Why is sarcoidosis associated with elevated Angiotensin-Converting Enzyme (ACE) levels?

From the Guidelines

Sarcoidosis is associated with elevated Angiotensin-Converting Enzyme (ACE) levels due to the production of ACE by epithelioid cells and activated macrophages within granulomas, as supported by the 2020 European position paper on rhinosinusitis and nasal polyps 1. The granulomas that characterize sarcoidosis contain these cells, which secrete excessive amounts of ACE into the bloodstream, leading to elevated serum ACE levels.

• The elevation in ACE serves as a biomarker for disease activity, though it is not specific to sarcoidosis alone.
• The degree of ACE elevation often correlates with the extent of granulomatous burden and disease activity, making it a useful tool for monitoring disease progression and response to treatment, as noted in the study 1.
• ACE levels typically decrease with successful treatment and disease remission, though normal ACE levels do not exclude the diagnosis of sarcoidosis. Key points to consider when interpreting ACE levels in sarcoidosis include:
• Elevated serum levels of ACE are usually associated with more aggressive disease and multiple-organ involvement, as stated in the 2020 study 1.
• Serum ACE is the most widely used laboratory test for the investigation of sarcoidosis, according to the same study 1. The use of ACE levels as a diagnostic and monitoring tool in sarcoidosis is supported by recent evidence, including the 2020 European position paper on rhinosinusitis and nasal polyps 1.

From the Research

Sarcoidosis and Angiotensin-Converting Enzyme (ACE) Levels

• Sarcoidosis is associated with elevated Angiotensin-Converting Enzyme (ACE) levels, as evidenced by studies that have found a statistically significant elevation of serum ACE in patients with sarcoidosis 2, 3.
• The elevation of ACE levels in sarcoidosis is thought to be related to the granulomatous inflammation characteristic of the disease, with ACE being produced by the granulomas themselves 3.
• The renin-angiotensin-aldosterone system (RAAS) is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and related inflammatory mediator responses 2.
• The relationship between clinical stage of sarcoidosis and serum values of ACE has been studied, with results indicating that serum ACE activity increases later on when active granulomas have been formed 4.

Clinical Utility of ACE Levels in Sarcoidosis

• Serum ACE levels are frequently ordered when a patient is diagnosed with cutaneous sarcoidosis, but their clinical utility in this setting remains unknown 5.
• Extremely elevated ACE activity can be suggestive of familial ACE hyperactivity, a benign condition that can be confirmed by genetic testing 6.
• Measurement of serum ACE activity can be helpful in the diagnosis and disease monitoring of sarcoidosis, but extremely elevated ACE activity should prompt consideration of a genetic cause 6.

Factors Affecting ACE Levels in Sarcoidosis

• The duration of disease and the presence of steroid therapy may affect serum ACE levels, with a trend towards diminution of serum ACE with increasing duration of disease 3.
• The composition of the clinical series of sarcoidosis patients can affect the correlation between ACE and other markers, such as beta2-microglobulin 4.
• The clinical utility of serum ACE and calcium levels as markers of cutaneous sarcoidosis or progression to systemic sarcoidosis is limited, with no patients having abnormal levels of serum calcium at presentation and only one patient having an abnormally elevated ACE level 5.