Dyspepsia

Dyspepsia is a common condition, defined as predominantly epigastric pain lasting at least one month, and is often attributed to conditions affecting the stomach. Heartburn (or pyrosis) is used to describe predominantly esophageal symptoms. Although heartburn and dyspepsia have distinct definitions, the clinical features overlap and may be indistinguishable. Common causes of dyspepsia include Helicobacter pylori infection, gastritis, esophagitis, gastroesophageal reflux (GERD), and peptic ulcer disease (PUD). A thorough medical history, physical examination, screening for risk factors for common etiologies, and assessment of red flag features for dyspepsia is imperative to guide initial management. Patients ≥ 60 years of age with/without red flag features should undergo an EGD to rule out neoplasia before initiating empirical pharmacotherapy. All patients with typical dyspepsia should be tested for H. pylori infection and, if detected, eradication therapy should be initiated. Patients < 60 years of age with typical heartburn and no major red flag features may be initiated on empirical therapy with acid suppression medications, such as proton pump inhibitors (PPIs). Inadequate response to empirical therapy warrants further diagnostics and management. Patients with atypical features should be assessed for other possible etiologies of dyspepsia, such as symptomatic cholelithiasis, chronic pancreatitis, and stable angina. Patients in whom no organic cause can be identified likely have functional dyspepsia (accounts for ∼ 70% of all cases of dyspepsia), the likelihood of which should be assessed based on the Rome IV criteria for functional dyspepsia.

• Dyspepsia: epigastric pain or burning that lasts for ≥ 1 month ^[1][2]
• Heartburn (pyrosis): burning retrosternal discomfort that often develops after eating and worsens when bending or lying down. Along with regurgitation, it is a classical symptom of gastroesophageal reflux disease (GERD). ^[3]

Dyspepsia can be associated with a variety of symptoms, e.g., heartburn, nausea, regurgitation, bloating, belching. Dyspepsia and heartburn may be clinically indistinguishable because of the significant overlap in symptoms. ^{[1][3] [1][3]}

Obtain a thorough medical history and physical examination, screen for risk factors for common etiologies (e.g., shared risk factors for PUD, GERD, and gastritis), and evaluate for red flag features in all patients.

Red flag features of dyspepsia

• Family history of gastrointestinal cancer
• Immunosuppression
• Clinically significant unintentional weight loss
• Anorexia
• Dysphagia, odynophagia
• Early satiety
• Persistent vomiting
• Noncardiac chest pain (specific for patients presenting with heartburn)
• Suspicion of gastrointestinal bleeding (e.g., unexplained iron deficiency anemia, melena)

Patients ≥ 60 years of age ^[1]

The following is applicable to patients ≥ 60 years of age with or without red flag features for dyspepsia.

• Refer for EGD to exclude neoplasia.
• Test for the presence of H. pylori during the endoscopy using biopsies and/or a rapid urease test.
• If a clear etiology is identified using EGD (e.g., visualization of peptic ulcer, gastritis), manage accordingly.
• If the etiology remains unclear after EGD, consider further testing based on clinical suspicion.

Patients < 60 years of age ^[1]

• Red flags of dyspepsia present: Consider EGD on a case-by-case basis.
• Red flags of dyspepsia absent
  • Typical dyspepsia; : test and treat strategy for H. pylori (noninvasive tests, e.g., urea breath test)
    • Positive: H. pylori eradication therapy
    • Negative: trial of acid suppression with proton pump inhibitors (PPIs)
  • Typical heartburn : trial of acid suppression with PPIs (empirical therapy) ^[3][4]

Patients with typical features of GERD and no features of concomitant or past PUD do not require routine testing for H. pylori infection. If H. pylori infection is detected in a patient with GERD, H. pylori eradication therapy should be initiated. ^[4]

EGD ^[1][3]

• Indications
  • Patients ≥ 60 years of age with dyspepsia with/without red flags for dyspepsia
  • Select patients < 60 years of age with red flags for dyspepsia, assessed on a case-by-case basis ^[1][3]
  • Inadequate response to empirical pharmacotherapy
• Findings: EGD (with or without biopsies) can help to identify the cause of dyspepsia; examples include
  • Gastritis
  • PUD
  • Gastric cancer
  • GERD
  • Esophagitis

