Dyspepsia (from the Greek “δυς-” (Dys-), meaning hard or difficult, and “πέψη” (Pepse), meaning digestion) is chronic or recurrent pain or discomfort centered in the upper abdomen ^[1] Discomfort, in this context, includes mild pain, upper abdominal fullness and feeling full earlier than expected with eating. It can be accompanied by bloating, belching, nausea or heartburn. Heartburn is excluded from the definition of dyspesia in ICD 10, as it usually has a different cause and management pathway. Many people get dyspepsia. It is often caused by lifestyle factors, such as smoking and diet, but there are some serious causes such as cancer of the stomach, peptic ulcer disease and some medications. When people have dyspepsia but no risk factors for any of the serious causes, it can be labeled undifferentiated dyspepsia and treated without further investigations. When people have been investigated for dyspepsia but no cause has been found it can be labeled as functional dyspepsia.

Dyspepsia has been recognized as a symptom complex since antiquity, but its mechanisms began to be understood only after peptic ulcer disease became a recognizable clinicopathologic entity. The isolation of Helicobacter pylori by Warren and Marshall in 1982 established that most chronic gastritis and peptic ulcer disease are infectious and curable.^[2] This discovery led to the classification of H. pylori as a group 1 human carcinogen in 1994,^[3] the noninvasive “test-and-treat” strategy for uninvestigated dyspepsia,^[4] and the current framing of H. pylori eradication as a gastric cancer prevention strategy.^[5]

Contemporary classification has moved away from the older dichotomy of “ulcer” versus “non-ulcer” dyspepsia. Patients are now categorized along a three-tier framework: uninvestigated dyspepsia (symptoms present but no diagnostic workup yet performed), organic (secondary) dyspepsia (an identifiable structural, H. pylori-related, metabolic, or drug-induced cause is found), and functional dyspepsia (FD) (no explanatory organic disease is found on evaluation, including a normal upper endoscopy). Functional dyspepsia, as redefined by the Rome IV criteria, is further split into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which frequently overlap.^[6] More than 70% of patients with uninvestigated dyspepsia ultimately meet criteria for functional dyspepsia rather than organic disease.^[7]

Functional dyspepsia is now classified as a disorder of gut-brain interaction, affecting approximately 7% of the community, and is diagnosed by the presence of one or more of bothersome epigastric pain, epigastric burning, early satiation, and/or postprandial fullness, present for the last 3 months with symptom onset at least 6 months before diagnosis, in the absence of an identifiable organic cause on evaluation including upper endoscopy.^[8] Functional dyspepsia is heterogeneous, with symptoms associated with several overlapping mechanisms: impaired gastric accommodation (~40%), visceral hypersensitivity to gastric distention (~40%), and mild delayed gastric emptying (~30%); approximately 30% of patients have none of these, and these abnormalities correlate poorly with symptoms and occur in asymptomatic controls. Increasing evidence implicates low-grade duodenal microinflammation (modestly increased eosinophils and mast cells with impaired barrier function) driving an aberrant type 2 helper T (Th2) immune response in a subgroup.^[9][10] These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes. The process may be modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, impaired duodenal mucosal barrier integrity, diet, and lifestyle.

Its causes are divided into two groups:^[6]

• Organic (secondary) dyspepsia: a structural, systemic, metabolic, infectious, or drug-related cause is identified, and symptoms resolve when it is treated.
• Functional dyspepsia (FD): no explanatory disease is found on evaluation.

Approximately 80% of patients with dyspepsia have no structural explanation and are classified as FD.^[9][11] History and examination cannot reliably distinguish organic from functional dyspepsia, and no accurate biomarker exists.^[9][11] The most common organic contributors are gastroesophageal reflux disease, peptic ulcer disease, and NSAID/aspirin use. Myocardial ischemia is the key extra-luminal cause that must not be missed.

Symptoms cannot reliably separate organic from functional dyspepsia, and no single history finding, examination finding, or biomarker distinguishes them. The differential diagnosis is therefore approached in three steps: exclude a limited set of organic mimics, keep myocardial ischemia in mind as the can’t-miss extra-luminal cause, and then apply Rome IV criteria to diagnose functional dyspepsia (FD).^[9] About 80% of patients with dyspepsia have no clinically significant finding at endoscopy. Fewer than 10% have peptic ulcer, and fewer than 0.5% have gastro-esophageal malignancy, so the pretest probability strongly favors FD.^[12] FD must then be distinguished from other disorders of gut–brain interaction (DGBI) and from the chronic nausea and vomiting disorders it overlaps with.^[13]

Dyspepsia is one of the most common upper gastrointestinal symptom complexes. Its frequency depends heavily on how it is defined. Uninvestigated dyspepsia (upper GI symptoms without prior endoscopy) affects approximately 21% of adults worldwide, and about 80% of these individuals have no organic cause at endoscopy.^[14][9] Functional dyspepsia is a disorder of gut–brain interaction defined by Rome criteria.^[6] Rome-criteria functional dyspepsia has a global pooled prevalence of 8.4%.^[15] Under Rome IV criteria, the prevalence is 7.2% worldwide and 10.1% in the United States, with an annual incidence of approximately 3–4%.^[16][13] Functional dyspepsia is more common in women and in adults younger than 40 years. Its prevalence has declined over the past three decades, partly because successive Rome criteria have become stricter.^[15][13] Postprandial distress syndrome accounts for about two-thirds of cases. Overlap with irritable bowel syndrome and other disorders of gut–brain interaction is common. Functional dyspepsia also carries substantial healthcare utilization and economic burden.^[16][9]

Risk factors for the development of dyspepsia are multifactorial and include Helicobacter pylori infection, chronic use of NSAIDs, family history of peptic ulcer disease, prior acute gastroenteritis (post-infectious dyspepsia), emotional stress and psychological comorbidity (particularly anxiety and depression), female sex, tobacco smoking, and dietary factors including increased intake of high-fiber, high-fat, and greasy foods and overconsumption of caffeine.^[6][14] A large meta-analysis of population-based studies found that the prevalence of uninvestigated dyspepsia was significantly higher among women, smokers, NSAID users, and individuals who were H. pylori-positive.^[14] A single Mendelian randomization study provides emerging, genetically-supported evidence for depression and gastroesophageal reflux disease as risk factors for functional dyspepsia; this inference rests on genetic-instrument assumptions and requires replication.^[17] The relationship with body mass index is bidirectional: higher BMI is the more consistent independent predictor of incident functional dyspepsia in longitudinal and large global data, while underweight/leanness is associated with functional dyspepsia in several Asian and primary-care cohorts, and a U-shaped relationship confined to women has been described. Alcohol consumption is a less consistent association. Age ≥60 years is the dominant risk marker for underlying organic or malignant disease and, per the 2017 ACG/CAG guideline, warrants upper endoscopy; alarm features (unintentional weight loss, gastrointestinal bleeding, dysphagia, persistent vomiting, family history of upper GI malignancy) raise concern but do not by themselves mandate endoscopy in patients under 60.^[4]

There is insufficient evidence to recommend routine screening for Dyspepsia.

