Dyspepsia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

The current understanding of the pathogenesis of dyspepsia began with the first description of gastric ulcer disease in 1799. The term was first used in its current form in 1916 by Walter Alvarez.

Dyspepsia is broadly classified into two major types: ulcer and non-ulcer dyspepsia. The latter is also known as functional dyspepsia.

The symptoms of functional dyspepsia are directly caused by two major pathophysiological abnormalities abnormal gastric motility and visceral hypersensitivity.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.

Life threatening causes of dyspepsia include coronary disease and ischemic bowel disease. Other common causes of dyspepsia include gastroesophageal reflux, gastritis, lactose intolerance, and peptic ulcer.

Dyspepsia must be differentiated from other diseases that presents with epigastric pain such as gastritis, gastroesophageal reflux disease, acute pancreatitis, primary biliary cirrhosis, cholelithiasis, gastric outlet syndrome, myocardial infarction, pleural empyemae appendicitis

The incidence of new cases of H. pylori infection each year ranges from 3,000 to 10,000 per 100,000 individuals in developing countries. It has been observed that with advancing age, the incidence of H. pylori infection increases. In united states, 20% of adolescents are infected with H. pylori when compared to 90% by 5 years of age in the developing countries. In United States, H. pylori infection associated gastritis is more common in African Americans (54%), Hispanics (52%), and the elderly compared to Whites (21%). In acute gastritis, females are usually more affected than men. In H. pylori infection associated gastritis, males are more commonly affected than females. The incidence rates of H. pylori infection are high in Japan, Columbia, Costa Rica and China, and comparatively low in the United States. H. pylori infection is common in Southern and Eastern Europe, Mexico, South America, Africa, most Asian countries, and aboriginal people in North America.

The secondary prevention strategies for gastritis following H. pylori infection to prevent recurrence of peptic ulcer disease and gastric cancer include the use of antibiotics to prevent recurrence of infection and the post-treatment confirmation of H. pylori eradication after treatment using diagnostic tests.

There is insufficient evidence to recommend routine screening for Dyspepsia.

Dyspepsia usually persists throughout life and the chance of spontaneous healing is rare. Dyspepsia is most commonly associated with Helicobacter pylori infection. Increase in the prevalence of dyspepsia is attributed to the increasing age and the onset varies among different ethnicities. The increased risk of developing duodenal and peptic ulcers have been observed in individuals with persistent dyspepsia.

Dyspepsia is associated with complications such as peptic ulcers, anemia due to gastritis, stomach cancer, vitamin B12 deficiency, pernicious anemia.

Functional dyspepsia is a long-lasting disorder with an excellent prognosis regardless of H. pylori infection.

The history and symptoms of dyspepsia are as follows: pain or a burning feeling in the upper portion of the stomach, nausea, bloating, sometimes uncontrollable burping, heartburn, fever, metallic taste, rumbling in the stomach, sense of fullness after eating, feeling as though something is lodged in the esophagus, pain and discomfort at the xiphoid region, sudden chills, comparable to those felt during fevers

Patients with dyspepsia may appear pale. Some patients may appear fatigued and in distress, is associated with abdominal pain. Vital signs generally appear to be normal. When associated with gastrointestinal bleed, vital signs include tachycardia. Pallor may observed in patients presenting with melena and hematemesis. On examination of the eyes, conjunctival pallor may be observed. Halitosis may be observed in case of chronic gastritis. Chest tenderness may be present on palpation in case of Helicobacter pylori infection associated gastritis. Epigastric tenderness may be present. Gastritis associated with gastric ulcers may result in blood loss and the stool test may be guaiac-positive.

There is no specific diagnostic laboratory test for dyspepsia but in the patient with the history of dyspepsia, the laboratory test is used to rule out bleeding and to document the status of eradication therapy and to test refractory ulcers

People without risk factors for serious causes of dyspepsia usually do not need investigation beyond an office-based clinical examination. However, people over the age of 55 years and those with alarm features are usually investigated by esophagogastroduodenoscopy (EGD or OGD in Britain). In this painless investigation the esophagus, stomach, and duodenum are examined through an endoscope passed down through the mouth. This will rule out peptic ulcer disease, medication-related ulceration, malignancy and other rarer causes.

There are no other diagnostic studies associated with dyspepsia.

Functional and undifferentiated dyspepsia have similar treatments. Decisions around the use of drug therapy are difficult because trials included heartburn in the definition of dyspepsia. This led to the results favoring proton pump inhibitors (PPIs), which are questionably effective for the treatment of heartburn.

