Laboratory tests - angiotensin converting enzyme (ACE)

What it is

A zinc metallopeptidase (dipeptidyl carboxypeptidase) - converts angiotensin I -> angiotensin II and degrades bradykinin
- The bradykinin arm explains ACE inhibitor cough and angioedema
Principal source: pulmonary capillary endothelium
*In disease, the source is different: EPITHELIOID CELLS OF GRANULOMAS* - hence its use in sarcoidosis
*A poor test - ordered far more often than it is useful*

Raised in only ~50-60% of sarcoidosis overall
- ~60-80% in ACTIVE pulmonary disease; *often normal in inactive, isolated extrapulmonary, or treated disease*
Specificity ~80-90% against healthy controls, but much lower against the diseases that actually enter the differential
*Up to 10% of the healthy population has a raised level - ACE gene insertion/deletion (I/D) polymorphism*
- DD genotype -> substantially higher baseline levels; some laboratories provide genotype-adjusted reference ranges

Activated macrophages differentiating into epithelioid cells within granulomas secrete ACE
-> serum ACE approximates TOTAL GRANULOMA BURDEN, not disease activity or organ damage
*Which is exactly why it fails clinically*: a patient with a small volume of dangerous disease (cardiac, neurological, ocular) may have a normal ACE, while an asymptomatic patient with extensive hilar nodes may have a high one
Also produced in other granulomatous and high-cell-turnover states, and by Gaucher macrophages

Granulomatous
- *SARCOIDOSIS* - the classic
- Tuberculosis, LEPROSY, histoplasmosis, coccidioidomycosis, berylliosis, silicosis, asbestosis
- Granulomatosis with polyangiitis, Crohn disease, primary biliary cholangitis
Storage / metabolic
- *GAUCHER DISEASE (lipid-laden macrophages*)
- HYPERTHYROIDISM, DIABETES MELLITUS
- Amyloidosis
Other - lymphoma, hypersensitivity pneumonitis, HIV, alcoholic liver disease, psoriasis, the ACE I/D DD genotype in healthy people

*ACE INHIBITOR THERAPY - the level is uninterpretable; stop the drug or do not order the test*
Hypothyroidism, corticosteroid therapy, advanced lung fibrosis, anorexia nervosa
*Effective treatment of the underlying granulomatous disease*

*It is NOT a diagnostic test for sarcoidosis - too insensitive to rule out, too non-specific to rule in*
Modest value in MONITORING known sarcoidosis when the level was high at baseline and the patient has active parenchymal disease
- Falls with corticosteroid response; rises with relapse
Serum soluble IL-2 receptor performs similarly and is increasingly preferred where available

Compatible clinical and radiological picture + NON-CASEATING GRANULOMAS on biopsy + exclusion of other causes
Imaging
- CXR staging: 0 normal; I bilateral hilar lymphadenopathy; II BHL + infiltrates; III infiltrates alone; IV fibrosis
- HRCT - perilymphatic nodules, beaded fissures, upper/mid zone predominance
- FDG-PET - occult cardiac and extrathoracic disease, and to target biopsy
Biopsy - EBUS-TBNA of mediastinal nodes is the highest-yield route; skin, lip/salivary gland, conjunctiva, liver where accessible
- *LOFGREN SYNDROME (erythema nodosum + bilateral hilar lymphadenopathy + fever + ankle arthritis) does NOT require biopsy* - it is diagnostic and self-limiting
Other bloods: HYPERCALCAEMIA and hypercalciuria (1-alpha-hydroxylase in granulomas -> unregulated calcitriol), raised ALP, lymphopenia, raised immunoglobulins, raised soluble IL-2 receptor
Exclude: TB (always - steroids in undiagnosed TB are disastrous), lymphoma, berylliosis, hypersensitivity pneumonitis, IgG4-related disease
Organ screening at diagnosis: ECG (+/- Holter and cardiac MRI), ophthalmology slit lamp, calcium, creatinine, LFTs, PFTs with DLCO

*Do not order ACE to screen for sarcoidosis in an undifferentiated patient* - the pre-test probability is too low and false positives are common
*Do not order it in a patient on an ACE inhibitor*
If ordering for monitoring, obtain a BASELINE before treatment - a single mid-treatment value is uninterpretable
A normal ACE never excludes sarcoidosis; a raised ACE never diagnoses it - biopsy is the answer where the diagnosis matters

Observation in asymptomatic stage I disease - *spontaneous remission in 60-80%*
Treat when there is organ threat or troublesome symptoms
- *Absolute indications: CARDIAC, NEUROLOGICAL, OCULAR (sight-threatening), HYPERCALCAEMIA with renal impairment, progressive pulmonary disease*
- Prednisolone 20-40 mg/day, tapered over 6-12 months
- Steroid-sparing: methotrexate (first choice), azathioprine, mycophenolate, leflunomide
- Refractory: infliximab or adalimumab (TNF inhibitors; note that TNF inhibitors can also CAUSE sarcoid-like granulomatous disease)
- Hydroxychloroquine for cutaneous disease and hypercalcaemia
Hypercalcaemia: avoid sun exposure and vitamin D supplements, hydration, corticosteroid
Monitor with symptoms, PFTs (FVC, DLCO), imaging and organ-specific tests - not with the ACE level alone**

*Sarcoidosis - and its syndromes: Lofgren (acute, good prognosis), Heerfordt (uveoparotid fever + facial nerve palsy), lupus pernio (chronic, disfiguring, poor prognosis*)
Tuberculosis and leprosy
Gaucher disease - and the other markers: chitotriosidase, low platelets, hepatosplenomegaly
Hyperthyroidism, diabetes mellitus
Berylliosis - clinically and histologically identical to sarcoidosis; occupational history plus a beryllium lymphocyte proliferation test distinguishes them
Histoplasmosis, coccidioidomycosis, HIV, lymphoma
ACE I/D polymorphism - and its separate associations with hypertension, diabetic nephropathy and ACE inhibitor response
*ACE inhibitor therapy* - suppresses the level entirely

The level tracks granuloma burden, and therefore falls with spontaneous remission or effective treatment
A persistently high or rising ACE in treated sarcoidosis suggests ongoing or relapsing disease - but confirm with clinical, functional and imaging assessment before escalating therapy
*Never escalate immunosuppression on the ACE level alone*
Sarcoidosis outcome: 60-80% remit spontaneously within 2-3 years (highest in Lofgren syndrome); ~20-30% develop chronic disease; ~5% die, usually from pulmonary fibrosis, pulmonary hypertension or CARDIAC involvement
- Stage I has the best prognosis; stage IV the worst
- Lupus pernio, African ancestry, age >40 at onset, hypercalcaemia and extrapulmonary disease predict a chronic course

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