How does thyrotoxicosis mask adrenal insufficiency and what are the treatment implications?

How Thyrotoxicosis Masks Adrenal Insufficiency

Thyrotoxicosis accelerates glucocorticoid metabolism and clearance, which can precipitate adrenal crisis in patients with underlying adrenal insufficiency by increasing cortisol requirements beyond what their compromised adrenal glands can produce. 1, 2

Mechanism of Masking

Metabolic Acceleration

• Thyroid hormone increases the metabolic clearance of glucocorticoids, creating a state of relative cortisol deficiency even when replacement doses were previously adequate 1
• In thyrotoxic states, individuals with adrenal insufficiency cannot increase endogenous cortisol production to compensate for the accelerated turnover, placing them at high risk for symptomatic glucocorticoid deficiency and adrenal crisis 2
• The hypermetabolic state of thyrotoxicosis (weight loss, tachycardia, increased energy expenditure) can obscure or mimic the typical symptoms of adrenal insufficiency 3

Clinical Presentation Overlap

• Weight loss is a cardinal feature of both conditions, making it difficult to distinguish which disorder is driving the clinical picture 3
• Fatigue, weakness, and gastrointestinal symptoms occur in both thyrotoxicosis and adrenal insufficiency, further complicating diagnosis 3
• The increased metabolic demands of thyrotoxicosis can unmask previously compensated adrenal insufficiency 4, 2

Biochemical Considerations

• Patients with adrenal insufficiency can have TSH levels in the range of 4-10 IU/L due to lack of cortisol's inhibitory effect on TSH production, which may delay recognition of concurrent thyrotoxicosis 3
• In primary adrenal insufficiency, the lack of cortisol feedback can lead to paradoxical thyroid function test abnormalities 5

Critical Treatment Implications

Sequencing of Hormone Replacement

Glucocorticoids must ALWAYS be initiated several days before thyroid hormone replacement to prevent precipitating adrenal crisis 3

This principle applies in two clinical scenarios:

• When treating hypophysitis with both central adrenal insufficiency and central hypothyroidism 3
• When managing any patient with known or suspected adrenal insufficiency who requires thyroid hormone initiation 3

Management Algorithm for Thyrotoxicosis with Adrenal Insufficiency

Step 1: Immediate Recognition

• Suspect thyrotoxicosis as a precipitant in patients with known adrenal insufficiency presenting with recurrent adrenal crises, escalating hydrocortisone requirements, or inadequate suppression of adrenal hormones (in CAH patients) 4, 2
• Check TSH, free T4, and total T3 in any patient with adrenal insufficiency experiencing unexplained weight loss, tachycardia, or symptoms suggesting increased metabolic rate 3

Step 2: Stabilize Adrenal Function First

• Increase glucocorticoid replacement immediately before addressing the thyrotoxicosis 1, 2
• For patients on maintenance hydrocortisone (typically 15-25 mg daily), consider increasing to 2-3 times maintenance dosing initially 3
• If presenting with adrenal crisis: hydrocortisone 100 mg IV bolus, followed by 100 mg every 6-8 hours, plus aggressive fluid resuscitation with normal saline 3

Step 3: Treat Thyrotoxicosis

• Initiate antithyroid therapy (methimazole for Graves' disease) only after glucocorticoid coverage is adequate 4, 2
• Distinguish between thyroiditis (self-limiting, most common with checkpoint inhibitors) and Graves' disease (persistent, requires definitive treatment) 3
• Consider beta-blockers for symptomatic management, but note these may mask some thyrotoxic symptoms 3

Step 4: Monitor and Adjust

• As thyrotoxicosis resolves, glucocorticoid requirements typically decrease back to maintenance levels 2
• In one pediatric case with SW-CAH, adrenal androgens normalized within 4 weeks of achieving euthyroid state, without changing hydrocortisone dose 2
• Follow free T4 levels (not TSH, which may be unreliable in the setting of adrenal insufficiency) to guide thyroid treatment 3

Common Pitfalls to Avoid

Diagnostic Errors

• Failing to screen for thyroid dysfunction during annual follow-up of adrenal insufficiency patients - guidelines recommend monitoring thyroid function every 12 months including TSH, free T4, and TPO antibodies 3
• Attributing weight loss solely to inadequate glucocorticoid replacement without considering thyrotoxicosis as an endocrine cause 3
• Missing the diagnosis during acute presentations when symptoms overlap significantly 4

Treatment Errors

• Starting thyroid hormone replacement before ensuring adequate glucocorticoid coverage - this is explicitly contraindicated and can precipitate acute adrenal crisis 3, 1
• Failing to increase glucocorticoid doses when thyrotoxicosis is diagnosed in a patient with known adrenal insufficiency 1, 2
• Not recognizing that previously adequate steroid replacement may become insufficient during thyrotoxic states 2

Monitoring Failures

• In patients with congenital adrenal hyperplasia, failing to recognize that inadequate suppression of adrenal androgens may indicate relative glucocorticoid insufficiency due to undiagnosed thyrotoxicosis 2
• Not reassessing glucocorticoid requirements as thyrotoxicosis is treated and metabolic rate normalizes 2

Special Populations

Autoimmune Polyglandular Syndromes

• Up to 50% of patients with autoimmune adrenalitis develop another autoimmune disorder during their lifetime 6
• Thyrotoxicosis from Graves' disease can develop in patients with established autoimmune adrenal insufficiency 3
• Maintain high clinical suspicion and low threshold for thyroid function testing in this population 3

Checkpoint Inhibitor Therapy

• Thyroiditis is more common than Graves' disease in patients receiving immune checkpoint inhibitors 3
• These patients may develop both hypophysitis (with secondary adrenal insufficiency) and thyroid dysfunction simultaneously 3
• The thyrotoxic phase of checkpoint inhibitor-induced thyroiditis typically occurs about one month after starting therapy and is usually followed by hypothyroidism 3