Serum Angiotensin-Converting Enzyme

Angiotensin converting enzyme (ACE) is a zinc metallopeptidase that converts angiotensin I to angiotensin II and inactivates bradykinin. It is found on the surface of pulmonary and renal endothelium and in epithelioid cells, and a soluble form circulates in serum. In sarcoidosis, epithelioid macrophages and granuloma cells make ACE, and serum activity reflects total granuloma burden. Serum ACE is measured by a kinetic colorimetric or fluorimetric assay and reported in U/L.

It has a limited role in the diagnosis of sarcoidosis, as an adjunct to clinical, imaging and tissue findings. It is also used as a marker of granuloma burden in known disease, for Gaucher disease and, rarely, for other granulomatous conditions.

Sarcoidosis has a prevalence of about 1 to 40 in 100 000 people, higher in people of African ancestry and in northern Europeans, with a peak at 25 to 45 years in both sexes and a second peak in women after 50. Serum ACE is raised in about 60% of patients with active, untreated disease, and is normal in about 40% of those with limited or inactive disease.

Indications. Suspected sarcoidosis (bilateral hilar lymphadenopathy, erythema nodosum, uveitis, parotid enlargement, hypercalcaemia, cardiac conduction block, neurological features), supporting evidence of granulomatous disease, monitoring of known sarcoidosis, Gaucher disease, and exclusion of an alternative cause of hypercalcaemia.

Specimen. Serum. Fasting is not needed. Stable for days at 2 to 8 °C. Avoid haemolysis and EDTA, citrate or fluoride, which inhibit the enzyme. Record any ACE inhibitor therapy.

Reference range. About 8 to 52 U/L in adults (assay specific). Values are higher in children and adolescents, and some laboratories give age specific ranges.

Raised ACE.

• Sarcoidosis: raised in about 60% of untreated active disease, more in extrathoracic and chronic disease, with a sensitivity of 41 to 84% and specificity of 83 to 99% in series, and low positive predictive value in unselected populations.
• Other granulomatous disease: tuberculosis (rarely), leprosy, berylliosis, silicosis, asbestosis, histoplasmosis and coccidioidomycosis.
• Metabolic and haematological: Gaucher disease (marked rise, up to 10 times), lymphoma, multiple myeloma, hyperthyroidism, diabetes, and cirrhosis.
• Other: HIV infection, alcoholic liver disease, amyloidosis, and in children.

Lowered ACE. ACE inhibitor therapy (levels fall sharply, so a normal result cannot be interpreted), corticosteroids (levels fall in 1 to 2 months), advanced chronic kidney disease, hypothyroidism, and the II genotype of the ACE insertion and deletion polymorphism.

Genotype effect. The D allele is associated with higher serum levels and the I allele with lower levels. The DD genotype raises ACE by about 50% over II, and this accounts for about 40% of the variation in healthy people. This variability reduces the value of fixed cut offs.

Role in sarcoidosis. A raised ACE in a patient with compatible radiology and clinical features supports the diagnosis, but a normal ACE does not exclude it. It cannot differentiate sarcoidosis from other granulomatous disease or lymphoma, and tissue (biopsy showing non-caseating granulomas) is needed for the diagnosis in most cases.

Monitoring. Serial ACE can follow response to corticosteroids in individual patients with a raised baseline, though the correlation with chest imaging, lung function and symptoms is weak, and treatment is not decided by ACE alone.

Cerebrospinal fluid ACE. Raised in some patients with neurosarcoidosis, but sensitivity is low (about 25 to 55%) and false positives occur in other neurological disease.

Critical values and findings needing immediate action. There are no ACE-specific critical values. Urgent action follows the clinical features: hypercalcaemia over 3.0 mmol/L, new heart block or ventricular arrhythmia, visual loss from uveitis or optic neuritis, and neurological deficit.

Interferences and pitfalls.

• ACE inhibitors suppress the activity measured, so a normal ACE in a treated patient is uninformative.
• Corticosteroids lower ACE and mask active disease.
• Normal ACE does not exclude sarcoidosis, and mildly raised ACE does not confirm it.
• Genotype variation produces wide inter-individual ranges.
• Higher values in children and young adults make adult cut offs misleading.
• EDTA, citrate and fluoride tubes, haemolysis and lipaemia give errors.
• Some laboratories have stopped offering the test because of low accuracy.
• The test is not reliable for screening asymptomatic people.

Special groups.

• Children: higher reference values, and sarcoidosis presents differently, with early onset disease causing arthritis, rash and uveitis.
• Pregnancy: no important change, and sarcoid often improves in pregnancy.
• Older adults: sarcoidosis may follow granulomatous reactions to drugs or malignancy.
• People of African ancestry: sarcoidosis is more frequent and more severe, with more extrathoracic involvement.
• Regions: tuberculosis and fungal infection are common causes of granulomatous disease, and they are excluded before diagnosing sarcoidosis.

Follow up tests. Chest radiograph and high resolution CT, corrected calcium, 1,25-dihydroxyvitamin D, 24-hour urinary calcium, full blood count, liver function tests, creatinine, spirometry and transfer factor, ECG, echocardiography and cardiac MRI, ophthalmic slit lamp examination, bronchoscopy with lavage (raised CD4 to CD8 ratio) and transbronchial biopsy or endobronchial ultrasound with needle aspiration, PET-CT, soluble interleukin-2 receptor, tuberculosis interferon gamma release assay, and tissue histology.