FD is a chronic, relapsing-remitting disorder of gut-brain interaction (DGBI). Its symptoms fluctuate over years, and it frequently overlaps with or converts to irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD).^[9][13] FD does not progress to structural disease, and longitudinal data show normal life expectancy. However, FD substantially impairs quality of life and carries a heavy burden of psychological comorbidity. Recent data also link FD to increased risks of hospitalization and death.^[18][13] Serious complications arise almost entirely from organic causes. These include peptic ulcer disease, ulcer-related bleeding and iron deficiency anemia, and upper gastrointestinal (GI) malignancy. Upper GI cancer is found in only a small minority of patients with dyspepsia, and approximately one in four of those cancers presents without alarm features.^[19] In organic dyspepsia, prognosis depends on age- and risk-based endoscopy triage. It also depends on eradicating Helicobacter pylori, which heals and prevents peptic ulcers and reduces the incidence of and mortality from gastric cancer.^[4][20]

The history in dyspepsia has three purposes: (1) confirm that symptoms are epigastric-predominant rather than heartburn-predominant; (2) screen for alarm features and age/risk factors that direct endoscopy; and (3) identify culprit medications and H. pylori risk. Symptom pattern alone discriminates poorly between functional and organic causes and should not be used to make an etiologic diagnosis.^[9][21]

The physical examination in dyspepsia is usually normal, and no examination finding reliably distinguishes functional dyspepsia (FD) from organic causes such as peptic ulcer disease, gastroesophageal reflux disease, or upper gastrointestinal malignancy.^[9][22] Mild epigastric tenderness is the most common finding but is nonspecific.^[23] The examination has two main purposes: to detect findings that fall outside the FD spectrum (a palpable mass, lymphadenopathy, organomegaly, jaundice, an acute abdomen, or signs of gastrointestinal blood loss), which redirect the diagnostic pathway, and to elicit Carnett’s sign, which distinguishes chronic abdominal-wall pain from visceral pain and can spare unnecessary gastrointestinal testing.^[9][22]

There is no diagnostic laboratory test for dyspepsia itself. Laboratory evaluation serves three purposes: to detect anemia or other findings that redirect the diagnosis away from functional dyspepsia (FD), to establish Helicobacter pylori status for a test-and-treat strategy and to confirm eradication, and, in selected patients, to investigate uncommon organic causes such as Zollinger-Ellison syndrome (ZES).^[21][10] Current guidance favors a targeted approach; reflexive laboratory panels are low-yield, costly, and may reinforce illness behavior.^[21][10]

Medical therapy for dyspepsia is stepwise, empiric, and symptom-directed. The same treatment sequence applies to uninvestigated dyspepsia and to functional dyspepsia (FD) once organic disease has been excluded: Helicobacter pylori test-and-treat, then a time-limited proton pump inhibitor (PPI) trial, then a central neuromodulator, then a prokinetic, with psychological therapy for non-responders. H. pylori eradication and empiric PPI therapy both carry strong ACG/CAG recommendations; eradication is the only therapy that is potentially disease-modifying, since sustained benefit reclassifies the patient as having H. pylori-associated dyspepsia. Effect sizes across all effective therapies are modest.^[4][10]

Surgery has a limited, narrowly defined role in dyspepsia and is directed almost exclusively at complications of organic disease — principally peptic ulcer disease (PUD) complicated by perforation, refractory haemorrhage, or gastric outlet obstruction, rather than at functional dyspepsia (FD) itself.^[24] Contemporary guidelines, including the British Society of Gastroenterology (BSG) 2022 guideline, explicitly recommend against surgery for refractory FD given the absence of high-quality evidence of benefit and the recognised risk of iatrogenic harm.^[8][13] The marked decline in elective peptic ulcer surgery over recent decades reflects the success of H. pylori eradication and proton pump inhibitor therapy.^[24][25] Procedural interventions such as gastric peroral endoscopic myotomy (G-POEM) and gastric electrical stimulation (GES) are established only in the context of scintigraphically confirmed gastroparesis, not FD per se.^[26]

Primary prevention of dyspepsia targets three modifiable domains: eradication of Helicobacter pylori, prevention of NSAID– and aspirin-related mucosal injury, and lifestyle modification.^[9][27][24] Prevention of organic dyspepsia (peptic ulcer disease, H. pylori-associated dyspepsia, gastric cancer) is supported by stronger evidence than prevention of functional dyspepsia (FD), for which the benefit of lifestyle and dietary measures remains disputed.^[9][13] H. pylori eradication is the only intervention with disease-modifying potential across PUD, gastric cancer, and dyspepsia.^[28][20]

Secondary prevention of dyspepsia aims to prevent symptom relapse and recurrence of the underlying lesion in patients who have already been diagnosed and treated. This includes treated uninvestigated dyspepsia, treated functional dyspepsia (FD), treated Helicobacter pylori-associated dyspepsia, and healed peptic ulcer disease (PUD). FD is a disorder of gut–brain interaction with a chronic, relapsing–remitting course.^[21][4] The main secondary prevention measures are:

• Confirmed and sustained H. pylori eradication
• The lowest effective acid suppression, with periodic deprescribing
• Removal or mitigation of NSAID exposure
• Psychological therapy and central neuromodulators for relapsing FD

Dyspepsia has been recognized as a symptom complex since antiquity, but its mechanisms began to be understood only after peptic ulcer disease became a recognizable clinicopathologic entity. The isolation of Helicobacter pylori by Warren and Marshall in 1982 established that most chronic gastritis and peptic ulcer disease are infectious and curable.^[1] This discovery led to the classification of H. pylori as a group 1 human carcinogen in 1994,^[2] the noninvasive “test-and-treat” strategy for uninvestigated dyspepsia,^[3] and the current framing of H. pylori eradication as a gastric cancer prevention strategy.^[4]

• In 1799, Matthew Baillie described the pathology of gastric ulcer; the development of barium contrast radiography by Walter Cannon in 1897 later allowed peptic ulcer disease to be recognized in living patients and correlated with symptoms.
• In 1916, Walter Alvarez (Mayo Clinic) applied the term “functional dyspepsia” to patients with ulcer-like symptoms and a normal X-ray. This concept is the forerunner of the current definition of functional dyspepsia as dyspepsia without organic pathology at upper gastrointestinal endoscopy.^[3]

• In 1889, Walery Jaworski (Jagiellonian University, Kraków) described spiral-shaped organisms in human gastric washings; similar organisms were later observed in animals by Bizzozero, but the findings were not taken seriously because the stomach was presumed sterile.^[5]
• In the late 1970s, J. Robin Warren, a pathologist in Perth, Australia, observed spiral bacteria overlying the gastric mucosa, predominantly over inflamed tissue.^[5]
• In 1982, Warren and Barry Marshall cultured the organism from 11 patients with gastritis and demonstrated a strong association between its presence and gastric mucosal inflammation; individuals without gastritis did not harbor the organism.^[5] Their 1984 report proposed a causal role in gastritis and peptic ulcer, challenging the prevailing view that ulcers were driven mainly by stress and diet.^[1]
• The organism was initially named Campylobacter pyloridis, then Campylobacter pylori, and finally Helicobacter pylori when its morphologic, structural, and genetic features justified a new genus.^[5]
• Marshall ingested a culture of the organism and developed acute gastritis, fulfilling Koch’s postulates for H. pylori-associated gastritis; the experiment was published in 1985.^[6]
• In 1993, Covacci and colleagues characterized the CagA gene product, an immunodominant antigen associated with cytotoxicity and duodenal ulcer, the first molecular evidence that strain-specific virulence factors influence disease risk.^[7]
• In 1997, the complete H. pylori genome was sequenced, accelerating identification of virulence determinants.^[8]
• In 2005, Warren and Marshall were awarded the Nobel Prize in Physiology or Medicine for the discovery of H. pylori and its role in gastritis and peptic ulcer disease.^[9]

