INTRODUCTION — Dyspepsia is a common symptom with an extensive differential diagnosis and a heterogeneous pathophysiology . It occurs in approximately 25 percent of the population each year, but most affected people do not seek medical care. Approximately 25 percent of patients with dyspepsia have an underlying organic cause. However, up to 75 percent of patients have functional (idiopathic or nonulcer) dyspepsia with no underlying cause on diagnostic evaluation [2-4]. This topic review will provide an overview of the pathophysiology and treatment of functional dyspepsia.
Our recommendations for the diagnosis and management of functional dyspepsia are largely consistent with the American College of Gastroenterology and American Gastroenterological Association guidelines [5,6]. The etiology, general approach to the evaluation, and management of the patient with uninvestigated dyspepsia are presented separately. (See "Approach to the adult with dyspepsia".)
EPIDEMIOLOGY AND PATHOPHYSIOLOGY — The prevalence of functional dyspepsia ranges from 5 to 11 percent worldwide . The pathophysiology of functional dyspepsia is not well understood. However, several potential mechanisms have been suggested. These mechanisms may differ between subtypes of functional dyspepsia (postprandial distress syndrome and epigastric pain syndrome) . (See 'Diagnostic criteria' below.)
●Gastric motility and compliance – Functional dyspepsia has been associated with several motility disorders. These include mild delays in gastric emptying, rapid gastric emptying, antral hypomotility, gastric dysrhythmias, and impaired gastric accommodation in response to a meal [8-11]. However, these findings are noted in only a subset of patients with dyspepsia. As examples, delayed gastric emptying and antral hypomotility are found in approximately 25 to 35 percent of patients with dyspepsia while up to 10 percent of patients with dyspepsia have rapid gastric emptying [3,12-14]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
●Visceral hypersensitivity – Visceral hypersensitivity is characterized by a lowered threshold for induction of pain in the presence of normal gastric compliance. Several studies have demonstrated visceral hypersensitivity in patients with functional dyspepsia that occurs independently of delayed gastric emptying [15-19]. Both mechanoreceptor dysfunction and aberrant processing of afferent input in the spinal cord or brain may play a role in the pathophysiology of visceral hypersensitivity [20,21]. In one study that included 270 patients with functional dyspepsia, 37 percent had hypersensitivity to gastric distension, and hypersensitive patients reported higher cumulative symptom scores as compared with normosensitive patients . Patients with functional dyspepsia may also have increased chemosensitivity .
●Helicobacter pylori infection – Although there are several hypotheses with regard to the role of Helicobacter pylori infection in the pathogenesis of functional dyspepsia, the mechanism remains unclear. H. pylori may cause altered smooth muscle dysfunction due to the induction of an inflammatory response or by the initiation of an antibody response [22,23]. However, studies have not found an association between H. pylori and abnormal gastric motor function in patients with functional dyspepsia . (See "Pathophysiology of and immune response to Helicobacter pylori infection".)
The inflammatory response induced by H. pylori may lower the discomfort threshold to gastric distension by causing alterations in the enteric or central nervous system . However, in at least one study, H. pylori positive and negative patients with functional dyspepsia had no difference in the perception of mechanically-induced gastric distension .
There is evidence from randomized controlled trials that eradication of H. pylori results in relief of dyspepsia in a minority of patients. However, studies have failed to establish a temporal relationship between H. pylori infection and functional dyspepsia, or the association of H. pylori with a specific symptom complex . Therefore, relief of dyspepsia may reflect other factors such as cure of unrecognized peptic ulcer disease in patients misdiagnosed with functional (nonulcer) dyspepsia, alterations in acid secretion, or changes in the gut microbiota.
●Altered gut microbiome – Alterations in the upper gastrointestinal tract microbiome may result in the development of dyspepsia. This hypothesis is supported by the observation that dyspeptic symptoms are more likely to occur after an episode of gastroenteritis [26-29]. In one study, patients were noted to have persistent symptoms eight years after exposure to a waterborne outbreak of bacterial dysentery . It has also been hypothesized that the efficacy of H. pylori therapy in improving symptoms of functional dyspepsia is due to the impact on the gut microbiome rather than the eradication of H. pylori alone [30,31].
