ImmunologyTier 1Medical Sciences concept

ACE production by granulomas in sarcoidosis

Core concept

ACE is synthesised by the epithelioid cells and multinucleated giant cells of the granuloma itself
- Serum ACE therefore reflects total granuloma burden, not disease activity or organ damage
Test performance is poor

	Approx
Sensitivity	~55-60%
Specificity	~70-90%

Neither sensitive enough to exclude nor specific enough to diagnose sarcoidosis
ACE is not part of any diagnostic criterion. Do not order it to make the diagnosis - the diagnosis is compatible clinical/radiological findings + non-caseating granulomas + exclusion of alternatives.

Raised serum ACE in

Group	Examples
Other granulomatous disease	Tuberculosis, leprosy, berylliosis, histoplasmosis, coccidioidomycosis, silicosis, hypersensitivity pneumonitis, Crohn's, PBC
Storage disease	Gaucher disease (classically very high)
Endocrine	Hyperthyroidism, diabetes, adrenal insufficiency
Other	Lymphoma, alcoholic liver disease, asbestosis, HIV, amyloidosis

Falsely LOW

ACE inhibitor therapy - the commonest reason for a normal result in genuine sarcoidosis; always check the drug chart before interpreting
ACE gene insertion/deletion (I/D) polymorphism shifts the reference range - DD genotype has roughly twice the level of II (a well-recognised source of both false positives and false negatives, and the reason genotype-adjusted ranges have been proposed)

Where ACE does earn a place

Serial measurement in an established case may loosely track burden during treatment; symptoms, spirometry, imaging and calcium are better
CSF ACE in neurosarcoidosis - specific but insensitive
Soluble IL-2 receptor (sIL-2R) performs somewhat better than ACE and is increasingly used

Better tests in suspected sarcoidosis
- Tissue - EBUS-TBNA of mediastinal nodes is the highest-yield first biopsy; skin, conjunctiva or minor salivary gland if accessible
- BAL CD4:CD8 ratio >3.5 supports the diagnosis
- Serum and 24 h urinary calcium - the granuloma's other, clinically important product
The metabolically important granuloma product is 1-alpha-hydroxylase, not ACE
- -> unregulated 1,25-dihydroxyvitamin D -> inc gut calcium absorption -> hypercalciuria (more common) and hypercalcaemia (~5-10%), with suppressed PTH
- Treat with corticosteroids, hydration, sun avoidance and caution with vitamin D supplementation
Some conditions do not need a biopsy at all - Lofgren's syndrome (erythema nodosum + bilateral hilar lymphadenopathy + fever + arthralgia) and Heerfordt syndrome are diagnosed clinically and carry an excellent prognosis

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