• In 1992, Pelayo Correa summarized the multistep model of intestinal-type gastric carcinogenesis: chronic gastritis → atrophy → intestinal metaplasia → dysplasia, with the initial stages linked to H. pylori infection and high salt intake.^[10]
• In 1991, Wotherspoon and colleagues reported H. pylori-associated gastritis in patients with primary gastric B-cell lymphoma.^[11] In 1993, the same group showed regression of low-grade gastric MALT lymphoma after H. pylori eradication in 5 of 6 patients, the first demonstration that a malignancy could respond to antibiotic therapy alone.^[12]
• In 1994, Parsonnet and colleagues confirmed a prospective association between H. pylori infection and gastric non-Hodgkin lymphoma.^[13]
• In 1994, the International Agency for Research on Cancer classified H. pylori infection as carcinogenic to humans (group 1).^[2]

• In 2002, the Maastricht 2-2000 Consensus Report endorsed a noninvasive “test-and-treat” strategy for H. pylori in younger patients with uninvestigated dyspepsia.^[14]
• In 2001, Chan and colleagues showed that in H. pylori-infected patients with prior ulcer bleeding, eradication alone was comparable to omeprazole in preventing recurrent bleeding with low-dose aspirin, whereas omeprazole was superior for patients taking naproxen.^[15]
• In 2017, the joint ACG/CAG dyspepsia guideline recommended upper endoscopy for patients aged ≥60 years and noninvasive H. pylori testing with treatment if positive for patients <60 years, with eradication also offered to infected patients with functional dyspepsia.^[3]
• In 2024, the ACG H. pylori guideline designated 14-day bismuth quadruple therapy as the preferred first-line regimen when antibiotic susceptibility is unknown and emphasized universal post-treatment test-of-cure.^[16]
• In 2025, an updated meta-analysis of randomized and observational studies found that eradication therapy reduces gastric cancer incidence in healthy H. pylori-positive individuals and in patients after endoscopic mucosal resection of gastric neoplasia, and reduces gastric cancer mortality (RR 0.78 in randomized trials of healthy individuals).^[17]
• In 2025, the Taipei Global Consensus II concluded that H. pylori eradication is an effective gastric cancer prevention strategy that should be offered to all infected adults, with the greatest risk reduction when performed before premalignant changes develop.^[4]

Dyspepsia is a symptom complex referring to chronic or recurrent pain or discomfort centered in the upper abdomen, including epigastric pain or burning, postprandial fullness, and early satiety. Contemporary classification has moved away from the older dichotomy of “ulcer” versus “non-ulcer” dyspepsia. Patients are now categorized along a three-tier framework: uninvestigated dyspepsia (symptoms present but no diagnostic workup yet performed), organic (secondary) dyspepsia (an identifiable structural, H. pylori-related, metabolic, or drug-induced cause is found), and functional dyspepsia (FD) (no explanatory organic disease is found on evaluation, including a normal upper endoscopy). Functional dyspepsia, as redefined by the Rome IV criteria, is further split into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which frequently overlap.^[1] More than 70% of patients with uninvestigated dyspepsia ultimately meet criteria for functional dyspepsia rather than organic disease.^[2]

Dyspepsia is classified according to whether a diagnostic evaluation has been performed and, if so, whether it reveals structural or biochemical disease.

• Refers to patients with dyspeptic symptoms who have not yet undergone endoscopy or other diagnostic testing.
• Initial management is guided by patient age and the presence of alarm features (see algorithm below), per the 2017 American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) joint guideline.^[3]

• Organic dyspepsia accounts for approximately 20-30% of all dyspepsia cases and is present when investigation reveals a structural, infectious, or biochemical explanation for symptoms.
• Recognized causes include peptic ulcer disease, gastroesophageal reflux disease (GERD), gastric or esophageal cancer, pancreatic or biliary disease, medication-induced dyspepsia (e.g., NSAIDs), and H. pylori-associated disease.
• Endoscopy is abnormal or another investigation identifies the causative lesion.
• The 2015 Kyoto Global Consensus Report designated H. pylori’-associated dyspepsia as a distinct clinicopathological entity, separate from functional dyspepsia, defined by dyspeptic symptoms attributable to H. pylori gastritis that resolve or improve following successful eradication; this entity should be excluded before a diagnosis of FD is assigned.^[4]

• Functional dyspepsia (FD) is now defined by the Rome IV criteria (superseding Rome III), which require the presence of one or more of the following symptoms, bothersome enough to interfere with usual activities, with onset at least 6 months before diagnosis and symptoms active for the last 3 months: postprandial fullness, early satiation, epigastric pain, or epigastric burning — with no evidence of structural disease (including a normal upper endoscopy) to explain the symptoms.^[1]
• Patients with predominant heartburn or reflux symptoms should be evaluated for GERD, and a coexisting reflux diagnosis does not exclude FD given the high rate of overlap between the two conditions.
• FD is subdivided into two, frequently overlapping, subtypes:

• Compared with Rome III, the Rome IV criteria significantly reduce diagnostic overlap between PDS and EPS; when patients with any postprandial symptom are classified as PDS, overlap falls to less than 20%.^[5]
• There is no evidence that symptom subtype (PDS versus EPS) predicts differential response to proton pump inhibitor (PPI) therapy, and subtype should not by itself be used to select treatment.^[5]
• Proposed pathophysiological mechanisms contributing to FD include:
  • Impaired gastric accommodation and delayed gastric emptying (motor dysfunction)
  • Visceral hypersensitivity
  • Low-grade duodenal eosinophilic inflammation and impaired mucosal integrity
  • Helicobacter pylori infection (when symptoms persist despite eradication, this is classified as FD rather than H. pylori-associated dyspepsia)
  • Psychosocial factors, anxiety, and depression, consistent with FD’s status as a disorder of gut-brain interaction

• FD commonly overlaps with gastroesophageal reflux disease and irritable bowel syndrome (IBS). In patients clinically fulfilling Rome IV criteria for FD, GERD-FD overlap is more common than either disorder alone, PDS overlaps with GERD more than EPS does, and organic dyspepsia is uncommon in this population.^[6]

Functional dyspepsia is now classified as a disorder of gut-brain interaction, affecting approximately 7% of the community, and is diagnosed by the presence of one or more of bothersome epigastric pain, epigastric burning, early satiation, and/or postprandial fullness, present for the last 3 months with symptom onset at least 6 months before diagnosis, in the absence of an identifiable organic cause on evaluation including upper endoscopy.^[1] Functional dyspepsia is heterogeneous, with symptoms associated with several overlapping mechanisms: impaired gastric accommodation (~40%), visceral hypersensitivity to gastric distention (~40%), and mild delayed gastric emptying (~30%); approximately 30% of patients have none of these, and these abnormalities correlate poorly with symptoms and occur in asymptomatic controls. Increasing evidence implicates low-grade duodenal microinflammation (modestly increased eosinophils and mast cells with impaired barrier function) driving an aberrant type 2 helper T (Th2) immune response in a subgroup.^[2][3] These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes. The process may be modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, impaired duodenal mucosal barrier integrity, diet, and lifestyle.