●Duodenal inflammation – An association between functional dyspepsia and increased duodenal eosinophilia has been reported, with an increase in duodenal eosinophils in patients with early satiety [32-36]. It is unclear if this upregulation in mucosal immunity is due to changes in the upper gut microbiome or diet. However, lower levels of duodenal eosinophilia can occur in a healthy population [37,38].
●Psychosocial dysfunction – Functional dyspepsia may result from a complex interaction of psychosocial and physiological factors . Dyspepsia has been associated with generalized anxiety disorder, somatization, and major depression [12,40-43]. There is also a higher prevalence of functional gastrointestinal disorders in patients with self-reported history of childhood abuse [44,45].
CLINICAL MANIFESTATIONS — Patients with functional dyspepsia usually describe postprandial fullness, early satiety, and/or epigastric pain/burning. Symptoms may be severe enough to limit usual activities. Some patients may have nausea, vomiting, or heartburn, however, these symptoms are usually infrequent.
Overview of diagnostic approach — Functional dyspepsia is suspected in patients with a clinical history of postprandial fullness, early satiety, or epigastric pain/burning. A clinical diagnosis of functional dyspepsia requires the fulfillment of symptom-based diagnostic criteria and an evaluation to exclude other causes of dyspepsia. This evaluation consists of a history, physical examination, laboratory studies, and endoscopic evaluation to exclude organic/structural disease to explain the symptoms (algorithm 1). An approach to the evaluation of a patient with dyspepsia is discussed in detail separately. (See "Approach to the adult with dyspepsia", section on 'Initial evaluation' and "Approach to the adult with dyspepsia", section on 'Diagnostic strategies and initial management'.)
Diagnostic criteria — Symptom-based criteria have been proposed to standardize the diagnosis of functional dyspepsia.
●Rome IV criteria for functional dyspepsia – According to the Rome IV criteria, functional dyspepsia is defined as the presence of one or more of the following symptoms: postprandial fullness, early satiation, epigastric pain or epigastric burning, and no evidence of structural disease (including at upper endoscopy) to explain the symptoms (table 1) .
While patients with these symptoms and a negative diagnostic evaluation likely have functional dyspepsia, according to the Rome IV guidelines, the criteria should be fulfilled for the last three months with symptom onset at least six months before diagnosis. Criteria for symptom frequency and duration are particularly useful in defining patient eligibility for research, but clinician judgement may allow diagnosis in practice without rigid adherence to them.
●Functional dyspepsia subtypes – Two subtypes of functional dyspepsia are recognized based on the predominant symptoms. However, overlap between these subtypes is common [8,47].
•Postprandial distress syndrome is characterized by bothersome postprandial fullness and/or early satiation (table 1).
•Epigastric pain syndrome is characterized by bothersome epigastric pain or burning that is not exclusively postprandial (table 1).
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of functional dyspepsia includes other organic causes of dyspepsia (table 2). Although there are several organic causes for dyspepsia, the main causes are peptic ulcer disease, gastroesophageal reflux, nonsteroidal anti-inflammatory drug (NSAID)-induced dyspepsia, and gastric malignancy. Functional dyspepsia is differentiated from these by clinical assessment, laboratory testing, and upper endoscopy. (See "Approach to the adult with dyspepsia", section on 'Dyspepsia secondary to organic disease'.)
●Gastroesophageal reflux disease – The most common symptoms of gastroesophageal reflux disease are retrosternal burning pain and regurgitation. Dyspepsia symptoms can coexist with heartburn, but in patients with functional dyspepsia, epigastric pain, and fullness are the predominant symptoms .
●Gastroparesis – Gastroparesis is less prevalent than functional dyspepsia, but may be confused with it, as gastric emptying may be slow and symptoms of dyspepsia occur in both disorders . Patients with functional dyspepsia may have nausea. However, in patients with gastroparesis, vomiting, rather than abdominal pain or epigastric fullness, is the predominant symptom.
