Internal Medicine & Pulmonology & Laboratory Medicine
Angiotensin-converting enzyme (ACE)
Angiotensin-converting enzyme (ACE) is a zinc dipeptidyl carboxypeptidase metalloprotease produced mainly by pulmonary capillary endothelial cells, but also by intestinal and renal epithelial cells and activated macrophages. Its physiological role is twofold: it converts angiotensin I (an inactive decapeptide) into angiotensin II (a potent vasoconstrictor octapeptide) - a central step in the renin-angiotensin-aldosterone system (RAAS) regulating blood pressure and blood volume - and it inactivates bradykinin (a potent vasodilator and cough mediator) into inactive fragments. It is precisely this accumulation of bradykinin that explains dry cough, a characteristic side effect of ACE inhibitors (ramipril, lisinopril, perindopril) used in cardiology and nephrology. In addition to its physiological role, serum ACE is used as a biological marker in the diagnosis and monitoring of sarcoidosis: the activated epithelioid macrophages making up sarcoidosis granulomas produce large quantities of ACE, in proportion to the total granulomatous mass. Serum ACE levels are thus elevated in 50-80 % of patients with active sarcoidosis, and fall with the initiation of treatment or spontaneous remission, making it a useful - if imperfect - marker of activity and therapeutic response. The normal value for serum ACE in adults is generally 20-70 U/L (reference values vary according to laboratory, assay method and age - children and adolescents have physiologically higher values than adults).
Indications, technique, and interferences
- Clinical indications for ACE testing: suspicion of sarcoidosis (bi-hilar adenopathy on chest X-ray + erythema nodosum + arthralgias or arthritis + uveitis + compatible neurological or cutaneous involvement); monitoring of activity in known sarcoidosis under corticosteroid or immunosuppressive treatment (normalization of ACE correlates with treatment response in 70–80 % of cases); etiological workup of granulomatous uveitis (combine ACE + calciuria + lysozyme + chest CT scan); unexplained hypercalcemia (sarcoidosis + other granulomatoses → production of 1,25-dihydroxyvitamin D3 by activated macrophages); workup of unexplained neurological involvement associated with systemic signs (neurosarcoidosis); evaluation of activity in other granulomatous diseases (berylliosis, histiocytosis, lepromatous leprosy, Gaucher's disease — less specific)
- Normal values and physiological variation: Healthy adults: 20 to 70 U/L (threshold value varies by laboratory—some use 40 U/L, others 40 or 70 U/L—always interpret in relation to the local laboratory's reference values); children and adolescents: physiologically elevated values (up to 2 to 3 times adult values) → risk of false positives in this age group; elderly people (>65 years): values slightly lower than those of young adults; pregnancy: slight physiological increase in ECA (to be considered during interpretation); significant genetic variation (ECA gene insertion/deletion polymorphism—II genotype—ID—DD): DD polymorphism (homozygous deletion) is associated with ECA values 40 to 50 % higher than the II genotype—source of significant inter-individual variation independent of the disease
- Medications interfering with ACE: ACE inhibitors (ACEIs - ramipril, lisinopril, enalapril, perindopril): lower serum ACE by 70-90%% - ACE level under ACEI is not interpretable (false negative - masks sarcoidosis elevation) → stop ACEIs at least 2 to 4 weeks before testing, if possible (discuss with prescriber); sartans/ARBs: do not directly inhibit ACE - level is interpretable under ARBs; corticosteroids (prednisone, methylprednisolone): lower ACE by reducing granulomatous activity and macrophage mass - level under corticosteroids reflects therapeutic response (decrease = good response); methotrexate, azathioprine: lower ACE by immunosuppressing granulomatous disease
- Diagnostic limitations: sensibilité pour la sarcoïdose : 55–70 % (ECA élevée chez 55–70 % des sarcoïdoses actives) — 30–45 % des sarcoïdoses actives ont une ECA normale → une ECA normale n'exclut pas la sarcoïdose ; spécificité : 85–90 % — ECA peut être élevée dans d'autres maladies granulomateuses et non granulomateuses (voir tableau) ; valeur prédictive positive (VPP) modeste dans une population à faible prévalence de sarcoïdose → ne jamais utiliser l'ECA seule pour affirmer ou exclure le diagnostic — toujours dans un contexte clinique + radiologique + histologique ; la biopsie avec mise en évidence de granulomes épithélioïdes sans nécrose caséeuse reste le gold standard diagnostique de la sarcoïdose
Clinical Interpretation of Results
| Situation / Result | Mechanism and clinical context | Action to be taken and implications |
|---|---|---|
| Elevated ACE - sarcoidosis Most common cause of AST >70 U/L |