Obtain gastric biopsies to evaluate for H. pylori infection from all patients who undergo EGD for dyspepsia. ^[4]

Helicobacter pylori diagnostics

Indications ^[4]

• Absolute indications
  • Uninvestigated dyspepsia in patients < 60 years of age and no red flag features
  • Low-grade MALT lymphoma
  • PUD
  • Endoscopically resected early gastric cancer
  • Patients who undergo EGD for dyspepsia
  • Prior to initiation of long-term treatment with NSAIDs
• Relative indications
  • Individuals already on long-term therapy with NSAIDs or aspirin
  • Unexplained iron deficiency anemia
  • Adults with idiopathic thrombocytopenic purpura

PPIs should be discontinued at least 2 weeks prior to most H. pylori testing modalities to minimize rates of false-negative results. However, some testing modalities, e.g., histology, are not affected by recent PPI treatment. ^[5]

Noninvasive methods ^[6]

Noninvasive methods to detect H. pylori infection are preferred for the initial diagnostics in patients < 60 years of age with typical dyspepsia symptoms who are low risk for malignancy as the underlying etiology. ^[1][6]

• Urea breath test
  • Detects a labeled carbon isotope in a breath sample
  • Can be used for initial diagnosis or confirmation of eradication
  • Sensitivity increases if PPIs have been discontinued for at least 2 weeks prior to testing.
• H. pylori stool antigen test: Can be used for initial diagnosis or confirmation of eradication
• Serum IgG antibodies against H. pylori
  • A positive result indicates exposure to H. pylori, but cannot distinguish between a past and current infection.
  • Antibodies may still be detected after eradication.

Invasive methods that require biopsies

Biopsies to identify H.pylori infection should be obtained in all patients undergoing EGD for dyspepsia. ^[4]

• Rapid urease test
  • Detects the amount of ammonia produced by H. pylori during urea hydrolysis
  • Ideally, one biopsy sample from the antrum and one sample from the corpus are required.
  • Sensitivity increases with multiple biopsy specimens and if PPIs have been discontinued for at least 2 weeks prior to testing.
• Histology (gold standard)
  • Staining and direct microscopic identification
  • Ideally, two biopsy samples from the antrum (peripyloric and angular incisure) and two samples from the corpus (lesser curvature and greater curvature) are required.
  • Curved, gram-negative rods with multiple flagella is the typical appearance of H.pylori.
• Culture and antibiogram
  • Culture of H. pylori requires a special nutrient broth.
  • Not widely available; consider culture if there is suspicion of antibiotic-resistant strains.
• PCR of biopsy samples
  • A highly sensitive and specific test that can provide rapid results and information regarding antibiotic resistance (e.g., identify specific mutations)
  • Its use is limited because of accessibility and cost.

Further workup

• Indications: inconclusive or negative EGD, negative H. pylori test, and/or inadequate response to empirical therapy
• Assess the pretest probability (PTP) of differential diagnoses of dyspepsia and workup accordingly.
• Examples include:
  • RUQ ultrasound for suspected symptomatic cholelithiasis
  • CT abdomen for suspected chronic pancreatitis
  • Assess the PTP of CAD; consider cardiac stress testing for stable angina.
  • Esophageal pH monitoring for persistent GERD symptoms despite adequate pharmacotherapy
  • Esophageal manometry or barium swallow for suspected esophageal motility disorders
  • Assess the Rome IV criteria for functional dyspepsia.

The differential diagnoses listed here are not exhaustive.

Approach ^[1][4]

• Typical heartburn (GERD) ^[3][11]
  • Trial of acid suppression therapy with PPIs for 8 weeks ^[3][4]
  • See “Management of GERD” for details on further management based on response to empirical therapy.
• Typical dyspepsia and negative test for H. pylori infection (PUD, gastritis) ^[12]
  • Trial of acid suppression therapy with PPIs for 8 weeks
  • See “Therapeutic approach to PUD” and “Gastritis subtypes” for further management.
• Positive test for H. pylori infection
  • H. pylori eradication therapy
  • Confirm eradication 4–6 weeks after completion of therapy.
• Other etiologies
  • See relevant articles for details on the management of conditions diagnosed on EGD and further diagnostics.
• All patients
  • Consider antacids for rapid symptomatic relief as needed.
  • Implement complementary nonpharmacological measures and lifestyle changes.