Surgical intervention is not recommended for the management of dyspepsia

Effective measures for the primary prevention of dyspepsia include avoiding long-term or extended use of medications such as NSAIDs, abstinence from alcohol, smoking cessation, coffee or acidic beverages, spicy foods and avoiding stress. Inculcating healthy eating habits, exercising regularly and maintaining healthy body weight may help in avoiding dyspepsia. Effective measures for primary prevention of the H. pylori infection include hand washing (antibacterial soaps), avoid contaminated food and water, maintain proper hygiene (hand sanitizers, antiseptic washes) and avoid close contact with infected family members ( e.g., kissing, sharing eating utensils and drinking glasses).

The secondary prevention strategies for dyspepsia following H. pylori infection to prevent recurrence of peptic ulcer disease and gastric cancer include the use of antibiotics to prevent recurrence of infection and the post-treatment confirmation of H. pylori eradication after treatment using diagnostic tests.

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The current understanding of the pathogenesis of dyspepsia began with the first description of gastric ulcer disease in 1799. The term was first used in its current form in 1916 by Walter Alvarez.

• Indigestion is an old english word meaning ‘lack of digestion’, and the symptoms of dyspepsia have known since the birth of medicine. However, the underlying pathogenesis of dyspepsia only began to be understood when Baillie in 1799 first described the pathology and symptoms of gastric ulcer disease.
• Development of barium X-ray radiology by Cannon in 1897 led to the clinical recognition of peptic ulcer disease and its relationship with symptoms.
• Walter Alvarez at the Mayo Clinic in Rochester, MN was the first to apply the term ‘functional dyspepsia’ in 1916 to describe patients with ulcer-like symptoms and a normal X-ray.
• In pre-16th century:
  • Hippocrates gave a detailed describtion of the symptoms of peptic ulcer disease
  • Avicenna described the relationship between abdominal pain and mealtimes in peptic ulcer patients^[1]
• In 1586, Marcellus Donatus of Mantua described gastric ulcers by performing autopsies
• In 1688, Johannes von Murault gave detailed description of duodenal ulcers
• In 1812, Broussais found that if acute gastritis is left untreated, it may lead to chronic gastritis
• In 1821, Nepveu found a relationship between gastritis and gastric cancer
• In 1857, William Brintonin described ulcer of the stomach and gastric cancer in his book
• In 1875, G.Bottcher and M. Letulle hypothesized that ulcers are caused by bacteria
• In 1880, J.Cohnheim found that ulcers may be caused by chemical factors
• In 1889, Walery Jaworski found spiral-shaped organisms in sediment washings of humans and proposed that these organisms may be involved with gastric disease
• In 1910, Moynihan wrote a book on duodenal ulcer^[2]
• In 1971, Howard Steer found H. pylori from biopsies of a patient with ulcers^[3][4]
• In late 1970, J.R Warren, a pathologist in Perth, Australia found the appearance of spiral bacteria overlying gastric mucosa^{[4]_CDC_Ulcer-5|[5]}
• In 1982 , Warren and B.J marshall cultured the organism and found a strong association between Helicobacter pylori and inflammation of gastric mucosa^{[4]_CDC_Ulcer-5|[5]}
• In an act of self-experimentation Marshall drank a petri-dish containing a culture of organisms extracted from a patient and soon developed gastritis.
• His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife.This experiment was published in 1984 in the Australian Medical Journal^[6]
• In 1994, Parsonnet et al found an association between H. pylori and lymphomas of the gastrointestinal tract^[7]
• In 1997 Tomb et al. completed sequencing of the entire 1,667,867 base pairs of the H. pylori genome. This helped in identifying new virulence factors for the infectivity of H. pylori at the molecular level^[8]
• In 2001, Chan et al. showed that eradication of H. pylori prevents bleeding from ulcers that is caused by aspirin and non-steroidal anti-inflammatory drugs^[9]
• In 2002, European Helicobacter pylori Study Group published the Maastricht 2-2000 Consensus Report, and found a “test-and-treat” strategy for H. pylori in young patients without typical symptoms. It suggested the use of noninvasive testing to evaluate for H. pylori ^[10]
• In 2005 Warren and Marshall awarded the Nobel Prize in medicine by Karolinska Institute in Stockholm for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease^[11]

• In 1992,Covacci discovered CagA gene, which encodes for a cytotoxin-associated surface protein, related with strains of H. pylori that caused duodenal ulcers and was discovered by molecular techniques were first involved in the pathogenesis of peptic ulcer disease ^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

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]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

