What are the differential diagnoses for nocturnal dyspepsia?

Differential Diagnosis for Nocturnal Indigestion

Nocturnal gastroesophageal reflux disease (GERD) is the most common and important cause of middle-of-the-night indigestion, affecting up to 25% of GERD patients with sleep disturbances and carrying increased risk for erosive esophagitis and respiratory complications. 1

Primary Gastrointestinal Causes

Gastroesophageal Reflux Disease (GERD)

• Nocturnal GERD is the leading diagnosis when heartburn, regurgitation, or epigastric burning wakes patients from sleep 2, 3
• Sleep-related physiological changes dramatically worsen acid exposure: saliva production drops, swallowing frequency decreases, esophageal clearance slows by 8-10 fold, and gastric emptying delays 4, 5
• Nighttime reflux episodes are less frequent than daytime but significantly longer in duration, resulting in prolonged acid-mucosal contact and greater tissue damage 5
• More than 50% of GERD patients have normal endoscopy (non-erosive reflux disease), so absence of esophagitis does not exclude the diagnosis 2
• Nocturnal GERD portends higher risk for Barrett's esophagus, strictures, and aspiration pneumonia compared to daytime-only symptoms 3, 1

Peptic Ulcer Disease (PUD)

• Accounts for approximately 10% of upper gastrointestinal symptoms presenting with nocturnal epigastric pain 2
• Nighttime gastric acid production increases during sleep, exacerbating ulcer pain 4
• Helicobacter pylori infection is the principal cause of non-NSAID peptic ulcers and should be tested in all patients with nocturnal epigastric pain 2
• Duodenal ulcers classically cause pain 2-5 hours after meals or in the middle of the night when the stomach is empty 6

Gastroparesis

• Presents with nausea, vomiting, and postprandial abdominal fullness that can worsen at night due to delayed gastric emptying 6
• Occurs in 20-40% of diabetic patients, particularly those with long-standing type 1 diabetes 6
• Hyperglycemia itself causes antral hypomotility and gastric dysrhythmias 6

Functional Dyspepsia

• Diagnosed when bothersome epigastric pain, burning, postprandial fullness, or early satiation persists for >8 weeks with normal endoscopy 2
• Accounts for the majority (>50%) of patients undergoing endoscopy for dyspepsia 2
• Persistent vomiting is a red-flag that excludes functional dyspepsia and mandates investigation for organic disease 2

Cardiac Causes (Critical to Exclude)

Acute Coronary Syndrome

• Myocardial infarction can present with isolated epigastric pain, especially in women, diabetics, and elderly patients 2
• An ECG must be obtained immediately to exclude cardiac ischemia in any patient with new nocturnal epigastric discomfort and cardiovascular risk factors 2
• Mortality reaches 10-20% when cardiac causes are missed 2

Congestive Heart Failure

• Nocturnal fluid redistribution from peripheral edema can trigger reflux symptoms and dyspnea 6
• Screen for ankle swelling and orthopnea 6

Sleep-Related Disorders

Obstructive Sleep Apnea (OSA)

• Creates negative intrathoracic pressure during apneic episodes, promoting reflux 6
• Ask: "Have you been told you gasp or stop breathing at night?" and "Do you wake up without feeling refreshed?" 6
• OSA and GERD have a bidirectional relationship, with each worsening the other 1

Primary Sleep Disorders

• Insomnia, restless legs syndrome, and parasomnias can cause nocturnal awakenings misattributed to indigestion 6
• Ask: "Do you have problems sleeping aside from needing to get up or feeling discomfort?" 6

Endocrine and Metabolic Causes

Diabetes Mellitus

• Both gastroparesis and autonomic neuropathy contribute to nocturnal symptoms 6
• Check HbA1c in all patients with nocturnal dyspepsia 6

Thyroid Dysfunction

• Overactive or profoundly underactive thyroid can alter gastrointestinal motility 6
• Obtain thyroid function tests as part of baseline evaluation 6