Pharmacological therapy

“Eat with aluminum CHOPSticKs”: The most important side effects of aluminum hydroxide are Constipation, Hypophosphatemia, Osteodystrophy, Proximal muscle weakness, Seizures, and hypoKalemia.

Nonpharmacological recommendations ^[17][18][19]

• Dietary recommendations
  • Reduce portion size.
  • Avoid eating at least 3 hours before lying down (e.g., before going to sleep). ^[3]
  • Avoid foods and beverages that appear to trigger symptoms. ^[20]
• Physical recommendations
  • Patients with obesity should be encouraged to lose weight and should also receive advice on the best approach. ^[3]
  • Elevate the head-end of the bed (10–20 cm) for patients who experience symptoms while sleeping. ^[3]
• Reduce or avoid triggers
  • Reduce or avoid stress.
  • Avoid nicotine, alcohol, and caffeine (especially if they appear to trigger symptoms).
  • If possible, avoid medications that may worsen symptoms (e.g., NSAIDs, aspirin, corticoids, calcium channel blockers, diazepam) ^[3][21]

Helicobacter pylori eradication therapy

All patients who test positive for H. pylori infection should receive H.pylori eradication therapy. ^[4]

First-line treatment options ^[4][22]

H. pylori eradication therapy typically comprises of PPIs twice daily PLUS two antibiotics with or without bismuth for 10–14 days. Local resistance patterns and adherence to treatment are the main determinants of the success of eradication therapy. ^[4]

Bismuth binds to the affected mucosa, providing physical protection from acids, and stimulates gastric HCO3- secretion, which helps to restore the mucosal pH gradient and is hence used to treat peptic ulcers and H.pylori infection (as a part of Bismuth quadruple therapy). Bismuth subsalicylate is also an antidiarrheal agent and is used to treat traveler's diarrhea (caused by enterotoxigenic Escherichia coli).

Second-line treatment options

• Choose different antibiotics to those used as first-line therapy.
• Bismuth quadruple therapy: if first-line clarithromycin triple therapy was unsuccessful
• Levofloxacin-containing therapy: e.g., levofloxacin triple therapy
  • PPIs at standard dose twice daily (e.g., omeprazole ) ^[4]
  • PLUS levofloxacin ^[4]
  • PLUS amoxicillin ^[4]
  • Duration: 10–14 days

Follow-up: Confirm H.pylori eradication ^[23]

• Confirm that H. pylori has been eradicated 4–6 weeks after completion of the treatment regimen. ^[5][24]
• Preferred modalities: Urea breath test, stool antigen test, or biopsy
• Stop PPIs at least 2 weeks before the urea breath test is performed for accurate results.
• Serology is not recommended to confirm eradication, as H. pylori antibodies may still be present for weeks or months after eradication.
• Acid suppression medication can be discontinued once eradication is confirmed. ^[24]

Functional dyspepsia (nonulcer dyspepsia) is a common GI disorder characterized by upper GI symptoms (e.g., epigastric pain, bloating) without any identifiable cause. Symptoms may vary in intensity and can have a significant impact on patients' lives. Functional dyspepsia is heterogeneous and multifactorial, and its pathophysiology is not fully understood.

Rome IV criteria for functional dyspepsia ^[2][18][25]

Functional dyspepsia is a diagnosis of exclusion that can be made if an organic cause cannot be identified after completing a diagnostic workup of dyspepsia and its differential diagnoses.

• Any of the following symptoms experienced at least 3 days per week over the past 3 months
  • Epigastric burning
  • Epigastric pain
  • Early satiety
  • Postprandial fullness
• Interference with daily activities
• Symptom duration ≥ 6 months

Treatment ^[1][18][25]

• First-line treatment: PPIs for 8 weeks at standard dose (see “Acid suppression medications”) ^[1]
• Second-line treatment (if no improvement after 8 weeks of PPIs): tricyclic antidepressants (e.g., amitriptyline )
• Third-line treatment: Consider if there is no response to PPIs or tricyclic antidepressants.
  • Prokinetic therapy (e.g., metoclopramide )
  • Psychological therapy (e.g., cognitive behavioral therapy)