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 bothersome epigastric pain or burning, early satiation, and/or postprandial fullness for longer than 8 weeks in the absence of an identifiable organic cause.^[1] The symptoms of functional dyspepsia are directly caused by two major pathophysiological abnormalities in gastric motility and visceral sensitivity, with recent evidence adding impaired gastric accommodation and low-grade duodenal mucosal inflammation, including duodenal eosinophilia and increased mast cell density, as key contributory mechanisms.^[2] 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:^{[3][4][5][6][7][8][9][1][2]}

• In humans, digestion begins in the mouth where food is chewed.
• Salivary amylase aids in the chemical breakdown of polysaccharides such as starch into disaccharides such as maltose.
• The chewed food is pushed down the esophagus into the stomach through peristaltic contraction of these muscles.
• Food enters the stomach where it is further broken down and thoroughly mixed with gastric acid, pepsin, and other digestive enzymes to break down proteins, fats and carbohydrates.
• After consumption of food, digestive “tonic” and peristaltic contractions begin, which helps break down the food and move it through the gastrointestinal tract. Gastric emptying is the release of food from the stomach into the duodenum.
• Gastric emptying has attracted medical interest as rapid gastric emptying is related to obesity and delayed gastric emptying syndrome is associated with diabetes mellitus, aging, gastroparesis and gastroesophageal reflux.
• After being processed in the stomach, food is passed to the small intestine. The majority of digestion and absorption occurs here after the milky chyme enters the duodenum. Here it is further mixed with three different digestive juices:
  • Bile which is produced by the liver and stored in the gallbladder emulsifies fats and neutralizes the chyme.
  • Pancreatic juice made by the pancreas. It secrete enzymes such as pancreatic amylase, pancreatic lipase, and trypsinogen.
  • Intestinal juice secreted by the intestinal glands in the small intestine. It contains enzymes such as enteropeptidase, erepsin, trypsin, chymotrypsin, maltase, lactase, and sucrase.

• The symptoms of functional dyspepsia (FD) are directly caused by multiple, overlapping physiological abnormalities, now understood to include:
  • Abnormal gastric motility, including delayed gastric emptying. Gastroparesis and functional dyspepsia may be the same entity, as tertiary-care cohorts show overlapping clinical and pathological features between the two syndromes.^[10]
  • Impaired gastric accommodation. Failure of the proximal stomach to relax normally in response to a meal results in uneven food distribution, antral pooling of chyme, and premature antral distension; impaired accommodation is present in up to one-third of patients and correlates most closely with early satiation and 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.^[9][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.^[11][12]
  • 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.^[7]
• 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.^[13]

• Gastric ulcers are most often localized on the lesser curvature of the stomach
• Duodenal ulcers are more located at bulb of duodenum
• Characteristic findings of a peptic ulcer on gross pathology include:
  • Round to oval
  • Two to four cm diameter
  • Smooth base with perpendicular borders.
  • Parietal scarring with radial folds may be evident in the surrounding mucosa

• 
  A benign gastric ulcer (from the antrum) of a gastrectomy Source:https://commons.wikimedia.org/wiki/File:Benign_gastric_ulcer_1.jpg#/media/File:Benign_gastric_ulcer_1.jpg
• 
  Duodenal ulcer specimen. Source: https://commons.wikimedia.org/wiki/File:Duodenal_ulcer01.jpg#/media/File:Duodenal_ulcer01.jpg
• 
  Gastric ulcer specimen Source:https://commons.wikimedia.org/wiki/File:Gastric_ulcer_3.jpg#/media/File:Gastric_ulcer_3.jpg

• A peptic ulcer is a mucosal defect produced by acid-pepsin aggression which penetrates the muscularis mucosae and muscularis propria
• There is increased plasma cells, neutrophilic infiltrate, villous blunting
• The surface epithelium usually shows mucous cell (pseudopyloric) metaplasia
• During the active phase, the base of the ulcer shows 4 zones:
  • Inflammatory exudate: polymorphonuclear infiltration which along with bacterial products stimulate the production of IL-8 and tumor necrosis factor alpha (TNF-α) and IL-1 released by macrophages in response to bacterial lipopolysaccharide
  • Fibrinoid necrosis
  • Granulation tissue
  • Fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis^[14]
• In functional dyspepsia specifically, routine histology is typically unremarkable on standard staining, but quantitative studies using specialized immunohistochemistry demonstrate increased duodenal eosinophil and mast cell counts per high-power field compared with controls, supporting a distinct microscopic correlate of the “leaky gut” model described above.^[11][15]

• 
  Erosive gastric ulcer source: https://commons.wikimedia.org/wiki/File:Erosive_gastric_ulcer.jpg#/media/File:Erosive_gastric_ulcer.jpg

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Life threatening causes of dyspepsia include coronary disease and ischemic bowel disease. Other common causes of dyspepsia include gastroesophageal reflux, gastritis, lactose intolerance, and peptic ulcer.