Macrophages épithélioïdes activés des granulomes sarcoïdosiques → surexpression de l'ECA → élévation sérique proportionnelle à la masse granulomateuse totale (activité de la maladie) ; ECA élevée dans 55–70 % des sarcoïdoses actives et dans 30–50 % des sarcoïdoses chroniques stables ; corrélation avec le stade radiologique : stades II et III (atteinte pulmonaire parenchymateuse + adénopathies) → ECA plus souvent élevée que le stade I (adénopathies hilaires isolées) ; ECA très élevée (>2 fois la limite supérieure) : plus spécifique de sarcoïdose active — associée à une charge granulomateuse importante ; normalisation de l'ECA sous corticoïdes dans 70–80 % des cas après 3 à 6 mois de traitement — persistance d'une ECA élevée sous corticoïdes suggère une maladie résistante ou une posologie insuffisante | An isolated elevated ACE does not confirm the diagnosis of sarcoidosis — it suggests and warrants further investigation: chest X-ray (bilateral hilar lymphadenopathy + infiltrates) + high-resolution chest CT (mediastinal lymphadenopathy + peribronchial nodules + ground-glass opacity) + BAL (bronchoalveolar lavage — CD4/CD8 ratio >3.5: specificity 93 %) + biopsy (accessible lymph node, skin, nasal mucosa, liver, muscle — epithelioid granulomas without caseous necrosis = histological confirmation); systematic complementary workup when sarcoidosis is suspected: CBC + liver function tests + creatinine + calcemia + 24-hour calciuria (hypercalciuria in 30–50 %— hypercalcemia in 10–20 %) + ECG (conduction abnormalities) + ophthalmological exam (uveitis); monitor ACE every 3 to 6 months under treatment to assess response |
| Elevated ACE - other granulomatous causes Differential diagnosis of sarcoidosis |
Chronic berylliosis (CBD): occupational exposure to beryllium (aerospace, nuclear, ceramic, electronics industries) → pulmonary granulomas identical to sarcoidosis → elevated ACE in 50-70 % of cases — indistinguishable from sarcoidosis without occupational history + beryllium lymphocyte proliferation test (BeLPT — diagnostic gold standard); lepromatous leprosy: diffuse macrophagic infiltration (Hansen's bacilli) → moderately elevated ACE; Gaucher disease (glucocerebrosidase): accumulation of foamy macrophages → elevated ACE in 80 % of untreated forms — ACE useful for monitoring under enzyme replacement therapy (normalization = good response); Langerhans cell histiocytosis: moderately elevated ACE; lymphomas (especially Hodgkin): Reed-Sternberg cells → sometimes elevated ACE | The presence of elevated ACE in a clinical context suggestive of berylliosis should systematically lead to a complete occupational assessment—the BeLPT (Beryllium Lymphocyte Proliferation Test) is available in specialized occupational health centers in Quebec and certain university hospitals; Gaucher disease: ACE is a useful and accessible monitoring marker—it generally normalizes within 12 to 24 months after the start of enzyme replacement therapy (imiglucerase—Cerezyme)—if elevated ACE persists under treatment → adjust dose or reconsider diagnosis; in lymphomas, ACE is not a diagnostic marker—LDH and beta-2 microglobulin have better prognostic value |
| High ECA — Non-granulomatous causes Various causes — reduced specificity |
Liver cirrhosis: activated hepatic stellate cells (myofibroblasts) and sinusoidal endothelial cells produce ACE → moderate elevation in advanced cirrhosis - correlates with liver fibrosis (moderate correlation with METAVIR score); hyperthyroidism: increased cardiac output + pulmonary hyperemia → increased endothelial mass → elevated ACE in 40-60 % of untreated hyperthyroidism - normalization after hyperthyroid treatment; diabetes mellitus: moderately elevated ACE in hyperglycemic phases (mechanism poorly understood - glucosylation of endothelial proteins); chronic kidney disease (CKD): paradoxically, ACE may be elevated in early stages (glomerular fibrosis → local activation of renal RAAS) and low in terminal stages; pneumoconioses (silicosis, asbestosis): pulmonary fibrosis + macrophage activation → moderately elevated ACE | These non-granulomatous causes are the main sources of false positives in the diagnosis of sarcoidosis by ACE—hence the importance of never interpreting ACE in isolation and always placing it in the overall clinical context; moderately elevated ACE (1 to 1.5 times the upper limit) in a patient with known cirrhosis or hyperthyroidism does not warrant an in-depth workup for sarcoidosis if the clinical picture is explanatory; however, very high ACE (>2 times the upper limit) in this context warrants further investigation to rule out associated sarcoidosis; in a diabetic patient, ACE will be difficult to interpret if unbalanced blood glucose is present—check HbA1c and glycemic control at the time of measurement. |
| Low or normal ejection fraction Causes of Low ECA and Significance |
