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]