Measure Plasma ACTH to Establish PAI Diagnosis
STEP 1 — Gather Information
Confirm cortisol deficiency via low morning cortisol (<140 nmol/L) or subnormal response to corticotropin stimulation test; obtain paired plasma ACTH sample (preferably with morning cortisol or baseline ACTH stimulation sample) using EDTA-plasma kept on ice and processed promptly.
STEP 2 — Rule In / Rule Out
Calculate whether plasma ACTH is ≥2-fold the assay-specific upper limit of reference range; if yes, rule in primary adrenal insufficiency; if no, rule out PAI and consider secondary adrenal insufficiency or other causes.
STEP 3 — Classify or Stratify
Classify as primary adrenal insufficiency when ACTH ≥2-fold ULN with confirmed cortisol deficiency; classify as secondary/tertiary adrenal insufficiency when ACTH is low or inappropriately normal despite cortisol deficiency.
STEP 4 — Decide
If PAI confirmed, proceed to etiologic workup (e.g., 21-hydroxylase autoantibodies) and initiate glucocorticoid and mineralocorticoid replacement; if secondary adrenal insufficiency suspected, evaluate pituitary/hypothalamic function and consider glucocorticoid replacement alone.
Clinical Guardrails / Mimics / Pitfalls
ACTH assays are subject to pre-analytical variability (hemolysis, delayed processing) and inter-assay differences; always use cold EDTA plasma and refer to assay-specific reference ranges. Do not rely on ACTH alone without confirming cortisol deficiency, and avoid using ACTH levels to adjust glucocorticoid replacement due to loss of negative feedback. Pitfalls include falsely elevated ACTH from stress, illness, or heterophilic antibodies, and falsely normal ACTH in secondary AI.
Concrete Clinical Example
A 48-year-old man presents with weight loss, hypotension, and morning cortisol 90 nmol/L (<140 nmol/L). Plasma ACTH measured at 110 pmol/L (assay ULN 45 pmol/L) is >2-fold ULN (90 pmol/L), supporting PAI; 21-hydroxylase antibodies are positive, and glucocorticoid/mineralocorticoid replacement is started.
Source: Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline, Endocrine Society, 2016, DOI:10.1210/jc.2015-1710
TODO: consider adding scripts/calc.py for the enda-acth-measurement-pai calculator