Traitement par IEC (inhibiteurs de l'ECA) : abaissement de 70 à 90 % de l'ECA sérique — dosage non interprétable si le patient est sous IEC (ramipril, lisinopril, énalapril, perindopril, captopril, quinapril, etc.) — faux négatif majeur — à signaler systématiquement lors de la prescription du dosage et dans l'interprétation du résultat ; sarcoïdose sous corticoïdes : l'ECA se normalise dans 70–80 % des cas bien contrôlés → une ECA normale sous corticoïdes peut refléter une réponse thérapeutique satisfaisante (à interpréter avec les données cliniques et radiologiques) ; sarcoïdose inactive ou en rémission : ECA normale dans 50–70 % des sarcoïdoses en rémission clinique ; hypothyroïdie : ECA basse (effet inverse de l'hyperthyroïdie) ; génotype II homozygote du polymorphisme ECA (insertion/insertion) : ECA physiologiquement basse (pas de signification pathologique) | L'absence d'élévation de l'ECA n'exclut pas la sarcoïdose — 30 à 45 % des sarcoïdoses actives ont une ECA normale ; si la suspicion clinique est forte malgré une ECA normale : poursuivre le bilan (TDM thoracique + LBA + biopsie) sans s'arrêter à ce résultat isolé ; vérifier systématiquement la liste des médicaments du patient avant d'interpréter une ECA normale ou basse — un IEC non signalé est la principale cause de faux négatif ; le dosage concomitant du lysozyme sérique et urinaire (produit par les macrophages activés — sensibilité 60–70 % pour la sarcoïdose + moins influencé par les IEC) peut compléter l'information apportée par l'ECA ; la calciurie des 24 heures (augmentée dans 30–50 % des sarcoïdoses actives) est un marqueur complémentaire utile, accessible et non influencé par les traitements cardiovasculaires |
| ECA and monitoring of sarcoidosis under treatment Activity marker — response kinetics |
Usefulness of ACE in monitoring treated sarcoidosis: progressive decrease under corticosteroids (prednisone 0.5-1 mg/kg/d) - normalization expected within 3 to 6 months if good therapeutic response; persistence or re-ascension of ACE under corticosteroid treatment → suggests : insufficient dosage + refractory disease + relapse + corticoresistance → compare with clinical (dyspnea, spirometry, CT) and biological (blood calcium, CBC, liver function tests) data before modifying treatment; recommended follow-up frequency: dosage every 3 months in active phase under treatment → every 6 months in stabilization phase → annually in remission; 2nd-line immunosuppressive treatment (methotrexate, azathioprine, mycophenolate) if corticodependent or corticoresistant: ACE decreases under these treatments - identical follow-up; anti-TNF (infliximab, adalimumab): used in refractory sarcoidosis - ACE generally normalizes under anti-TNF biotherapy if clinical response | ACE should never be the sole parameter for monitoring sarcoidosis—it should be interpreted in conjunction with spirometry (FEV1, FVC, DLCO), thoracic CT scan, symptoms (dyspnea, cough), serum and urinary calcium, and other potentially affected organs (ECG + Holter—cardiac conduction abnormalities, funduscopy + slit lamp—uveitis, neurological assessment if neurosarcoidosis); an isolated rise in ACE without clinical or radiological changes does not, in itself, justify a treatment modification—first look for a confounding cause (intercurrent infection, involuntary corticosteroid withdrawal); sarcoidosis relapses during corticosteroid tapering are often signaled by a rise in ACE before symptom recurrence—hence the value of measurement with each dose reduction. |
ℹ️
Genetic Polymorphism of ACE and Interpretation: The gene encoding ACE (chromosome 17q23) exhibits an insertion/deletion (I/D) polymorphism of a 287 bp sequence in intron 16. The three genotypes (II — ID — DD) account for 40–50 % of the interindividual variation in basal serum ACE: DD genotype is associated with the highest ACE values, II genotype with the lowest, and ID genotype with intermediate values. This genetic variation can lead to false positives (DD genotype in a healthy subject → ACE slightly above normal) and false negatives (II genotype in a sarcoidosis patient → ACE within normal limits despite active disease). In equivocal cases, ACE genotyping may be useful for interpreting a borderline value — available in some university reference laboratories.
Situations requiring swift investigation
See your doctor quickly if a high ACE is associated with: progressive dyspnea + bilateral hilar adenopathy on radiography → pulmonary sarcoidosis to confirm (CT + BAL + biopsy); ; granulomatous uveitis (redness of the eye + decreased visual acuity + photophobia) → urgent ocular sarcoidosis workup (risk of blindness without treatment); ; Rhythm or conduction disturbances on ECG in a patient with known sarcoidosis → cardiac sarcoidosis (Holter monitor + cardiac MRI + PET scan) — risk of sudden death; ; Focal neurological deficit or aseptic lymphocytic meningitis → Neurosarcoidosis (brain MRI + lumbar puncture).
Consult at Clinique Omicron
Clinique Omicron physicians prescribe and interpret ACE levels as part of the workup for suspected sarcoidosis or other granulomatous diseases, coordinate further assessments (chest CT scan, bronchoalveolar lavage, biopsy), and refer patients to pulmonology or specialized internal medicine for diagnostic confirmation and management. The follow-up of known sarcoidosis, including ACE monitoring and corticosteroid treatment management, is provided at our service locations in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for the advice of a qualified healthcare professional. The ACE dosage should always be interpreted within its overall clinical context and cannot alone confirm or exclude a diagnosis of sarcoidosis.
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