How to ensure a patient with a history of adrenal insufficiency is not in adrenal crisis before initiating levothyroxine replacement therapy?

Ensuring Absence of Adrenal Crisis Before Levothyroxine Initiation

Before starting levothyroxine in any patient with known or suspected adrenal insufficiency, you must first initiate glucocorticoid replacement therapy to prevent precipitating a potentially fatal adrenal crisis. 1, 2

Critical Pathophysiology

Thyroid hormone accelerates the metabolic clearance of cortisol, and in patients with inadequate adrenal reserve, this can unmask or precipitate acute adrenal crisis. 2 The FDA explicitly warns that initiation of thyroid hormone therapy prior to glucocorticoid therapy may precipitate acute adrenal crisis in patients with adrenal insufficiency. 2

Step-by-Step Diagnostic Algorithm

1. Identify High-Risk Patients Requiring Screening

Screen for adrenal insufficiency before levothyroxine in patients with:

• Central hypothyroidism (low/normal TSH with low free T4), as this suggests pituitary or hypothalamic disease that may also affect ACTH production 1, 3
• Hypophysitis or pituitary disease from any cause, including immune checkpoint inhibitor therapy 1
• Autoimmune hypothyroidism (Hashimoto's thyroiditis), as these patients have increased risk of concurrent autoimmune adrenal insufficiency (Addison's disease) 3
• Unexplained hypotension, hyponatremia, or hyperpigmentation that cannot be fully explained by hypothyroidism alone 3, 4, 5
• History of prolonged glucocorticoid use (≥20 mg/day prednisone or equivalent for ≥3 weeks), which causes iatrogenic secondary adrenal insufficiency 3, 4

2. Obtain Morning Diagnostic Tests (Around 8 AM)

Measure the following before administering any corticosteroids: 1, 3, 4, 5

• Serum cortisol (baseline, early morning)
• Plasma ACTH
• Basic metabolic panel (sodium, potassium, glucose)
• DHEAS (dehydroepiandrosterone sulfate) if available

Interpretation of baseline results:

• Primary adrenal insufficiency: Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH, often with hyponatremia and hyperkalemia (though hyperkalemia occurs in only ~50% of cases) 3, 4, 5
• Secondary/tertiary adrenal insufficiency: Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH, hyponatremia without hyperkalemia 3, 4
• Glucocorticoid-induced adrenal insufficiency: Low cortisol with suppressed ACTH in patients with recent glucocorticoid exposure 3, 4

3. Confirmatory Testing When Baseline Results Are Indeterminate

If morning cortisol is between 5-18 μg/dL (140-500 nmol/L), perform cosyntropin (Synacthen) stimulation test: 3, 5

Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 3
• Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration 3

Interpretation:

• Normal response: Peak cortisol >500-550 nmol/L (>18-20 μg/dL) 3
• Diagnostic of adrenal insufficiency: Peak cortisol <500 nmol/L (<18 μg/dL) 3, 5

4. Critical Management Decision Point

If adrenal insufficiency is confirmed or strongly suspected clinically:

• DO NOT start levothyroxine 1, 2
• Initiate glucocorticoid replacement FIRST and wait at least 1 week before starting thyroid hormone 1, 3
• Physiologic glucocorticoid dosing: Hydrocortisone 15-25 mg daily (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) or prednisone 3-5 mg daily 3, 4
• For primary adrenal insufficiency: Add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement 3, 4

If patient is clinically unstable with suspected adrenal crisis:

• Treatment must NEVER be delayed for diagnostic testing 3, 5, 6
• Immediately administer IV hydrocortisone 100 mg bolus 3, 4, 5, 6
• Infuse 0.9% saline at 1 L/hour (at least 2L total) 1, 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment 3, 5
• If you still need to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 3, 6

Common Clinical Pitfalls to Avoid

Do not rely on electrolyte abnormalities alone to exclude adrenal insufficiency—hyperkalemia is present in only ~50% of cases, and some patients have normal electrolytes at presentation. 3, 4

Do not assume normal thyroid function testing rules out central hypothyroidism in patients with pituitary disease—both TSH and free T4 may appear deceptively normal in early or partial pituitary dysfunction. 7

Do not start levothyroxine in patients on recent high-dose corticosteroids without assessing for HPA axis suppression—approximately one-third to one-half of patients taking 5-20 mg prednisolone daily have inadequate adrenal reserve. 3

Do not attempt diagnostic testing in patients already on corticosteroids—morning cortisol measurements are unreliable as the assay measures both endogenous cortisol and therapeutic steroids. Wait until treatment is ready to be discontinued, with hydrocortisone held for 24 hours and other steroids for longer washout periods. 3

Patient Education Requirements

All patients diagnosed with adrenal insufficiency must receive: 1, 3, 4

• Stress dosing instructions: Double or triple glucocorticoid dose during illness, fever, or physical stress
• Emergency injectable hydrocortisone kit (100 mg IM) with self-injection training
• Medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency personnel
• Education on warning signs of impending adrenal crisis (severe weakness, confusion, vomiting, hypotension)