What clinical features differentiate Whipple disease from tropical sprue, and what clues aid diagnosis?

Clinical Differentiation Between Whipple Disease and Tropical Sprue

The key distinguishing features are geographic exposure history, specific vitamin deficiency patterns, histologic findings, and extraintestinal manifestations—with Whipple disease showing PAS-positive macrophages and frequent systemic involvement (arthritis, neurologic symptoms), while tropical sprue demonstrates marked eosinophilia, pan-enteric inflammation with ileal predominance, and responds rapidly to folate plus tetracycline therapy.

Geographic and Demographic Clues

Travel and residence history is the most critical initial distinguishing factor:

• Tropical sprue requires documented travel to or residence in tropical regions, specifically South Asia, Papua New Guinea, or other endemic tropical areas 1
• Whipple disease shows no geographic restriction and predominantly affects middle-aged Caucasian males (male:female ratio 3-6:1, mean age 55 years) 2, 3
• Tropical sprue affects both sexes equally (6 men, 6 women in case series) with median age 59 years 1

Vitamin Deficiency Patterns

The pattern of vitamin deficiencies provides a crucial diagnostic clue:

• Tropical sprue characteristically causes both folate AND vitamin B12 deficiency as a defining feature 4, 1
• This dual deficiency reflects pan-enteric involvement affecting both proximal (folate) and distal (B12) small bowel absorption sites 1
• Whipple disease causes malabsorption but folate/B12 deficiency is not a characteristic or defining feature 4, 2

Clinical Presentation Differences

Gastrointestinal Manifestations

Both conditions present with malabsorption, but the pattern differs:

• Tropical sprue: Profuse diarrhea with steatorrhea as the dominant presenting feature, weight loss, and malabsorption symptoms 1
• Whipple disease: Abdominal pain with persistent diarrhea (steatorrhea), but gastrointestinal symptoms may be preceded by extraintestinal manifestations for many years 2, 5, 3

Extraintestinal Manifestations

This is the most discriminating clinical feature:

• Whipple disease frequently presents with systemic symptoms:

  • Polyarthritic symptoms (often preceding GI symptoms by years) 2, 5, 3
  • Fever 2, 6
  • Lymphadenopathy (may be conspicuous or tumor-like) 2, 5
  • Skin hyperpigmentation 2, 6
  • Neurological symptoms (can be fatal if untreated) 3, 6
  • Cardiac involvement 2
  • Ocular symptoms 2

• Tropical sprue is primarily an enteric disease with minimal to no extraintestinal manifestations 1

Laboratory Findings

Specific laboratory patterns help differentiate:

• Tropical sprue: Marked eosinophilia in duodenal mucosa (mean 26.6/HPF) and peripheral blood 1
• Whipple disease: Anemia, hypoalbuminemia, reduced IgA, but eosinophilia is not characteristic 2, 6

Histologic Differentiation

Biopsy findings provide definitive differentiation:

Whipple Disease

• PAS-positive macrophages in the lamina propria (pathognomonic finding) 4, 2, 3
• PCR detection of Tropheryma whipplei DNA 5, 3
• Villous atrophy present but not the defining feature 4

Tropical Sprue

• Partial villous blunting in 75% of cases (never complete/flat mucosa as in celiac disease) 1
• Marked intraepithelial lymphocytosis (mean 77.3 per 100 epithelial cells) without villous tip accentuation 1
• Conspicuous eosinophil infiltrate in lamina propria (significantly higher than celiac disease: 26.6/HPF vs 14.6/HPF, p=0.009) 1
• Pan-enteric involvement: Terminal ileum shows more severe villous blunting than duodenum (critical distinguishing feature) 1
• Mild intraepithelial lymphocytosis and eosinophilia in colonic mucosa in 50% of cases 1
• No PAS-positive macrophages 1

Temporal Course and Response to Therapy

Treatment response provides retrospective diagnostic confirmation:

• Tropical sprue responds rapidly to oral folate plus doxycycline, with histologic improvement on follow-up biopsies 4, 1
• Whipple disease requires prolonged antibiotic therapy (combination of tetracyclines/doxycycline with corticosteroids, or chloramphenicol for CNS involvement) 2
• Whipple disease has a progressive or remittent course and is fatal without treatment 2, 6
• Symptoms in Whipple disease may persist for decades before diagnosis (one case diagnosed 36 years after symptom onset) 5

Critical Diagnostic Pitfalls

Common errors to avoid:

• Do not confuse tropical sprue with celiac disease: Tropical sprue never shows complete villous blunting (Marsh 3c), has more ileal than duodenal involvement, and shows prominent eosinophilia 1
• Do not miss Whipple disease by focusing only on GI symptoms: Extraintestinal manifestations (especially arthritis) often precede GI symptoms by many years 5, 3
• Do not rely solely on PCR for Whipple disease: False positives can occur; PAS-positive macrophages remain the gold standard 3
• Always obtain travel history: Absence of tropical exposure essentially excludes tropical sprue 4, 1
• In tropical sprue, always biopsy the terminal ileum if accessible: More severe inflammation here than in duodenum is highly suggestive 1