What is the diagnostic approach for adrenal insufficiency in adults?

Diagnosis of Adrenal Insufficiency in Adults

Begin with an early morning (8 AM) serum cortisol, plasma ACTH, and DHEAS measurement; if morning cortisol is <140 nmol/L (<5 µg/dL) with ACTH elevated >2-fold above the upper limit of normal, primary adrenal insufficiency is highly likely and should be confirmed with a 250 µg cosyntropin stimulation test unless basal results are absolutely unequivocal 1.

Algorithmic Diagnostic Approach

Step 1: Initial Screening Tests (Morning, ~8 AM)

• Serum cortisol: The critical first test

  • <140 nmol/L (<5 µg/dL): Highly suggestive of adrenal insufficiency
  • 140-500 nmol/L (5-18 µg/dL): Indeterminate—requires dynamic testing

  • 500 nmol/L (>18 µg/dL): Excludes adrenal insufficiency 1, 2

• Plasma ACTH: Differentiates primary from secondary/tertiary causes

  • Elevated (>2-fold above upper limit, or >66 pmol/L): Primary adrenal insufficiency
  • Low or inappropriately normal: Secondary/central adrenal insufficiency 1, 2

• DHEAS: Age- and sex-adjusted levels

  • Well below lower limit of normal: Useful sign of primary adrenal insufficiency (cannot diagnose in isolation, especially in elderly)
  • Low or low-normal with low cortisol: Suggests secondary adrenal insufficiency 1, 3, 2

Step 2: Confirmatory Testing

For Primary Adrenal Insufficiency:

The standard-dose cosyntropin (ACTH) stimulation test is the diagnostic gold standard 1:

• Administer 250 µg cosyntropin IV or IM as bolus
• Measure cortisol at baseline, 30 minutes, and 60 minutes
• Sensitivity: 92% (95% CI: 81-97%) for primary adrenal insufficiency
• Can be performed at any time of day (not affected by diurnal variation)
• The 1 µg low-dose test provides no better diagnostic accuracy than the 250 µg test 1

For Secondary/Central Adrenal Insufficiency:

• Cosyntropin test may be normal early in disease (adrenal glands not yet atrophied)
• Insulin tolerance test remains gold standard for central causes 3, 4
• Overnight metyrapone test is an alternative 3

Step 3: Identify the Underlying Cause

Primary Adrenal Insufficiency (elevated ACTH, low cortisol):

• Autoimmune adrenalitis (most common in developed countries)
• Tuberculosis, fungal infections (endemic areas)
• Congenital adrenal hyperplasia
• Adrenal hemorrhage/infarction
• Medications: azole antifungals (high doses), mitotane, abiraterone
• Surgical adrenalectomy 2

Secondary/Central Adrenal Insufficiency (low/normal ACTH, low cortisol):

• Pituitary tumors, surgery, radiation
• Inflammatory conditions: hypophysitis, sarcoidosis, hemochromatosis
• Pituitary hemorrhage (Sheehan syndrome, apoplexy)
• Medications: opioids, checkpoint inhibitors 2

Glucocorticoid-Induced Adrenal Insufficiency (most common overall):

• History of supraphysiological glucocorticoid use
• Any formulation: oral, inhaled, topical, intra-articular
• Risk highest during tapering or within weeks-months after discontinuation
• Consider in patients on prednisolone >5 mg daily (or equivalent) for >3-4 weeks 5, 2, 6

Critical Clinical Pitfalls

When to Suspect Adrenal Insufficiency

Look for the constellation of:

• Fatigue (50-95% of cases)
• Nausea/vomiting (20-62%)
• Anorexia and weight loss (43-73%)
• Hypotension (especially orthostatic)
• Hyponatremia
• Hyperpigmentation (primary AI only—from elevated ACTH)
• Salt craving and hyperkalemia (primary AI only—from aldosterone deficiency) 2, 4, 7

Assay Interference

Caution required in rare conditions that affect test interpretation:

• Cortisol-binding globulin (CBG) deficiency: falsely low total cortisol
• Glucocorticoid resistance syndromes
• Glucocorticoid hypersensitivity 1

Acute Presentation: Adrenal Crisis

If adrenal crisis is suspected (hypotension/shock with nausea, vomiting, severe fatigue, fever, or impaired consciousness), treatment takes absolute precedence over diagnosis 5:

• Immediately administer 100 mg hydrocortisone IV or IM
• Rapid volume resuscitation with 0.9% saline
• Treat identifiable triggers (infections, trauma)
• Diagnostic testing can be performed after stabilization

Glucocorticoid-Induced AI: High-Risk Periods

• During glucocorticoid tapering below physiological doses
• Immediately after discontinuation (can persist for months)
• When switching inhaled glucocorticoid formulations (variable systemic absorption)
• When starting CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) that accelerate glucocorticoid metabolism 5

Emerging Diagnostic Strategies

Recent evidence suggests adjunctive markers may reduce unnecessary dynamic testing 3:

• Lowering morning cortisol cutoffs to reduce cosyntropin testing
• Age- and sex-adjusted DHEAS to rule out primary AI in indeterminate cases
• Salivary cortisone as home-based screening (circumvents CBG variability)

However, these approaches require further validation and are not yet incorporated into formal guidelines. The 2016 Endocrine Society guideline remains the authoritative framework 1, with the 2024 joint ESE/Endocrine Society guideline providing specific guidance for glucocorticoid-induced AI 5.