Sarcoidosis
A board-focused sarcoidosis lesson tracing pathophysiology (CD4⁺ Th1 noncaseating granulomas; macrophage 1α-hydroxylase → PTH-independent hypercalcemia; granuloma-derived ACE) through presentation, diagnosis (Scadding stages, restrictive PFTs with low DLCO, EBUS-TBNA biopsy, labs), and management, with classic buzzwords, named syndromes, and next-best-step vignettes for STEP 1 and STEP 2 CK.
Pathophysiology & Epidemiology
Sarcoidosis is a multisystem disorder defined by noncaseating (non-necrotizing) granulomas. An unknown antigen drives an exaggerated CD4⁺ Th1 (and Th17) response: antigen-presenting cells release IL-12, activated CD4⁺ T cells secrete IFN-γ and IL-2, and macrophages aggregate into epithelioid granulomas maintained by TNF-α. Lung and intrathoracic nodes are involved in >90% of cases.
Classic board demographics: young-to-middle-aged adults (20–40), African-American women (higher incidence and severity), and Northern Europeans/Scandinavians.
Two separate granuloma products explain the classic labs: (1) activated macrophages express 1α-hydroxylase, converting 25-OH-D to active 1,25-(OH)₂-vitamin D independent of PTH → hypercalciuria (more common) and hypercalcemia; (2) granuloma epithelioid cells secrete angiotensin-converting enzyme (ACE), giving the classically elevated serum ACE (do not conflate the two pathways). Because noncaseating granulomas are nonspecific, sarcoidosis remains a diagnosis of exclusion — infection (TB, fungi), berylliosis, and other granulomatous disease must be ruled out first.
- Noncaseating granulomas = hallmark: epithelioid histiocytes + CD4⁺ T cells + Langhans giant cells (horseshoe nuclei)
- Inclusions: asteroid bodies (stellate) and Schaumann bodies (laminated calcium) — suggestive, not specific
- Bilateral hilar lymphadenopathy (BHL) = most common CXR finding
- Labs: ↑ACE, hypercalcemia/hypercalciuria, ↑ESR, polyclonal hypergammaglobulinemia, cutaneous anergy (negative PPD)
- PFTs: restrictive with ↓DLCO (obstruction possible in advanced fibrotic disease)
- BAL CD4:CD8 ratio >3.5 supports the diagnosis (specific, not sensitive)
- Skin: erythema nodosum (good prognosis) vs lupus pernio (violaceous nose/cheek plaques; chronic, worse prognosis)
- Eye: anterior uveitis (most common ocular finding)
- Löfgren syndrome = fever + BHL + erythema nodosum + polyarthralgia → excellent prognosis, usually self-resolves
- Heerfordt (uveoparotid fever) = uveitis + parotitis + fever + CN VII palsy
A 34-year-old African-American woman has 3 weeks of low-grade fever, ankle pain, and tender erythematous nodules on both shins. CXR shows bilateral hilar lymphadenopathy with clear lung fields. Serum ACE and calcium are mildly elevated.
- Diagnosis: Löfgren syndrome (acute sarcoidosis: BHL + erythema nodosum + polyarthralgia ± fever).
- Next best step: the triad is diagnostic — no biopsy needed. Manage supportively with NSAIDs; expect spontaneous resolution in most.
- Contrast trap: if the picture were atypical (asymmetric adenopathy, weight loss, older smoker), biopsy the most accessible site — usually EBUS-guided mediastinal node — to exclude lymphoma/TB before calling it sarcoid.
- Remember: ACE is neither sensitive nor specific — do not use it to diagnose or to follow disease activity.
Diagnosis — Imaging, PFTs, Labs, Biopsy
Diagnosis = compatible clinical/radiographic picture + noncaseating granulomas + exclusion of other causes (Löfgren is the exception needing no biopsy).
Scadding CXR stages:
- 0: normal
- I: bilateral hilar lymphadenopathy (BHL) alone
- II: BHL + parenchymal infiltrates
- III: parenchymal infiltrates alone
- IV: fibrosis (honeycombing, upper-lobe volume loss)
Lower stage = higher spontaneous-remission rate.
