What is the appropriate workup for a patient suspected of having Addison's disease, particularly in adults with a history of autoimmune disorders or other risk factors?

Workup of Addison Disease

The diagnostic workup of Addison's disease begins with measurement of early morning (8 AM) serum cortisol and plasma ACTH, followed by cosyntropin stimulation testing if results are equivocal, and then etiologic investigation with 21-hydroxylase autoantibodies and adrenal CT imaging. 1, 2

Initial Clinical Assessment

Look specifically for these clinical features that suggest Addison's disease:

• Hyperpigmentation of skin, particularly in sun-exposed areas, palmar creases, buccal mucosa, and areas of friction—this occurs due to elevated ACTH stimulating melanocytes 3, 4, 5
• Orthostatic hypotension with postural blood pressure drops, reflecting mineralocorticoid deficiency 1, 2
• Salt craving, a highly specific symptom of mineralocorticoid deficiency 3, 4
• Weight loss, fatigue, anorexia, and nausea—particularly morning nausea and lack of appetite 3, 5, 6
• Gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain 4

Initial Laboratory Testing

First-Line Tests

• Early morning (8 AM) serum cortisol and plasma ACTH are the cornerstone diagnostic tests 1, 2

  • Cortisol <250 nmol/L (<9 μg/dL) with markedly elevated ACTH (often >200 pg/mL) is diagnostic of primary adrenal insufficiency 2, 7
  • Cortisol 250-550 nmol/L (9-20 μg/dL) requires confirmatory cosyntropin stimulation testing 2

• Basic metabolic panel to assess for characteristic electrolyte abnormalities 2

  • Hyponatremia is present in approximately 90% of newly diagnosed cases 2, 7
  • Hyperkalemia occurs in only about 50% of cases—its absence does NOT rule out Addison's disease 2, 7

• Additional baseline labs may reveal 2

  • Mild hypercalcemia
  • Mild eosinophilia and lymphocytosis
  • Anemia
  • Elevated liver transaminases
  • Hypoglycemia (particularly in children)

Critical Caveat

If clinical suspicion for adrenal crisis exists (unexplained hypotension, collapse, severe vomiting), immediately administer 100 mg IV hydrocortisone and 0.9% saline infusion at 1 L/hour WITHOUT waiting for laboratory results. Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment. 1, 2, 7

Confirmatory Testing: Cosyntropin Stimulation Test

Perform this test when initial cortisol is 250-550 nmol/L or when partial adrenal insufficiency is suspected 1, 2:

• Protocol: Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 2
• Timing: Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 2
• Interpretation:
  • Peak cortisol >550 nmol/L (>18-20 μg/dL) at 30 or 60 minutes is normal and excludes adrenal insufficiency 1, 2
  • Peak cortisol <500-550 nmol/L (<18-20 μg/dL) confirms adrenal insufficiency 2, 7

Important Testing Considerations

• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound results—avoid testing while on these medications 1, 7
• If you must treat suspected adrenal crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 7
• The test is also useful for screening patients at risk, such as those with 21-hydroxylase autoantibodies without overt disease 1

Etiologic Diagnosis

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

First-Line Etiologic Test

• 21-hydroxylase autoantibodies (21OH-Ab) should be measured first, as autoimmunity accounts for approximately 85% of cases in Western Europe 1, 2
• Positive 21OH-Ab confirms autoimmune Addison's disease 1, 2
• Important caveat: Previously positive patients may become negative over time, so negative antibodies do not completely exclude autoimmunity 1

If 21OH-Ab is Negative

Proceed with additional investigations 1:

• CT scan of the adrenal glands to evaluate for:

  • Calcifications typical of tuberculosis
  • Tumors or metastatic disease
  • Adrenal hemorrhage
  • Other infiltrative processes
  • Note: Autoimmune Addison's shows small or unidentifiable adrenal glands 4

• Very long-chain fatty acids (VLCFA) in males to screen for adrenoleukodystrophy, an X-linked condition with variable presentation 1

• Consider interferon-ω antibodies if APS-1 (autoimmune polyendocrine syndrome type 1) is suspected 2

• NR0B1 (DAX1) gene testing in males with delayed or incomplete puberty and hypogonadotropic hypogonadism 1

Screening for Associated Autoimmune Conditions

In patients with confirmed autoimmune Addison's disease, screen for other autoimmune disorders 2, 8:

• Thyroid function tests (TSH, free T4, TPO antibodies)—autoimmune hypothyroidism is common 1, 8
• Plasma glucose and HbA1c for diabetes mellitus 8
• Complete blood count for pernicious anemia 8
• Vitamin B12 levels for autoimmune gastritis 8
• Tissue transglutaminase antibodies and total IgA if frequent diarrhea suggests celiac disease 7

Diagnostic Algorithm Summary

1. Suspect Addison's based on hyperpigmentation, salt craving, orthostatic hypotension, fatigue, weight loss, and GI symptoms
2. Measure morning cortisol and ACTH plus basic metabolic panel
3. If cortisol <250 nmol/L with high ACTH: Diagnosis confirmed—proceed to etiologic workup
4. If cortisol 250-550 nmol/L: Perform cosyntropin stimulation test
5. Determine etiology: Check 21OH-Ab first; if negative, obtain adrenal CT and VLCFA (in males)
6. Screen for associated conditions: Thyroid, diabetes, B12, celiac disease

Common Pitfalls to Avoid

• Do not rely on hyperkalemia to make or exclude the diagnosis—it's present in only 50% of cases 2, 7
• Do not delay emergency treatment for diagnostic testing in suspected adrenal crisis—mortality is high if untreated 1, 2, 7
• Do not attempt diagnostic testing in patients taking exogenous corticosteroids—wait until after appropriate washout period 7
• Do not assume negative 21OH-Ab excludes autoimmunity—antibodies can become negative over time 1
• Do not forget to screen for other autoimmune conditions in confirmed autoimmune Addison's disease 2, 8