Medication-Related Causes

Diuretics and Antihypertensives

• Diuretics (especially when taken in evening) cause nocturia that disrupts sleep and may be confused with indigestion-related awakenings 7
• Calcium channel blockers reduce lower esophageal sphincter pressure and worsen reflux 6
• NSAIDs cause gastropathy and increase ulcer risk 6, 2

Renal Causes

Chronic Kidney Disease (CKD)

• Impaired renal concentrating ability causes nocturnal polyuria (>33% of 24-hour urine output at night) 8
• CKD causes xerostomia, prompting increased fluid intake that worsens nocturnal reflux 6
• Check electrolytes, renal function, and urine albumin:creatinine ratio 6

Structured Diagnostic Approach

Initial Red-Flag Assessment

1. Obtain ECG immediately if patient has cardiovascular risk factors, exertional symptoms, or is diabetic/elderly 2
2. Check for alarm features requiring urgent endoscopy (2-week wait): 2
   • Age ≥55 years with new-onset symptoms
   • Unintentional weight loss
   • Anemia on complete blood count
   • Dysphagia (food sticking sensation)
   • Persistent vomiting
   • Hematemesis or melena
   • Palpable epigastric mass

Baseline Laboratory Testing

• Complete blood count (to detect anemia) 2
• Electrolytes and renal function 6
• HbA1c 6
• Thyroid function tests 6
• Calcium level 6

Symptom Characterization

• Determine the predominant symptom: heartburn/regurgitation versus epigastric pain 2
• Document timing: does pain wake patient from sleep or prevent falling asleep? 9
• Assess relationship to meals and body position 3
• Quantify sleep disruption and next-day functional impairment 9, 1

Testing Algorithm Based on Presentation

If predominant heartburn/regurgitation without alarm features:

• Start empiric PPI therapy (omeprazole 20-40 mg once daily before breakfast) for 4-8 weeks 2
• Endoscopy is NOT required for initial diagnosis 2
• If symptoms persist after 8 weeks of twice-daily PPI, schedule endoscopy 2

If predominant epigastric pain without alarm features:

• Perform H. pylori testing using ¹³C-urea breath test or stool antigen (serology not recommended) 2
• If H. pylori-positive: treat with standard eradication regimen 2
• If H. pylori-negative or symptoms persist after eradication: start PPI trial (omeprazole 20-40 mg daily) for 4-8 weeks 2
• Persistent symptoms beyond 8 weeks warrant endoscopy 2

If alarm features present:

• Urgent endoscopy (2-week wait) after CT abdomen/pelvis with IV contrast to exclude perforation 2
• CT findings suggesting perforation: extraluminal gas (97%), fluid/fat stranding (89%), ascites (89%), focal wall defect (84%) 2

Sleep and Nocturia Screening

• Ask standardized "SCREeN" questions to identify undiagnosed conditions: 6
  • Sleep disorders: "Do you gasp or stop breathing at night?"
  • Cardiac: "Do you experience ankle swelling or shortness of breath?"
  • Endocrine: "Have you been feeling excessively thirsty?"
  • Neurological: "Do you have problems controlling your legs or tremor?"

Common Diagnostic Pitfalls

• Assuming nocturnal symptoms are purely GERD without obtaining an ECG in at-risk patients can miss fatal myocardial infarction 2
• Delaying endoscopy in patients ≥55 years with new-onset nocturnal symptoms; age alone is an alarm feature 2
• Attributing persistent vomiting to functional dyspepsia or GERD ignores its status as a red-flag for organic disease 2
• Not recognizing the bidirectional relationship between sleep disturbances and GERD: poor sleep worsens esophageal hyperalgesia, creating a vicious cycle 9
• Ordering upper GI barium series to diagnose GERD or dyspepsia is not recommended and may produce false-positive results 2
• Missing medication-induced causes: failing to review timing of diuretics, calcium channel blockers, and NSAIDs 6, 7