Biopsy: least-invasive site; EBUS-guided transbronchial needle aspiration (EBUS-TBNA) is first-line for intrathoracic disease — non-necrotizing granulomas with negative AFB/fungal stains and cultures.
PFTs: restrictive pattern with reduced DLCO; used to grade severity and follow therapy.
Adjuncts: hypercalcemia/hypercalciuria, ↑ACE (nonspecific), BAL CD4:CD8 >3.5.
Screen every patient for silent, organ-threatening involvement: ECG (± echo/cardiac MRI) for cardiac sarcoid and a baseline ophthalmologic exam.
Sarcoidosis vs Tuberculosis
| Feature | Sarcoidosis | Tuberculosis |
|---|---|---|
| Granuloma | Noncaseating | Caseating (necrotic) |
| Cause | Unknown antigen, Th1 | M. tuberculosis |
| AFB stain/culture | Negative | Positive |
| Adenopathy | Bilateral, symmetric hilar | Often unilateral, may calcify |
| PPD / IGRA | Anergic (negative) | Positive |
| Hypercalcemia | Common (macrophage 1α-hydroxylase) | Can also occur (same mechanism) |
| Lung pattern | Upper-zone fibrosis (late) | Upper-lobe cavitation (reactivation) |
| Treatment | Corticosteroids | Anti-TB antibiotics |
"A GRUELING disease" — each letter maps to a genuine sarcoidosis feature:
- G — noncaseating Granulomas
- R — aRthralgias / arthritis
- U — Uveitis (anterior)
- E — Erythema nodosum
- L — Lymphadenopathy (bilateral hilar)
- I — Interstitial fibrosis
- N — Negative TB test (anergy)
- G — hyperGammaglobulinemia (+ ↑ACE)
Two named syndromes to memorize:
- Löfgren = fever + BHL + erythema nodosum + polyarthralgia (acute, good prognosis)
- Heerfordt (uveoparotid fever) = uveitis + parotid enlargement + fever + facial nerve (CN VII) palsy
Management
Many patients — especially stage I and Löfgren syndrome — remit spontaneously, so observation is correct for asymptomatic or minimally symptomatic disease.
Treat when disease is organ-threatening or significantly symptomatic:
- Cardiac sarcoid (arrhythmia, heart block, cardiomyopathy)
- Neurosarcoidosis
- Ocular disease uncontrolled by topical therapy
- Hypercalcemia
- Progressive/symptomatic pulmonary disease
- Disfiguring skin (lupus pernio) or renal involvement
First-line: systemic corticosteroids (prednisone). Steroid-sparing/second-line: methotrexate (most common), azathioprine; refractory → anti-TNF (infliximab).
Hypercalcemia pearls: avoid vitamin D supplements, excess sun, and high calcium intake; hydrate; treat with corticosteroids (shut down macrophage 1α-hydroxylase — first-line here); bisphosphonates if severe.
Monitor with symptoms, PFTs/DLCO, and imaging — not ACE levels.
A 45-year-old man with known pulmonary sarcoidosis presents with syncope. ECG shows complete (third-degree) AV block.
- Recognize: cardiac sarcoidosis — granulomas infiltrate the conduction system; a leading cause of AV block in a younger adult and of sudden cardiac death.
- Next best step (diagnosis): cardiac MRI with late gadolinium enhancement and/or FDG-PET to confirm active myocardial involvement (endomyocardial biopsy has low yield — disease is patchy).
- Management: systemic corticosteroids for active inflammation plus device therapy — permanent pacemaker for high-grade AV block and consider an ICD given sudden-death risk.
- Board trap: don't dismiss new heart block in a sarcoid patient as ordinary conduction disease — always work up cardiac sarcoid.
Practice Pulmonary now
Board-style questions, spaced-repetition flashcards, and a Socratic AI tutor — free to start.