The pathophysiology of dyspepsia is as follows:^{[4][5][6][7][8][9][10][1][2]}

• The symptoms of functional dyspepsia (FD) are directly caused by multiple, overlapping physiological abnormalities, now understood to include:
  • Abnormal gastric motility. Mild delayed gastric emptying is present in ∼30% of patients (associated with postprandial fullness, nausea, and vomiting), but emptying rate correlates inconsistently with symptoms and accelerating it does not reliably improve them. FD and gastroparesis are increasingly viewed as overlapping ends of a spectrum of gastric sensorimotor disorders rather than identical entities; the distinction remains clinically relevant because FD carries a better prognosis, and part of the reported overlap is an artifact of the low-calorie/low-fat emptying meal and the >10%-retention-at-4-h cutoff.^[11][12][13]
  • Impaired gastric accommodation. Failure of the proximal stomach to relax normally in response to a meal redistributes food to the distal stomach; impaired accommodation is present in up to ~40% of patients and is the abnormality most closely associated with early satiation, postprandial fullness, and unintentional weight loss.^[2][3]
  • Visceral hypersensitivity, characterized by heightened perception of normal gastric distension and duodenal chemosensitivity (particularly to lipids and acid), which correlates with meal-related symptom severity.^[10][2]
  • Low-grade duodenal mucosal inflammation and impaired barrier integrity. Duodenal biopsies in FD show increased intraepithelial and lamina propria eosinophil and mast cell infiltration, with associated downregulation of the tight-junction proteins occludin and claudin, increased paracellular permeability, and abnormal β-catenin and desmosomal protein expression. This “leaky gut” phenotype is thought to allow luminal antigens to activate submucosal immune and neural pathways, driving symptom generation.^[14][15]
  • Duodenal microinflammation and subtype controversy. A 2022 systematic review and meta-analysis confirmed higher duodenal eosinophil and mast cell counts in FD — most pronounced in post-infection FD — but found no significant association with FD subtype (PDS vs EPS), which challenges the concept of eosinophilia as a PDS-specific driver. Post-infection FD accounts for ~10% of cases, with roughly a 2.5–3-fold increased risk ≥6 months after acute gastroenteritis.^[16][2]
  • Altered gut-brain axis signaling. FD is now classified as a disorder of gut-brain interaction; peripheral duodenal signals (immune activation, chemosensitivity) are relayed via vagal and spinal afferent pathways to central pain-processing and emotional regulation centers, which are further modulated by psychological comorbidity, anxiety, and depression.^[1][2]
  • Helicobacter pylori infection and post-infectious states (following acute gastroenteritis) can trigger or perpetuate the above mechanisms through sustained low-grade mucosal inflammation.^[8]
• These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes, with the process modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, diet, and lifestyle.
• If the basis of this model of FD pathogenesis is excessive responsiveness of gastrointestinal function to stress and external stimuli, psychosomatic approaches to alter stress perception could be important treatment options.^[17]

• In functional dyspepsia, routine histology on standard staining is typically unremarkable; the microscopic correlates are quantitative. Case-control studies and meta-analysis show increased duodenal eosinophil and mast cell counts (most marked in post-infection FD), with impaired barrier integrity — reduced expression of tight-junction proteins including ZO-1 (TJP1), increased paracellular permeability, and eosinophils/mast cells located close to submucosal plexus neurones with associated fine-nerve-fibre sprouting. Eosinophil activation/degranulation may correlate with symptoms better than counts alone, and no consistent association with FD subtype has been demonstrated.^[14][16][2]

Dyspepsia is a symptom complex of epigastric pain or burning, postprandial fullness, and early satiation arising from the gastroduodenal region. Its causes are divided into two groups:^[1]

• Organic (secondary) dyspepsia: a structural, systemic, metabolic, infectious, or drug-related cause is identified, and symptoms resolve when it is treated.
• Functional dyspepsia (FD): no explanatory disease is found on evaluation.

Approximately 80% of patients with dyspepsia have no structural explanation and are classified as FD.^[2][3] History and examination cannot reliably distinguish organic from functional dyspepsia, and no accurate biomarker exists.^[2][3] The most common organic contributors are gastroesophageal reflux disease, peptic ulcer disease, and NSAID/aspirin use. Myocardial ischemia is the key extra-luminal cause that must not be missed.

• Myocardial ischemia can present as epigastric pain that mimics dyspepsia, particularly in women, older adults, and patients with diabetes mellitus.
• The 2021 AHA/ACC chest pain guideline explicitly lists the upper abdomen as a location of ischemic pain and notes that among outpatients presenting with chest pain, approximately 10–20% have a gastrointestinal cause, which can mimic myocardial ischemia; symptoms alone do not reliably distinguish the two.^[4]
• Use a low threshold for ECG and troponin testing in these situations:
  • Pain that is exertional or radiates.
  • Pain accompanied by diaphoresis or dyspnea.
  • Patients at higher cardiovascular risk.

Among organic causes, erosive esophagitis, gastric ulcer, and duodenal ulcer are the principal clinically significant findings in primary-care patients undergoing prompt endoscopy for uninvestigated dyspepsia.^[5] In an updated meta-analysis of 15 studies (41,763 participants), erosive esophagitis was the most common abnormality (pooled 11.0%; 95% CI 8.9–13.2%), followed by peptic ulcer (4.4%; 95% CI 2.5–6.7%); more than 85% of examinations were completely normal and gastroesophageal cancer was rare (<0.4%). Notably, only peptic ulcer — and specifically duodenal ulcer — was significantly more common in dyspeptic than non-dyspeptic patients (OR 1.61; 95% CI 1.08–2.39); erosive esophagitis was equally prevalent in both groups (OR 0.89).^[6]

• Under the Kyoto consensus, H. pylori gastritis is an organic (infectious) disease and is not part of FD.^[1][2]
• Classification depends on the response to eradication:
  • Sustained symptom remission for ≥6 months after successful eradication defines H. pylori-associated dyspepsia.
  • Persistent or recurrent symptoms after eradication reclassify the patient as FD.
• Most H. pylori-positive dyspeptic patients are not cured by eradication. Roughly 91% remain symptomatic, and the overall number needed to treat is about 14.^[12]

• Acute infectious gastroenteritis (bacterial, viral, or parasitic) is an established cause of new-onset dyspepsia, termed post-infection FD.
• In a meta-analysis, the pooled odds ratio for FD after gastroenteritis was 2.18 (95% CI 1.70–2.81). Risk was highest within 12 months and declined thereafter.^[13]
• Post-infection FD has a prevalence of approximately 10%.^[14]
• Post-infection onset is associated with weight loss, early satiety, and increased duodenal eosinophils.^[10]

• FD accounts for the large majority of dyspepsia and is a disorder of gut-brain interaction.^[2]
• Its mechanisms are covered in the Pathophysiology microchapter:
  • Impaired gastric accommodation
  • Visceral hypersensitivity
  • Delayed gastric emptying
  • Low-grade duodenal microinflammation
  • Psychological comorbidity
• Associations that increase FD risk are covered in the Risk Factors microchapter; they are not organic causes. They include:
  • Female sex
  • Smoking
  • NSAID use
  • H. pylori status
  • High body mass index
  • Anxiety and depression

• H. pylori-associated dyspepsia: The construct is contested. The same consensus that defines it reclassifies non-responders as FD, and because most eradicated patients remain symptomatic, the entity is small and its long-term validity is debated.^[12]
• FD and gastroparesis: The two may be overlapping or interchangeable syndromes rather than distinct entities, which blurs delayed gastric emptying as a discrete cause.
• Post-infection FD: The magnitude and durability of risk vary widely across studies. The mechanism (residual immune activation vs. change in the duodenal microbiome) is unsettled.^[13][14]

Symptoms cannot reliably separate organic from functional dyspepsia, and no single history finding, examination finding, or biomarker distinguishes them. The differential diagnosis is therefore approached in three steps: exclude a limited set of organic mimics, keep myocardial ischemia in mind as the can’t-miss extra-luminal cause, and then apply Rome IV criteria to diagnose functional dyspepsia (FD).^[1] About 80% of patients with dyspepsia have no clinically significant finding at endoscopy. Fewer than 10% have peptic ulcer, and fewer than 0.5% have gastro-esophageal malignancy, so the pretest probability strongly favors FD.^[2] FD must then be distinguished from other disorders of gut–brain interaction (DGBI) and from the chronic nausea and vomiting disorders it overlaps with.^[3]

The organic mimics below are listed in descending order of frequency in Europe and North America.^[1] For drug-induced dyspepsia, see causes.

