What is the appropriate work‑up for a patient with suspected adrenal insufficiency, including clinical assessment, laboratory testing, and imaging?

Work-up for Adrenal Insufficiency

Begin with early morning (8 AM) serum cortisol and plasma ACTH measurements as your first-line diagnostic tests, followed by a cosyntropin stimulation test if initial results are indeterminate. 1, 2

Initial Clinical Assessment

Look specifically for these clinical features that distinguish primary from secondary adrenal insufficiency:

• Hyperpigmentation (darkening of skin, particularly in skin creases, scars, and mucous membranes) indicates primary adrenal insufficiency due to elevated ACTH 3, 4
• Orthostatic hypotension suggests mineralocorticoid deficiency in primary adrenal insufficiency 3, 4
• Salt craving is a specific clue for primary adrenal insufficiency 4
• Absence of hyperpigmentation with normal skin color points toward secondary adrenal insufficiency 3
• Fatigue, nausea, vomiting, weight loss, and anorexia occur in both primary and secondary forms 2, 4

Initial Laboratory Panel

Draw these tests simultaneously in the early morning (approximately 8 AM):

• Serum cortisol - morning measurement is essential for accurate interpretation 1, 2
• Plasma ACTH - distinguishes primary (high ACTH) from secondary (low/normal ACTH) adrenal insufficiency 1, 2
• Basic metabolic panel (sodium, potassium, CO2, glucose) - hyponatremia occurs in 90% of cases, hyperkalemia in ~50% of primary adrenal insufficiency 5, 1
• Dehydroepiandrosterone sulfate (DHEAS) - low levels support the diagnosis 2

Interpretation of Initial Results

Primary adrenal insufficiency:

• Morning cortisol <250 nmol/L (<9 μg/dL or <5 μg/dL) with elevated ACTH is diagnostic 5, 2
• Hyponatremia plus hyperkalemia strongly suggests primary adrenal insufficiency 5

Secondary adrenal insufficiency:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 5, 2
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 5

Important caveat: The absence of hyperkalemia cannot rule out adrenal insufficiency—it occurs in only ~50% of primary cases 3, 5

Confirmatory Testing: Cosyntropin Stimulation Test

Perform this test when morning cortisol is indeterminate (between 5-18 μg/dL or 140-500 nmol/L):

Protocol: 5, 1

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously
• Obtain baseline serum cortisol before administration
• Measure serum cortisol at exactly 30 and 60 minutes post-administration

Interpretation: 5, 1

• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal and excludes adrenal insufficiency

Critical pitfall: Never perform this test in patients actively taking corticosteroids (prednisone, hydrocortisone, inhaled fluticasone)—exogenous steroids suppress the HPA axis and produce false-positive results 5, 1

Etiologic Work-up for Primary Adrenal Insufficiency

Once primary adrenal insufficiency is confirmed biochemically, determine the underlying cause:

First step: Measure 21-hydroxylase (anti-adrenal) autoantibodies 5, 1

• Autoimmunity accounts for ~85% of primary adrenal insufficiency cases in Western populations 5
• Positive antibodies confirm autoimmune adrenalitis 1

If autoantibodies are negative: Obtain CT imaging of the adrenals to evaluate for: 5, 1

• Adrenal hemorrhage
• Metastatic disease
• Tuberculosis or fungal infections
• Tumors or other structural abnormalities

In male patients with negative antibodies: Assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 5

Imaging Considerations

Do NOT routinely order adrenal imaging as a first-line test unless:

• Autoantibodies are negative in confirmed primary adrenal insufficiency 5, 1
• You suspect adrenal hemorrhage, metastasis, or infection based on clinical context 1

Special Situations and Critical Pitfalls

If acute adrenal crisis is suspected (hypotension, shock, altered mental status, severe vomiting):

• NEVER delay treatment for diagnostic procedures 3, 1
• Immediately administer 100 mg IV hydrocortisone bolus plus 0.9% saline infusion at 1 L/hour 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results 3

Patients on chronic corticosteroids:

• Do not attempt diagnostic testing until corticosteroids have been discontinued with adequate washout time 5, 1
• Morning cortisol will be falsely low due to iatrogenic secondary adrenal insufficiency 5
• If diagnosis is uncertain and patient is on steroids, use dexamethasone 4 mg IV for emergency treatment—it does not interfere with cortisol assays 5

Patients with hyponatremia:

• Always exclude adrenal insufficiency before diagnosing SIADH—both present with identical laboratory findings (euvolemic hypo-osmolar hyponatremia with inappropriately high urine osmolality and elevated urinary sodium) 5
• Perform cosyntropin stimulation test to definitively rule out adrenal insufficiency 5

Screening for Associated Autoimmune Conditions

Once primary adrenal insufficiency is diagnosed, screen annually for: 5

• Thyroid function (TSH, free T4) - hypothyroidism frequently coexists
• Diabetes mellitus (fasting glucose, HbA1c)
• Vitamin B12 deficiency (serum B12, methylmalonic acid)
• Celiac disease (tissue transglutaminase 2 antibodies and total IgA) if patient has episodic diarrhea 5

Critical warning: When treating concurrent hypothyroidism and adrenal insufficiency, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 5