What is the differential diagnosis for nocturnal epigastric pain with isolated leukocytosis?

Differential Diagnosis for Nocturnal Epigastric Pain with Isolated Leukocytosis

The combination of nightly stomach pain and leukocytosis demands immediate exclusion of life-threatening conditions—particularly perforated peptic ulcer, acute pancreatitis, and atypical myocardial infarction—before considering benign causes, as delayed diagnosis of these emergencies carries mortality rates of 10-30%. 1, 2

Life-Threatening Causes to Rule Out First

Perforated Peptic Ulcer

• Presents with sudden, severe epigastric pain that may initially be localized before becoming generalized, accompanied by fever, abdominal rigidity, and absent bowel sounds, with mortality reaching 30% if treatment is delayed 1, 3
• Critical pitfall: Absence of abdominal rigidity does not exclude perforation early in the presentation; perforated ulcers may initially present with only localized tenderness 2
• Leukocytosis occurs in 40% of patients with iatrogenic bowel perforation and is a marker of bacterial infection and peritoneal contamination 4
• CT with IV contrast shows extraluminal gas in 97% of cases, fluid or fat stranding in 89%, ascites in 89%, and focal wall defect in 84% 1, 3
• Requires emergent surgical consultation 1

Acute Pancreatitis

• Characteristically presents with epigastric pain radiating to the back, often worse at night when lying supine 1, 3
• Diagnosed by serum amylase ≥4× normal or lipase ≥2× normal with 80-90% sensitivity and specificity 1, 2, 3
• Leukocytosis is common and reflects the inflammatory response 4
• Can progress to necrotizing pancreatitis with multiorgan failure 1

Atypical Myocardial Infarction

• Myocardial infarction presents atypically with epigastric pain as the primary manifestation in women, diabetics, and elderly patients, with mortality rates of 10-20% if missed 1, 3
• Obtain ECG within 10 minutes of presentation and serial troponins at 0 and 6 hours—never rely on a single troponin measurement 1, 2, 3
• Nocturnal pain may represent unstable angina or NSTEMI 1

Mesenteric Ischemia

• Causes severe epigastric pain with pain out of proportion to examination findings 1
• Leukocytosis is usually present except in immunocompromised patients or those taking steroids, and serves as a potential predictor for transmural bowel necrosis 4
• Elevated lactate indicates poor tissue perfusion and bowel ischemia 4
• Requires CT angiography for diagnosis 4, 1

Common Gastrointestinal Causes

Peptic Ulcer Disease (Most Likely Given Nocturnal Pattern)

• Nocturnal epigastric pain is classic for duodenal ulcer, occurring 2-5 hours after meals when gastric acid secretion peaks and the stomach is empty 1
• Has an incidence of 0.1-0.3%, with complications occurring in 2-10% of cases 1, 3
• CT findings include gastric or duodenal wall thickening due to submucosal edema, mucosal hyperenhancement, fat stranding, and focal outpouching from ulcerations 1, 3
• Leukocytosis may indicate impending perforation or penetration into adjacent organs 4

Gastric Cancer

• May present with ulcer associated with nodularity of adjacent mucosa, mass effect, or irregular radiating folds 1, 3
• Now the most common cause of gastric outlet obstruction in adults with 5-year survival rate of 32% 1, 3
• Paraneoplastic leukocytosis occurs in 30% of nonhematologic malignancies, particularly lung and colorectal cancers, and is associated with metastatic disease and shorter survival 5, 6
• Alarm features include weight loss, dysphagia, hematemesis, persistent vomiting, and anemia 1, 3

Gastroesophageal Reflux Disease

• Affects 42% of Americans monthly and 7% daily, presenting with heartburn, regurgitation, and epigastric pain 1, 3
• Nocturnal reflux is common due to supine positioning and decreased salivary clearance 4
• Distal esophageal wall thickening (≥5 mm) on CT has 56% sensitivity and 88% specificity for reflux esophagitis 1, 3

