Sarcoidosis

Classic presentation

• HiIar lymphadenopathy
• Cough, dyspnea
• Often asymptomatic, detected on routine chest x-ray

Etiology

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Pathophysiology

Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of noncaseating granulomas.

• General
  • Inhalation of foreign antigen → monocyte differentiation → activation of interstitial dendritic cells and alveolar macrophages
  • Interstitial dendritic cells migrate towards mediastinal lymph nodes and alveolar macrophages differentiate, serving as antigen-presenting cells to circulating T helper (Th) cells → differentiation and clonal expansion of T cells
  • T cell recruitment and ↑ B-cell activity → local immune hyperactivity and inflammation → formation of noncaseating granulomas in the lungs and the lymphatic system
• Granuloma formation: Mature granulomas are composed of epithelioid cells and macrophages surrounded by lymphocytes and fibroblasts.
  • Macrophages activate Th1 cells.
  • Th1 cells stimulate the formation of epithelioid cells and multinucleated giant cells by releasing IFN-γ.
  • Epithelioid cells produce angiotensin-converting enzyme (ACE) and release cytokines that recruit more immune cells.
  • Asteroid bodies: star-shaped, eosinophilic inclusion bodies consisting of various lipids (e.g., from sarcoidosis, foreign body reactions)

Tip

Compared with TB, which has caseating granulomas.

• Fibrosis: Epithelioid cells secrete cytokines to recruit fibroblasts, leading to fibrosis → damage of organs and tissue
• Calcium dysregulation: activated pulmonary alveolar macrophages → ↑ 1-alpha hydroxylase expression and activity → ↑ 1,25-dihydroxyvitamin D (calcitriol) → hypervitaminosis D → hyperphosphatemia, hypercalcemia, and, possibly, renal failure

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Clinical features

Pulmonary sarcoidosis

• Lungs are the most commonly affected organ (90% of affected individuals).
• Often asymptomatic in the early stages
• Classic finding is hilar lymphadenopathy
• Interstitial fibrosis
  • Cough, exertional dyspnea, chest pain
  • Mild rales on pulmonary auscultation

Extrapulmonary sarcoidosis

Cutaneous sarcoidosis

• Erythema nodosum: most common nonspecific cutaneous manifestation
• Lupus pernio
  • A pathognomonic manifestation of sarcoidosis characterized by extensive, violaceous skin plaques (i.e., epithelioid granulomas of the dermis) on the nose, cheeks, chin, and/or ears

Butterfly rash as seen in systemic lupus erythematosus

Neurosarcoidosis

• Cranial nerve palsy (unilateral or bilateral facial nerve palsy is the most common)
• Diabetes insipidus

Ocular sarcoidosis

• Sarcoid uveitis
  • Most common ocular manifestation
  • Manifests with pain, redness, and photophobia

Cardiac sarcoidosis

• AV block, arrhythmias, restrictive cardiomyopathy. c

Symptoms of hypercalcemia

Clinical features

• “Stones”: Nephrolithiasis, nephrocalcinosis.
• “Bones”: Bone pain, pathological fractures, osteitis fibrosa cystica (subperiosteal bone resorption in PHPT).
• “Groans”: Constipation, nausea, vomiting, anorexia, abdominal pain, pancreatitis.
• “Thrones”: Polyuria, polydipsia (due to nephrogenic diabetes insipidus). c
  • Due to acquired renal ADH resistance. Although ADH is being secreted, the kidneys no longer respond to it adequately (nephrogenic diabetes insipidus).
  • Physiological teleology: Stone Prevention: If the kidney concentrated urine in the setting of hypercalciuria (high urinary Ca), the calcium would precipitate into stones (nephrolithiasis)
• “Psychiatric overtones”: Fatigue, depression, confusion, lethargy, stupor/coma.
• Cardiac: Bradycardia, AV block, shortened QT interval on ECG.

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Diagnostics

Tip

Increased ACE levels may be seen. However, they are not specific for sarcoidosis and should not be used in isolation for diagnosis or monitoring.

• Initial: CXR showing Bilateral Hilar Lymphadenopathy (BHL) (mediastinal fullness) +/- reticular infiltrates. c
• Key Labs:
  • Hypercalcemia/Hypercalciuria: Due to ↑ 1-alpha hydroxylase activity in sarcoid macrophages (↑ 1,25-dihydroxyvitamin D). c
  • ↑ ACE levels (high sensitivity, low specificity; used to monitor disease activity).
  • PFTs: Restrictive pattern (↓ FVC, ↓ TLC, ↓ DLCO). c
  • Elevated LFTs (if hepatic involvement).
• Confirmatory/Gold Standard: Tissue biopsy showing Non-caseating granulomas.
  • Must rule out TB (AFB stain) and Fungal (GMS/Silver stain).
  • Biopsy most accessible site (e.g., palpable node, skin lesion). If only BHL, use Transbronchial Biopsy (TBBx).
  • Schaumann bodies: cellular inclusion bodies consisting of intracytoplasmic calcium and protein with laminar stratification (e.g., sarcoidosis, tuberculosis, Crohn disease, berylliosis)

Additional studies

• Bronchoalveolar lavage (BAL):↑ CD4:CD8 ratio
  • CD4+ lymphocytes release interferon-gamma and TNF-alpha to drive macrophage activation and granuloma formation.

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Treatment

• Steroids
• Other immunosuppressants

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