• Congestive heart failure
• Coronary disease

• Aerophagia
• Anxiety
• Gastroesophageal reflux
• Gastritis
• Irritable bowel syndrome
• Lactose intolerance
• Peptic ulcer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

Dyspepsia must be differentiated from other organic and functional disorders that present with epigastric pain or discomfort. Per the American College of Gastroenterology/Canadian Association of Gastroenterology (ACG/CAG) 2017 guideline and the British Society of Gastroenterology (BSG) 2022 guideline on functional dyspepsia, dyspepsia is first classified as uninvestigated dyspepsia (symptoms without prior endoscopic evaluation), organic (structural) dyspepsia, and functional dyspepsia (Rome IV criteria, in the absence of a structural, metabolic, or systemic explanation for symptoms after endoscopic evaluation).^[1][2][3]

Organic causes that mimic dyspepsia and must be excluded include peptic ulcer disease, gastritis, gastroesophageal reflux disease, gastric adenocarcinoma, gastric lymphoma, acute pancreatitis, chronic pancreatitis, biliary colic/cholelithiasis, gastroparesis, gastric outlet obstruction, celiac disease, drug/medication-induced dyspepsia (e.g., NSAIDs, bisphosphonates, iron, potassium salts), and, less commonly, acute appendicitis, pleural empyema, and myocardial infarction, all of which can present with epigastric pain.^[4][5] Age ≥60 years or the presence of alarm features (unintentional weight loss, progressive dysphagia, odynophagia, unexplained iron-deficiency anemia, persistent vomiting, a palpable mass or lymphadenopathy, family history of upper GI cancer, or GI bleeding) should prompt prompt upper endoscopy to exclude malignancy or other significant structural disease.^[1]

Dyspepsia must be differentiated from other diseases that present with epigastric pain, such as gastritis, gastroesophageal reflux disease, acute pancreatitis, chronic pancreatitis, biliary colic/cholelithiasis, gastric outlet obstruction, myocardial infarction, pleural empyema, and acute appendicitis.^{[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]}

The ACG/CAG 2017 guideline and the BSG 2022 guideline recommend a two-tier, age- and alarm-feature-based approach to distinguish dyspepsia from other diseases before a label of functional dyspepsia is applied.^[1][2] Patients younger than 60 years without alarm features should undergo non-invasive testing for H. pylori (13C-urea breath test or stool antigen test, both preferred over serology) and treatment if positive (test-and-treat strategy, strong recommendation, high-quality evidence); alarm features alone should not automatically trigger endoscopy in this age group but should be assessed on a case-by-case basis.^[1] Patients aged 60 years or older, or of any age with alarm features, should undergo upper endoscopy to exclude upper GI neoplasia and other structural disease (conditional recommendation for age alone).^[1]

An updated systematic review and meta-analysis of endoscopic findings in dyspepsia (Ford AC, Moayyedi P, et al) found that more than 85% of upper endoscopies performed for dyspepsia are entirely normal; erosive esophagitis is the most common abnormality (pooled prevalence 11.0%, 95% CI 8.9–13.2%), followed by peptic ulcer (pooled prevalence 4.4%, 95% CI 2.5–6.7%), while gastroesophageal cancer is rare (<0.4%) and equally prevalent in dyspeptic and non-dyspeptic populations, supporting a conservative, alarm-feature/age-based approach to endoscopy rather than routine endoscopy in all comers.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

Dyspepsia is a common upper gastrointestinal symptom complex encompassing both uninvestigated dyspepsia and functional dyspepsia (a disorder of gut-brain interaction defined by Rome IV criteria). Global pooled prevalence estimates vary substantially by definition: uninvestigated dyspepsia affects approximately 20.8% of the general population (95% CI 17.8–23.9%), while Rome-criteria-defined functional dyspepsia has a global pooled prevalence of 8.4% (95% CI 7.4–9.5%), and in the most recent Rome Foundation internet-based epidemiology study, 7.2% (range 2.2%–12.3% across countries). Prevalence is consistently higher in women than in men across all diagnostic criteria and is higher in developing countries than in developed countries. The global prevalence of functional dyspepsia has declined gradually over the past three decades, from 12.4% in studies conducted during 1990–2002 to 7.3% in studies conducted during 2013–2020, and it decreases with advancing age, findings that contrast with the age-related increase seen with H. pylori infection. Postprandial distress syndrome is the dominant clinical subtype of functional dyspepsia, accounting for approximately two-thirds of cases, followed by epigastric pain syndrome and an overlapping PDS/EPS phenotype. Functional dyspepsia is strongly associated with anxiety, depression, reduced physical quality of life, and increased healthcare utilization, but has not been shown to be associated with increased long-term mortality.

