What is sarcoidosis in a patient with a history of cardiovascular disease and elevated hemoglobin levels, presenting with tongue swelling and systemic symptoms such as fever, fatigue, and weight loss?

What is Sarcoidosis?

Sarcoidosis is a chronic multisystem inflammatory disease characterized by the formation of non-caseating (non-necrotic) granulomas that can affect virtually any organ, most commonly the lungs, intrathoracic lymph nodes, eyes, and skin. 1, 2

Pathophysiology

Sarcoidosis fundamentally represents a T-cell mediated inflammatory disorder where genetically susceptible individuals mount an exaggerated immune response to unidentified antigens. 3, 2 The disease mechanism involves:

• Abnormal cellular immune activation with accumulation of CD4+ T helper cells at sites of disease activity, releasing pro-inflammatory cytokines (particularly IL-2 and TNF-alpha) that drive the inflammatory cascade. 3, 4

• Formation of compact, well-organized non-caseating granulomas consisting of a central core of tightly packed epithelioid histiocytes and multinucleated giant cells, surrounded by a peripheral zone of loosely organized lymphocytes. 3, 2

• Characteristic perilymphatic distribution where granulomas locate around bronchovascular bundles, fibrous septa containing pulmonary veins, and near visceral pleura. 3, 5

• Abnormal vitamin D metabolism within granulomatous lesions, producing elevated 1,25-dihydroxyvitamin D levels with normal-to-low parathyroid hormone, leading to hypercalcemia and hypercalciuria. 1, 3

Clinical Presentation

Highly Probable Features (Strongly Suggest Sarcoidosis)

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) 1
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears) 1
• Uveitis and optic neuritis 1
• Bilateral hilar adenopathy on chest imaging 1
• Perilymphatic nodules on chest CT 1

Common Systemic Manifestations

Pulmonary involvement (most common) presents with persistent dry cough, bilateral hilar lymphadenopathy, upper lobe or diffuse infiltrates, and peribronchial thickening. 2, 6

Skin manifestations include lupus pernio, maculopapular/erythematous/violaceous lesions, erythema nodosum, and subcutaneous nodules. 1, 2

Ocular involvement presents as uveitis, scleritis, retinitis, lacrimal gland swelling, or conjunctival nodules/granulomas. 1

Cardiac involvement (less common but high morbidity) manifests as treatment-responsive cardiomyopathy, new-onset third-degree AV block in young/middle-aged adults, spontaneous/inducible ventricular tachycardia without risk factors, or reduced left ventricular ejection fraction without risk factors. 1, 2

Constitutional symptoms include fever, fatigue, weight loss, and night sweats. 6, 7

Other organ involvement includes hepatosplenomegaly, symmetrical parotid enlargement, seventh cranial nerve paralysis, granulomatous lesions on laryngoscopy, and treatment-responsive renal failure. 1, 2

Context-Specific Considerations

In your patient with cardiovascular disease history, elevated hemoglobin, tongue swelling, and systemic symptoms, consider:

• Tongue swelling may represent oral sarcoidosis or parotid/salivary gland involvement (symmetrical parotid enlargement is a probable feature). 1
• Elevated hemoglobin is atypical; sarcoidosis more commonly causes anemia of chronic disease or reactive thrombocytosis from chronic inflammation. 2
• Cardiovascular disease history requires heightened vigilance for cardiac sarcoidosis, which significantly impacts morbidity and mortality. 2

Diagnostic Approach

Diagnosis requires three essential components: 1, 2

1. Compatible clinical and radiologic presentation (see features above)
2. Pathologic evidence of non-caseating granulomas on tissue biopsy
3. Exclusion of alternative causes of granulomatous inflammation (especially infections like tuberculosis, fungal diseases; also malignancy, drug reactions, IgG4-related disease, vasculitides)

Key Diagnostic Tests

• High-resolution chest CT showing bilateral hilar adenopathy and perilymphatic nodules 2
• Tissue biopsy from accessible involved organs (lung, lymph node, skin) demonstrating non-caseating granulomas 1, 2
• Bronchoalveolar lavage showing lymphocytosis or elevated CD4:CD8 ratio 1, 2
• Laboratory testing: elevated ACE level (>50% above upper limit of normal), hypercalcemia/hypercalciuria with abnormal vitamin D metabolism, alkaline phosphatase >3× upper limit of normal 1
• Cardiac MRI for suspected cardiac involvement 2
• PET scan showing parotid uptake or increased inflammatory activity 1

Epidemiology

Sarcoidosis demonstrates bimodal age distribution with highest incidence between ages 20-39 years. 1 The disease shows higher prevalence in African Americans compared to Caucasians, with African American women experiencing 2.4 times higher mortality and greater extrapulmonary involvement. 2

Prognosis and Natural History

Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease and do not require treatment. 2 Löfgren's syndrome typically has excellent prognosis with high spontaneous remission rates. 2, 4 However, one-third or more of patients develop chronic, unremitting inflammation with progressive organ impairment requiring long-term immunosuppression. 8