How should I work up a patient with suspected adrenal insufficiency?

Workup of Suspected Adrenal Insufficiency

The diagnostic workup begins with paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, with cortisol <250 nmol/L (<9 µg/dL) plus elevated ACTH confirming primary adrenal insufficiency, while equivocal cases require cosyntropin stimulation testing with peak cortisol <500 nmol/L diagnostic of adrenal insufficiency 1.

Initial Clinical Assessment

Suspect adrenal insufficiency in patients presenting with:

• Unexplained collapse, hypotension, or shock
• Vomiting, diarrhea, or severe gastrointestinal symptoms
• Hyperpigmentation (suggests primary adrenal insufficiency)
• Electrolyte abnormalities: hyponatremia, hyperkalemia, acidosis, hypoglycemia
• Nonspecific symptoms: fatigue (50-95% of cases), anorexia, weight loss (43-73%), nausea 1, 2

Critical caveat: If acute adrenal crisis is suspected, never delay treatment for diagnostic testing—immediately administer hydrocortisone 100 mg IV/IM and isotonic saline before obtaining labs 1.

Diagnostic Algorithm

Step 1: Initial Laboratory Testing

Obtain early morning (8 AM) measurements:

• Serum cortisol
• Plasma ACTH
• Dehydroepiandrosterone sulfate (DHEAS)
• Electrolytes (sodium, potassium)
• Plasma renin activity (if primary AI suspected)

Interpretation of morning cortisol 2, 3:

• <140 nmol/L (<5 µg/dL): Highly suggestive of adrenal insufficiency—proceed to ACTH interpretation
• 140-275 nmol/L (5-10 µg/dL): Grey zone—requires dynamic testing
• >275 nmol/L (>10 µg/dL): Generally excludes adrenal insufficiency (unless acute illness present)

Step 2: Distinguish Primary vs Secondary Adrenal Insufficiency

Primary adrenal insufficiency 1, 2:

• Low cortisol (<140 nmol/L)
• Elevated ACTH (typically >2x upper limit of normal)
• Low DHEAS
• Elevated plasma renin activity
• Low aldosterone
• May have mild TSH elevation (4-10 IU/L)

Secondary/tertiary adrenal insufficiency 2, 3:

• Low or intermediate cortisol (140-275 nmol/L)
• Low or inappropriately normal ACTH
• Low or low-normal DHEAS
• Normal aldosterone and renin (mineralocorticoid axis intact)

Glucocorticoid-induced adrenal insufficiency 2, 4:

• Similar biochemical pattern to secondary AI
• Key distinguishing feature: Recent history of supraphysiological glucocorticoid use (oral, inhaled fluticasone, or topical)

Step 3: Confirmatory Dynamic Testing (When Needed)

Cosyntropin (Synacthen) stimulation test 1:

• Indicated when morning cortisol is in the grey zone (140-275 nmol/L)
• Standard dose: 250 µg cosyntropin IV or IM
• Measure cortisol at baseline and 60 minutes post-injection
• Diagnostic threshold: Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1

Important technical considerations 5, 6:

• Newer highly specific cortisol assays may require lower cut-offs (some suggest <414 nmol/L for Abbott platform)
• Test can be performed at any time of day if acute illness present
• Low-dose testing (1 µg) is feasible but not standardized
• Pitfall: Exogenous steroids (prednisolone, dexamethasone) interfere with cortisol measurement—use dexamethasone if testing must occur during treatment

Alternative: Salivary cortisol upon awakening may be useful when cortisol-binding globulin is abnormal (pregnancy, oral contraceptives) 3, 6.

Step 4: Etiological Workup (After Diagnosis Confirmed)

For Primary Adrenal Insufficiency:

First-line: Measure 21-hydroxylase (anti-adrenal) autoantibodies 1, 3

• If positive → Autoimmune Addison's disease (most common cause)
• Screen for other autoimmune conditions (thyroid, diabetes, hypoparathyroidism)

If antibodies negative, proceed with:

• CT imaging of adrenals to assess for:
  • Hemorrhage
  • Tuberculosis (calcifications)
  • Metastatic disease
  • Infiltrative processes
• In males: Measure very long-chain fatty acids (VLCFA) to exclude adrenoleukodystrophy 1, 7

In children/young adults with PAI plus hypoparathyroidism or chronic candidiasis:

• Consider autoimmune polyglandular syndrome type 1 (APS-1)
• Test for anti-interferon omega antibodies or AIRE gene mutations 1

For Secondary Adrenal Insufficiency:

• MRI of pituitary/hypothalamus to evaluate for:
  • Pituitary adenoma
  • Hemorrhage (Sheehan syndrome, apoplexy)
  • Infiltrative disease (sarcoidosis, hemochromatosis, hypophysitis)
  • History of radiation or surgery
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGF-1)
• Medication review: Opioids, checkpoint inhibitors, megestrol acetate can suppress ACTH 2, 6

Special Populations and Emerging Considerations

Immune checkpoint inhibitor (ICI) therapy 6:

• Increasingly recognized cause of both primary and secondary AI
• Requires high index of suspicion in cancer patients on immunotherapy
• Morning cortisol screening recommended; assay-specific cut-offs may improve diagnostic accuracy

Acute illness context 1:

• Cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic of primary AI
• Cortisol <400 nmol/L with elevated ACTH raises strong suspicion and warrants empiric treatment

Common Pitfalls to Avoid

1. Delaying treatment in suspected adrenal crisis: Always treat first, diagnose later
2. Missing glucocorticoid-induced AI: Specifically ask about all forms of steroid exposure (oral, inhaled, topical, intra-articular)
3. Interpreting "normal" cortisol in acute illness: A cortisol level in the normal range may be inappropriately low for a stressed state 1
4. Using wrong cortisol assay cut-offs: Newer specific assays have different thresholds than older immunoassays 3, 5
5. Forgetting to check ACTH: This single test distinguishes primary from secondary AI and is essential for proper workup
6. Not investigating etiology: Identifying the underlying cause (autoimmune, infectious, neoplastic) impacts long-term management and screening for associated conditions