What is the diagnosis for a patient with low Thyroid-Stimulating Hormone (TSH), elevated Free Thyroxine (FT4), weight gain, and hair loss?

Diagnosis: Central (Secondary) Hypothyroidism or Pituitary Dysfunction

The combination of low TSH with elevated FT4, accompanied by weight gain and hair loss, is paradoxical and strongly suggests central hypothyroidism, hypophysitis, or pituitary dysfunction—not primary thyroid disease. This pattern requires immediate evaluation for hypopituitarism and concurrent adrenal insufficiency before any thyroid hormone adjustment 1.

Why This Pattern is Paradoxical

• Low TSH with elevated FT4 typically indicates hyperthyroidism or excessive thyroid hormone replacement, but the presence of hypothyroid symptoms (weight gain, hair loss) contradicts this 2, 3
• In central hypothyroidism, the pituitary fails to produce adequate TSH despite low thyroid hormone levels, but your patient has elevated FT4, making this an unusual presentation that suggests pituitary dysfunction affecting multiple hormone axes 1, 4
• The TSH may be inappropriately low relative to tissue thyroid hormone needs, meaning the elevated FT4 is not translating into adequate T3 effect at the cellular level 5

Immediate Diagnostic Workup Required

Critical First Steps (Do Not Delay)

• Obtain morning (9 AM) cortisol and ACTH levels immediately, as central hypothyroidism frequently coexists with adrenal insufficiency, and any thyroid hormone adjustment before corticosteroid replacement can trigger life-threatening adrenal crisis 1, 6
• Measure free T3 (FT3) alongside TSH and FT4, as the elevated FT4 may not be converting adequately to active T3, explaining the hypothyroid symptoms despite high FT4 2, 3, 4
• Check complete pituitary hormone panel: FSH, LH, testosterone (men) or estradiol (women), prolactin, and IGF-1 to assess for hypopituitarism 1, 6

Imaging and Antibody Testing

• Order MRI pituitary with contrast (pituitary protocol) to evaluate for pituitary mass, hypophysitis, or structural abnormalities 1, 6
• Measure anti-TPO antibodies to exclude concurrent autoimmune thyroid disease, though this pattern is more consistent with central pathology 1

Differential Diagnosis

Most Likely: Hypophysitis or Pituitary Dysfunction

• Immune checkpoint inhibitor-induced hypophysitis causes this pattern in 1-16% of patients on ipilimumab and 8% on combination ipilimumab/nivolumab 1
• Falling TSH with normal or elevated T4 across serial measurements strongly suggests pituitary dysfunction requiring weekly cortisol monitoring 1, 6
• Look for associated symptoms: headache, visual disturbances, severe fatigue beyond typical hypothyroidism, or signs of hypocortisolism 1, 6

Alternative Considerations

• Nonthyroidal illness syndrome (NTIS) can produce low TSH with variable T4 levels in critically ill patients, but elevated FT4 with hypothyroid symptoms is atypical 7
• Peripheral thyroid hormone resistance or conversion defects where elevated FT4 fails to convert to adequate T3, producing tissue hypothyroidism despite high FT4 5
• Medication effects including amiodarone, high-dose steroids, or dopamine can suppress TSH while affecting thyroid hormone levels 3

Critical Management Principles

Before Any Treatment

• Never initiate or increase thyroid hormone before confirming adequate cortisol levels, as this can precipitate adrenal crisis in patients with concurrent adrenal insufficiency 1, 8
• If cortisol is low (<250 nmol/L on 9 AM testing or <150 nmol/L random), start hydrocortisone 20/10/10 mg immediately and wait 1 week before considering thyroid hormone 6, 8

Endocrinology Referral

• Immediate endocrinology consultation is mandatory for all cases of suspected central hypothyroidism or hypophysitis, as this represents complex pathology requiring specialized management 1
• The endocrinologist will determine: whether multiple pituitary hormone deficiencies exist, appropriate hormone replacement sequencing, and whether immunosuppression is needed for hypophysitis 1, 6

If Hypophysitis is Confirmed

• Moderate to severe symptoms (headache, visual changes, hemodynamic instability) require IV methylprednisolone 1 mg/kg after sending pituitary axis bloods 6
• Mild symptoms may be managed with oral prednisolone 0.5-1 mg/kg with close monitoring 6
• Most patients require lifelong hormone replacement for both adrenal insufficiency and hypothyroidism 1

Common Pitfalls to Avoid

• Do not assume hyperthyroidism based solely on elevated FT4 with low TSH—the presence of hypothyroid symptoms indicates this is not straightforward hyperthyroidism 1, 2
• Do not start levothyroxine empirically for "hypothyroid symptoms" without checking cortisol first, as this is the most dangerous error in central hypothyroidism management 1, 8
• Do not rely on TSH alone to guide diagnosis or treatment in suspected central hypothyroidism, as TSH is unreliable in pituitary/hypothalamic disease 2, 4, 5
• Do not dismiss patient symptoms because FT4 is elevated—tissue T3 effect may be inadequate despite high FT4 if conversion is impaired 5

Monitoring Protocol

• If on immune checkpoint inhibitors: check thyroid function tests every cycle for first 3 months, then every second cycle, with weekly cortisol measurements if TSH is falling 1
• Once diagnosis is established: monitor both FT4 and FT3 levels together, as TSH cannot be used to monitor adequacy of replacement in central hypothyroidism 4, 2
• All patients with confirmed adrenal insufficiency must obtain medical alert bracelet and receive education on "sick day rules" and emergency IM steroid use 6, 1