated with delayed emptying of solids and liquids in functional dyspepsia

Functional dyspepsia symptoms, gastric emptying and satiety provocative test: analysis of relationships

Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia

Concurrent assessment of reservoir and emptying of the stomach for dyspepsia patients

Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia

Symptoms and visceral perception in severe functional and organic dyspepsia

Differences in gastric mechanosensory function after repeated ramp distensions in non-consulters with dyspepsia and healthy controls

Evaluation of individual symptoms acannot predict presence of gastric hypersensitivity in functional dyspepsia

Functional dyspepsia, hypersensitivity to postprandial distention correlates with meal-related symptom severity

visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: consistent findings from five different patient cohorts

Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study

Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia

Duodenal eosinophilia and early satiety in functional dyspepsia: confirmation of a positive association in an Australian cohort

Vanden Berghe P. Evidence for neuronal and structural changes in submucous ganglia of patients with functional dyspepsia

Activation of eosinophils and mast cells in functional dyspepsia: an ultrastructural evaluation

Novel concepts in the pathophysiology and treatment of functional dyspepsia

Duodenal inflammation: an emerging target for functional dyspepsia?

Immune dysfunction in patients with functional gastrointestinal disorders

Intestinal immune activation in presumed post-infectious functional dyspepsia

Basal gastric acid secretion in nonulcer dyspepsia with or without duodenitis

A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea

Prolonged recording of duodenal acid exposure in patients with functional dyspepsia and controls using a 328 -UNITED EUROPEAN GASTROENTEROLOGY JOURNAL radiotelemetry pH monitoring system

The role of GI peptides in functional dyspepsia and gastroparesis: a systematic review

Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY

Clinical efficacy and prokinetic effect of the CCK-A antagonist loxiglumide in nonulcer dyspepsia

Role of duodenal lipid and cholecystokinin A receptors in the pathophysiology of functional dyspepsia

Gender differences in ghrelin, nociception genes, psychological factors and quality of life in functional dyspepsia

Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease

Gastroduodenal mechanisms underlying functional gastric disorders

The role of fat and cholecystokinin in functional dyspepsia

Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients

Chemospecific alterations in duodenal perception and motor response in functional dyspepsia

Dyspepsia and the microbiome: time to focus on the small intestine

Gastric microbiota in the functional dyspepsia patients treated with probiotic yogurt

Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction

Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia

Impaired gastric response to modified sham feeding in patients with postprandial distress syndrome

Vagal activation by sham feeding improves gastric motility in functional dyspepsia

Breathing exercises with vagal biofeedback may benefit patients with functional dyspepsia

Impaired vagal activity to meal in patients with functional dyspepsia and delayed gastric emptying

Abnormal regional brain activity during rest and (anticipated) gastric distension in functional dyspepsia and the role of anxiety: a H(2)(15)O-PET study

Alterations of the default mode network in functional dyspepsia patients: a resting-state fmri study

Brain-based correlations between psychological factors and functional dyspepsia

Regional brain disorders of serotonin neurotransmission are associated with functional dyspepsia

Increased cerebral cannabinoiD−1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study

Functional neuroimaging studies in functional dyspepsia patients: a systematic review

Familial association in adults with functional gastrointestinal disorders

Association of genetic variants in GNβ3 with functional dyspepsia: a metA−analysis

The C825T polymorphism of the G-protein β3 gene as a risk factor for functional dyspepsia: a metA−analysis

Gene polymorphisms associated with functional dyspepsia

American gastroenterological association technical review on the evaluation of dyspepsia

ACG and CAG clinical guideline: management of dyspepsia

Can the clinical history distinguish between organic and functional dyspepsia?

A simple pre-endoscopy score for predicting risk of malignancy in patients with dyspepsia: a 5-year prospective study

Management of dyspepsia

Clinical trial: a randomized trial of early endoscopy, Helicobacter pylori testing and empirical therapy for the management of dyspepsia in primary care

The clinical relevance of endoscopic and histologic inflammation of gastroduodenal mucosa in dyspepsia of unknown origin

Functional dyspepsia and the Rome criteria: a success story

Rome III functional dyspepsia subdivision in PDS and EPS: recognizing postprandial symptoms reduces overlap

Analysis of postprandial symptom patterns in subgroups of patients with Rome III or Rome IV functional dyspepsia

Effect of lansoprazole on the epigastric symptoms of functional dyspepsia (ELF study): a multicentre, prospective, randomized, double-blind, placebo-controlled clinical trial

Symptom improvement after helicobacter pylori eradication in patients with functional dyspepsia-a multicenter, randomized, prospective cohort study

Proton pump inhibitor versus prokinetic therapy in patients with functional dyspepsia: is therapeutic response predicted by Rome III subgroups?

