Why is serum Angiotensin-Converting Enzyme (ACE) elevated in sarcoidosis?

Why Serum ACE is Elevated in Sarcoidosis

Serum Angiotensin-Converting Enzyme (ACE) is elevated in sarcoidosis because it is actively synthesized by the epithelioid cells and multinucleated giant cells within sarcoid granulomas throughout the body. 1

Mechanism of ACE Elevation

The pathophysiology behind elevated ACE levels in sarcoidosis follows a specific pattern:

1. Granuloma Production: Sarcoidosis is characterized by the formation of non-caseating granulomas composed of epithelioid cells and multinucleated giant cells.

2. ACE Synthesis: These granulomatous cells actively produce ACE, with studies showing up to 12-fold elevation of ACE in granulomatous lymph nodes of sarcoidosis patients compared to normal tissue. 1

3. Systemic Release: The ACE produced by these granulomas is released into the bloodstream, resulting in elevated serum ACE levels.

4. Correlation with Disease Activity: The elevation of serum ACE often correlates with the total body mass of active granulomas, suggesting that more extensive disease leads to higher ACE levels. 1

Clinical Significance

• ACE elevation above 50% of the upper limit of normal is considered abnormal and is included as a diagnostic criterion in the American Thoracic Society guidelines. 2

• Approximately 34-60% of sarcoidosis patients have elevated serum ACE levels, making it a useful but not definitive diagnostic marker. 1, 3

• The pattern of ACE elevation varies by disease stage:

  • Patients with newly detected sarcoidosis typically have increased ACE activity 4
  • Patients with chronic active sarcoidosis often have high ACE activity 4
  • Patients with resolved sarcoidosis generally have normal ACE values 4

Important Caveats

• Not Specific to Sarcoidosis: While elevated in sarcoidosis, ACE can also be increased in other conditions, though less frequently (approximately 1% in non-sarcoid conditions). 3

• Normal ACE Doesn't Rule Out Sarcoidosis: A normal serum ACE level does not exclude sarcoidosis, as more than half of patients may have normal levels, particularly in early or resolved disease. 1

• Disease Duration Effect: There is a trend toward diminishing serum ACE with increasing duration of disease, possibly correlating with the total body mass of active granulomas. 1

• Special Clinical Presentations:

  • In acute sarcoidosis with erythema nodosum, ACE is initially normal and only increases later 3
  • In hypercalcemic sarcoidosis, ACE is almost universally elevated 3

• Limited Utility in Cutaneous Sarcoidosis: Recent research suggests that serum ACE may not be a reliable marker for isolated cutaneous sarcoidosis. 5

Understanding the relationship between granuloma formation and ACE production helps explain why this enzyme serves as a useful biomarker for monitoring disease activity in sarcoidosis, despite its limitations in sensitivity and specificity.