Patient has suppressed TSH, low free T4, normal‑high free T3, low thyroglobulin, low‑normal cortisol, and normal anti‑TPO antibodies. What is the most likely diagnosis and what work‑up and treatment should be pursued?

Biochemical Pattern Consistent with Central Hypothyroidism Requiring Urgent Pituitary Evaluation

This patient's laboratory profile—suppressed TSH (0.27 mIU/L), low free T4 (0.30), normal‑high free T3 (2.7), low thyroglobulin (<2), low‑normal cortisol (8.5), and normal anti‑TPO antibodies (11)—is most consistent with central (secondary) hypothyroidism due to pituitary or hypothalamic dysfunction, and requires immediate assessment for life‑threatening adrenal insufficiency before any thyroid hormone replacement is initiated. 1

Diagnostic Interpretation

Central Hypothyroidism Pattern

• The combination of inappropriately normal or low TSH (0.27 mIU/L) with low free T4 (0.30) is the hallmark biochemical signature of central hypothyroidism caused by pituitary or hypothalamic failure, not primary thyroid disease 1
• TSH alone is unreliable in this setting because it may appear "normal" yet be inappropriately low relative to the degree of thyroid hormone deficiency 1
• The low thyroglobulin (<2) further supports central etiology, as thyroglobulin levels typically remain normal or elevated in primary thyroid disease but fall when TSH drive is absent 1
• Normal anti‑TPO antibodies (11) effectively exclude autoimmune (Hashimoto's) thyroiditis as the cause 2

Preserved T3 Conversion

• The normal‑high free T3 (2.7) despite low T4 reflects compensatory peripheral conversion of the limited T4 substrate to the more metabolically active T3, a pattern commonly seen in early central hypothyroidism or non‑thyroidal illness 3
• This preserved T3 may mask the severity of hypothyroidism clinically, as T3 is the primary active hormone at tissue level 3

Critical Cortisol Finding

• The low‑normal cortisol (8.5 µg/dL) is deeply concerning in the context of suspected hypopituitarism and represents a medical emergency 1
• A morning cortisol <15 µg/dL in a patient with suspected pituitary disease warrants immediate ACTH stimulation testing before any intervention 1

Urgent Work‑Up Algorithm

Step 1: Exclude Life‑Threatening Adrenal Insufficiency (DO THIS FIRST)

• Obtain 8 AM serum cortisol and ACTH immediately—if cortisol is <5 µg/dL, assume adrenal crisis risk; if 5–15 µg/dL, perform 1 µg cosyntropin stimulation test before any therapy 1
• Do not initiate levothyroxine until adrenal status is clarified—thyroid hormone accelerates cortisol metabolism and can precipitate fatal adrenal crisis in undiagnosed ACTH deficiency 1
• If adrenal insufficiency is confirmed, start physiologic hydrocortisone (20 mg morning, 10 mg afternoon) at least one week before levothyroxine 1

Step 2: Pituitary Imaging and Axis Evaluation

• Order dedicated pituitary MRI with contrast to identify mass lesions (adenoma, craniopharyngioma), empty sella, stalk thickening, or infiltrative disease (sarcoidosis, hemochromatosis, lymphocytic hypophysitis) 1
• Evaluate all pituitary axes: LH, FSH, testosterone (men) or estradiol (women), prolactin, IGF‑1 to determine if this is isolated TSH deficiency or panhypopituitarism 1
• Review recent history for pituitary‑damaging events: head trauma, subarachnoid hemorrhage, postpartum hemorrhage (Sheehan syndrome), meningitis, or seizure‑related injury 1

Step 3: Exclude Non‑Thyroidal Illness Syndrome

• Assess for acute or chronic systemic illness—severe infection, cardiac failure, renal failure, or recent hospitalization can transiently suppress TSH and lower T4 while preserving T3 (euthyroid sick syndrome) 3
• If non‑thyroidal illness is suspected, repeat thyroid function tests after clinical recovery (3–6 weeks) before diagnosing permanent central hypothyroidism 3
• An elevated reverse T3 (rT3) would argue against true hypothyroidism and support non‑thyroidal illness, though this test is not routinely necessary 3

Step 4: Rule Out Medication Effects

• Review all medications—dopamine, glucocorticoids, and certain anticonvulsants can suppress TSH without causing true hypothyroidism 4
• If the patient is on such medications, repeat testing off the drug (if medically feasible) to confirm persistent abnormality 4

Treatment Sequencing (Critical Safety Protocol)

If Both Adrenal Insufficiency and Central Hypothyroidism Are Confirmed

1. Start hydrocortisone first (20 mg morning, 10 mg afternoon) and wait at least one week before initiating levothyroxine 1
2. Begin levothyroxine at 1.6 µg/kg/day (or 25–50 µg/day in elderly or cardiac patients) only after glucocorticoid coverage is established 2
3. Monitor free T4 (not TSH) to guide levothyroxine dosing, as TSH remains unreliable in central hypothyroidism; target free T4 in the mid‑to‑upper normal range 1
4. Recheck free T4 every 6–8 weeks during titration, adjusting levothyroxine by 12.5–25 µg increments until target is achieved 2

If Adrenal Function Is Normal

• Initiate levothyroxine immediately at standard replacement doses (1.6 µg/kg/day for adults <70 years without cardiac disease; 25–50 µg/day for elderly or cardiac patients) 2
• Monitor free T4 (not TSH) every 6–8 weeks during dose titration 1

Common Pitfalls to Avoid

• Never start levothyroxine before excluding adrenal insufficiency in suspected central hypothyroidism—this is the single most dangerous error and can cause sudden cardiovascular collapse 1
• Do not rely on TSH to guide levothyroxine dosing in central hypothyroidism—TSH will remain low regardless of adequate replacement; use free T4 as the primary monitoring parameter 1
• Do not assume primary hypothyroidism based on low T4 alone—always measure TSH and free T4 together to distinguish central from primary disease 1
• Do not overlook seizure history as a clue to pituitary injury—head trauma, subarachnoid hemorrhage, or severe metabolic disturbances from seizures can damage the hypothalamic‑pituitary axis 1
• Do not treat non‑thyroidal illness syndrome with thyroid hormone—studies show no benefit and potential harm; wait for recovery and retest 3

Prognosis and Long‑Term Management

• If pituitary imaging reveals a mass lesion, neurosurgical consultation is required for possible resection or radiation 1
• If infiltrative disease (sarcoidosis, hemochromatosis) is identified, treat the underlying condition while providing hormone replacement 1
• Lifelong thyroid and adrenal hormone replacement will be necessary if hypopituitarism is permanent 1
• Annual reassessment of all pituitary axes is recommended, as additional hormone deficiencies may develop over time 1