Dyspepsia differential diagnosis

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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]]

Overview

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).

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. 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.

Differentiating Dyspepsia from other Diseases

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.

Diagnostic Approach Based on Current Guidelines

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. 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. 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).

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.

Feature	Age <60 years, no alarm features	Age ≥60 years, or any alarm feature
Initial strategy	Non-invasive H. pylori test-and-treat (13C-urea breath test or stool antigen test)	Upper endoscopy to exclude malignancy/structural disease
Alarm features	Unintentional weight loss, GI bleeding/iron deficiency anemia, progressive dysphagia, persistent vomiting, palpable mass, family history of upper GI cancer	Same features mandate endoscopy regardless of age
If H. pylori negative and symptoms persist	Empiric proton pump inhibitor trial (4–8 weeks); if refractory, proceed to endoscopy	Not applicable (endoscopy already performed)
Diagnosis if endoscopy normal and no metabolic/structural cause found	Functional dyspepsia per Rome IV criteria (postprandial distress syndrome or epigastric pain syndrome, or overlap)

Classification of pain in the abdomen based on etiology			Disease	Clinical manifestations									Diagnosis
				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
			Chronic pancreatitis/pancreatic fibrosis	−	−	Epigastric, radiating to back	±	−	−	−	−	N	Fecal elastase low; amylase/lipase may be normal	Endoscopic ultrasound with shear-wave elastography detects early parenchymal fibrosis missed on CT/MRI
			Biliary colic/dyskinesia	−	−	RUQ/Epigastric, may radiate to back or mimic chest pain	±	−	−	−	−	N	Normal LFTs between episodes	Reduced gallbladder ejection fraction on cholecystokinin-HIDA scan (<38%)
		Cholelithiasis	±	−	RUQ/Epigastric	±	−	−	+	+	N to hyperactive for dislodged stone	Leukocytosis	Ultrasound shows gallstone	Murphy’s sign
		Gastric/duodenal 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
			Gastritis	±	−	Epigastric		+ in chronic gastritis	−				H. pylori stool antigen or 13C-urea breath test preferred over serology
			Gastroesophageal reflux disease	−	−	Epigastric	−	−	−	−	−			Pooled prevalence of erosive esophagitis on endoscopy for dyspepsia ≈11.0%
			Gastric outlet obstruction	−	−	Epigastric	−	−	±			Hyperactive
Celiac disease	−		−	Epigastric/diffuse, with bloating	−	−	−	−	−	Chronic diarrhea/steatorrhea	Anti-tissue transglutaminase IgA, total IgA	Duodenal biopsy: villous atrophy, scalloping of folds
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	Troponin elevated; electrocardiogram with ST changes	Regional wall motion abnormality on echocardiogram
	Vascular disorders	Mesenteric ischemia (chronic)		−	−	Postprandial epigastric pain ("intestinal angina")	−	−	−	−	−	N	Weight loss, food fear	CT angiography/mesenteric duplex ultrasound shows stenosis of ≥2 splanchnic vessels
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

Disease	Cause	Symptoms									Diagnosis	Other findings
		Pain			Nausea & Vomiting	Heartburn	Belching or Bloating	Weight loss	Loss of Appetite	Stools	Endoscopy findings
		Location	Aggravating Factors	Alleviating Factors
Acute gastritis	H. pylori NSAIDS Corticosteroids Alcohol Spicy food Viral infections Crohn's disease Autoimmune diseases Bile reflux Cocaine use Breathing machine or ventilator Ingestion of corrosives	Epigastric pain	Food	Antacids	✔	✔	✔	-	✔	Black stools	Pangastritis or antral gastritis Erosive (Superficial, deep, hemorrhagic) Nonerosive (H. pylori)	-
Chronic gastritis	H. pylori Alcohol Medications Autoimmune diseases Chronic stress	Epigastric pain	Food	Antacids	✔	✔	✔	✔	✔	-	H. pylori gastritis Atrophy Intestinal metaplasia Lymphocytic gastritis Enlarged folds Aphthoid erosions	-
Atrophic gastritis	H. pylori Autoimmune disease	Epigastric pain	-	-	✔	-		✔	✔	-	H. pylori Mucosal atrophy Autoimmune Mucosal atrophy	Iron deficiency anemia Autoimmune gastritis diagnosis include: Antiparietal and anti-IF antibodies Achlorhydria and hypergastrinemia Low serum cobalamine
Crohn's disease	Autoimmune disease	Abdominal pain	-	-	-	-	-	✔	✔	Chronic diarrhea often bloody with pus or mucus Rectal bleeding	Mucosal nodularity with cobblestoning Multiple aphthous ulcers Linier or serpiginous ulcerations Thickened antral folds Antral narrowing Hypoperistalsis Duodenal strictures	Fever Fatigue Anemia (pernicious anemia)
GERD	Lower esophageal sphincter abnormalities Hiatal hernia Abnormal esophageal contractions Prolonged emptying of stomach Gastrinomas	Epigastric pain	Spicy food Tight fitting clothing	Antacids Head elevation during sleep	✔ (Suspect delayed gastric emptying)	✔	-	-	-	-	Esophagitis Barrette esophagus Strictures	Other symptoms: Dysphagia Regurgitation Nocturnal cough Hoarseness Complications Esophagitis Strictures Barrette esophagus
Peptic ulcer disease	H. pylori Smoking Alcohol Radiation therapy Medications Zollinger-ellison syndrome	Epigastric pain sometimes extending to back Right upper quadrant pain	Duodenal ulcer Pain aggravates with empty stomach Gastric ulcer Pain aggravates with food	Antacids Duodenal ulcer Pain alleviates with food	✔	✔	-	-	-	Black stools	Gastric ulcers Discrete mucosal lesions with a punched-out smooth ulcer base with whitish fibrinoid base Most ulcers are at the junction of fundus and antrum 0.5-2.5cm Duodenal ulcers Well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum Found in the first part of duodenum <1cm	Other diagnostic tests Serum gastrin levels Secretin stimulation test Biopsy H. pylori 13C-urea breath test or stool antigen test (preferred non-invasive tests per ACG/CAG 2017)
Gastrinoma	Associated with MEN type 1	Abdominal pain	-	-	✔ (suspect gastric outlet obstruction)	✔	-	-	-	Black stools	Useful in collecting the tissue for biopsy	May present with symptoms of GERD or peptic ulcer disease Associated with MEN type 1 Diagnostic tests Serum gastrin levels Somatostatin receptor scintigraphy CT and MRI
Gastric Adenocarcinoma	H. pylori infection Smoked and salted food	Abdominal pain	-	-	✔	✔	✔	✔	✔	Black stools, or blood in stools	Esophagogastroduodenoscopy Multiple biopsies are taken to establish the diagnosis Pooled prevalence on endoscopy for dyspepsia <0.4%, similar to non-dyspeptic populations	Other symptoms Dysphagia Early satiety Frequent burping
Primary gastric lymphoma	H. pylori infection	Abdominal pain Chest pain	-	-	-	-	-	✔	-	-	Useful in collecting the tissue for biopsy	Other symptoms Painless swollen lymph nodes in neck and armpit Night sweats Fatigue Fever Cough or trouble breathing

