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

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][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][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: Ajay Gade MD[2]]

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

Dyspepsia may be broadly classified into two major sub-types:

• Ulcer dyspepsia accounts for 20-30 % of all dyspepsia cases and is caused by peptic ulcer disease and gastroesophageal reflux disease (GERD).
• Structural disease of the gastrointestinal tract exists in ulcer dyspepsia and hence endoscopy is abnormal.

• Non-ulcer dyspepsia, also called functional dyspepsia (FD), is defined by the Rome III criteria as symptoms of epigastric pain or discomfort (found in 89-90% of cases), postprandial fullness (75-88%), and early satiety (50-82%) within the last 3 months with symptom onset at least 6 months earlier.
• Patients should not have any evidence of structural disease and predominant symptoms of gastroesophageal reflux are exclusionary.^[1]

• Causes of functional dyspepsia are not clear but researchers have focused on the following factors:
  • Gastric motor function dysfunction
  • Visceral sensitivity
  • Helicobacter pylori infection
  • Psychosocial factors

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

The symptoms of functional dyspepsia are directly caused by two major pathophysiological abnormalities in gastric motility and visceral sensitivity. 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, diet, and lifestyle.

The pathophysiology of dyspepsia is as follows:^{[1][2][3][4][5][6][7]}

• 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 two major physiological abnormalities
  • Abnormal gastric motility. Gastroparesis and functional dyspepsia may be the same entity^[8]
  • 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.
• 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.^[9]

There are no significant gross or microscopic pathology associated with dyspepsia, however the gross and microscopic pathology of peptic ulcer disease should be kept in mind.

• 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

There are no significant gross or microscopic pathology associated with dyspepsia however, the gross and microscopic pathology of peptic ulcer disease should be kept in mind.

• 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^[10]

