Sarcoidosis: A High-Yield USMLE Review

Sarcoidosis is a multisystem granulomatous disease characterized by non-caseating granulomas that can affect virtually any organ, though the lungs and thoracic lymph nodes are involved in over 90% of cases. It is a diagnosis of exclusion and a favorite USMLE topic because of its classic imaging, characteristic extrapulmonary findings, and the need to distinguish it from infection, malignancy, and berylliosis. Peak incidence is in patients aged 25–40, with higher incidence and more severe disease in African Americans.

Presentation

• Pulmonary disease is most common—often asymptomatic and found incidentally on chest X-ray, or presenting with cough and dyspnea when symptomatic
• Eye involvement (25–50%): uveitis (anterior or posterior) and dry eyes
• Skin findings: erythema nodosum in acute disease and lupus pernio (violaceous facial plaques) in chronic disease
• Cardiac involvement: arrhythmias, heart block, and cardiomyopathy—potentially life-threatening
• Neurologic involvement: facial nerve (VII) palsy, CNS lesions, and small fiber neuropathy
• Hypercalcemia and hypercalciuria from granuloma 1-alpha-hydroxylase activity
• Löfgren syndrome (acute sarcoidosis): bilateral hilar adenopathy, erythema nodosum, fever, and arthralgias (especially ankles), with an excellent prognosis

Diagnosis

• Chest imaging (CXR and CT): staged by degree of hilar adenopathy and parenchymal involvement; bilateral hilar adenopathy is characteristic
• PFTs: may be normal, obstructive, restrictive, or mixed
• Laboratory: ACE level elevated in ~60% but nonspecific; check serum calcium for hypercalcemia and 24-hour urine calcium for hypercalciuria; assess liver enzymes and renal function
• Tissue biopsy is required for definitive diagnosis—shows non-caseating granulomas with negative stains/cultures for infection; easiest sites include skin lesions, peripheral lymph nodes, or bronchoscopy with transbronchial biopsy
• Because it is a diagnosis of exclusion, rule out infection (especially TB and fungal), malignancy (lymphoma can cause hilar adenopathy), and berylliosis

Management

• Observation (watchful waiting) for asymptomatic patients—e.g., Stage I disease with bilateral hilar adenopathy only and normal PFTs, given the >80% spontaneous remission rate
• Corticosteroids when indicated: symptomatic or progressive pulmonary disease, extrapulmonary involvement requiring treatment (cardiac, neurologic, eye disease not responding to topical therapy), or hypercalcemia
• Baseline evaluation should include eye exam, ECG, calcium, and liver enzymes, with serial monitoring of PFTs and imaging

High-yield

• Non-caseating granulomas are the histologic hallmark
• Type IV delayed-type hypersensitivity mechanism—CD4+ T cells activate macrophages to form granulomas
• Hypercalcemia/hypercalciuria from 1-alpha-hydroxylase in granulomas
• Löfgren syndrome = bilateral hilar adenopathy + erythema nodosum + fever + arthralgias, with excellent prognosis
• Higher incidence and more severe disease in African Americans; also common in Scandinavians; peak age 25–40
• Stage I disease has >80% spontaneous remission rate—observation is appropriate
• Lupus pernio (violaceous facial plaques) is characteristic of chronic disease

Pitfalls

• Sarcoidosis and berylliosis are clinically, radiologically, and histologically nearly identical—always obtain a detailed occupational history (aerospace, electronics/semiconductor, nuclear, dental alloy) and use the beryllium lymphocyte proliferation test (BeLPT), which is positive in berylliosis and negative in sarcoidosis
• Do not treat every patient with steroids—asymptomatic patients with normal PFTs should be observed given the high spontaneous remission rate
• Failing to rule out infection (TB, fungal) and malignancy (lymphoma) before diagnosing granulomatous disease—biopsy must show negative stains/cultures
• ACE level is elevated in only ~60% and is nonspecific, so it cannot confirm or exclude the diagnosis on its own
• Overlooking extrapulmonary disease—cardiac and neurologic involvement can be life-threatening