What laboratory findings are characteristic of adrenal insufficiency?

Laboratory Findings Characteristic of Adrenal Insufficiency

The hallmark laboratory findings in adrenal insufficiency are low morning cortisol with elevated ACTH in primary disease, or low cortisol with low/inappropriately normal ACTH in secondary disease, accompanied by hyponatremia in 90% of cases and hyperkalemia in only ~50% of primary cases. 1, 2

Initial Diagnostic Laboratory Panel

Morning Hormonal Assessment:

• Morning serum cortisol <250 nmol/L (<9 µg/dL) with markedly elevated ACTH (>300 pg/mL) establishes the diagnosis of primary adrenal insufficiency without further testing 1, 2
• Morning cortisol <140 nmol/L (<5 µg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 2, 3
• Morning cortisol 140-275 nmol/L (5-10 µg/dL) with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 1, 3
• Morning cortisol >550 nmol/L (>18-20 µg/dL) effectively rules out adrenal insufficiency 1

Distinguishing Primary from Secondary:

• Primary adrenal insufficiency: High ACTH + low cortisol + low DHEAS 1, 3
• Secondary adrenal insufficiency: Low or low-normal ACTH + low cortisol + low or low-normal DHEAS 1, 3

Electrolyte and Metabolic Abnormalities

Common Findings:

• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 1, 2
• Hyperkalemia occurs in only approximately 50% of primary adrenal insufficiency cases—its absence does NOT rule out the diagnosis 1, 2
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency, while hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1

Additional Laboratory Abnormalities:

• Hypoglycemia may occur, particularly in children 1
• Increased creatinine from prerenal renal failure 1
• Mild hypercalcemia in 10-20% of cases 1
• Mild anemia, lymphocytosis, and eosinophilia 4

Confirmatory Testing When Initial Results Are Indeterminate

Cosyntropin Stimulation Test Protocol:

• Perform when morning cortisol is 140-500 nmol/L (5-18 µg/dL) 1, 2
• Administer 0.25 mg (250 µg) cosyntropin intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes post-administration 1, 2

Interpretation:

• Peak cortisol <500-550 nmol/L (<18-20 µg/dL) at 30 or 60 minutes confirms adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1, 2
• The test should preferably be performed in the morning, though not strictly necessary 1

Critical Pitfalls in Laboratory Interpretation

Do Not Rely on Electrolytes Alone:

• The absence of hyperkalemia cannot rule out adrenal insufficiency—it is present in only ~50% of cases 1
• Between 10-20% of patients have mild or moderate hypercalcemia, and some may have completely normal electrolytes 1

Confounding Factors:

• Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound cortisol measurements—do not attempt diagnostic testing until adequate washout 1, 2
• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic due to assay cross-reactivity with therapeutic steroids 1
• Conditions affecting cortisol-binding globulin (CBG) and albumin can produce falsely low total cortisol values 1

Rare Presentation:

• Approximately 10% of patients with confirmed primary adrenal insufficiency present with normal basal cortisol concentrations despite clearly elevated ACTH—do not dismiss the diagnosis if clinical suspicion is high 5

Etiologic Laboratory Workup for Primary Adrenal Insufficiency

First-Line Testing:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies—positive in ~85% of autoimmune Addison's disease in Western populations 1, 2

If Autoantibodies Are Negative:

• Obtain CT imaging of the adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or structural abnormalities 1, 2
• In males with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 1

Mineralocorticoid Assessment:

• Measure renin and aldosterone levels to evaluate mineralocorticoid deficiency in primary adrenal insufficiency 1

Emergency Laboratory Considerations

Never Delay Treatment for Diagnostic Testing:

• In suspected acute adrenal crisis (unexplained hypotension, collapse, severe vomiting, altered mental status), immediately administer 100 mg IV hydrocortisone and 0.9% saline at 1 L/hour 1, 2
• Draw blood for cortisol and ACTH before steroid administration if possible, but do not delay treatment 1, 2
• Basal cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1
• Basal cortisol <400 nmol/L with elevated ACTH in acute illness raises strong suspicion 1