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

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

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

Cardiovascular	Congestive heart failure, coronary disease, hypercalcaemia
Chemical / poisoning	Aluminium hydroxide, amanita phalloides, smoking, sodium dichloroisocyanurate, iron, potassium
Dermatologic	Herpes simplex
Drug Side Effect	4-Chlorodehydromethyltestosterone, acarbose, acetylsalicylic acid, achalasia, achillea millefolium, adefovir, alendronate, alpha-glucosidase inhibitor, alvimopan, amitriptyline, amlodipine, amlodipine and Benazepril, ampicillin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonist, aprotinin, artemether and lumefantrin, asenapine maleate, aspirin, atazanavir, bezafibrate, biguanide, bisphosphonates, buprenorphine, calcium channel blockers, caspofungin acetate, cefadroxil, cefixime, cholestyramine, cholestyramine resin, cidofovir, codeine , colchicine, collinsonia canadensis, colofac, corticosteroids, coptis, daptomycin, diflunisal, digitalis, digoxin, donepezil, dopamine agonist, duloxetine, efavirenz, eflornithine, eletriptan, elvitegravir, emtricitabine, epoetin alfa injection, eribulin, erythromycin, estrogen, ethosuximide, febuxostat, fentanyl skin patches, fesoterodine, fibrates, fluoxetine, fluticasone, fluvastatin, fluvoxamine, frovatriptan, gemfibrozil, glucocorticoids, H2 antagonist, heroin, iberogast, ibuprofen, imatinib, indomethacin, infliximab, interferon beta-1b injection, interferon gamma, ketorolac, lacosamide, levalbuterol, levodopa, lithium, lovaza, macrolides, meloxicam, meropenem, meropenem injection, metformin, methocarbamol, methylprednisolone, methylxanthin, metronidazole , misoprostol, monoamine oxidase-b inhibitors, mosapride, nabilone, nabumetone, nalbuphine, naproxen and esomeprazole magnesium, narcotics, niacin, nicotine polacrilex, non-steroidal anti-inflammatory drug, omeprazole, opioids, oprelvekin, oral contraceptives, orlistat, oxcarbazepine, oxycodone, oxycodone and aspirin, PDE5 inhibitor, pentamidine Isethionate, pergolide, pirfenidone, potassium supplements, pramlintide injection, prednisone, proton pump inhibitor, quazepam, quetiapine, quinidine, rasagiline, rimabotulinumtoxinb, rivastigmine, sertraline, sildenafil, simvastatin, sorafenib, steroid medications,strongyloides, sunitinib, tadalafil, tenofovir disoproxil fumarate, tetracycline, thalidomide, theophylline, thyroid medicines, tiotropium Oral inhalation), tobacco, tolmetin, topiramate, travoprost, triamcinolone acetonidevaldecoxib, valproic acid, venlafaxine, vigabatrin, vilazodone, vortioxetine, zolmitriptan, zopiclone
Ear Nose Throat	Thyroglossal cyst
Endocrine	Adrenal fatigue, carcinoid syndrome, diabetes mellitus, estrogens, hyperparathyroidism, hyperthyroidism, multiple endocrine neoplasia type 1, overeating, parathyroid disorders, primary hyperparathyroidism, thyroid disease, thyroglossal cyst
Environmental	Multiple chemical sensitivity
Gastroenterologic	Achlorhydria, aerophagia, acid reflux, acute viral hepatitis, acute pancreatitis, adult hypertrophic pyloric stenosis, aerophagy, amebic dysentery, ascites, biliary disease, biliary pain, burping, carbohydrate malabsorption, carcinoid syndrome, celiac artery compression syndromee, celiac disease, cholecystitis, cholelithiasis, chronic abdominal wall pain, chronic gastritis, chronic hepatitis, chronic intestinal ischemia, chronic pancreatitis, cirrhosis of liver, colon cancer,constipation, crohn’s disease, delayed gastric emptying, Diarrhea,duodenal cancer, duodenal lymphoma, duodenal polyps, duodenal ulcer, duodenal webs, duodenitis, esophageal carcinoma, esophageal disease, esophageal spasm, esophagitis, functional bowel disorder, gallstones, gastric cancer, gastroenteritis, gastric lymphoma, gastric motility disorder, gastric ulcer, gastritis, gastroesophageal reflux disease, gastrointestinal neoplasm, gastroparesis,gastrointestinal zygomycosis, giardiasis, helicobacter pylori infection, hepatitis, hepatitis c, hepatocellular carcinoma, hepatoma, hiatus hernia, hypertrophic gastritis, inflammatory bowel disease, intestinal motility disorder, intestinal obstruction, irritable bowel syndrome, ischemic bowel disease, lactose intolerance, malabsorption, Ménétriér’s disease, non-ulcer dyspepsia, pancreatic cancer, pancreatitis, peptic ulcers, Rome process, small intestinal bacterial overgrowth, Stomach cancer, Superior mesenteric artery syndrome, tropical sprue, ulcerative colitis, visceroptosis
Genetic	Celiac disease, connective tissue disease, Gulf War syndrome, multiple endocrine neoplasia type 1
Hematologic	Chlorosis, extranodal marginal zone B-cell lymphoma
Iatrogenic	After gastrointestinal surgery, esophagogastroduodenoscopy, multiple chemical sensitivity, SSRI discontinuation syndrome
Infectious Disease	Acute viral hepatitis, amebic dysentery, chronic gastritis, fascioliasis, gastritis, gastroenteritis, gastrointestinal mucormycosis, giardiasis, H. pylori, Helicobacter pylori infection, hepatitis, hepatitis C, herpes simplex, hookworm, opisthorchiasis, strongyloidiasis, syphilis, trichinosis, tuberculosis
Musculoskeletal / Ortho	No underlying causes
Neurologic	Autonomic neuropathy, Gulf War syndrome
Nutritional / Metabolic	Bitter melon Brat diet, capsicum annuum, chocolate, cyclooxygenase, eating high-fiber foods, food allergy, food intolerance, garlic, ginger, gluten allergy, high-fat diet, hydrogen potassium atpase, indian gooseberry, lactose intolerance, niacin, obesity, oranges, overeating, radish, s-adenosyl methionine, spicy foods, suillus luteus tomatoes, tropical sprue, vitamin C
Obstetric/Gynecologic	Estrogens, herpes simplex, oral contraceptives, ovarian cancer, pregnancy
Oncologic	Abdominal cancer, Cancer, carcinoid syndrome, colon cancer, duodenal cancer, duodenal lymphoma, esophageal cancer, extranodal marginal zone B-cell lymphoma, gastric cancer, gastric lymphoma, gastrointestinal neoplasm, hepatocellular carcinoma, hepatoma, ovarian cancer, pancreatic cancer, stomach cancer
Opthalmologic	No underlying causes
Overdose / Toxicity	Alcohol, excess caffeine consumption, hangover, heroin, narcotics, opioids
Psychiatric	Alexithymia, anxiety, Charles Darwin’s illness, depression, diabulimia, fasting girls, overeating, stress, trichophagia
Pulmonary	Sarcoidosis, smoking, tuberculosis
Renal / Electrolyte	Chronic renal disease, hypercalcaemia, hyperkalemia, malabsorption, uremia
Rheum / Immune / Allergy	Gluten allergy, Gulf War syndrome, oral allergy syndrome, sarcoidosis, scleroderma, ulcerative colitis
Sexual	Herpes simplex, syphilis
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	Collinsonia canadensis, coptis, couvade, mint, strychnine tree, vinca

