What is sarcoidosis?

What is Sarcoidosis?

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

Core Pathophysiology

The disease involves an abnormal immune response with these key features:

• Granuloma formation: Compact, tightly formed collections of large "epithelioid" histiocytes and multinucleated giant cells that remain discrete and non-necrotic 1
• T cell-driven inflammation: Central accumulation of CD4+ T cells with release of IL-2 and pro-inflammatory cytokines like TNF, creating a chronic inflammatory state 2, 3
• Perilymphatic distribution: Granulomas characteristically locate around bronchovascular bundles, fibrous septa containing pulmonary veins, and near visceral pleura 1

Epidemiology and Risk Factors

Sarcoidosis predominantly affects young and middle-aged adults (typically under 50 years), with significant racial and geographic variation. 1, 4

• Age-adjusted incidence is approximately 11 cases per 100,000 in Caucasians, with higher prevalence in northern Europe 2
• In the United States, African Americans have higher prevalence than whites, with African American women experiencing 2.4 times higher mortality compared to matched cohorts 2
• Women experience higher morbidity, mortality, and extrapulmonary involvement overall 2
• Environmental exposures to insecticides, herbicides, bioaerosols, and agricultural employment increase risk 4

Clinical Manifestations

Pulmonary Features (>90% of patients)

• Bilateral hilar adenopathy on chest imaging (highly characteristic) 1
• Perilymphatic nodules on high-resolution chest CT 1
• Cough (present in 40-80% of symptomatic patients), often dry and persistent 1
• Shortness of breath and chest pain 3
• Small airway involvement with airflow limitation in over half of patients 1

Highly Probable Diagnostic Features

These clinical presentations strongly suggest sarcoidosis 1, 2:

• Löfgren's syndrome: Bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis (often self-limited with excellent prognosis)
• Lupus pernio: Violaceous, indurated plaques typically affecting nose, cheeks, and ears 5
• Uveitis and optic neuritis: Ocular inflammation
• Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (normal-to-low PTH, normal-to-elevated 1,25-dihydroxyvitamin D, normal-to-low 25-hydroxyvitamin D) 1

Extrapulmonary Manifestations

Skin involvement (up to 30% of patients, often initial manifestation) 5:

• Specific lesions with granulomas: papules, plaques, subcutaneous nodules, lupus pernio, cicatricial sarcoidosis 5
• Non-specific lesions: erythema nodosum 1

Cardiac involvement (life-threatening potential) 2:

• Cardiomyopathy with reduced left ventricular ejection fraction
• Atrioventricular block (new-onset third-degree AV block in young/middle-aged adults is highly suggestive)
• Ventricular tachycardia

Other organ systems 1, 2:

• Neurologic: Seventh cranial nerve paralysis, CNS lesions with gadolinium enhancement on MRI
• Hepatic/splenic: Hepatosplenomegaly, alkaline phosphatase >3× upper limit of normal
• Renal: Treatment-responsive renal failure, nephrolithiasis with calcium stones
• Upper respiratory tract: Affects 3-4% of patients with generalized disease 2
• Musculoskeletal: Bone lesions showing osteolysis, cysts, or trabecular patterns 1

Diagnostic Approach

Diagnosis requires three essential criteria: (1) compatible clinical and radiologic presentation, (2) pathologic evidence of non-caseating granulomas, and (3) exclusion of alternative causes of granulomatous disease. 2, 6

Key Diagnostic Steps

1. Imaging studies 1, 2:

   • High-resolution CT scan of chest showing bilateral hilar adenopathy and/or perilymphatic nodules
   • Cardiac MRI for suspected cardiac involvement
   • PET scanning can identify metabolically active disease

2. Tissue sampling (when needed) 2:

   • Biopsy from accessible involved organs (lung, lymph node, skin)
   • Endobronchial ultrasound-guided biopsy has improved diagnostic yield 4
   • Look for compact, non-necrotic granulomas with perilymphatic distribution 1

3. Laboratory testing 1, 2:

   • Bronchoalveolar lavage showing lymphocytosis or elevated CD4:CD8 ratio
   • Serum calcium, creatinine, alkaline phosphatase
   • ACE levels should NOT be used alone for diagnosis (only 60% sensitivity, can be elevated in other granulomatous conditions) but are useful for monitoring treatment response in patients with initially elevated levels 5

4. Exclusion of mimics 1:

   • Infections (perform microorganism stains and cultures on tissue)
   • Chronic beryllium disease (blood lymphocyte proliferation test is diagnostic) 1
   • Malignancy (especially lymphoma)
   • Granulomatosis with polyangiitis (check MPO/PR3 ANCA antibodies) 1
   • IgG4-related disease (check serum IgG4 levels and IgG4:IgG ratio) 1
   • Drug-induced sarcoid-like reactions (immune checkpoint inhibitors, anti-TNF agents) 1

When Biopsy May Not Be Necessary

In patients with Löfgren's syndrome or asymptomatic bilateral hilar lymphadenopathy with highly characteristic features, lymph node sampling may not be necessary, but close clinical follow-up is required. 1, 2 These phenotypes are almost always sarcoidosis and typically self-limited 1.

Clinical Course and Prognosis

The clinical course is highly variable, ranging from mild, self-limiting disease to progressive, organ-threatening complications. 7, 6

• Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease requiring no treatment 1, 2
• Over 50% of patients identified by radiographic screening are asymptomatic 1
• Löfgren's syndrome typically has excellent prognosis with spontaneous resolution 1
• Some patients develop life-threatening pulmonary fibrosis, cardiac complications, or neurologic damage requiring aggressive treatment 6
• End-stage disease may ultimately require lung or heart transplantation 6
• Disease often remits permanently (spontaneously or following treatment), though recurrences during corticosteroid tapering are common 5, 7

Common Pitfalls

• Do not rely on ACE levels alone for diagnosis—they lack sufficient sensitivity and specificity 5
• Do not assume all bilateral hilar adenopathy is benign—always exclude malignancy and infection, especially in atypical presentations 1
• Do not overlook cardiac screening—cardiac involvement can be life-threatening and may be subclinical; consider cardiac MRI in appropriate cases 2
• Do not forget to check for beryllium exposure—chronic beryllium disease is clinically and pathologically identical to sarcoidosis but has a known cause and requires different management 1