How do you rule out adrenal insufficiency, especially when initiating levothyroxine (T4) therapy for hypothyroidism?

Ruling Out Adrenal Insufficiency Before Initiating Levothyroxine

Measure early morning (8 AM) serum cortisol and ACTH simultaneously—this is your first-line test to rule out adrenal insufficiency before starting levothyroxine therapy. 1, 2

Critical Context: Why This Matters

Levothyroxine is absolutely contraindicated in uncorrected adrenal insufficiency and can precipitate life-threatening adrenal crisis. 3 The FDA drug label explicitly states this contraindication because thyroid hormone replacement increases metabolic demand and cortisol clearance, potentially unmasking or worsening underlying adrenal insufficiency. 3

When both conditions coexist, corticosteroids must be started several days before thyroid hormone replacement to prevent adrenal crisis. 4

Diagnostic Algorithm

Step 1: Morning Cortisol and ACTH (8 AM)

Obtain paired measurements of:

• Serum cortisol (baseline)
• Plasma ACTH (baseline)
• Basic metabolic panel (sodium, potassium) 1

Interpretation:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = Primary adrenal insufficiency confirmed—no further testing needed 1, 2

• Cortisol <140 nmol/L (5 μg/dL) with low/normal ACTH = Secondary adrenal insufficiency confirmed 1

• Cortisol >550 nmol/L (>20 μg/dL) = Adrenal insufficiency ruled out—safe to start levothyroxine 1, 2

• Cortisol 140-550 nmol/L (5-20 μg/dL) = Indeterminate—proceed to Step 2 1, 5

Step 2: ACTH Stimulation Test (If Cortisol Indeterminate)

When morning cortisol is 140-550 nmol/L, perform cosyntropin stimulation test to definitively rule out adrenal insufficiency. 1, 2

Protocol:

• Administer 250 mcg cosyntropin (tetracosactide) IM or IV 4, 1
• Measure cortisol at baseline and 30 minutes post-administration 4, 1
• Can be performed any time of day (morning not strictly required) 1

Interpretation:

• Peak cortisol >550 nmol/L (>18-20 μg/dL) = Normal response—adrenal insufficiency ruled out 1, 2
• Peak cortisol <500-550 nmol/L (<18 μg/dL) = Adrenal insufficiency confirmed 1, 2

Special Considerations and Pitfalls

Patients on Exogenous Steroids

If the patient is currently taking corticosteroids (including inhaled fluticasone or topical steroids), morning cortisol testing is unreliable and will be falsely low due to iatrogenic secondary adrenal insufficiency. 4, 1 Laboratory confirmation should not be attempted until corticosteroid treatment is ready to be discontinued—consult endocrinology for a weaning protocol. 4

Electrolyte Abnormalities Are Unreliable

Do not rely on the absence of hyperkalemia or hyponatremia to exclude adrenal insufficiency. 1 While hyponatremia occurs in 90% of newly diagnosed cases, hyperkalemia is present in only ~50% of primary adrenal insufficiency cases. 1 Between 10-20% of patients have normal electrolytes at presentation. 1

Normal Cortisol Does Not Always Rule Out Early Disease

Approximately 10% of patients with confirmed primary adrenal insufficiency present with normal basal cortisol concentrations but have clearly elevated ACTH levels. 6 If clinical suspicion is high (fatigue, weight loss, hyperpigmentation) and ACTH is markedly elevated (>300 pg/mL), consider adrenal insufficiency even with normal cortisol and proceed with stimulation testing. 6

Emergency Situations

If the patient is clinically unstable with suspected adrenal crisis (hypotension, collapse, severe weakness), do NOT delay treatment for diagnostic testing. 1, 2 Give hydrocortisone 100 mg IV immediately plus 0.9% saline infusion at 1 L/hour. 1 If you still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead, as it does not interfere with cortisol assays. 4, 1

Clinical Scenarios Requiring High Suspicion

Consider adrenal insufficiency testing mandatory before levothyroxine in patients with:

• Unexplained fatigue, weakness, weight loss, or orthostasis 2, 7
• History of pituitary disease, hypophysitis, or panhypopituitarism 4
• Recent or current use of immune checkpoint inhibitors (ipilimumab, nivolumab) 4
• Chronic opioid therapy (suppresses ACTH) 2
• Recent discontinuation of chronic corticosteroid therapy (≥20 mg/day prednisone for ≥3 weeks) 1, 2
• Retinoid therapy (alitretinoin, isotretinoin) 7
• Low or low-normal TSH with low free T4 (suggests central hypothyroidism with possible concurrent central adrenal insufficiency) 4

Summary Algorithm

1. Measure 8 AM cortisol + ACTH + electrolytes before starting levothyroxine 1, 2
2. If cortisol >550 nmol/L → Adrenal insufficiency ruled out, safe to start levothyroxine 1
3. If cortisol <250 nmol/L with high ACTH → Primary AI confirmed, start hydrocortisone first 1
4. If cortisol 140-550 nmol/L → Perform cosyntropin stimulation test 1, 5
5. If stimulation test peak <550 nmol/L → Adrenal insufficiency confirmed, start hydrocortisone several days before levothyroxine 4
6. If both conditions present → Always start corticosteroids first, wait several days, then add levothyroxine 4