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

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

Dyspepsia must be differentiated from other diseases that presents with epigastric pain such as gastritis, gastroesophageal reflux disease,acute pancreatitis,prmary biliary cirrhosis,cholelithiasis,gastric outlet syndrome,myocardial infaraction ,pleural empyema,acute appendicitis ^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]}

Classification of pain in the abdomen based on etiology			Disease	Clinical manifestations									Diagnosis		Comments
				Symptoms					Signs
				Fever	Rigors and chills	Abdominal Pain	Jaundice	GI Bleed	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Abdominal causes	Inflammatory causes	Pancreato-biliary disorders
			Acute pancreatitis	+	−	Epigastric	±	−	±	−	−	N	Increased amylase / lipase	Ultrasound shows evidence of inflammation	Pain radiation to back
			Primary biliary cirrhosis	−	−	RUQ/Epigastric	+	−	−	−	−	N	Increased AMA level, abnormal LFTs
			Cholelithiasis	±	−	RUQ/Epigastric	±	−	−	+	+	N to hyperactive for dislodged stone	Leukocytosis	Ultrasound shows gallstone	Murphy’s sign
		Gastric causes	Peptic ulcer disease	±	−	EpisodicEpigastric	−	Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia	+ in perforated	+	+	N	Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl	Air under diaphragm in upright CXR	Upper GI endoscopy for diagnosis
			Gastritis	±	−	Epigastric		+ in chronic gastritis	−
			Gastroesophageal reflux disease	−	−	Epigastric	−	−	−	−	−
			Gastric outlet obstruction	−	−	Epigastric	−	−	±			Hyperactive
		Intestinal causes	Acute appendicitis	+	+in pyogenic appendicitis	Starts in epigastrium, migrates to RLQ	−	−	+ in perforated appendicitis	+	+	Hypoactive	Leukocytosis	Ultrasound shows evidence of inflammation	Nausea & vomiting, decreased appetite
Extra-abdominal causes	Pulmonary disorders	Pleural empyema		+	±	RUQ/Epigastric	−	−	−	−	−	N
	Cardiovascular disorders	Myocardial Infarction		−	−	Epigastric	−	−	+ in cardiogenic shock	−	−	N
Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM=Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein

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

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 incidence of new cases of H. pylori infection each year ranges from 3,000 to 10,000 per 100,000 individuals in developing countries.^[1]
• The incidence of new cases of H. pylori infection each year is around 500 per 100,000 individuals in developed countries.^[1]
• It has been observed that with advancing age, the incidence of H. pylori infection increases. ^[2]

• The prevalence of eosinophilic gastritis is approximately 6.3 per 100,000 individuals worldwide. ^[3]

• All age groups can develop dyspepsia.
  • The prevalence of H. pyloriinfection increases with age.^[4]
• About 30%-50% of H. pylori infections are acquired during childhood which increases to 90% during adulthood in developing countries.^[5]
  • H. pylori infection in developed countries is less common in children and reaches up to 60% with increasing age.^[6]
  • In United States, 20% of adolescents are infected with H. pylori when compared to 90% by 5 years of age in developing countries.^[7]
  • Children differ from adults with respect to H. pylori infection in terms of:^[8][9]
    • Prevalence of infection
    • High rate of antibiotic resistance
    • The near-absence of gastric malignancies
    • Age specific problems with diagnostic tests and medications

• In United States, H. pylori infection is more common in African Americans (54%), Hispanics (52%), and the elderly compared to Whites (21%).^[10][11]

