Symptoms of Whipple's Disease
Whipple's disease presents with four cardinal symptoms: arthralgias, weight loss, diarrhea, and abdominal pain, though joint manifestations often precede gastrointestinal symptoms by years, making early diagnosis challenging. 1, 2
Classic Clinical Presentation
The disease typically follows a characteristic temporal pattern:
- Arthralgias are the most common initial manifestation, often appearing 6-8 years before diagnosis and evolving intermittently 1, 3, 4
- Migratory polyarthralgias affect multiple joints in a non-specific pattern 5
- Joint symptoms may be the sole complaint for years before other manifestations develop 3
Gastrointestinal Manifestations
The classic abdominal stage includes:
- Chronic diarrhea with steatorrhea in advanced cases 1, 5
- Abdominal pain that may be convulsive or non-specific 2, 6, 4
- Weight loss that can be progressive and severe 1, 3, 6
- Anorexia and weakness 3, 5
Important caveat: Diarrhea may be absent in some patients, which significantly delays diagnosis 2. The absence of gastrointestinal symptoms should not exclude Whipple's disease if other features are present.
Systemic and Constitutional Symptoms
- Intermittent low-grade fever or recurrent febrile episodes 2, 3
- Progressive weakness and fatigue 3, 5
- Generalized lymphadenopathy 1, 4, 5
- Hyperpigmentation in advanced disease 5
- Cachexia in the generalized stage 5
Neurological Manifestations
Neurological involvement includes:
- Nystagmus and ophthalmoplegia 3
- Cranial nerve defects 3
- Sensory and motor polyneuropathy 5
- Cognitive changes may occur in advanced cases 1
Cardiovascular Involvement
- Endocarditis, particularly affecting the tricuspid valve 1, 4
- Cardiovascular system involvement can occur as part of the generalized stage 5
Clinical Stages
Whipple's disease progresses through three stages:
- Prodromal stage: Non-specific migratory polyarthralgias lasting years 5
- Classic abdominal stage: Weight loss, weakness, chronic diarrhea, and abdominal pain 5
- Generalized stage: Steatorrhea, cachexia, lymphadenopathy, hyperpigmentation, and multi-organ involvement including cardiovascular, pulmonary, and neurological dysfunction 5
Diagnostic Pitfalls
The average time to diagnosis is 6 years due to the variable and non-specific presentation 2, 4. Key pitfalls include:
- Misdiagnosis as sarcoidosis when lymph node biopsies show granulomatous inflammation 4
- Failure to consider Whipple's disease when diarrhea is absent 2
- Attributing isolated arthritis to other rheumatologic conditions 3
- The disease predominantly affects white men in the fourth to sixth decades of life 3, 4
Diagnostic Confirmation
Diagnosis requires demonstration of PAS-positive macrophagic infiltration of the lamina propria on intestinal biopsy or positive PCR for Tropheryma whipplei in affected tissues 1. Even without gastrointestinal symptoms, duodenal biopsy should be pursued when clinical suspicion is high based on the constellation of arthralgias, weight loss, fever, and lymphadenopathy 6, 4.