What are the causes of non‑cardiac chest pain with a normal esophagogastroduodenoscopy (EGD)?

Causes of Non-Cardiac Chest Pain with Normal EGD

When upper endoscopy is normal and chest pain persists despite cardiac exclusion, the primary causes are esophageal motility disorders, functional chest pain of presumed esophageal origin, and psychological disorders—particularly anxiety and depression.

Esophageal Causes Despite Normal Endoscopy

Esophageal Motility Disorders

• Esophageal motility disorders (achalasia, distal esophageal spasm, nutcracker esophagus) are less common but present as squeezing retrosternal pain or spasm, often accompanied by dysphagia. 1
• These disorders require esophageal function testing and high-resolution manometry for diagnosis, as endoscopy appears normal. 1
• Esophageal spasm can mimic myocardial ischemia and may respond to nitroglycerin, which is why nitroglycerin response should not be used to differentiate cardiac from esophageal pain. 1

Functional Chest Pain of Presumed Esophageal Origin

• Functional chest pain is diagnosed when all esophageal testing (endoscopy, pH monitoring, manometry) is negative but symptoms persist. 2, 3
• This represents visceral hypersensitivity—abnormal perception of otherwise normal esophageal stimuli. 1, 2
• Functional chest pain accounts for approximately 32% of non-GERD-related NCCP cases. 2, 3

Occult GERD Despite Normal Endoscopy

• Negative upper endoscopy is quite common in GERD-related chest pain; up to 67.7% of patients with abnormal pH monitoring have normal endoscopy. 4
• If symptoms persist despite normal endoscopy and a trial of acid suppression, impedance-pH monitoring should be performed to detect non-erosive reflux disease. 1, 2

Psychological and Psychiatric Causes

High Prevalence of Psychiatric Comorbidity

• Psychological disorders—particularly anxiety, panic disorder, and major depression—are present in 52% of patients with non-cardiac chest pain. 4
• Depression, anxiety, and gastroesophageal syndromes each exceed coronary artery disease by almost 10-fold in low-risk chest pain patients. 1
• The close association with anxiety, panic attack, depression, somatoform disorder, and cardiophobia suggests a psychogenic origin in many patients. 1

Mechanisms of Psychogenic Chest Pain

• Central nervous system-visceral interactions, low pain thresholds, hyperbody vigilance, sympathetic activation, anxiety, depression, and panic disorder contribute to non-cardiac chest pain. 1
• Cognitive-behavioral therapy has shown a 32% reduction in chest pain frequency over 3 months in patients with non-cardiac chest pain and psychological disorders. 1, 5, 6

Musculoskeletal Causes

• Musculoskeletal causes are the most common non-cardiac causes overall, with costochondritis accounting for approximately 43% of cases when cardiac causes are excluded. 1, 5, 6
• Costochondritis is characterized by pain reproducible with palpation of costochondral junctions and affected by breathing, turning, twisting, or bending. 1, 5, 6
• Muscle strain and cervical radiculopathy can cause pain radiating from the cervical spine to the chest. 1, 5, 6

Other Non-Esophageal Causes

Pulmonary Causes

• Pulmonary embolism presents with tachycardia (>90% of patients), dyspnea, and pleuritic chest pain. 1, 5, 6
• Pneumonia causes localized pleuritic chest pain with fever and friction rub. 1, 5, 6
• Pneumothorax is characterized by pleuritic chest pain with unilateral decreased or absent breath sounds. 1, 5, 6

Medication-Related Esophageal Irritation

• NSAIDs, potassium supplements, iron, and bisphosphonates can cause esophageal irritation leading to chest discomfort despite normal endoscopy. 1, 5, 6

Other Cardiac Causes

• Pericarditis presents with sharp, pleuritic chest pain that worsens supine and improves leaning forward, with a friction rub. 1, 5, 6

Diagnostic Algorithm After Normal EGD

Step 1: Trial of Empiric Acid Suppression

• Patients without alarm symptoms (dysphagia, odynophagia, GI bleeding, anemia, weight loss, recurrent vomiting) merit a trial of empiric acid suppression therapy with high-dose proton pump inhibitors. 1, 2

Step 2: Advanced Esophageal Testing if PPI Trial Fails

• If symptoms persist despite acid suppression and normal endoscopy, perform esophageal function testing (high-resolution manometry) and pH-impedance monitoring to exclude motility disorders and non-erosive reflux disease. 1, 2, 3

Step 3: Evaluate for Psychological Factors

• For patients with recurrent presentations and negative physiological workup including negative cardiac and esophageal testing, referral to a cognitive-behavioral therapist is reasonable. 1
• Assessment and treatment of psychological comorbidity should be considered in all NCCP patients. 5, 6, 3

Step 4: Consider Musculoskeletal Evaluation

• Assess for chest wall tenderness, pain with movement, and reproduction with palpation. 1, 5, 6

Treatment Approaches Based on Etiology

For Esophageal Motility Disorders

• Calcium channel blockers, nitrates, anticholinergics, or botulinum toxin injection have been used for hypercontractile or spastic motility disorders. 2
• Recent trials with endoscopic myotomy show promise. 2

For Visceral Hypersensitivity/Functional Chest Pain

• Neuromodulators (venlafaxine, sertraline, imipramine) show significant improvement compared to placebo. 2, 3
• Cognitive-behavioral therapy is effective. 1, 2

For Occult GERD

• Potent antireflux treatment with high-dose PPIs. 2, 3

Critical Pitfalls to Avoid

• Do not assume normal endoscopy excludes GERD; pH monitoring may still be abnormal in up to 68% of cases. 4
• Do not overlook psychological factors—these are common (52% prevalence) but frequently under-recognized and under-referred (<10% referral rate). 1, 4
• Patients with non-cardiac chest pain undergo extensive and repetitive cardiac testing with low referral to cognitive-behavioral therapists, representing a lost opportunity for effective therapy. 1
• Do not dismiss the need for continued evaluation; the broad range of causes are not mutually exclusive. 7