●Irritable bowel syndrome – Up to 40 percent of patients with functional dyspepsia may have overlapping irritable bowel syndrome symptoms [1,6,46]. Rather than epigastric pain associated with functional dyspepsia, irritable bowel syndrome is characterized by abdominal pain or discomfort associated with a change in stool form or frequency.
Initial approach — Patients with functional dyspepsia should be tested and treated for Helicobacter pylori. We treat patients with functional dyspepsia who test negative for H. pylori and those with persistent symptoms four weeks after eradication of H. pylori with a proton pump inhibitor (PPI) (table 3). However, approximately 90 percent of patients will continue to have symptoms despite PPI therapy and require additional treatment. (See 'Subsequent approach' below and 'Helicobacter pylori test and treat' below and 'Proton pump inhibitors' below.)
Helicobacter pylori test and treat — The diagnosis of H. pylori should be made with a test for active infection (stool antigen assay or urea breath test) if testing was not performed at the time of upper endoscopy performed for evaluation of dyspepsia (algorithm 1). Serologic testing should not be performed due to the low positive predictive value. (See "Indications and diagnostic tests for Helicobacter pylori infection", section on 'Approach to diagnostic testing' and "Approach to the adult with dyspepsia", section on 'Diagnostic strategies and initial management'.)
H. pylori eradication may improve dyspeptic symptoms by altering acid secretion or modification of intestinal microbiota [51,52]. It also has the benefit of preventing unrecognized peptic ulcers associated with H. pylori. A systematic review of 22 randomized controlled trials included 4896 patients with functional dyspepsia and H. pylori who were treated with eradication therapy or placebo. Eradication of H. pylori was associated with a small but significant benefit in relieving functional dyspepsia, with treatment of 13 patients needed to cure one case of functional dyspepsia (RR persistent dyspepsia 0.91, 95% CI 0.88-0.94) [52,53]. (See "Treatment regimens for Helicobacter pylori" and 'Epidemiology and pathophysiology' above.)
Proton pump inhibitors — PPIs appear to be moderately effective in the treatment of some patients with functional dyspepsia (table 3) [54-56]. A meta-analysis of 15 randomized trials that included 5853 patients with functional dyspepsia PPIs were significantly more effective as compared with placebo in reducing symptoms of dyspepsia (RR dyspepsia remaining 0.87, 95% CI 0.82-0.94) . In general, twice daily PPIs are no better than once daily PPIs for the treatment of functional dyspepsia and dosing should not be increased to twice daily in patients who do not respond after eight weeks of once daily PPI therapy [54-56]. In patients with functional dyspepsia who respond to PPI therapy, attempts should be made to discontinue PPIs every 6 to 12 months to minimize long-term risk of therapy.
Patients with functional dyspepsia are more likely to respond to H2 receptor antagonists (H2RA) as compared with placebo. However, the effect of H2RAs in relieving symptoms of functional dyspepsia is likely to be small. There are also insufficient data comparing PPI therapy with H2RAs [6,57]. In a 2006 meta-analysis that included 12 trials with a total of 2183 patients, H2RAs were associated with a 23 percent reduction in symptoms compared to placebo (RRR 23 percent, 95% CI 8-35 percent) . The NNT with H2RAs to improve one case of dyspepsia was seven subjects. However, the quality of most trials included was poor and there was significant heterogeneity among studies. Another limitation of these studies is that patients with gastroesophageal reflux disease may have been misclassified as having functional dyspepsia.
Antacids are often used, occasionally in combination with viscous lidocaine, to treat dyspepsia, although evidence of their efficacy is lacking . (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Antacids'.)
