Diagnostic Criteria and Testing for Primary Adrenal Insufficiency

Hormonal Patterns Indicative of Primary Adrenal Insufficiency

Any cortisol concentration combined with ACTH > 2 × the upper limit of normal strongly suggests primary adrenal insufficiency, even when cortisol has not fallen below the reference range. 2
ACTH > 66 pmol/L (>300 pg/mL) represents maximal adrenal stimulation; a normal or only mildly elevated cortisol in this setting indicates inadequate adrenal response. 2
Low serum DHEAS levels (well below age‑ and sex‑specific lower limits) support adrenal cortex failure, although they cannot be used in isolation. 2

Hyponatremia with low serum osmolality is present in ~90 % of newly presenting primary adrenal insufficiency cases, reflecting sodium loss and impaired free‑water clearance. 4
Hyperkalemia is absent in ~50 % of patients at diagnosis; its absence does not rule out primary adrenal insufficiency. 4

A normal thyroid profile helps exclude secondary (pituitary) adrenal insufficiency; modest TSH elevation (≈ 4–10 IU/L) may be seen in primary disease due to loss of cortisol‑mediated inhibition. 4

Standard ACTH (cosyntropin) stimulation test: a peak serum cortisol < 500 nmol/L (18 µg/dL) at 30 or 60 minutes confirms adrenal insufficiency. 2
Baseline cortisol < 140 nmol/L (5 µg/dL) together with ACTH > 300 pg/mL establishes the diagnosis without need for stimulation testing. 2
The cosyntropin test has a sensitivity of ~92 % for primary adrenal insufficiency and is considered the diagnostic gold standard. 2
Cortisol results are not affected by diurnal variation; testing may be performed at any time of day. 2

21‑hydroxylase (anti‑adrenal) autoantibodies are positive in ~65 % of primary adrenal insufficiency cases, indicating autoimmune Addison’s disease. 4
If autoantibodies are negative, contrast‑enhanced CT of the adrenal glands should be obtained to assess for infiltrative, infectious, hemorrhagic, or neoplastic causes. 4
In male patients, measurement of very long‑chain fatty acids is recommended to screen for X‑linked adrenoleukodystrophy. 4

In suspected adrenal crisis, a cortisol < 250 nmol/L (9 µg/dL) with elevated ACTH is diagnostic; treatment must begin immediately without awaiting confirmatory tests. 4
Administer hydrocortisone 100 mg IV promptly; obtain cortisol and ACTH samples before the first dose. 4
Long‑term replacement therapy: hydrocortisone 15–25 mg daily in divided doses plus fludrocortisone 0.05–0.3 mg daily for mineralocorticoid replacement. 4
Patient education: instruct on stress‑dosing, provision of emergency injectable hydrocortisone, and wearing medical‑alert identification. 4