• According to a 2015 meta-analysis of 100 study populations comprising 312,415 subjects, the global pooled prevalence of uninvestigated dyspepsia was 20.8% (95% CI 17.8–23.9%), ranging from 1.8% to 57.0% depending on the country and diagnostic definition used.^[1]
• A 2024 systematic review and meta-analysis of 44 studies, including 256,915 participants from 40 countries across six continents, found the global pooled prevalence of Rome-criteria-defined functional dyspepsia to be 8.4% (95% CI 7.4–9.5%).^[2]
• Prevalence estimates vary substantially according to the Rome diagnostic criteria version applied, being highest with Rome I criteria (11.9%; 95% CI 5.1–25.4%) and lowest with Rome IV criteria (6.8%; 95% CI 5.8–7.9%).^[2]
• The 2025 Rome Foundation Global Epidemiology Study, an internet survey of 54,127 respondents from 26 countries, found a pooled Rome IV functional dyspepsia prevalence of 7.2%, ranging from 2.2% in Japan to 12.3% in Egypt.^[3]
• Global prevalence of functional dyspepsia has declined gradually over time, from 12.4% (95% CI 8.2–18.3%) in studies conducted during 1990–2002 to 7.3% (95% CI 6.1–8.7%) in studies conducted during 2013–2020.^[2]

^[2]

^[2]

• In the 2015 meta-analysis of uninvestigated dyspepsia, several factors were only modestly associated with dyspepsia in the community: female sex (OR 1.24, 95% CI 1.13–1.36), current smoking (OR 1.25, 95% CI 1.12–1.40), NSAID use (OR 1.59, 95% CI 1.27–1.99), and H. pylori-positive status (OR 1.18, 95% CI 1.04–1.33).^[1]
• The authors concluded that because these classic risk factors showed only modest associations, cultural, ethnic, genetic, and dietary factors may play a more important role in the community prevalence of dyspepsia.^[1]

^[1]

• The prevalence of eosinophilic gastritis is approximately 6.3 per 100,000 individuals worldwide.^[4]
• The global pooled prevalence of uninvestigated dyspepsia is 20.8% (95% CI 17.8–23.9%), while Rome-criteria-defined functional dyspepsia has a global pooled prevalence of 8.4% (95% CI 7.4–9.5%), most recently estimated at 7.2% (range 2.2–12.3%) in the 2025 Rome IV Global Epidemiology Study (see above).^[1][2][3]

• In the 2025 Rome IV Global Epidemiology Study, postprandial distress syndrome was the dominant subtype of functional dyspepsia (66.6%), followed by epigastric pain syndrome (15.3%) and an overlapping postprandial distress syndrome/epigastric pain syndrome phenotype (18.1%).^[3]
• Both postprandial distress syndrome (OR 1.60, 95% CI 1.49–1.72) and epigastric pain syndrome (OR 1.42, 95% CI 1.27–1.59) were significantly more prevalent in women, and both decreased in prevalence with advancing age.^[3]
• Among individuals meeting criteria for functional dyspepsia, overlap with other disorders of gut-brain interaction was common: irritable bowel syndrome (Rome IV) in 26.1%, functional heartburn in 9.0%, and chronic nausea and vomiting syndrome in 7.0%.^[3]

^[3]

• In the 2025 Rome IV Global Epidemiology Study, 53.1% (95% CI 51.6–54.7%) of individuals with functional dyspepsia had visited a physician for their symptoms, including 39.9% (95% CI 38.4–41.4%) who saw a primary care physician and 27.1% (95% CI 25.8–28.5%) who saw a gastroenterologist.^[3]
• Individuals with the overlapping PDS/EPS phenotype had the highest rate of physician visits (70.1%, 95% CI 66.7–73.5%), compared with 34.4% (95% CI 34.0–34.8%) for PDS alone and 34.5% (95% CI 34.1–34.9%) for EPS alone.^[3]
• Medication use was substantially higher among individuals with functional dyspepsia compared with those without: acid-suppressive medications 43.0% (95% CI 41.5–44.6%) versus 18.7% (95% CI 18.3–19.0%); prescription pain medications 32.9% (95% CI 31.5–34.4%) versus 16.1% (95% CI 15.8–16.5%); anxiolytics 19.7% (95% CI 18.5–20.9%) versus 8.1% (95% CI 7.8–8.3%); and antidepressants 17.2% (95% CI 16.1–18.4%) versus 8.0% (95% CI 7.7–8.2%).^[3]

^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2]