Differentials of functional dyspepsia

Functional dyspepsia is diagnosed using Rome IV criteria and is subclassified into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), which may overlap. Functional dyspepsia should be differentiated from other diseases that cause chronic nausea and vomiting, including gastroparesis (particularly diabetic gastroparesis, which shares overlapping pathophysiology and symptoms with functional dyspepsia), anorexia nervosa, bulimia nervosa, rumination syndrome, cyclic vomiting syndrome, pancreatitis, and gastric outlet obstruction. The differentials include the following:

Disorder	Clinical features												Laboratory findings
	Chronic nausea	Vomiting	Diarrhea	Retching	Lethargy	Social withdrawal	Photophobia	Epigastric pain/burning	Lanugo hair	Hypogonadism	Russel's sign	Body mass index (normal range: 18.5 to 24.9)	Complete blood count (CBC)	Electrolyte imabalance	Lipase and amylase levels	Gastric scintigraphy	Ambulatory esophageal pH and impedance testing
Gastroparesis	✔	✔ (within 1 hour of eating)	-	✔	✔	-	-	✔	-	-	-	↓	Anemia	✔	Normal (maybe elevated if chronic renal failure is the cause of gastroparesis- usually less than threefold)	Periodic measurement of radiolabeled solid meal: Grade 1 (mild), 11%-20% retention at 4 h Grade 2 (moderate), 21%-35% retention at 4 h Grade 3 (severe), 36%-50% retention at 4 h Grade 4 (very severe), > 50% retention at 4 h	Impedance testing (antroduodenal manometery): Loss of normal fasting migratory motor complexes (MMCs) and reduced postprandial antral contractions and, in some cases pylorospasm
Anorexia nervosa	✔	✔	✔	-	✔	✔	-	-	✔	✔	-	↓	Leukocytosis, anemia	✔	Increased	Gastric emptying may be delayed but may become normal as feeding recommences (short lived)	Esophageal pH: May be decreased if patient develops gastroesophageal reflux disease
Bulimia nervosa	✔	✔	✔	✔	✔	✔	-	-	-	✔	✔	Normal	Leukocytosis, anemia	✔	Increased	Gastric emptying delayed for a longer duration as compared to anorexia nervosa	Esophageal pH: May be decreased if patient develops gastroesophageal reflux disease
Rumination syndrome	✔	✔ (Regurgitation more common- within minutes of meal intake)	✔	-	✔	✔	✔	✔	-	-	-	↓	Normal	✔	Normal	Delayed gastric emptying	Esophageal pH: Fall in esophageal pH immediately after reguritation (occurs while patient is awake and erect; this is in contrast to GERD, where reflux occurs diurnally and supine position) Impedance testing:Increased intra-abdominal pressure leading to regurgitation of gastric contents (Tall R waves)
Functional dyspepsia	✔	✔	✔	✔	-	-	-	-	-	-	-	Normal	Normal	✔	Increased (especially lipase)	Delayed gastric emptying (present in ~25-30% of patients; not required for diagnosis per Rome IV)	Esophageal pH: May be decreased if patient develops reflux
Cyclic vomiting syndrome	✔	✔	-	✔	✔	-	-	-	-	-	-	↓	Leukocytosis, anemia	✔	Increased (alongwith increased lactic acid - in cases of concomitant mitochondrial disease)	Rapid or normal	Esophageal pH: Decreased
Pancreatitis	✔	✔	✔	✔	✔	-	-	✔	-	-	-	Normal	Leukocytosis	✔	Increased	Not indicated	Esophageal pH: Normal
Gastric outlet obstruction	✔	✔ (within 1 hour of eating)	-	-	-	-	-	✔	-	-	-	↓	Leukocytosis	✔	Increased (in cases of pancreatic disease)	Delayed gastric emptying	Esophageal pH: Increased Esophageal manometery: High manoraetric score

References