What is the best approach to rule out adrenal insufficiency in a patient with hypothyroidism and potential cardiovascular disease?

How to Rule Out Adrenal Insufficiency

Measure early morning (8 AM) serum cortisol and plasma ACTH simultaneously—if morning cortisol is >13 mcg/dL (>360 nmol/L), adrenal insufficiency is reliably excluded. 1

Initial Diagnostic Approach

Step 1: Obtain baseline morning measurements (around 8 AM):

• Serum cortisol
• Plasma ACTH
• Basic metabolic panel (sodium, potassium, glucose) 2

Interpretation of baseline results:

• Morning cortisol >13 mcg/dL (>360 nmol/L): Rules out adrenal insufficiency—no further testing needed 1
• Morning cortisol <5 mcg/dL (<140 nmol/L) with elevated ACTH: Diagnostic of primary adrenal insufficiency 3, 4
• Morning cortisol 5-13 mcg/dL (140-360 nmol/L): Proceed to cosyntropin stimulation test 5, 3, 1

Cosyntropin Stimulation Test Protocol

When baseline cortisol is indeterminate (5-13 mcg/dL), perform the standard high-dose test:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 2, 5, 4
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 5, 4
• Peak cortisol >18-20 mcg/dL (>500-550 nmol/L): Rules out adrenal insufficiency 2, 5, 4
• Peak cortisol <18 mcg/dL (<500 nmol/L): Confirms adrenal insufficiency 2, 5, 4

The high-dose (250 mcg) test is preferred over the low-dose (1 mcg) test due to easier administration, comparable diagnostic accuracy, and FDA approval. 5

Critical Context for Patients with Hypothyroidism

In patients with concurrent hypothyroidism, adrenal insufficiency MUST be ruled out before initiating thyroid hormone replacement, as levothyroxine can precipitate adrenal crisis in undiagnosed adrenal insufficiency. 5, 6

• Both conditions frequently coexist in autoimmune polyendocrine syndrome type-2 (APS-2), where primary adrenal insufficiency occurs with autoimmune hypothyroidism 2
• If both conditions are present, always start corticosteroids several days before initiating thyroid hormone to prevent adrenal crisis 5, 6

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency pattern:

• Low cortisol (<5 mcg/dL) with high ACTH 3, 4
• Hyponatremia present in 90% of cases 2, 5
• Hyperkalemia present in only ~50% of cases—absence does NOT rule out diagnosis 2, 5
• Hyperpigmentation may be present 2

Secondary adrenal insufficiency pattern:

• Low or intermediate cortisol (5-10 mcg/dL) with low or inappropriately normal ACTH 5, 3
• Hyponatremia without hyperkalemia 5
• No hyperpigmentation (normal skin color) 5

Special Considerations for Cardiovascular Disease Context

Patients with cardiovascular disease and suspected adrenal insufficiency may present with:

• Unexplained hypotension, particularly orthostatic hypotension 5, 7
• Smaller cardiac chamber sizes and features consistent with hypovolemia 7
• Nocturnal hypotension 7

Critical Pitfalls to Avoid

Never delay treatment if adrenal crisis is suspected clinically—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion at 1 L/hour, even before diagnostic testing. 2, 5

Do not rely on electrolyte abnormalities alone:

• Hyponatremia may be only marginally reduced 2
• Hyperkalemia is absent in ~50% of cases 2, 5
• 10-20% of patients have normal electrolytes at presentation 2

Exogenous corticosteroids confound testing:

• Patients taking prednisone, prednisolone, dexamethasone, or inhaled fluticasone will have suppressed cortisol due to iatrogenic secondary adrenal insufficiency 2, 5
• Do not attempt diagnostic testing until corticosteroids have been discontinued with adequate washout time 5
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 5

Adrenal insufficiency can mimic SIADH:

• Both present with euvolemic hypo-osmolar hyponatremia, inappropriately high urine osmolality, and elevated urinary sodium 5
• The cosyntropin stimulation test is medically necessary to distinguish these conditions, as treatment approaches differ fundamentally 5

Etiologic Workup After Diagnosis Confirmed

Once adrenal insufficiency is confirmed, determine the underlying cause:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies—positive in ~85% of primary adrenal insufficiency cases in Western populations 2, 5, 4
• If autoantibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes 2, 5
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 2, 5