• In H. pylori infection associated gastritis, males are more commonly affected than females.^[12]

• H. pylori infection is common in Southern and Eastern Europe, Mexico, South America, Africa, most Asian countries, and aboriginal people in North America.^[13][14]

• The incidence of new cases of H. pylori infection each year is 0.5 percent in developed countries.^[1]
• The prevalence of H. pylori is declining in the United States.
• In developed countries such as the United States, children acquire the H. pylori infection at a rate of about less than 1% per year.
• It is estimated that 30%-40% of the US population is infected with H. pylori.^[15][16]
• In United States, approximately 25% of children between 6-19 years old are infected.^[17]
• The incidence rates of H. pylori infection are high in Japan, Columbia, Costa Rica and China, and comparatively low in the United States.

• The prevalence of H. pylori is higher in developing countries than that in developed countries.^[18]
• 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.^[1]
• In the developing countries, children in the age group of 2 to 8 years acquire the H.pylori infection at a rate of about 10% per year.
• H. pylori infection is common in Southern and Eastern Europe, Mexico, South America, Africa, most Asian countries, and aboriginal people in North America.^[13][14]

Prevalence of H. pylori infection globally^[19]

Prevalence of Helicobacter pylori Infection Globally
Country		Prevalence per 100,000
		Children	Adult
Africa	Ethiopia	48,000	>95,000
	Nigeria	82,000	91,000
Central America	Gautemala	51,000	65,000
	Mexico	43,000	90,000
North America	Canada	7100	23,000
	USA and Canada		30,000
South America	Bolivia	54,000
	Brazil	30,000	82,000
	Chile	36,000	>70,000
Asia	Bangladesh	60,000	>90,000
	Hong Kong	13,000
	India	22,000	>80,000
	Japan		>70,000
	Siberia	30,000	85,000
	South Korea	56,000	40,600
	Sri Lanka	67,000	72,000
	Taiwan	11,000	>50,000
Australia	Australia		20,000
Europe	Eastern		70,000
	Albania		70700
	Bulgaria	61,700
	Czech Republic		42,000
	Estonia		60,000
	Germany		48,800
	Iceland		36,000
	Netherlands	12000
	Serbia	36,400
	Sweden		11,000
	Switzerland		11,900
Middle East	Egypt	50,000	90,000
	Libya	50,000	94,000
	Saudi Arabia	40,000	80,000
	Turkey	64,000	80,000

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

Common risk factors for the development of dyspepsia include, Helicobacter pylori infection, chronic use of NSAIDs, family history of peptic ulcer disease, emotional stress, increased intake of high-fiber diet, overconsumption of caffeine, high-fat and greasy foods. Less common risk factors for the development of dyspepsia include tobacco, alcohol consumption, psychological stress and Zollinger-Ellison syndrome.

Risk factors for the development of dyspepsia can be divided into common and less common risk factors, which include the following:^{[1][2][3][4][5][6][7][8]}

Common risk factors in the development of dyspepsia include:

• Helicobacter pylori infection
• Chronic use of NSAIDs
• Family history of peptic ulcer
• Eating meals too quickly
• Emotional stress while eating
• Overabundance of high-fiber foods
• Overconsumption of caffeine
• Spicy, high-fat, and greasy foods
• Too much food at meals

Less common risk factors in the development of dyspepsia include:

• Tobacco
• Alcohol
• Psychological stress
• Nosocomial stress ulcers due the 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

