Serum ACE Has Poor Negative Predictive Value for Sarcoidosis
A normal serum ACE level does NOT reliably exclude sarcoidosis, with a negative predictive value (NPV) ranging from 58-95% depending on disease activity and clinical context. The test's limited sensitivity (41-58% overall, up to 92% in active disease) means that many patients with true sarcoidosis will have normal ACE levels 1, 2.
Diagnostic Performance of Serum ACE
Sensitivity and Specificity
- Overall sensitivity: 41-58% in unselected sarcoidosis populations 1, 2
- Sensitivity increases to 86-92% in clinically active disease 1
- Specificity: 84-90% when excluding military tuberculosis and silicosis 1, 2
- Positive predictive value: 25-84% 1, 2
- Negative predictive value: 58-95% 1, 2
The wide range in NPV reflects the critical influence of disease activity status. In populations with predominantly inactive disease, NPV drops to approximately 58%, meaning that 42% of patients with normal ACE actually have sarcoidosis 1. In more active disease populations, NPV improves to 95%, but still misses 5% of cases 2.
Clinical Context Matters
The diagnostic utility of serum ACE is heavily influenced by when it is measured:
- At initial presentation with suspected active disease: sensitivity 86% 1
- In clinically active sarcoidosis: sensitivity 92% 1
- In inactive or chronic disease: sensitivity drops significantly, with 7.9% of active cases still showing normal levels 1
Guideline Recommendations on ACE Testing
The American Thoracic Society (2020) acknowledges serum ACE as "the most widely used laboratory test for the investigation of sarcoidosis" but emphasizes it is an adjunct tool, not a standalone diagnostic test 3. The European Rhinology Society similarly notes that ACE levels are "useful tools in the diagnosis of sarcoidosis and for evaluating disease activity" but must be combined with clinical, radiological, and histological evidence 3.
Sarcoidosis diagnosis requires:
- Clinical presentation consistent with disease
- Radiological findings
- Histological evidence of non-caseating granulomas
- Exclusion of other causes 3
Critical Limitations and False Negatives
Why Normal ACE Doesn't Exclude Sarcoidosis
Disease activity is the primary determinant of ACE elevation:
- 7.9% of patients with clinically active sarcoidosis have normal ACE 1
- Inactive or chronic sarcoidosis frequently shows normal ACE levels 1
- Early or limited disease may not elevate ACE sufficiently 1
ACE levels do NOT correlate with:
- Age, sex, or population group 1
- Duration of disease 1
- Presence of disease in some patients with active multi-organ involvement 1
False Positives to Consider
Conditions that can elevate serum ACE:
- Gaucher's disease: 100% false positive rate with levels often exceeding those in sarcoidosis 1, 4
- Military tuberculosis: 38.9% false positive rate 1
- Silicosis: 48% false positive rate 1
- Hyperthyroidism, diabetes mellitus, and liver disease can also elevate ACE 1
Practical Clinical Algorithm
When to Use (and Not Use) Serum ACE
DO use serum ACE:
- As a supportive test when sarcoidosis is already suspected based on clinical and radiological findings 3
- To monitor disease activity longitudinally in established sarcoidosis 1
- To assess response to corticosteroid therapy (levels normalize with adequate treatment) 1, 4
DO NOT rely on serum ACE:
- As a screening test in low-probability populations 2
- To exclude sarcoidosis when clinical suspicion is high 1, 2
- As the sole diagnostic criterion without biopsy confirmation 3
Improving Diagnostic Accuracy
Combined biomarker testing significantly improves diagnostic performance:
- ACE combined with chitotriosidase (CTO) achieves 90.5% sensitivity and 79.3% specificity 5
- This "double product" (ACE × CTO) has superior diagnostic accuracy (AUC 0.898) compared to ACE alone 5
- Chitotriosidase alone shows better correlation with disease activity than ACE 6
Bottom Line for Clinical Practice
Given the poor NPV of serum ACE (58-95%), a normal result should never be used to exclude sarcoidosis in patients with compatible clinical and radiological findings. Proceed with tissue biopsy to confirm non-caseating granulomas when sarcoidosis remains in the differential diagnosis, regardless of ACE level 3.
Reserve serum ACE primarily for monitoring known disease activity and treatment response rather than initial diagnosis 1, 4. Consider combined biomarker testing (ACE plus chitotriosidase) if available to improve diagnostic accuracy in cases where biopsy is not immediately feasible 5.