A multicenter randomized trial comparing rabeprazole and itopride in patients with functional dyspepsia in Japan: the NAGOYA study

DyspepsiA−-how noisy are gallstones? A metA−analysis of epidemiologic studies of biliary pain, dyspeptic symptoms, and food intolerance

Abdominal symptoms: do they predict gallstones? A systematic review

Pathophysiology and treatment of functional dyspepsia

The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis

Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and metA −analysis

Effects of promotility agents on gastric emptying and symptoms: a systematic review and metA−analysis. Gastroenterology

Prevalence of acid reflux in functional dyspepsia and its association with symptom profile

A prospective study of oesophageal 24-h ambulatory pH monitoring in patients with functional dyspepsia

Prevalence and symptom pattern of pathologic esophageal acid reflux in patients with functional dyspepsia based on the Rome III criteria

Micro-inflammation in functional dyspepsia: a systematic review and metA−analysis

Proximal and distal gastric distension in normal subjects and H. pylori-positive and -negative dyspeptic patients and correlation with symptoms

Drink tests in functional dyspepsia: which drink is best?

The water load test: observations from healthy controls and patients with functional dyspepsia

Reproducibility and symptomatic predictors of a slow nutrient drinking test in health and in functional dyspepsia

Helicobacter pylori infection in functional dyspepsia

Surveillance of gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management

Asian consensus report on functional dyspepsia

Evidence-based clinical practice guidelines for functional dyspepsia

Effects of proton-pump inhibitors on functional dyspepsia: a metA−analysis of randomized placebo-controlled trials

Proton pump inhibitors for functional dyspepsia. Cochrane Database Syst Rev

Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group

A comparison of lansoprazole vs ranitidine in the treatment of functional ulcer-like dyspepsia as defined by the Rome II criteria

Current management strategies and emerging treatments for functional dyspepsia

Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan

Prokinetics for functional dyspepsia: a systematic review and meta−analysis of randomized control trials

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders

Relief of epigastric pain in nonulcer dyspepsia: controlled trial of the promotility drug cisapride

A placebocontrolled trial of itopride in functional dyspepsia

Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials

Review article: treatment options for functional dyspepsia

383-The therapeutic outcome of itopride in functional dyspepsia postprandial distress syndrome: a double-blind randomized, multicenter, placebo-controlled study

Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis

Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology

Effects of antidepressants on gastric function in patients with functional dyspepsia

Low-dose imipramine for refractory functional dyspepsia: a randomised, double-blind, placebo-controlled trial

Treatment of functional dyspepsia with sertraline: a double-blind randomized placebo-controlled pilot study

Effect of the antidepressant venlafaxine in functional dyspepsia: a randomized, double-blind, placebocontrolled trial

Efficacy of mirtazapine in patients with functional dyspepsia and weight loss

Beneficial effects of antidepressant mirtazapine in functional dyspepsia patients with weight loss

Efficacy of the 5-HT1A agonist tandospirone citrate in improving symptoms of patients with functional dyspepsia: a randomized controlled trial

HT agonist R-137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia

Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia

Influence of buspirone on gastric sensorimotor function in man

MetA−analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast)

Complementary and alternative medicine in gastroenterology: the good, the bad, and the ugly

A combination of peppermint oil and caraway oil for the treatment of functional dyspepsia: a systematic review and meta-analysis

Rikkunshito for upper gastrointestinal symptoms: a systematic review and metaanalysis

Chinese herbal medicine for functional dyspepsia: systematic review of systematic reviews

Randomised clinical trial: rifaximin versus placebo for the treatment of functional dyspepsia

Longterm improvement in functional dyspepsia using hypnotherapy

Psychotherapy in functional dyspepsia

Is there a benefit from intensified medical and psychological interventions in patients with functional dyspepsia not responding to conventional therapy?

Efficacy of acupuncture treatment for functional dyspepsia: a systematic review and meta-analysis

Efficacy and safety of acupuncture for the treatment of functional dyspepsia: meta-analysis

Acupuncture and related therapies used as add-on or alternative to prokinetics for functional dyspepsia: overview of systematic reviews and network meta-analysis

Electroacupuncture for patients with refractory functional dyspepsia: a randomized controlled trial

Mindfulness-based therapies in the treatment of functional gastrointestinal disorders: a metaanalysis

Outcome of percutaneous jejunal feeding tube placement for refractory idophatic severe gatroparesis: a retrospective review

One-year prognosis of primary care dyspepsia: predictive value of symptom pattern, Helicobacter pylori and GP management

Natural history of functional gastrointestinal disorders: a 12-year longitudinal population-based study. Gastroenterology

Natural history of functional gastrointestinal disorders: comparison of two longitudinal population-based studies

Impact of functional gastrointestinal disorders on survival in the community

Fluctuation of gastrointestinal symptoms in the community: a 10-year longitudinal follow-up study

How to cite this article

United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia