What is the diagnostic workup for a patient with suspected Addison's disease?

Diagnostic Workup for Addison's Disease

Begin with paired measurement of serum cortisol and plasma ACTH levels as the initial diagnostic test, followed by cosyntropin stimulation testing if results are equivocal, and then pursue etiologic workup with 21-hydroxylase autoantibodies as the first-line test for determining autoimmune etiology. 1

Initial Biochemical Testing

• Measure early morning serum cortisol and plasma ACTH simultaneously as the cornerstone diagnostic tests 1
• Serum cortisol <250 nmol/L (<9 µg/dL) with markedly elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 2
• If cortisol levels are equivocal (between 250-550 nmol/L), proceed directly to confirmatory testing 1

Baseline Laboratory Panel

Obtain the following tests to assess for characteristic abnormalities:

• Serum sodium: Hyponatremia is present in approximately 90% of newly diagnosed cases 3, 1
• Serum potassium: Hyperkalemia occurs in about 50% of patients, though its absence does not exclude the diagnosis 3, 1
• Serum calcium: Mild to moderate hypercalcemia occurs in 10-20% of patients at presentation 3
• Complete blood count: Look for anemia, mild eosinophilia, and lymphocytosis 1
• Liver transaminases: May be elevated 1
• Blood glucose: Particularly important in children who may present with hypoglycemia 3, 1
• Creatinine: May be elevated due to prerenal renal failure 3

Confirmatory Testing: Cosyntropin Stimulation Test

Perform when partial adrenal insufficiency is suspected or initial results are equivocal 1:

• Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline, 30 minutes, and/or 60 minutes post-administration 1
• A peak cortisol <500-550 nmol/L at either 30 or 60 minutes confirms the diagnosis 1, 2

Critical Caveat

If acute adrenal crisis is suspected clinically, never delay treatment for diagnostic testing 1. Draw blood samples for cortisol and ACTH before administering hydrocortisone if possible, but immediate treatment takes absolute priority 1.

Etiologic Workup

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

First-Line Etiologic Test

• Measure 21-hydroxylase autoantibodies (21OH-Ab) as the initial test to establish autoimmune etiology, which accounts for approximately 85% of cases in Western populations 4, 1
• Note that previously positive patients may become antibody-negative over time, so absence does not definitively exclude autoimmunity 4

If 21OH-Ab is Negative

Pursue additional investigations based on clinical context 4, 1:

• CT imaging of the adrenals: To assess for structural abnormalities, hemorrhage, or infiltrative processes 1
• Very long-chain fatty acids: Screen all males for adrenoleukodystrophy, an X-linked condition with variable presentation 4
• Chest imaging and tuberculosis testing: Tuberculosis remains a significant cause, particularly in endemic areas 4
• Interferon-ω antibodies: May indicate autoimmune polyendocrine syndrome type 1 1
• NR0B1 (DAX1) gene testing: Consider in males with associated hypogonadotropic hypogonadism 4

Screening for Associated Autoimmune Conditions

Screen for other autoimmune diseases, as approximately 50% of patients with autoimmune Addison's disease have coexisting autoimmune conditions 2:

• Thyroid function tests and thyroid antibodies: Essential screening, as autoimmune thyroid disease is common 1, 2
• Consider screening for type 1 diabetes, hypoparathyroidism, and other components of autoimmune polyendocrine syndromes 2

Key Clinical Features to Recognize During Evaluation

Look for these specific findings that support the diagnosis:

• Hyperpigmentation with uneven distribution: Particularly in sun-exposed areas, palmar creases, buccal mucosa, and frictional surfaces 3, 5
• Salt craving: A specific symptom reflecting mineralocorticoid deficiency 3, 2
• Morning nausea and lack of appetite: Common early symptoms present in 20-62% of patients 3
• Muscle pain or cramps: Especially during acute presentations 3
• Orthostatic hypotension: Reflects volume depletion from mineralocorticoid deficiency 3

Common Diagnostic Pitfalls

• Do not rely solely on electrolyte abnormalities: Some patients present with normal electrolytes or only mild abnormalities 3
• Recognize the insidious nature: Symptoms develop over months to years, leading to frequent delays in diagnosis 3
• Exogenous steroid use confounds interpretation: Recent corticosteroid administration can suppress ACTH and alter cortisol levels 1
• Non-specific early symptoms: Fatigue, weight loss, and malaise are easily attributed to other conditions 3, 6