Subsequent approach — In patients with functional dyspepsia whose symptoms do not improve after eight weeks of PPI therapy, we initiate a therapeutic trial with a tricyclic antidepressant [1,5,6,50]. For patients with a partial clinical response to a PPI, a tricyclic antidepressant can be initiated as combination therapy. For patients who fail to improve on a PPI, the PPI should be stopped and a tricyclic antidepressant initiated. Given the side effects associated with prokinetics and the limited evidence of efficacy, we reserve the use of prokinetics for patients who fail tricyclic antidepressant (TCAs). We suggest psychotherapy in motivated patients who associate symptoms with stressors and in patients who fail medical therapy.
Antidepressants — Central mechanisms may contribute to functional dyspepsia either through increased upper gastrointestinal sensitivity or through other mechanisms. We suggest TCAs in patients with functional dyspepsia and persistent symptoms despite PPI therapy for eight weeks .
We begin with a TCA at a low dose (eg, amitriptyline 10 mg or desipramine 25 mg at night). The dose may be increased at two-week intervals. A dose of 20 to 30 mg is adequate in many patients, and we do not exceed a dose of 75 mg in most patients. Higher doses may not be more effective than lower doses and may be associated with daytime sedation and other anticholinergic side effects. We usually continue the TCA for 8 to 12 weeks before stopping, if it is ineffective. If the patient responds in a few weeks, we usually continue the drug for about six months and then try stopping the drug. The TCA can be resumed if dyspepsia recurs. While some clinicians prefer to use trazodone rather than amitriptyline or desipramine, there is little clinical data to support its use.
The use of TCAs is limited by their side effects which include constipation, dry mouth, urinary retention, and somnolence. In a randomized controlled trial, 107 patients with functional dyspepsia refractory to PPI therapy and prokinetics were assigned to low dose imipramine (50 mg daily) or placebo for 12 weeks . Patients treated with imipramine were significantly less likely to have had a treatment failure at 12 weeks as compared with placebo (22 versus 46 percent). However, patients on imipramine were significantly more likely to have withdrawn from the study due to side effects. Low dose TCAs may also improve associated symptoms of insomnia and fibromyalgia in patients with functional dyspepsia [60,61].
Evidence to support the use of selective serotonin reuptake inhibitors in patients with functional dyspepsia are lacking . In one randomized trial, 292 patients with functional dyspepsia were assigned to amitriptyline (50 mg), escitalopram (10 mg) or placebo for 10 weeks . The primary end point of this study was adequate relief of functional dyspepsia symptoms for >5 weeks of the last 10 weeks of the study. Patients randomized to amitriptyline but not escitalopram were more likely to report adequate relief of symptoms as compared with placebo (53, 38, 40 percent, respectively). Based on Rome II symptom criteria, subjects with ulcer-like functional dyspepsia were more than three times as likely to report adequate relief when treated with amitriptyline compared with those who received placebo (OR 3.1; 95% CI 1.1–9.0), but drug and placebo responses in patients with dysmotility-like dyspepsia were similar. In patients with delayed gastric emptying, neither drug differed from placebo in providing adequate relief. Amitriptyline and escitalopram did not delay gastric emptying.
In a subsequent small, randomized trial in which 34 patients were assigned to mirtazapine, an antagonist for histamine, serotonin, and adrenergic receptors or placebo, patients treated with mirtazapine noted an improvement in symptoms of early satiety and weight loss . However, larger studies are required to confirm these results.
Prokinetic agents — We reserve the use of prokinetics (eg, metoclopramide 5 to 10 mg three times daily one-half an hour before meals and at night for four weeks), to patients in whom other therapies have failed and limit their duration to four weeks before discontinuing treatment. If symptoms recur, we repeat a course of therapy, recognizing that up to 30 percent of patients may have side effects, most of which are generally mild and resolve with cessation of therapy . Alternatively, if postprandial nausea is a predominant symptom, then trials of other antiemetic agents can be employed (eg, promethazine, prochlorperazine, meclizine), although data from clinical trials is lacking.