Dyspepsia is a common condition, with a global pooled prevalence of approximately 8.4% (95% CI 7.4–9.5%) according to a 2024 systematic review and meta-analysis of population-based studies 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 (OR 1.24), smokers (OR 1.25), NSAID users (OR 1.59), and individuals who were H. pylori-positive (OR 1.18).^[3] Emerging genetic evidence from a comprehensive Mendelian randomization study additionally supports depression and gastroesophageal reflux disease as causally-linked risk factors for functional dyspepsia.^[4] Less common risk factors include alcohol consumption, low body mass index/underweight status, nosocomial stress ulcers related to prolonged mechanical ventilation and coagulopathy, and rare conditions causing gastric acid hypersecretion such as Zollinger-Ellison syndrome. Age ≥60 years and the presence of alarm features (such as unintentional weight loss, gastrointestinal bleeding, dysphagia, or a family history of upper gastrointestinal malignancy) are also recognized as risk markers for underlying organic or malignant disease and warrant prompt upper endoscopy per the 2017 ACG/CAG guideline on the management of dyspepsia.^[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:

• 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
• Emotional stress and psychological comorbidity, particularly anxiety and depression
• Overabundance of high-fiber foods
• Overconsumption of caffeine
• Spicy, high-fat, and greasy foods
• Coexisting gastroesophageal reflux disease

Less common risk factors in the development of dyspepsia include:

• Alcohol consumption
• Psychological stress (independent of anxiety/depression)
• Low body mass index (underweight, BMI <18.5 kg/m²)
• Older age (>50–60 years)
• Nosocomial stress ulcers due to the use of mechanical ventilation for more than 48 hours, and coagulopathy
• Rare conditions associated with gastric acid hypersecretion such as:
  • Zollinger-Ellison syndrome, mastocytosis, or a retained antrum following partial gastrectomy
  • Gastrinoma or multiple endocrine neoplasia type I (MEN-I), antral G cell hyperplasia, basophilic leukemias, short bowel syndrome

According to the 2017 ACG/CAG Clinical Guideline on the Management of Dyspepsia, the presence of alarm features increases the pre-test probability of underlying upper gastrointestinal malignancy by 2- to 3-fold and should prompt upper endoscopy regardless of age; endoscopy is also recommended for new-onset dyspepsia in patients ≥60 years of age to exclude organic pathology, with consideration of earlier endoscopy in patients at increased gastric cancer risk (e.g., those who spent childhood in a high-incidence region or with a positive family history of gastric cancer).^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

Dyspepsia is defined clinically as predominant epigastric pain or discomfort lasting at least one month, encompassing symptoms of epigastric pain, epigastric burning, postprandial fullness, and early satiety, occurring in the absence of an obvious structural cause.^[1] Dyspepsia is among the most common reasons for primary care consultation. Using a broad clinical definition, the prevalence of dyspepsia approaches 30% at any one point in time in the general population, while application of the Rome IV criteria yields a more conservative global pooled prevalence of approximately 7–8.4% (95% CI 7.4–9.5%) across 40 countries.^[2]

Dyspepsia is broadly categorized as:

• Uninvestigated dyspepsia (UD): Epigastric symptoms that have not yet been subject to diagnostic investigation.
• Investigated dyspepsia: Where an underlying cause has been identified (e.g., peptic ulcer disease, gastroesophageal reflux disease, Helicobacter pylori gastritis).
• Functional dyspepsia (FD): Dyspepsia without an identifiable organic, systemic, or metabolic cause on thorough evaluation, meeting Rome IV criteria for either postprandial distress syndrome (PDS) or epigastric pain syndrome (EPS).^[3]

The Rome IV criteria define FD as one or more of: bothersome postprandial fullness, early satiation, epigastric pain, or epigastric burning, present for at least the last 3 months with symptom onset at least 6 months before diagnosis, with no evidence of structural disease to explain the symptoms.^[3] PDS (postprandial symptoms) accounts for 66.6% of FD, EPS (pain-predominant) for 15.3%, and overlapping PDS/EPS for 18.1%.^[4]

The global burden is higher in women (prevalence 9.0% vs. 7.0% in men) and higher in developing countries (9.1% vs. 8.0% in developed countries), and the overall prevalence has been declining from 12.4% (1990–2002) to 7.3% (2013–2020).^[2]

The diagnosis of functional dyspepsia requires exclusion of organic, systemic, or metabolic disorders that may present with overlapping epigastric symptoms. The following table summarizes key differential diagnoses:

There is no evidence supporting population-level mass screening for dyspepsia or functional dyspepsia in asymptomatic individuals. Screening and diagnostic workup is indicated when patients present with dyspeptic symptoms. The key clinical decision in the evaluation of uninvestigated dyspepsia is stratification by age, symptom pattern, and risk features to guide appropriate investigation.

