Angiotensin-Converting Enzyme (ACE) is an enzyme primarily associated with the system that regulates blood pressure and fluid balance. It functions by converting the inactive protein angiotensin I into the potent vasoconstrictor angiotensin II. This conversion causes blood vessels to narrow, which increases blood pressure. Although ACE is produced throughout the body, the highest concentration is found in the endothelial cells lining the blood vessels of the lungs. Measuring serum ACE levels is often used as a diagnostic marker, offering insights into disease processes where this enzyme is produced in excess, sometimes independent of its blood pressure-regulating function.
Sarcoidosis
Sarcoidosis is a multi-system inflammatory disorder characterized by the formation of small clumps of inflammatory cells known as granulomas. These granulomas can develop in almost any organ, but they most frequently affect the lungs and lymph nodes. The elevation of serum ACE levels in sarcoidosis is a direct result of these granulomas.
The cells forming the core of the granulomas—specifically the epithelioid cells and multinucleated giant cells—actively synthesize and release ACE into the bloodstream. This increased production by the inflammatory tissue is the mechanism responsible for the high ACE levels seen in many patients. The amount of circulating ACE often correlates with the total body mass of active granulomas.
Elevated ACE is observed in approximately 50% to 80% of individuals with active sarcoidosis, making it a commonly used indicator of the disease. Because ACE levels may rise and fall with disease activity, the test is frequently used to monitor a patient’s response to treatment, such as corticosteroids. A decrease in the serum ACE level during therapy suggests that the treatment is successfully reducing the granuloma burden.
Infectious and Inflammatory Granulomatous Conditions
While sarcoidosis is the most common condition associated with elevated ACE, other diseases involving granuloma formation can also cause high levels. These conditions involve a similar immune response where the body attempts to wall off an invading foreign substance or organism. The resulting granulomas contain the same ACE-producing epithelioid cells found in sarcoidosis.
Infectious diseases that trigger this granulomatous response, such as tuberculosis, are known to increase ACE levels. Tuberculosis, especially the miliary form where the infection is widespread, causes ACE elevation due to extensive granuloma formation. Leprosy, a chronic bacterial infection causing granulomas in the skin and nerves, is another infectious disease where ACE levels may be high.
Deep fungal infections, including histoplasmosis and coccidioidomycosis, also lead to elevated ACE levels as granulomas form in response to the fungal organisms. These conditions are generally considered less frequent causes of ACE elevation compared to sarcoidosis. Furthermore, certain non-infectious environmental exposures, like chronic inhalation of irritant particles such as beryllium, can induce a granulomatous lung disease that elevates ACE levels.
Systemic Conditions Not Related to Granulomas
A separate group of conditions can lead to elevated ACE levels through mechanisms that do not involve granuloma formation. This distinction is important for differential diagnosis, as the enzyme source is not the epithelioid cell. The elevation is related to changes in the function or health of endothelial cells and other tissue-specific cells.
Hyperthyroidism, an overactive thyroid gland, is one such condition where ACE levels can be increased, possibly due to the general metabolic stimulation caused by high thyroid hormone levels. Certain types of liver disease, particularly alcoholic cirrhosis, may also lead to elevated ACE, potentially relating to altered liver function or production by non-granulomatous inflammatory cells.
Gaucher disease, a rare inherited disorder of lipid metabolism, is known to cause markedly high ACE levels, sometimes exceeding those seen in sarcoidosis. The elevated ACE in Gaucher disease originates from activated macrophages in the spleen and liver, reflecting a unique cellular pathology. Additionally, diabetes mellitus with microvascular complications, and certain malignancies like lymphoma, have been documented to cause increased circulating ACE.
Interpreting High ACE Levels
An elevated ACE level should not be used as a standalone tool for diagnosing any specific disease. The test lacks specificity, meaning a high result can occur in many different conditions. Furthermore, approximately 20% to 50% of patients with active sarcoidosis may have a normal ACE level, demonstrating that a normal result does not exclude the disease.
A high ACE result is most valuable when interpreted within a broader clinical picture that includes a patient’s symptoms, physical examination, and results from other diagnostic procedures. Imaging studies, such as a chest X-ray or CT scan, are frequently used alongside the ACE test to look for evidence of lung disease or granulomas. If a high ACE level is found, a healthcare provider uses this information to decide which other tests, like biopsies or cultures, are necessary to rule out infectious causes and confirm a diagnosis. The test serves best as evidence suggesting an active granulomatous process that requires further investigation.