The possible relationship between functional dyspepsia and abnormal gastric emptying provided the rationale for treatment trials of prokinetic agents . In a meta-analysis that included 26 trials with a total of 8788 patients, prokinetics were associated with a reduction in risk of symptom as compared with placebo (RR 0.92 percent, 95% CI 0.88-0.97) . In seven trials that included 263 patients treated with domperidone, the risk of remaining symptomatic was significantly decreased with domperidone (RR 0.7, 95% CI 0.53-0.97) as compared with placebo. Although meta-analyses have demonstrated an improvement in functional dyspepsia in patients treated with prokinetics, these results are driven by small positive studies as larger studies were negative [56,63]. The effect may also reflect publication bias. In addition, several prokinetics are also associated with serious side effects with long-term use and have limited worldwide availability. As examples, metoclopramide is associated with dystonia, parkinsonism type movements, and/or tardive dyskinesia. Both metoclopramide and domperidone are associated with a risk of QT prolongation and arrhythmias.
●Other prokinetic agents
•Acotiamide – Acotiamide is an anticholinesterase drug that may improve gastric motility and gastric accommodation [64-67]. While acotiamide is not widely commercially available, data suggest that acotiamide may improve symptoms in patients with functional dyspepsia. In a meta-analysis of three trials that included 1682 patients with functional dyspepsia, treatment with acotiamide lowered the risk of dyspepsia symptoms as compared with placebo (0.95-0.91-0.99) . However, additional long-term trials are needed to confirm these findings.
•Psychological therapy – Psychological therapy (eg, cognitive behavioral therapy, hypnotherapy, psychotherapy) have been demonstrated to reduce dyspepsia symptoms. In a systematic review of 12 randomized trials that included 1563 patients with functional dyspepsia, all trials reported a benefit of psychological therapy as compared with medical management. In four trials that included 789 patients with functional dyspepsia, psychological therapies reduced the incidence of dyspepsia by 47 percent (RR 0.53; 95% CI 0.44–0.65). However, these studies had significant limitations including a high risk of bias, lack of blinding, and heterogeneity in the type of psychotherapy. Psychotherapy has a high cost and requires patient motivation and commitment [68-71]. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies' and 'Subsequent approach' above.)
THERAPIES WITH UNCLEAR ROLE
●Fundic relaxant drugs – There is limited evidence that relaxing the gastric fundus may improve early satiation and postprandial fullness. In a small randomized trial, buspirone (10 mg, three times daily for four weeks) as compared with placebo increased gastric accommodation and reduced the overall severity of symptoms of dyspepsia, despite slowing gastric emptying of liquids .
●Antinociceptive agents – It is hypothesized that antinociceptive agents (eg, carbamazepine, tramadol, or pregabalin) may impact the central processing of pain, thereby decreasing visceral hypersensitivity that has been associated with functional dyspepsia. However, it is important to recognize there are no successful trials of antinociceptives in patients with functional dyspepsia and evidence to support their use in patients with functional dyspepsia is indirect. As an example, a post hoc analysis of data obtained from six randomized controlled trials in patients with generalized anxiety disorder and prominent gastrointestinal symptoms showed that pregabalin was significantly more effective than placebo in treating both anxiety and gastrointestinal symptoms .
●Complementary and alternative medicine – Several complementary and alternative medicine approaches to functional dyspepsia have been described. However, further studies are needed before they can be recommended [74,75]. A systematic review of several low quality studies involving herbal and natural products, acupuncture, and homeopathy suggested a benefit from peppermint oil and STW5, a European multiherbal preparation that includes peppermint and caraway . STW5 may improve symptoms of functional dyspepsia by stimulating gastric fundic relaxation and antral motility . A subsequent eight-week placebo-controlled trial also found symptomatic improvement in patients treated with STW5 .
●Dietary modification – Although wheat and lipids, can induce dyspepsia, there are limited data to support dietary modification in patients with functional dyspepsia [78-80]. A population case–control study failed to find an association between various culprit foods and functional gastrointestinal disorders .