The ACG/CAG (2017) joint guideline and the BSG (2022) guideline provide the principal evidence-based frameworks for this stratification.^[1][3]

The following alarm (or “red flag”) features should prompt evaluation for organic pathology and lower the threshold for urgent upper endoscopy (esophagogastroduodenoscopy; EGD), regardless of patient age:

Please note that the ACG/CAG guideline emphasizes that alarm features have a low positive predictive value for malignancy (each individual alarm feature, such as weight loss or anemia, carries a positive predictive value of less than 1% for malignancy in patients younger than 60 years). Alarm features confer a 2–3-fold relative increased risk of upper GI malignancy compared to dyspepsia without alarm features, but the absolute risk in individuals under 60 years remains well below 1%, making routine endoscopy for all young patients with alarm features cost-ineffective.^[1] Alarm features should be assessed on a case-by-case basis and do not automatically mandate upper endoscopy in younger patients.

Guidelines universally recommend age-based stratification as the cornerstone of the investigation strategy for uninvestigated dyspepsia:

The ACG/CAG guideline notes that the age threshold for endoscopy should be lowered in patients from high-risk gastric cancer regions (e.g., East Asia, parts of South America), and that sex may also be considered, as age-adjusted upper GI cancer risk is approximately twice as high in men as in women.^[1]

For patients under 60 years with uninvestigated dyspepsia and without alarm features, the ACG/CAG (2017) guideline provides a strong recommendation (high quality evidence) for the H. pylori test and treat strategy as initial management.^[1] The BSG (2022) guideline similarly endorses non-invasive testing for H. pylori in all eligible patients with dyspepsia before initiating empirical acid suppression.^[3]

Preferred non-invasive tests include:

• Urea breath test (UBT): High sensitivity (>95%) and specificity (>95%); preferred test. Requires 2-week washout from proton pump inhibitors and 4-week washout from antibiotics.
• Stool antigen test (SAT): Comparable sensitivity and specificity to UBT; useful where UBT is unavailable.
• H. pylori serology: Not recommended as an alternative to UBT or SAT due to lower specificity, inability to distinguish active from past infection, and persistence of antibody positivity after eradication.^[3]

H. pylori test and treat was shown in six trials (2,399 patients) to be non-inferior to prompt endoscopy for dyspepsia symptom outcomes at one year (74% vs. 77% symptomatic at follow-up; RR 0.94, 95% CI 0.84–1.04), while substantially reducing endoscopy utilization and cost.^[1]

A 2022 updated systematic review and meta-analysis (29 trials, 6,781 patients) confirmed that H. pylori eradication therapy provides statistically significant cure or improvement of functional dyspepsia symptoms, with the benefit particularly pronounced when eradication is confirmed.^[6]

Given that most patients with dyspepsia in primary care will have FD (rather than ulcer disease), the BSG (2022) guideline states that routine confirmatory testing to verify H. pylori eradication is not recommended after an initial course of eradication therapy in the typical primary care dyspepsia patient. Confirmatory testing should be reserved for patients at increased risk of gastric cancer (e.g., those from high-prevalence gastric cancer regions, those with a family history of gastric cancer, or prior documentation of peptic ulcer disease).^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Ajay Gade MD[3]]

Dyspepsia is a symptom complex referable to the gastroduodenal region that includes epigastric pain or burning, postprandial fullness, and early satiety. Approximately 80% of individuals with dyspepsia have no structural or biochemical explanation for their symptoms after investigation and are labeled as having functional dyspepsia (FD), which affects up to 16% of otherwise healthy individuals in the general population.^[1] Dyspepsia usually persists throughout life as a chronic, relapsing-remitting condition, and spontaneous, permanent resolution is rare. Dyspepsia, particularly its organic subtype, is most commonly associated with Helicobacter pylori infection, while functional dyspepsia frequently overlaps with gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS), an overlap associated with a more severe and persistent symptom course.^[2] The increasing prevalence of dyspepsia with age, together with an increased risk of peptic ulcers in individuals with persistent symptoms, underlies the rationale for age- and alarm feature-based investigation strategies recommended by current guidelines.^[3][4] Complications of dyspepsia when an underlying organic cause is present include peptic ulcers, anemia due to gastritis or ulcer-related blood loss, stomach cancer or esophageal cancer, vitamin B12 deficiency, and pernicious anemia. Fewer than 1–3% of patients presenting with dyspepsia harbor an underlying upper gastrointestinal malignancy, but alarm features have limited sensitivity (11.6–29.3%), and approximately one in four patients with upper gastrointestinal cancer lack alarm features at diagnosis.^[5] Functional dyspepsia carries an excellent prognosis with normal life expectancy regardless of H. pylori status, but it is associated with substantial impairment in quality of life and a high burden of psychological comorbidity, and outcomes are worse when FD overlaps with GERD or IBS.