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

Disease	Distinguishing Features	Key Investigations
Peptic ulcer disease	Epigastric pain relieved by food (duodenal ulcer) or worsened by food (gastric ulcer); history of NSAID use or Helicobacter pylori infection	Upper endoscopy (gold standard); urea breath test; fecal antigen test
Gastroesophageal reflux disease	Predominant heartburn, acid regurgitation; symptoms worse when supine or postprandial; may overlap with dyspepsia	Clinical diagnosis; empirical proton pump inhibitor trial; ambulatory pH monitoring if needed
Gastroparesis	Postprandial fullness, nausea, vomiting, early satiety; often in diabetes mellitus or post-surgical context	Gastric emptying scintigraphy (4-hour solid-phase study); wireless motility capsule
Gastric cancer	Age ≥55 years, unexplained weight loss, dysphagia, persistent vomiting, GI bleeding, family history of gastric cancer, new-onset dyspepsia	Upper endoscopy with biopsy; computed tomography of abdomen/pelvis
Esophageal cancer	Dysphagia (progressive), odynophagia, weight loss, male sex, smoking, Barrett esophagus history	Upper endoscopy with biopsy; endoscopic ultrasound; computed tomography
Pancreatic cancer	Epigastric or back pain, jaundice, weight loss, new-onset diabetes mellitus, pancreatic insufficiency	Computed tomography of abdomen (triple phase); endoscopic ultrasound; CA 19-9; MRCP
Biliary tract disease / Cholelithiasis	Post-prandial right upper quadrant pain, particularly after fatty meals; crescendo-decrescendo character; nausea, vomiting	Abdominal ultrasound; liver function tests; lipase
Celiac disease	Diarrhea, weight loss, iron deficiency, bloating; may present without classic malabsorption	Tissue transglutaminase IgA antibodies; duodenal biopsy on endoscopy
Irritable bowel syndrome	Overlapping symptoms; lower abdominal cramping, altered bowel habit, relief with defecation; upper GI overlap in 26.1%	Rome IV criteria; clinical diagnosis of exclusion
Eosinophilic gastroenteritis	May mimic FD; associated with atopy, food allergy, peripheral eosinophilia	Upper endoscopy with gastric and duodenal biopsies (eosinophil counts)
Medication-induced dyspepsia	Temporal relationship to NSAID, aspirin, bisphosphonate, or iron use	Careful drug history; trial of medication withdrawal
Myocardial infarction / Ischemic heart disease	Atypical presentation especially in women, elderly, and diabetes mellitus; epigastric pain with radiation, diaphoresis, dyspnea	Electrocardiogram; cardiac troponins; risk factor assessment

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:

Alarm Feature	Clinical Significance
Dysphagia (progressive)	Risk of esophageal or gastric cancer; requires urgent EGD
Unexplained significant weight loss	Risk of upper GI malignancy
Hematemesis or recurrent gastrointestinal bleeding	Risk of peptic ulcer, gastric cancer, or esophageal varices
Iron deficiency anemia (unexplained)	May signify upper GI blood loss or celiac disease
Persistent vomiting	May indicate obstruction or malignancy
Palpable upper abdominal mass or lymphadenopathy	Strongly suspicious for upper GI malignancy
Jaundice	Risk of pancreatic cancer, biliary obstruction, hepatocellular carcinoma
Family history of upper GI cancer (first-degree relative)	Increased risk for gastric cancer or esophageal cancer
Previous gastric surgery or known Barrett esophagus	Increased cancer risk; requires endoscopic surveillance

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:

Age Group	Recommended Strategy	Guideline Source
< 60 years, no alarm features	Non-invasive Helicobacter pylori test and treat (urea breath test or fecal antigen test) as first-line. If H. pylori-negative or symptoms persist after eradication, empirical proton pump inhibitor (PPI) therapy.	ACG/CAG 2017 (Strong recommendation, High quality evidence)[1]; BSG 2022[3]
≥ 60 years	Upper endoscopy (EGD) to exclude upper GI neoplasia. This is a conditional recommendation; the threshold may be lowered in higher-risk populations (e.g., high gastric cancer prevalence regions, family history).	ACG/CAG 2017 (Conditional recommendation, Very low quality evidence)[1]
≥ 55 years, treatment-resistant dyspepsia or weight loss	Urgent direct-access endoscopy (within 2 weeks) per NICE NG12 guidance for suspected upper GI cancer	NICE NG12 (suspected cancer referral guidance)[5]
Any age with progressive dysphagia	Urgent EGD regardless of age	ACG/CAG 2017; BSG 2022; NICE NG12
Any age with palpable abdominal mass	Urgent investigation (EGD and/or computed tomography)	ACG/CAG 2017; NICE NG12

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: Ajay Gade MD[2]]

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. An increased risk of developing peptic ulcers has 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.

• 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.
• An increased risk of developing peptic ulcers has been observed in individuals with persistent dyspepsia.^[1][2][3]

• Peptic ulcers
• Anemia due to gastritis
• Stomach cancer
• Vitamin B12 deficiency
• Pernicious anemia
• Increased risk of developing benign or malignant growths in the lining of the stomach.

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

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