Diagnostic Algorithm

Step 1: Immediate Assessment

• Check vital signs: Tachycardia ≥110 bpm, fever ≥38°C, or hypotension predict perforation, anastomotic leak, or sepsis 1, 2, 3
• Examine for peritoneal signs: Rigidity, rebound tenderness, absent bowel sounds indicating perforation 1, 2
• Obtain ECG within 10 minutes to exclude myocardial ischemia 1, 2, 3

Step 2: Laboratory Evaluation

• Complete blood count with differential to characterize the leukocytosis 7, 8
• Peripheral blood smear is essential: Look for toxic granulations suggesting infection, immature cells suggesting leukemia, or monomorphic lymphocytes suggesting lymphoproliferative disorder 8, 9
• Serum amylase or lipase to exclude acute pancreatitis 1, 2, 3
• Cardiac troponins at 0 and 6 hours 1, 2, 3
• C-reactive protein, procalcitonin, and serum lactate to assess for infection and ischemia 4
• Liver and renal function tests 4

Step 3: Imaging

• CT abdomen and pelvis with IV contrast is the gold standard when diagnosis is unclear, identifying pancreatitis, perforation, and vascular emergencies 1, 2, 3
• Use neutral oral contrast (water or dilute barium) when gastric disease is suspected 1, 3
• CT angiography if mesenteric ischemia or aortic dissection suspected 4, 1

Step 4: Endoscopy

• Upper endoscopy is definitive for PUD, gastritis, and esophagitis when patient is stable 1
• Request urgent endoscopy if alarm features present: weight loss, dysphagia, hematemesis, persistent vomiting, anemia 1, 3

Leukocytosis-Specific Considerations

Benign Causes of Leukocytosis

• Infection is the most common cause, particularly bacterial, and should prompt search for other signs and symptoms 8
• Medications, smoking, obesity, chronic inflammatory conditions, and stress can cause secondary leukocytosis 8
• The peripheral white blood cell count can double within hours after surgery, exercise, trauma, or emotional stress 8

Malignant Causes Requiring Hematology Referral

• Constitutional symptoms (fever, weight loss, bruising, fatigue) along with abnormal peripheral blood smear indicate need for evaluation for malignancy 7, 8
• Paraneoplastic leukemoid reaction occurs in 10% of solid tumor patients with extreme leukocytosis, typically with neutrophil predominance (96%) and metastatic disease (78%), carrying a poor prognosis with 78% mortality within 12 weeks unless effective antineoplastic therapy is received 6
• If malignancy cannot be excluded or another more likely cause is not suspected, referral to hematologist/oncologist is indicated 8

Empiric Management While Awaiting Diagnosis

• Maintain NPO status until surgical emergency is excluded 1, 2
• Establish IV access and provide fluid resuscitation if hemodynamically unstable 1, 2
• Start high-dose PPI therapy (omeprazole 20-40 mg once daily) for suspected acid-related pathology, with healing rates of 80-90% for duodenal ulcers and 70-80% for gastric ulcers 1, 3
• Avoid NSAIDs as they worsen PUD and bleeding risk 1, 3
• Initiate broad-spectrum antibiotics if septic shock develops 2

Critical Pitfalls to Avoid

• Never dismiss cardiac causes in patients with "atypical" epigastric pain, regardless of age 1, 3
• Do not delay imaging in patients with peritoneal signs, as perforated ulcer mortality increases significantly with delayed diagnosis 1, 2
• Never rely on single troponin measurement; serial measurements at least 6 hours apart are required to exclude NSTEMI 1, 2, 3
• Do not assume absence of abdominal rigidity excludes perforation; perforated ulcers may initially present with localized tenderness 2
• Do not attribute leukocytosis solely to stress or benign causes without excluding infection, malignancy, and surgical emergencies first 7, 8, 5
• Persistent vomiting with epigastric pain excludes functional dyspepsia and mandates investigation for structural disease such as peptic ulcer or acute coronary syndrome 3