Myocardial ischemia can present as epigastric pain that mimics dyspepsia, especially in women, older adults, and patients with diabetes. Symptoms alone do not reliably separate cardiac from gastrointestinal epigastric pain. The Fourth Universal Definition of Myocardial Infarction lists epigastric discomfort as a recognized ischemic symptom that overlaps with gastrointestinal complaints. Obtain an ECG and troponin in higher-risk patients, and whenever the pain is exertional or radiating or comes with diaphoresis or dyspnea.^[10]

Age and alarm features determine who needs upper endoscopy before FD is diagnosed. Both thresholds have shifted from older teaching; see other diagnostic studies for details.

• Age ≥60 years: ACG/CAG recommends upper endoscopy to exclude neoplasia. This is a conditional recommendation based on very low-quality evidence.^[9] ASGE uses a lower threshold of ≥50 years.^[6] AGA has used ≥55 years.
• Age <60 years without alarm features: use non-invasive H. pylori test-and-treat. Urea breath test or stool antigen is preferred over serology. If the test is negative or symptoms persist, start an empiric PPI trial.^[9]
• Alarm features: these include progressive dysphagia, unexplained weight loss, GI bleeding or iron-deficiency anemia, persistent vomiting, palpable mass or lymphadenopathy, jaundice, and family history of upper-GI cancer.
  • Each alarm feature has a low positive predictive value for upper-GI malignancy.
  • ACG/CAG does not recommend endoscopy in patients <60 years solely because an alarm feature is present.
  • Decisions are individualized, for example when there is clinically significant weight loss, rapidly progressive dysphagia, or multiple alarm features.^[9]
• Suspected pancreatic or biliary source (pain radiating to the back, jaundice): obtain ultrasound or CT rather than endoscopy alone.

Once organic disease is excluded, FD must be separated from adjacent DGBI and from chronic nausea and vomiting disorders. Under Rome IV, FD comprises postprandial distress syndrome, epigastric pain syndrome, or an overlap of the two.^[3]

• Review and stop culprit drugs (NSAIDs, aspirin), and establish H. pylori status before further testing.^[11]
• A complete blood count is reasonable because anemia changes the differential. Obtain liver tests when severe episodic epigastric pain suggests a hepatobiliary source. Routine amylase/lipase, thyroid tests, and celiac serology are not recommended because of low yield; see laboratory findings.^[1][11]
• Reserve abdominal ultrasound or CT for suspected biliary or pancreatic disease; routine imaging has low yield.
• Use Carnett’s sign to separate abdominal-wall pain from visceral pain (diagnostic accuracy >90% for chronic abdominal wall pain).^[1]
• Do not reflexively relabel meal-related epigastric burning as GERD, because it is more often FD.^[4]

• Age is the dominant predictor of malignancy. Alarm features have a low positive predictive value, and in patients <60 years they no longer automatically trigger endoscopy.^[9]
• FD and gastroparesis are framed as a shared sensorimotor spectrum rather than mutually exclusive diagnoses.^[3]
• Peptic ulcer is the only endoscopic finding enriched in dyspepsia versus controls. Erosive esophagitis is the most common finding but is similarly prevalent in non-dyspeptic individuals.^[2]

• Endoscopy age threshold: the threshold differs across ASGE (50), AGA (55), and ACG/CAG (60), and should be lower in regions with high gastric cancer incidence.^[9][6]
• FD–gastroparesis boundary: it remains debated whether delayed gastric emptying defines a distinct disease or a point on a continuum.^[12]
• DGBI overlap: FD, IBS, GERD, and functional heartburn frequently coexist, which complicates any single-diagnosis differential.^[1]

• About 80% of dyspepsia is functional, and symptoms cannot separate organic from functional disease.^[1]
• Recurrent or persistent vomiting should prompt consideration of gastroparesis, gastric outlet obstruction, cyclic vomiting, or cannabinoid hyperemesis rather than FD.
• A positive Carnett’s sign points to the abdominal wall and can spare an unnecessary GI workup.

• Ordering endoscopy in a patient <60 years solely because of an isolated alarm feature
• Labeling meal-related epigastric burning as GERD
• Over-relying on gastric emptying studies to separate FD from gastroparesis
• Missing myocardial ischemia presenting as epigastric pain

Dyspepsia is one of the most common upper gastrointestinal symptom complexes. Its frequency depends heavily on how it is defined. Uninvestigated dyspepsia (upper GI symptoms without prior endoscopy) affects approximately 21% of adults worldwide, and about 80% of these individuals have no organic cause at endoscopy.^[1][2] Functional dyspepsia is a disorder of gut–brain interaction defined by Rome criteria.^[3] Rome-criteria functional dyspepsia has a global pooled prevalence of 8.4%.^[4] Under Rome IV criteria, the prevalence is 7.2% worldwide and 10.1% in the United States, with an annual incidence of approximately 3–4%.^[5][6] Functional dyspepsia is more common in women and in adults younger than 40 years. Its prevalence has declined over the past three decades, partly because successive Rome criteria have become stricter.^[4][6] Postprandial distress syndrome accounts for about two-thirds of cases. Overlap with irritable bowel syndrome and other disorders of gut–brain interaction is common. Functional dyspepsia also carries substantial healthcare utilization and economic burden.^[5][2]

• A meta-analysis of 100 study populations (312,415 subjects) estimated the global pooled prevalence of uninvestigated dyspepsia at 20.8% (95% CI 17.8–23.9%). Estimates ranged from 1.8% to 57.0% depending on country and definition.^[1]
• Approximately 80% of individuals with uninvestigated dyspepsia have no organic explanation at endoscopy. Community symptom surveys therefore serve as a reasonable proxy for functional dyspepsia burden.^[2]

• A 2024 meta-analysis of 44 studies (256,915 participants, 40 countries) found a global pooled prevalence of Rome-defined functional dyspepsia of 8.4% (95% CI 7.4–9.5%).^[4]
• Prevalence depends on the Rome iteration used. It is highest under Rome I and lowest under Rome IV, which reflects progressively stricter criteria rather than a true change in disease frequency.^[4]
• The Rome Foundation Global Epidemiology Study surveyed 54,127 internet respondents in 26 countries. It found a pooled Rome IV functional dyspepsia prevalence of 7.2%, ranging from 2.2% in Japan to 12.3% in Egypt.^[7][5]
• In the United States, the prevalence of Rome IV functional dyspepsia is approximately 10.1%. The estimated annual incidence is 3–4%.^[6]

^[4]

• The global prevalence of functional dyspepsia fell from 12.4% in studies conducted during 1990–2002 to 7.3% in studies conducted during 2013–2020.^[4]
• Proposed explanations include:
  • declining Helicobacter pylori prevalence
  • improved sanitation, with fewer post-infectious cases
  • better endoscopic detection, which reclassifies cases as organic disease
  • stricter Rome criteria
• Whether the decline is real or a methodologic artifact remains unsettled.^[4]
• Older epidemiologic figures based on Rome I–III or pre-endoscopy surveys therefore overstate the current Rome IV burden.^[4]

^[4]

• Under Rome IV, community prevalence is highest in young adults and declines with age. In the Rome IV Global Study, the odds ratio was 1.98 for ages 18–39 compared with ages 65 and older.^[5][6]
• This age gradient is the inverse of H. pylori infection, whose prevalence rises with age.^[4]
• Older patients are more likely to seek care, so clinical populations skew older than community populations.^[8]

