What are the clinical presentation, diagnostic workup, and management recommendations for sarcoidosis?

Sarcoidosis: Clinical Presentation, Diagnosis, and Management

Diagnostic Approach

Sarcoidosis diagnosis requires three essential criteria: (1) compatible clinical and radiologic presentation, (2) histologic evidence of noncaseating granulomas (except in highly specific presentations), and (3) exclusion of alternative granulomatous diseases including infections, malignancy, berylliosis, and drug-induced reactions. 1

When Biopsy Can Be Avoided

Certain clinical presentations are so specific that they are considered diagnostic without tissue confirmation 1:

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) 1, 2
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears) 1
• Heerfordt's syndrome (fever, parotid enlargement, uveitis, facial nerve palsy) 1

Clinical Presentation by Probability

Highly Probable Features (Nearly Diagnostic)

Physical examination findings:

• Lupus pernio 1
• Uveitis 1
• Optic neuritis 1
• Erythema nodosum 1

Imaging findings:

• Bilateral hilar adenopathy on chest X-ray, CT, or PET 1
• Perilymphatic nodules on chest CT 1
• Gadolinium enhancement on brain MRI 1
• Osteolysis, cysts, or trabecular bone patterns on skeletal imaging 1, 3
• Parotid uptake on gallium or PET scan 1

Laboratory findings:

• Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (normal-to-low PTH, normal-to-elevated 1,25-dihydroxyvitamin D) 1

Probable Features (Strongly Suggestive)

Clinical manifestations:

• Seventh cranial nerve paralysis 1
• Treatment-responsive renal failure 1
• Treatment-responsive cardiomyopathy or AV node block 1
• Spontaneous or inducible ventricular tachycardia without traditional risk factors 1
• New-onset third-degree AV block in young or middle-aged adults 1

Imaging findings:

• Upper lobe or diffuse pulmonary infiltrates 1
• Two or more enlarged extrathoracic lymph nodes 1
• Increased inflammatory activity in heart on MRI, PET, or gallium 1
• Inflammatory bone lesions on advanced imaging 1, 3

Laboratory findings:

• Elevated serum ACE level 1
• BAL lymphocytosis or elevated CD4:CD8 ratio 1
• Alkaline phosphatase >3× upper limit of normal 1

Mandatory Screening Tests for All Sarcoidosis Patients

Baseline Organ Screening (Even Without Symptoms)

Renal function:

• Obtain baseline serum creatinine in all patients, regardless of symptoms 1, 4
• Renal sarcoidosis is often asymptomatic but progressive without treatment 1, 4
• Abnormal renal function occurs in 7% of patients (95% CI: 3-11%) 1, 4
• If creatinine is elevated, immediately assess calcium metabolism (serum calcium, 24-hour urinary calcium, vitamin D levels) 4

Hepatic function:

• Obtain baseline transaminases and alkaline phosphatase 1
• Liver function abnormalities occur in 12% of asymptomatic patients (95% CI: 6-19%) 1

Cardiac Evaluation Algorithm

Initial assessment for all patients:

• Obtain baseline ECG and assess for symptoms (chest pain, syncope, palpitations) 1, 2

If abnormal ECG + cardiac symptoms present:

• Risk of cardiac sarcoidosis increases to 27.5% 2
• Proceed directly to cardiac MRI (preferred) or dedicated cardiac PET if MRI unavailable 1
• Do NOT rely on transthoracic echocardiography alone for diagnosis 1

Cardiac findings warranting advanced imaging:

• Reduced left ventricular ejection fraction without traditional risk factors 1
• Ventricular tachycardia without traditional risk factors 1
• AV block or cardiomyopathy responsive to treatment 1

Pulmonary Hypertension Screening

When to suspect PH:

• Exertional chest pain or syncope 1
• Prominent P2 or S4 on examination 1
• Reduced 6-minute walk distance or desaturation with exercise 1
• Reduced DLCO 1
• Increased pulmonary artery diameter relative to ascending aorta on CT 1
• Elevated brain natriuretic peptide 1
• Fibrotic lung disease 1

Diagnostic algorithm:

• Initial test: transthoracic echocardiogram 1
• If TTE suggests PH: proceed to right heart catheterization for definitive diagnosis 1
• If TTE does NOT suggest PH: determine need for right heart catheterization case-by-case 1

Exclusion of Alternative Diagnoses

Critical Differential Diagnoses to Exclude

Infectious causes requiring specific testing:

• Mycobacterial infections (tuberculosis, atypical mycobacteria) 1
• Fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis) 1
• Consider BAL for infection exclusion when diagnosis uncertain 1

Occupational/environmental exposures:

• Chronic beryllium disease: obtain blood lymphocyte proliferation test (diagnostic for berylliosis) 1
• Berylliosis has identical histologic features to sarcoidosis 1

Drug-induced granulomatous reactions:

• Immune checkpoint inhibitors 1
• Anti-TNF-α agents 1
• Other immunotherapeutics 1

Malignancy:

• Lymphoma can present with sarcoid-like granulomas 1
• BAL may help identify malignant cells 1

Other granulomatous diseases:

• Hypersensitivity pneumonitis (BAL shows characteristic cellular patterns) 1
• Eosinophilic pneumonia (BAL shows eosinophilia) 1

Management Principles

First-Line Treatment

Corticosteroids remain the mainstay of therapy for:

• Significantly symptomatic or progressive pulmonary disease 5, 6
• Serious extrapulmonary disease 5, 6
• Renal sarcoidosis (90% response rate with immunosuppression) 4

Corticosteroids address both pathogenic mechanisms:

• Suppression of granulomatous inflammation 4
• Correction of vitamin D-mediated hypercalcemia 4

Refractory Disease

• Immunosuppressive therapy for corticosteroid-refractory cases 5, 6
• Biologic therapies for complex cases 6
• Transplantation (lung or heart) for end-stage disease in eligible patients 5, 6

Prognostic Considerations

High-Risk Features for Mortality

• African American women have 2.4-times higher mortality compared to matched controls without sarcoidosis 1
• Progressive pulmonary fibrosis (occurs in 25% of patients) 7
• Cardiac involvement (sudden cardiac death from arrhythmias or heart failure from myocarditis) 1
• Neurologic complications 5

Favorable Prognosis

• Löfgren's syndrome typically has self-limited course and excellent prognosis 2
• However, if atypical features develop (e.g., uveitis in Löfgren's syndrome), more comprehensive evaluation is required 2

Common Pitfalls

Diagnostic errors to avoid:

• Failing to exclude berylliosis in patients with occupational exposure (histology is identical) 1
• Missing drug-induced sarcoid reactions in patients on immunotherapeutics 1
• Relying solely on histology without clinical correlation (granulomas are nonspecific) 1
• Delaying renal biopsy when renal dysfunction is detected (enables targeted therapy and excludes alternatives) 4

Screening failures:

• Not obtaining baseline creatinine in asymptomatic patients (renal disease is often silent and progressive) 1, 4
• Using only TTE for cardiac sarcoidosis diagnosis (cardiac MRI or PET required for definitive diagnosis) 1
• Missing cardiac involvement by not obtaining ECG in all patients 1, 2