• Dyspepsia usually persists throughout life as a chronic, relapsing-remitting condition, and complete spontaneous resolution is uncommon.
• In more than 50% of patients presenting with uninvestigated dyspepsia, and up to 80% in population-based cohorts, no obvious organic cause is identified on investigation, a condition termed functional dyspepsia.^[1][6] Functional dyspepsia affects up to 16% of otherwise healthy individuals in the general population and is subdivided into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which frequently overlap and can transition from one to the other over time.^[1][4]
• Organic dyspepsia is most commonly associated with Helicobacter pylori infection; increasing age, and an increased risk of peptic ulcers have been observed in individuals with persistent dyspepsia and chronic gastritis.^[7][8][9]
• Increase in the prevalence of dyspepsia is attributed to increasing age, and the age of onset and clinical pattern vary among different ethnicities.
• Functional dyspepsia frequently overlaps with other disorders of gut-brain interaction. In a longitudinal cohort of 807 individuals meeting Rome IV criteria for IBS, 446 (55.3%) also met criteria for FD; those with IBS-FD overlap had significantly more severe and continuous abdominal pain, greater limitation of daily activities, higher rates of physician consultation and new treatment initiation, and higher rates of abnormal anxiety, depression, and somatization scores at follow-up compared with IBS alone.^[2]
• Overlap between FD and GERD is also common and alters the natural history and diagnostic yield of endoscopy. Among patients clinically fulfilling Rome IV criteria for FD, gastroduodenal ulcer was found in 0.6% of those without reflux symptoms compared with 4.7% of those with overlapping reflux symptoms, and 20.7% of this cohort had clinically significant endoscopic findings, including reflux esophagitis in 16.6%.^[10]
• Risk factors associated with the development and persistence of functional dyspepsia include psychological comorbidity, prior acute gastroenteritis (post-infectious FD), female sex, cigarette smoking, use of non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection.^[1]

• Peptic ulcers
• Anemia due to gastritis or ulcer-related blood loss
• Stomach cancer and esophageal cancer
• Vitamin B12 deficiency
• Pernicious anemia
• Increased risk of developing benign or malignant growths in the lining of the stomach
• Chronic impairment of quality of life and elevated psychological comorbidity, including anxiety and depression
• Upper gastrointestinal malignancy accounts for approximately 1–3% of patients presenting with dyspepsia; the risk rises substantially in patients ≥60 years of age or those with alarm features, although alarm features alone have limited diagnostic accuracy.^[5]

The table below summarizes the diagnostic performance of alarm features for upper gastrointestinal malignancy in patients with dyspepsia, based on systematic review and meta-analysis data:

^[5]

Differentiating organic from functional causes of persistent or complicated dyspepsia is essential, as management and prognosis differ substantially:

Functional dyspepsia is a long-lasting disorder with an excellent prognosis and normal life expectancy regardless of H. pylori infection status, but it is associated with a considerable reduction in health-related quality of life and substantial healthcare utilization and cost.^[3][1]

• Anxiety and depression are markedly more prevalent in patients with functional dyspepsia than in healthy controls (anxiety 50.4% vs 13.3%; depression 42.4% vs 6.66%), with higher mean anxiety scores (7.93 vs 4.17) and depression scores (6.94 vs 3.40); symptom severity correlates positively with anxiety/depression scores and negatively with quality of life.^[11]
• Overlap with IBS or GERD worsens prognosis: patients with IBS-FD overlap report more severe, continuous abdominal pain, greater activity limitation, higher rates of new treatment initiation, and higher anxiety, depression, and somatization scores than those with IBS alone.^[2]
• Although the overall risk of upper gastrointestinal malignancy in dyspepsia is low, prognosis is guideline-dependent on appropriate risk stratification; the ACG/CAG and BSG guidelines recommend prompt endoscopy in patients ≥60 years of age (or a locally-defined threshold) or those with alarm features, given that approximately one in four upper GI cancers present without alarm features.^[3][4][5]
• Organic dyspepsia due to Helicobacter pylori-associated peptic ulcer disease has a favorable prognosis with eradication therapy, which heals ulcers and reduces the long-term risk of recurrent peptic ulcers, gastritis-related anemia, and progression to gastric cancer.
• An increased risk of developing peptic ulcers has been observed in individuals with persistent dyspepsia and chronic gastritis.^[7][8][9]

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