• Functional dyspepsia is more common in women than in men regardless of the diagnostic criteria used (9.0% vs. 7.0%).^[4]
• Women are affected about 1.6 times as often as men.^[6] In the Rome IV Global Study, female sex was associated with both subtypes:^[5]
  • postprandial distress syndrome: OR 1.60 (95% CI 1.49–1.72)
  • epigastric pain syndrome: OR 1.42 (95% CI 1.27–1.59)

• Prevalence is modestly higher in developing countries than in developed countries (9.1% vs. 8.0%), with wide variation between countries.^[4]
• Ethnic differences are poorly characterized because most surveys sample ethnically homogeneous populations. A multiethnic Malaysian study found higher prevalence among Indian and Malay participants than among Chinese participants. This suggests cultural, dietary, and genetic contributions.^[2]

• In the uninvestigated-dyspepsia meta-analysis, classic risk factors showed only modest associations. The authors concluded that cultural, ethnic, genetic, and dietary factors may contribute more to community prevalence.^[1]
• Acute gastroenteritis roughly triples the odds of new functional dyspepsia more than 6 months later. Post-infectious onset accounts for at least 10% of cases.^[2][6]
• The association with anxiety and depression is bidirectional. About one-third of patients have anxiety, depression, or both.^[9][6]
• Heritability is weak, at approximately 5%.^[9]

^[1]

• In the Rome IV Global Study, postprandial distress syndrome (PDS) was the dominant subtype. It was followed by an overlapping PDS/EPS phenotype and then by epigastric pain syndrome (EPS) alone.^[5]
• Both subtypes decrease in prevalence with advancing age.^[5]
• Overlap with other disorders of gut–brain interaction is common among people meeting functional dyspepsia criteria:^[5]
  • Rome IV irritable bowel syndrome: 26.1%
  • functional heartburn: 9.0%
  • chronic nausea and vomiting syndrome: 7.0%
• Clinical series report IBS overlap in one-third to one-half of patients and GERD-symptom overlap in more than 30%. Overlap is associated with more severe symptoms.^[6]

^[5]

• In the Rome IV Global Study, 53.1% of individuals with functional dyspepsia had seen a physician for their symptoms. This included 39.9% who saw a primary care physician and 27.1% who saw a gastroenterologist.^[5]
• Care-seeking was highest in the overlapping PDS/EPS phenotype (70.1%), compared with about 34% for PDS alone or EPS alone.^[5]
• Medication use was roughly 2 to 2.5 times higher in people with functional dyspepsia than in those without it. Rates of cholecystectomy were also higher (see table below).^[5]
• Symptoms persist in roughly two-thirds of patients. Quality-of-life impairment is comparable to that of other chronic diseases.^[2]
• U.S. cost estimates exceed $5,000 per affected person per year and about $18 billion in aggregate.^[8][2]

^[5]

• Older reviews state that functional dyspepsia does not increase mortality.^[8]
• A 2026 review cites nationwide data suggesting increased risks of hospitalization and death, including suicide.^[6]

• Uninvestigated dyspepsia (about 20%) and functional dyspepsia (about 7–8%) are separate populations. Combining them inflates the functional estimate roughly threefold.^[1][4]
• Community burden skews young and female, while care-seeking populations skew older. Age alone should not lower clinical suspicion of organic disease.^[5][8]
• Prior gastroenteritis, active anxiety or depression, and overlapping IBS or GERD symptoms identify patients at higher probability of functional dyspepsia and greater symptom severity.^[2][6]

Dyspepsia is common: uninvestigated dyspepsia affects approximately 20.8% of the general population under broad definitions, while functional dyspepsia has a global pooled prevalence of approximately 8.4% according to a 2024 systematic review and meta-analysis applying Rome I–IV criteria; prevalence is higher in women (9.0% versus 7.0% in men) and in developing countries (9.1% versus 8.0% in developed countries).^[1] Risk factors for the development of dyspepsia are multifactorial and include Helicobacter pylori infection, chronic use of NSAIDs, family history of peptic ulcer disease, prior acute gastroenteritis (post-infectious dyspepsia), emotional stress and psychological comorbidity (particularly anxiety and depression), female sex, tobacco smoking, and dietary factors including increased intake of high-fiber, high-fat, and greasy foods and overconsumption of caffeine.^[2][3] A large meta-analysis of population-based studies found that the prevalence of uninvestigated dyspepsia was significantly higher among women, smokers, NSAID users, and individuals who were H. pylori-positive.^[3] A single Mendelian randomization study provides emerging, genetically-supported evidence for depression and gastroesophageal reflux disease as risk factors for functional dyspepsia; this inference rests on genetic-instrument assumptions and requires replication.^[4] The relationship with body mass index is bidirectional: higher BMI is the more consistent independent predictor of incident functional dyspepsia in longitudinal and large global data, while underweight/leanness is associated with functional dyspepsia in several Asian and primary-care cohorts, and a U-shaped relationship confined to women has been described. Alcohol consumption is a less consistent association. Age ≥60 years is the dominant risk marker for underlying organic or malignant disease and, per the 2017 ACG/CAG guideline, warrants upper endoscopy; alarm features (unintentional weight loss, gastrointestinal bleeding, dysphagia, persistent vomiting, family history of upper GI malignancy) raise concern but do not by themselves mandate endoscopy in patients under 60.^[5]

Risk factors for the development of dyspepsia can be categorized as common (well-established, higher-strength evidence), less common, and markers of underlying organic/malignant diseases.^{[6][7][8][9][10][11][12][13]}

Common risk factors in the development of dyspepsia include:

• Psychological comorbidity is the strongest risk association: baseline anxiety conferred an ~8-fold higher odds of developing FD in a Swedish population survey, and the gut–brain relationship is bidirectional (anxiety/depression precede FD, and FD predicts later anxiety/depression).^[17]
• Helicobacter pylori infection
• Chronic use of NSAIDs (including low-dose aspirin)
• Family history of peptic ulcer or upper gastrointestinal disease
• Prior episode of acute gastroenteritis (post-infectious dyspepsia)
• Female sex
• Tobacco smoking
• Eating meals too quickly or consuming too much food at meals
• Overabundance of high-fiber foods
• Overconsumption of caffeine
• Spicy, high-fat, and greasy foods
• Coexisting gastroesophageal reflux disease
• Downgrade note: meal-related dietary factors (high-fat/greasy, spicy, high-fiber foods, caffeine) are better characterized as symptom triggers and primary-prevention targets than as validated risk factors for the development of functional dyspepsia; see primary prevention.

