In an adult without known pituitary disease who has a suppressed thyroid‑stimulating hormone, low free thyroxine, and low free triiodothyronine, what is the most likely diagnosis and how should it be evaluated and managed?

Central (Secondary) Hypothyroidism

This patient has central hypothyroidism—a pituitary or hypothalamic disorder causing inadequate TSH secretion despite low thyroid hormone levels—and requires immediate evaluation for hypopituitarism (especially adrenal insufficiency) before starting levothyroxine, followed by hormone replacement guided by free T4 rather than TSH.

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Diagnostic Interpretation

Pattern Recognition

• A suppressed or low-normal TSH (0.299 mIU/L) combined with low free T4 (0.73) and low free T3 (1.5) defines central hypothyroidism, where the pituitary fails to mount an appropriate TSH response to low thyroid hormone levels 1.
• In primary hypothyroidism, TSH would be markedly elevated (>10 mIU/L) in response to low thyroid hormones; the inappropriately low TSH here indicates pituitary or hypothalamic failure 2.
• TSH has 98% sensitivity and 92% specificity for detecting primary thyroid dysfunction, but TSH cannot be used as a screening test when central hypothyroidism is suspected because the TSH level is misleadingly normal or low 2.

Differential Considerations

• Exclude nonthyroidal illness (sick euthyroid syndrome): Critically ill patients can have transiently suppressed TSH with low free T4, but this typically occurs in hospitalized patients with severe acute illness 1, 3.
• Exclude medication effects: Dopamine infusions can suppress TSH and induce secondary hypothyroidism in critically ill patients 1.
• Exclude recovery phase of thyroiditis: Transient TSH suppression can occur during recovery from subacute thyroiditis, but free T4 would typically be normal or elevated, not low 2, 4.

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Critical Pre-Treatment Evaluation

Rule Out Adrenal Insufficiency FIRST

• Before initiating levothyroxine, measure morning (8 AM) serum cortisol and ACTH to exclude concurrent adrenal insufficiency, as thyroid hormone replacement accelerates cortisol metabolism and can precipitate life-threatening adrenal crisis in undiagnosed patients 2, 4.
• If morning cortisol is low (<10 µg/dL) or clinical features suggest adrenal insufficiency (hypotension, hyponatremia, hyperpigmentation), start hydrocortisone 20 mg in the morning and 10 mg in the afternoon for at least one week before initiating levothyroxine 2.
• In suspected central hypothyroidism or hypophysitis, always replace cortisol before thyroxine to prevent adrenal crisis 2.

Comprehensive Pituitary Assessment

• Obtain baseline pituitary hormone panel: prolactin, IGF-1, morning cortisol, ACTH, LH, FSH, testosterone (in men) or estradiol (in women) to identify other pituitary hormone deficiencies 5.
• Order pituitary MRI with gadolinium contrast to evaluate for pituitary adenoma, empty sella, infiltrative disease, or other structural lesions causing hypopituitarism 5.
• Assess visual fields if pituitary mass is suspected, as macroadenomas can cause optic chiasm compression 5.

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Treatment Algorithm

Levothyroxine Initiation

• For patients <70 years without cardiac disease: Start levothyroxine at full replacement dose of approximately 1.6 µg/kg/day (typically 100–125 µg daily) 2, 4.
• For patients >70 years or with cardiac disease/multiple comorbidities: Start at a lower dose of 25–50 µg daily and titrate gradually by 12.5–25 µg every 6–8 weeks to avoid unmasking cardiac ischemia or precipitating arrhythmias 2, 4.
• Administer levothyroxine as a single daily dose on an empty stomach, one-half to one hour before breakfast with a full glass of water 4.

Monitoring Strategy for Central Hypothyroidism

• Do NOT use TSH to monitor therapy in central hypothyroidism—TSH is unreliable because the pituitary cannot respond appropriately 2, 4.
• Use serum free T4 to titrate levothyroxine dosing: Target the upper half of the normal reference range (typically 1.2–1.8 ng/dL) to ensure adequate replacement 2, 4.
• Recheck free T4 (and free T3 if needed) every 6–8 weeks after dose adjustments until the target range is achieved 2.
• Once stable, monitor free T4 every 6–12 months or sooner if symptoms change 2.

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Common Pitfalls and Caveats

Critical Safety Errors to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism—this can precipitate adrenal crisis and is potentially fatal 2, 4.
• Never use TSH to guide levothyroxine dosing in central hypothyroidism—TSH will remain inappropriately low regardless of adequate replacement 2, 4.
• Do not assume isolated thyroid dysfunction—central hypothyroidism often coexists with other pituitary hormone deficiencies requiring replacement (cortisol, growth hormone, sex steroids) 5.

Diagnostic Pitfalls

• Failing to distinguish central from primary hypothyroidism: A low TSH with low free T4 is pathognomonic for central hypothyroidism, whereas primary hypothyroidism presents with high TSH and low free T4 2, 1.
• Missing nonthyroidal illness: Critically ill hospitalized patients can have transiently suppressed TSH with low free T4 that normalizes after recovery; repeat testing 4–6 weeks after acute illness resolution before diagnosing central hypothyroidism 1, 3.
• Overlooking medication effects: Dopamine, glucocorticoids, and certain other medications can suppress TSH; review medication list before attributing findings to pituitary disease 1, 3.

Treatment Pitfalls

• Overtreatment risk: Approximately 25% of patients on levothyroxine are unintentionally overtreated with suppressed TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiovascular mortality—though TSH monitoring is unreliable in central hypothyroidism, avoid excessive free T4 elevation 2.
• Undertreatment risk: Targeting mid-normal rather than upper-normal free T4 may leave patients symptomatic; aim for free T4 in the upper half of the reference range 2, 4.

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Prognosis and Long-Term Management

Expected Outcomes

• Prompt treatment of cortisol, growth hormone, or sex steroid deficiencies is recommended to optimize surgical outcomes, growth (in children), and well-being 5.
• Levothyroxine therapy significantly improves quality of life by resolving hypothyroid symptoms including fatigue, cognitive impairment, and metabolic dysfunction 2.
• Treatment of central hypothyroidism prevents cardiovascular dysfunction (delayed relaxation, abnormal cardiac output) and adverse lipid profiles associated with untreated hypothyroidism 2.

Ongoing Surveillance

• Annual pituitary MRI if structural lesion identified, or sooner if symptoms of mass effect develop 5.
• Periodic reassessment of other pituitary axes (every 6–12 months) to detect evolving hormone deficiencies 5.
• Monitor for development of other autoimmune conditions if autoimmune hypophysitis is the underlying cause 2.