ADDITIONAL EVALUATION OF PERSISTENT SYMPTOMS — Patients with functional dyspepsia who have persistent symptoms of dyspepsia may require additional testing for an alternate diagnosis. We perform a gastric emptying study to evaluate for gastroparesis in selected patients with refractory functional dyspepsia who have persistent nausea and vomiting or risk factors for delayed gastric emptying (eg, diabetes mellitus). Delayed gastric emptying has been found in approximately 30 percent of patients complaining of dyspeptic symptoms. However, it is important to note that a significant overlap exists between dyspepsia and gastroparesis; and treatment directed at accelerating delayed gastric emptying in these patients may not necessarily improve symptoms. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Evaluation' and "Treatment of gastroparesis".)
PROGNOSIS — Functional dyspepsia has a chronic disease course with symptoms that vary in severity over time . Patients may be asymptomatic for periods of time and subsequently have symptomatic relapses. In two population-based studies of the natural history of functional dyspepsia, over a follow-up of 10 to 12 years approximately 15 to 20 percent of individuals had persistent symptoms and 40 to 52 percent had symptom resolution . In 30 to 35 percent of patients symptoms fluctuated over time and patients met criteria for another functional gastrointestinal disorder.
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SUMMARY AND RECOMMENDATIONS
●The prevalence of functional dyspepsia ranges from 5 to 11 percent worldwide. The pathophysiology of functional dyspepsia is not well understood. Several potential mechanisms have been suggested. (See 'Epidemiology and pathophysiology' above.)
●Patients with functional dyspepsia describe postprandial fullness, early satiety, and/or epigastric pain/ burning. Some patients may have nausea, vomiting, or heartburn, however, these symptoms are usually infrequent. (See 'Epidemiology and pathophysiology' above and 'Clinical manifestations' above.)
●Functional dyspepsia is suspected in patients with a clinical history of postprandial fullness, early satiety, or epigastric pain/burning. A clinical diagnosis of functional dyspepsia requires the fulfillment of symptom-based diagnostic criteria and an evaluation to exclude other causes of dyspepsia (algorithm 1 and table 1). This evaluation consists of a history, physical examination, laboratory studies, and endoscopic evaluation to exclude organic/structural disease to explain the symptoms. The evaluation of a patient with dyspepsia to establish the underlying cause is discussed in detail, separately. (See "Approach to the adult with dyspepsia".)
●The diagnosis of functional dyspepsia is made by the exclusion of other causes of dyspepsia with an upper endoscopy and additional testing, as indicated, based on the symptoms.
●Non-invasive testing for active Helicobacter pylori infection should be performed in patients with functional dyspepsia if gastric biopsies were not obtained for H. pylori on upper endoscopy (algorithm 1). We suggest treatment for H. pylori in patients with functional dyspepsia who test positive for an infection (Grade 2A). (See "Treatment regimens for Helicobacter pylori".)
●We suggest a four- to eight-week trial of a once daily proton pump inhibitor (PPI) in patients with functional dyspepsia and no evidence of H. pylori and patients with persistent symptoms after eradication of H. pylori (table 3) (Grade 2A). (See 'Proton pump inhibitors' above.)
●We suggest a tricyclic antidepressant drug for patients with persistent symptoms after an eight-week trial of a PPI (Grade 2C). We start with a low dose (eg, amitriptyline 10 mg at bedtime or desipramine 25 mg at bedtime) and gradually increase the dose as tolerated. (See 'Antidepressants' above.)
●We suggest the use of prokinetics in patients in whom eradication of H. pylori and a trial of proton pump inhibitor and tricyclic antidepressant has failed (Grade 2C). In such patients, we generally limit a trial of metoclopramide to 5 to 10 mg three times daily one-half an hour before meals and at night for about four weeks. The risk of side effects, including tardive dyskinesia, increase with the cumulative dose and duration of treatment. We refer motivated patients who fail medical therapy and associate symptoms with stressors for psychotherapy. (See 'Prokinetic agents' above.)
●Functional dyspepsia has a chronic disease course with symptoms that vary in severity over time. Patients may be asymptomatic for periods of time followed by symptomatic relapses. (See 'Prognosis' above.)