What labs should be ordered for a male patient with fatigue, irritability, and weight gain, and a history of potential hypothyroidism, sleep apnea, or depression, to evaluate for adrenal insufficiency?

Laboratory Evaluation for Adrenal Insufficiency

Order morning (8 AM) serum cortisol, plasma ACTH, TSH, free T4, and a basic metabolic panel as the initial laboratory workup for suspected adrenal insufficiency in this patient with fatigue, irritability, and weight gain. 1, 2

Initial Morning Laboratory Panel

The core hormonal assessment should include:

• Morning (8 AM) serum cortisol and plasma ACTH are the first-line diagnostic tests, as these paired measurements distinguish primary from secondary adrenal insufficiency 1, 2, 3
• TSH and free T4 must be obtained simultaneously because hypothyroidism commonly presents with fatigue (66% of cases) and can coexist with adrenal insufficiency in hypophysitis 4, 1
• Basic metabolic panel (sodium, potassium, glucose) to assess for hyponatremia (present in 90% of newly diagnosed adrenal insufficiency) and hyperkalemia (present in ~50% of primary adrenal insufficiency cases) 1, 5, 2

Interpreting Initial Results

Primary Adrenal Insufficiency Pattern:

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic 1, 5, 3
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency 1

Secondary Adrenal Insufficiency Pattern:

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 1, 2
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1
• Low free T4 with low/normal TSH suggests hypophysitis affecting multiple pituitary hormones 4, 1

Indeterminate Results:

• Morning cortisol between 3-15 μg/dL requires ACTH stimulation testing for definitive diagnosis 1, 2

ACTH Stimulation Test Protocol (When Needed)

If morning cortisol is indeterminate, proceed with:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 5, 3
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 5
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 5, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1, 6

Additional Testing Based on Initial Results

If Primary Adrenal Insufficiency Confirmed:

• 21-hydroxylase autoantibodies to identify autoimmune etiology (accounts for ~85% of cases in Western populations) 1
• Adrenal CT imaging if autoantibodies are negative, to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1

If Secondary Adrenal Insufficiency or Multiple Pituitary Deficiencies:

• FSH, LH, and testosterone (in males) to evaluate for hypogonadism 1
• MRI brain with pituitary cuts if ≥2 pituitary hormone deficiencies are identified 4, 1

Critical Pitfalls to Avoid

• Never start thyroid hormone replacement before addressing adrenal insufficiency, as this can precipitate adrenal crisis 4, 1
• Do not rely on electrolyte abnormalities alone to make or exclude the diagnosis—hyperkalemia is present in only ~50% of cases and some patients have normal electrolytes 1, 5
• Never delay treatment of suspected adrenal crisis for diagnostic testing—if the patient is clinically unstable with hypotension, give IV hydrocortisone 100 mg immediately and draw cortisol/ACTH before treatment if possible 1, 5, 3
• Exogenous steroids (including inhaled fluticasone) suppress the HPA axis and confound test results—document any steroid use 1, 5
• Morning cortisol alone has limited diagnostic value with sensitivity of 100% but specificity of only 33% at a cutoff of 500 nmol/L 6

Timing Considerations

• All tests should be performed in the morning around 8 AM to capture peak cortisol levels 4, 1, 2
• Hold hydrocortisone for 24 hours before testing if the patient is already on replacement therapy and diagnostic confirmation is needed 1
• If the patient is on prednisone or other corticosteroids, wait until they have been weaned off before performing definitive HPA axis testing, as therapeutic glucocorticoids cause iatrogenic secondary adrenal insufficiency 1