Less common risk factors in the development of dyspepsia include:

• Alcohol consumption
• Psychological stress (independent of anxiety/depression)

According to the 2017 ACG/CAG Clinical Guideline, the presence of alarm features confers a 2- to 3-fold relative increase in the pre-test probability of upper gastrointestinal malignancy, but the absolute risk in patients under 60 remains well below 1%, and the guideline conditionally recommends against upper endoscopy on the basis of alarm features alone in this age group. Alarm features have a low positive predictive value for GI cancer (<11%) with a high negative predictive value (>97%). Upper endoscopy is recommended for new-onset dyspepsia in patients ≥60 years, with a lower threshold in those at increased gastric cancer risk (childhood in a high-incidence region, family history of gastric cancer, male sex) and, on a case-by-case basis, in patients <60 with prominent or combined alarm features (e.g., weight loss >20 lb, rapidly progressive dysphagia).^[5][19][20]

Template:WikiDoc Sources

Secondary prevention of dyspepsia aims to prevent symptom relapse and recurrence of the underlying lesion in patients who have already been diagnosed and treated. This includes treated uninvestigated dyspepsia, treated functional dyspepsia (FD), treated Helicobacter pylori-associated dyspepsia, and healed peptic ulcer disease (PUD). FD is a disorder of gut–brain interaction with a chronic, relapsing–remitting course.^[1][2] The main secondary prevention measures are:

• Confirmed and sustained H. pylori eradication
• The lowest effective acid suppression, with periodic deprescribing
• Removal or mitigation of NSAID exposure
• Psychological therapy and central neuromodulators for relapsing FD

• When H. pylori is the cause, eradication is the most durable secondary prevention measure.
  • In PUD, eradication reduces ulcer recurrence from ~50–60% to 0–2%.^[3]
  • Confirmed eradication essentially eliminates recurrent ulcer bleeding without the need for maintenance antisecretory therapy.^[5]
• Long-term follow-up (up to ~4.25 years) showed no ulcer recurrence in H. pylori-negative patients. Patients who remained H. pylori-positive relapsed progressively. Eradication therapy was superior to long-term maintenance antisecretory therapy.^[6]
• Confirm eradication with a test of active infection:^[2]
  • Use a urea breath test or monoclonal stool antigen test, not serology.
  • Test at least 4 weeks after completing therapy and at least 2 weeks after stopping PPI.
  • US post-eradication reinfection is uncommon (~1% per year; 95% CI 0.3–3%), except in Alaska Native populations (>8% per year); recurrent symptoms therefore rarely reflect true reinfection.^[7]
  • Failure to confirm eradication is a common cause of avoidable recurrence.
• Recurrent dyspepsia or ulcer after presumed successful eradication warrants retesting for active infection. Persistent infection or reinfection, not inadequate acid suppression, drives most true ulcer recurrence.^[6][3]
• In FD, H. pylori is considered causal only when eradication produces sustained symptom benefit.
  • The benefit is modest (NNT 14 for symptom cure, 9 for improvement; larger when eradication is confirmed, NNT 4.5), and most eradicated FD patients do not become symptom-free.^[7]
  • Recurrent FD symptoms should therefore not be reflexively attributed to reinfection.
• If eradication fails, vonoprazan-based regimens are an option in clarithromycin-resistant infection.^[8] Regimen details belong in the medical therapy microchapter.

• In H. pylori-negative FD, or FD persisting after eradication, PPI therapy is first-line.^[2][4]
  • Give a standard once-daily PPI for 4–8 weeks.
  • Stop it if the response is insufficient; dose escalation offers no benefit.
• Long-term PPI should not be continued without a withdrawal attempt every 6–12 months.^[2]
• The 2022 AGA Clinical Practice Update on PPI de-prescribing recommends:^[9]
  • Offer a de-prescribing trial to all patients without a definite chronic PPI indication. FD is not a definite chronic indication.
  • Step twice-daily users down to once-daily.
  • Either tapering or abrupt discontinuation is acceptable.
  • On-demand PPI, or an as-needed H2RA or antacid, is an effective partial de-prescribing strategy for breakthrough symptoms.
• Rebound acid hypersecretion can follow PPI withdrawal, even after only a few months of use.^[9][10]
  • Counsel patients in advance.
  • Consider a 2–4 week taper to improve the proportion who remain off therapy.
  • Symptoms persisting more than 2 months after discontinuation suggest a continuing indication.

• Discontinuing the NSAID heals ~95% of ulcers and reduces recurrence from ~40% to ~9%.^[3]
• If an NSAID must be continued, reduce recurrence by:^[3]
  • Co-prescribing a PPI
  • Eradicating H. pylori
  • Switching to a COX-2 inhibitor combined with a PPI
• In patients taking low-dose aspirin for secondary cardiovascular prevention who have had ulcer bleeding, continue (or promptly resume, typically within 1–7 days of hemostasis) aspirin with long-term PPI co-therapy rather than discontinuing it, and eradicate H. pylori if present. Aspirin plus PPI is superior to switching to clopidogrel alone for preventing rebleeding.^[5][8][11]

• Psychological comorbidity is common in FD and is a major contributor to relapse and healthcare utilization.^[1]
• Psychological therapy:
  • The ACG/CAG guideline recommends psychological therapy for FD not responding to drug therapy (conditional recommendation, very low quality evidence). The pooled NNT was 3 across 12 RCTs.^[2][1]
  • Benefits of cognitive behavioral therapy and gut-directed hypnotherapy appear durable and reduce healthcare utilization.^[12][1]
  • In one hypnotherapy trial, no treated patient required medical therapy at 1 year, compared with 82–90% of controls.^[12][1]
  • A 2022 meta-analysis (14 RCTs, 1,434 patients) found that psychological interventions improve dyspeptic symptoms and reduce anxiety and depression.^[13]
• Central neuromodulators are used for refractory or relapsing FD within a stepwise treatment algorithm.^[14][15]
  • Options include tricyclic antidepressants and 5-HT1A agonists such as buspirone for the postprandial distress subtype.
  • Benefit among central neuromodulators is concentrated in tricyclic antidepressants (NNT 6, greatest in epigastric-pain/EPS phenotypes); SSRIs are ineffective and most SNRIs are unproven.^[2][16]
  • Dosing belongs in the medical therapy microchapter.

• Sustained dietary measures (small, frequent, low-fat meals) and moderate exercise are low-risk adjuncts.
• Evidence that these measures prevent relapse is weak.^[4][14]

• Confirmatory eradication testing. The 2024 ACG guideline recommends universal post-treatment test of cure in all patients with dyspepsia treated for H. pylori, irrespective of symptom response, because symptom response correlates poorly with eradication success.^[7] Older frameworks that reserved confirmation for higher-risk patients are now superseded; residual uncertainty is limited mainly to unselected, low-risk, asymptomatic populations.
• Optimal deprescribing method: whether tapering reduces rebound more than abrupt discontinuation is unproven.^[9][10]
• Evidence for eradication therapy in preventing ulcer recurrence is rated very low quality in the Cochrane review, and older regimens limit applicability.^[17]
• Durability of FD symptom control with any modality is limited by the relapsing natural history. Dedicated relapse-prevention trials are few.^[14]

• Continuing indefinite standard- or double-dose PPI in FD without periodic withdrawal attempts.^[2]
• Failing to confirm H. pylori eradication, then mislabeling recurrent symptoms as refractory FD.^[2]
• Escalating PPI for recurrent ulcer instead of retesting for persistent H. pylori infection.^[6]
• Stopping cardioprotective aspirin after an ulcer instead of continuing it with PPI cover.^[5]
• Attributing rebound hyperacidity after PPI withdrawal to disease relapse, which leads to unnecessary lifelong PPI.^[10]
• Overlooking psychological comorbidity in patients with relapsing FD.^[1]

Dyspepsia is a symptom complex of the gastroduodenal region. It comprises epigastric pain or burning, postprandial fullness, and early satiety. After investigation, most patients have no structural explanation and are classified as having functional dyspepsia (FD).^[1] FD is a chronic, relapsing-remitting disorder of gut-brain interaction (DGBI). Its symptoms fluctuate over years, and it frequently overlaps with or converts to irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD).^[1][2] FD does not progress to structural disease, and longitudinal data show normal life expectancy. However, FD substantially impairs quality of life and carries a heavy burden of psychological comorbidity. Recent data also link FD to increased risks of hospitalization and death.^[3][2] Serious complications arise almost entirely from organic causes. These include peptic ulcer disease, ulcer-related bleeding and iron deficiency anemia, and upper gastrointestinal (GI) malignancy. Upper GI cancer is found in only a small minority of patients with dyspepsia, and approximately one in four of those cancers presents without alarm features.^[4] In organic dyspepsia, prognosis depends on age- and risk-based endoscopy triage. It also depends on eradicating Helicobacter pylori, which heals and prevents peptic ulcers and reduces the incidence of and mortality from gastric cancer.^[5][6]

