What is the initial workup for a patient suspected of having primary adrenal insufficiency?

Workup of Primary Adrenal Insufficiency

Begin with early morning (8 AM) serum cortisol and plasma ACTH measurements—if cortisol is <250 nmol/L (<9 μg/dL) with elevated ACTH in the presence of clinical symptoms, this is diagnostic of primary adrenal insufficiency and no further testing is needed. 1, 2

Initial Laboratory Testing

Critical first-line tests to order simultaneously:

• Early morning (8 AM) serum cortisol and plasma ACTH 1, 2, 3
• Basic metabolic panel (sodium, potassium, glucose, creatinine) 2
• Serum osmolality and urine sodium (if hyponatremia present) 2

Interpreting Initial Results

Diagnostic thresholds for primary adrenal insufficiency:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = diagnostic of primary AI 1, 2, 3
• Cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH = strong suspicion of primary AI 1, 2
• Cortisol 250-500 nmol/L (9-18 μg/dL) = proceed to cosyntropin stimulation test 2, 3
• Cortisol >550 nmol/L (>20 μg/dL) = rules out adrenal insufficiency 2

Key electrolyte patterns:

• Hyponatremia occurs in 90% of newly diagnosed cases 2, 4
• Hyperkalemia is present in only ~50% of cases—its absence does NOT rule out primary AI 1, 2
• Hyponatremia + hyperkalemia together strongly suggests primary AI (mineralocorticoid deficiency) 2
• Hyponatremia without hyperkalemia suggests secondary AI 2

Cosyntropin (Synacthen) Stimulation Test

When to perform: If morning cortisol is indeterminate (250-500 nmol/L or 9-18 μg/dL) 2, 3, 5

Test Protocol

• Obtain baseline serum cortisol and ACTH 1, 2
• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1, 2, 5
• Measure serum cortisol at 30 and 60 minutes post-administration 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) = diagnostic of adrenal insufficiency 1, 2, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) = normal, excludes AI 2, 3

Critical timing consideration: Preferably perform in the morning, though not strictly required 1

Important Testing Pitfalls to Avoid

Never delay treatment for diagnostic testing if adrenal crisis is suspected—draw blood for cortisol and ACTH, then immediately give 100 mg IV hydrocortisone and 0.9% saline 1, 2, 5

Medications that interfere with testing:

• Exogenous steroids (prednisone, hydrocortisone, inhaled fluticasone) suppress the HPA axis and cause false results 1, 2
• If you must treat suspected crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—it doesn't interfere with cortisol assays 2
• Wait until the patient has been weaned off corticosteroids before performing definitive testing 2

Etiologic Workup (Determining the Cause)

Once primary adrenal insufficiency is biochemically confirmed, proceed systematically:

First-Line Etiologic Test

Measure 21-hydroxylase (21OH-Ab) autoantibodies—autoimmunity accounts for ~85% of primary AI cases in Western populations 1, 2

If Autoantibodies Are Positive

• Diagnosis: Autoimmune Addison's disease 1
• Screen for other autoimmune conditions (thyroid disease, diabetes, pernicious anemia, celiac disease) 2
• Consider testing for autoimmune polyglandular syndrome (APS-1) if patient is young with hypoparathyroidism, candidiasis, dental enamel dysplasia, keratitis, autoimmune hepatitis, or premature ovarian insufficiency 1

If Autoantibodies Are Negative

A more thorough investigation is required 1:

• CT scan of the adrenal glands—look for calcifications (tuberculosis), hemorrhage, tumors, metastases, or infiltrative disease 1, 2
• In males: measure very long-chain fatty acids (VLCFA)—screens for adrenoleukodystrophy, an X-linked condition 1, 2
• Consider tuberculosis testing (QuantiFERON, culture, PCR) if CT shows calcifications 1
• Urine steroid profile and genetic sequencing if congenital adrenal hyperplasia suspected 1
• Consider NR0B1 (DAX1) gene sequencing if male with hypogonadotropic hypogonadism 1

Note: 21OH-Ab are often absent in children and the elderly, and previously positive patients may become negative over time 1

Additional Diagnostic Considerations

Distinguishing Primary from Secondary AI

Primary AI (adrenal gland failure):

• High ACTH, low cortisol 2, 3
• Both glucocorticoid AND mineralocorticoid deficiency 2, 3
• Skin hyperpigmentation present 6, 4
• Salt craving common 2, 4

Secondary AI (pituitary/hypothalamic failure):

• Low or inappropriately normal ACTH, low cortisol 2, 3
• Glucocorticoid deficiency only (mineralocorticoid function intact) 2
• No hyperpigmentation 4
• No salt craving 4

Special Diagnostic Scenario: Hyponatremia

If patient presents with hypo-osmolar hyponatremia, adrenal insufficiency can mimic SIADH exactly 2:

• Both present with euvolemic hypo-osmolar hyponatremia 2
• Both have inappropriately high urine osmolality and elevated urinary sodium 2
• The cosyntropin stimulation test is medically necessary to rule out AI before diagnosing SIADH 2

Early/Subclinical Primary AI

Approximately 10% of patients with confirmed primary AI present with normal cortisol concentrations 7:

• Normal to high basal cortisol with clearly elevated ACTH (>300 pg/mL) is indicative of early primary AI when clinical history is suggestive 7
• These patients still require treatment and will progress to overt disease 7

Clinical Features That Should Trigger Testing

Classic symptoms (present in varying frequencies):

• Fatigue (50-95% of cases) 4, 3
• Nausea and vomiting (20-62%) 2, 4, 3
• Anorexia and weight loss (43-73%) 4, 3
• Postural hypotension 4, 5
• Skin hyperpigmentation (primary AI only) 6, 4
• Salt craving (primary AI only) 2, 4
• Abdominal and muscle pain 4

High-risk scenarios requiring immediate testing:

• Any patient on ≥20 mg/day prednisone for ≥3 weeks who develops unexplained hypotension 2
• Vasopressor-resistant hypotension 2
• Unexplained collapse with hypotension and GI symptoms 2