Laboratory Diagnosis of Primary Adrenal Insufficiency

Hormonal Abnormalities

Low serum cortisol at presentation is the norm, with most patients having values below the laboratory reference range【1, 2, 3】.
Plasma ACTH is markedly elevated, typically exceeding twice the upper limit of normal, which together with low cortisol defines primary adrenal insufficiency【4】.
In acute illness, a cortisol concentration < 250 nmol/L (9 µg/dL) combined with an elevated ACTH is diagnostic of primary adrenal insufficiency【1, 2, 3】.
A cortisol level < 400 nmol/L (14.5 µg/dL) with elevated ACTH raises strong suspicion for the disease【1, 2, 3】.
About 10 % of patients may have cortisol within the normal laboratory range; however, an inappropriately normal cortisol together with clearly elevated ACTH indicates early‑stage primary adrenal insufficiency【1】.
Plasma renin activity is consistently increased in primary adrenal insufficiency【1, 2, 3】.
Serum aldosterone is low or inappropriately normal despite the elevated renin, confirming mineralocorticoid deficiency【1, 4】.
Dehydroepiandrosterone sulfate (DHEAS) concentrations are reduced in affected individuals【1, 2, 3】.

Hyponatremia occurs in roughly 90 % of newly presenting patients【2, 3, 5】.
Hyperkalaemia is observed in about 50 % of cases at diagnosis【2, 3, 5】.
The classic hyponatraemia‑hyperkalaemia pattern is not reliable for diagnosis because sodium may be only mildly reduced and potassium can be normal in many patients【2, 3, 5】.
In the setting of severe vomiting, patients may instead present with hypokalaemia and metabolic alkalosis【2, 3, 5】.
Mild‑to‑moderate hypercalcaemia is present in 10‑20 % of patients at presentation【1, 2, 3】.
Metabolic acidosis may be detected in some individuals【1, 2, 3】.
Hypoglycaemia is common in children with primary adrenal insufficiency and rare in adults, but can precipitate seizures when it occurs【1, 2, 3】.

Serum TSH is modestly elevated (typically 4–10 IU/L) due to loss of cortisol‑mediated inhibition; levels usually normalize after glucocorticoid replacement【1, 2, 3】.

Initial screening: Obtain a morning (08:00–09:00 h) serum cortisol and plasma ACTH simultaneously【1, 4】.
Screening thresholds: A cortisol < 140 nmol/L (5 µg/dL) together with ACTH > 300 pg/mL (66 pmol/L) is highly predictive of primary adrenal insufficiency【4】.
Confirmatory testing: Perform a standard ACTH (cosyntropin) stimulation test (0.25 mg IM or IV); a peak serum cortisol < 500 nmol/L (18 µg/dL) confirms the diagnosis【1, 4】.
Mineralocorticoid assessment: Measure plasma renin and aldosterone concurrently; an elevated renin with low or inappropriately normal aldosterone confirms mineralocorticoid deficiency【4】.

Recent or ongoing exogenous glucocorticoid therapy (oral, injectable, or inhaled) can suppress endogenous cortisol and confound test results; discontinuation before testing is advisable when feasible【1, 2, 3】.
ACTH immunoassays exhibit significant inter‑laboratory analytical bias; interpretation must be based on the specific assay’s reference intervals【4】.
Early disease may present with elevated ACTH while cortisol remains within the normal range, and mineralocorticoid deficiency can be the sole initial manifestation【4】.