• FD is a chronic, relapsing-remitting condition. Permanent spontaneous resolution is uncommon, but symptom intensity fluctuates substantially over time.^[1][3]
• In population cohorts followed for 10 years, FD prevalence stays stable at approximately 13–16%, which reflects continuous turnover of cases.^[1] Worldwide pooled prevalence is 7.2% (10.1% in the United States). FD affects women 1.6 times as often as men and is more common before age 40. Annual incidence is approximately 3–4%.^[2]
• Long-term trajectories in population studies:^[1]
  • Approximately 50% of patients have symptom resolution.
  • 10–20% have persistent symptoms.
  • 30–40% transition to IBS, GERD, or both.
• In a referral-center cohort followed for 5 years, symptoms disappeared in 17.4%, improved in 38.3%, were unchanged in 30.8%, and worsened in 13.4%.^[7]
• The Rome IV subtypes, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), frequently coexist and interconvert over time. Subtype assignment therefore has limited long-term prognostic value.^[1][8]

• Anxiety is the most reproducible predictor of trajectory. Lower baseline anxiety predicts symptom resolution. Higher anxiety predicts new-onset FD and transition to GERD or IBS.^[1]
• At 5 years, baseline symptom severity, trait anxiety, and weight loss at presentation independently predicted symptom burden and quality of life.^[7]
• Factors associated with development or persistence of FD include:^[1][2]
  • Psychological comorbidity
  • Prior acute gastroenteritis (post-infectious FD)
  • Female sex
  • Smoking
  • Non-steroidal anti-inflammatory drug (NSAID) use
  • H. pylori infection

• FD frequently overlaps with IBS and GERD. Patients with overlap have more severe symptoms.^[2]
• In a longitudinal cohort of 807 individuals meeting Rome IV criteria for IBS, 446 (55.3%) also met criteria for FD. At follow-up, the IBS-FD overlap group had more severe and continuous abdominal pain than the IBS-only group. The overlap group also had:^[9]
  • Greater limitation of daily activities
  • More physician consultations and new treatments
  • Higher anxiety, depression, and somatization scores
• Among 202 patients with Rome IV FD, overlapping IBS or reflux was associated with greater GI and psychological symptom burden. Gastric emptying, duodenal immune activation and permeability, and salivary cortisol were similar with or without overlap. This suggests that central symptom processing, rather than more severe peripheral pathophysiology, drives the worse phenotype.^[10]

• Organic dyspepsia is most often due to H. pylori-associated gastritis or peptic ulcer disease, drug-induced injury (NSAIDs), or, rarely, malignancy.^[5]
• Chronic H. pylori gastritis can progress through atrophic gastritis and gastric intestinal metaplasia (GIM) to dysplasia and intestinal-type gastric adenocarcinoma (the Correa cascade). GIM is the key precursor lesion that warrants endoscopic surveillance in selected patients.^[11]

Uncomplicated FD does not progress to structural disease. Clinically significant complications arise from organic causes.^[3][5]

• Peptic ulcer disease and upper gastrointestinal bleeding
• Iron deficiency anemia from chronic blood loss due to gastritis or ulcers
• Upper GI malignancy: gastric adenocarcinoma and esophageal cancer
• Vitamin B12 deficiency and pernicious anemia in patients with atrophic or autoimmune gastritis
• Chronically impaired health-related quality of life, with high psychological comorbidity (anxiety, depression, somatization). This is the dominant morbidity of FD.^[1][9]

• In a meta-analysis of 16,161 patients from cohort studies, the mean prevalence of upper GI malignancy was 2.8%.^[4] A later systematic review of 57,363 patients found cancer in 0.8%.^[12]
• Alarm features have a high negative predictive value but a low positive predictive value. Approximately 25% of patients with upper GI cancer have no alarm features at diagnosis.^[4]
• The features with the strongest predictive value are persistent vomiting, dysphagia, and GI bleeding or anemia, particularly in patients younger than 50 years.^[13]
• A multicenter Dutch study compared 7,209 patients younger than 60 with alarm symptoms against 13,978 younger patients with dyspepsia alone. Major endoscopic findings were significantly more common with alarm symptoms (9.5% vs. 3.7%), as was cancer (1.7% vs. 0.3%). Dysphagia, unintentional weight loss, and persistent vomiting were significantly associated with cancer. These findings challenge guideline advice against routine endoscopy below age 60.^[14]

• FD has an excellent prognosis for survival. Longitudinal studies show normal life expectancy regardless of H. pylori status.^[3][1]
• More recent data suggest that FD may be associated with increased risks of hospitalization and death. This signal is not attributed to structural GI progression.^[2]
• Health-related quality of life is consistently reduced, and healthcare use and costs are substantial.^[5][1]
• Psychological comorbidity is a major determinant of symptom severity, persistence, and quality of life. The gut-brain relationship is bidirectional: anxiety can precede or follow the onset of FD.^[1][7]
• Overlap with other conditions defines a higher-burden phenotype with worse outcomes across all domains. Symptom burden rises and quality of life falls as overlapping conditions accumulate, including IBS, GERD, and bladder pain syndrome.^[9][10][15]

• H. pylori eradication heals peptic ulcers and prevents their recurrence.^[16]
• In a 2025 meta-analysis of randomized controlled trials (RCTs), eradication reduced gastric cancer incidence in the following groups:^[6]
  • Healthy H. pylori-positive individuals: 8 RCTs; relative risk (RR) 0.64; 95% CI 0.48–0.84
  • Patients undergoing endoscopic mucosal resection for gastric neoplasia: 3 RCTs; RR 0.52; 95% CI 0.38–0.71
• In the same meta-analysis, eradication also reduced death from gastric cancer in healthy infected individuals (5 RCTs; RR 0.78; 95% CI 0.62–0.98). Observational studies showed consistent effects.^[6]
• Most trial evidence comes from high-incidence East Asian populations. Extrapolation to low-incidence Western populations is less certain.^[6][17]
• Once GIM or dysplasia is established, eradication alone is insufficient. Patients with confirmed GIM or dysplasia, especially severe or extensive GIM, may need surveillance endoscopy approximately every 3 years. Patients with resected dysplasia or early cancer need ongoing surveillance for metachronous lesions.^[11]
• Prognosis in organic dyspepsia is therefore triage-dependent. It hinges on:
  • Age-based endoscopy. ACG/CAG recommends endoscopy for patients 60 years or older; ASGE recommends initial endoscopy at 50 years or older or with alarm features.^[5][18]
  • Non-invasive H. pylori test-and-treat in younger patients.^[5]
  • Confirmation of eradication after therapy.^[16]
  • Targeted gastric cancer screening in high-risk US groups. These include first-generation immigrants from high-incidence regions, patients with a first-degree relative with gastric cancer, and carriers of hereditary cancer syndromes.^[11]

• There is no consensus on the age threshold for endoscopy, and recommendations differ across guideline bodies.^[5][18]
• The value of routine endoscopy for alarm features in patients younger than 60 is contested.^[14]
• It is unclear how far eradication benefits apply to low-incidence Western populations.^[6][17]
• The reported association between FD and excess hospitalization and mortality requires confirmation and mechanistic clarification.^[2]