What is the treatment approach for a patient with low Thyroxine (T4) hormone levels and normal Thyroid-Stimulating Hormone (TSH) levels?

Low T4 with Normal TSH: Central Hypothyroidism Until Proven Otherwise

This pattern of low T4 with normal (or inappropriately normal) TSH indicates central hypothyroidism requiring immediate evaluation for pituitary/hypothalamic dysfunction and concurrent adrenal insufficiency before any treatment is initiated. 1

Immediate Diagnostic Priorities

Before starting any thyroid hormone replacement, you must rule out adrenal insufficiency—starting levothyroxine before corticosteroids can precipitate life-threatening adrenal crisis. 1

Essential Initial Testing

• Obtain morning ACTH and cortisol levels or perform a 1 mcg cosyntropin stimulation test to assess adrenal function 1
• Order MRI of the sella with pituitary cuts to evaluate for hypophysitis, pituitary enlargement, stalk thickening, or suprasellar masses 1
• Measure additional pituitary hormones including FSH, LH, and gonadal hormones to assess for panhypopituitarism 1
• Check free T4 by equilibrium dialysis for the most accurate measurement in this setting 1

Clinical Context Matters

• Hypophysitis presents with headache (85% of cases) and fatigue (66%), with central hypothyroidism occurring in >90% and central adrenal insufficiency in >75% 1
• Patients on immune checkpoint inhibitors (anti-PD-1/PD-L1 therapy) are at particular risk for hypophysitis causing central hypothyroidism 1
• Recent history of acute illness, hospitalization, or critical illness may cause non-thyroidal illness syndrome (NTIS), where low T4 with normal TSH can occur transiently 2

Treatment Protocol for Confirmed Central Hypothyroidism

Critical Safety First: Address Adrenal Insufficiency

If both adrenal insufficiency and central hypothyroidism are confirmed, start corticosteroids before initiating levothyroxine—this sequence is mandatory to prevent adrenal crisis. 1

• Begin physiologic dose steroids at least 1 week prior to thyroid hormone replacement 3
• Patients with confirmed adrenal insufficiency should obtain and carry a medical alert bracelet 1

Levothyroxine Dosing Strategy

For patients under 70 years without cardiac disease:

• Start levothyroxine 1.6 mcg/kg/day as the initial dose 1
• This more aggressive approach is appropriate in younger patients without cardiac risk factors 1

For patients over 70 years or with cardiac disease:

• Start with 25-50 mcg/day and titrate gradually to avoid cardiac complications 1
• Monitor closely for cardiac arrhythmias, angina, or decompensation 3

Dose Adjustment Protocol

• Make dose adjustments in 12.5-25 mcg increments based on free T4 levels 1
• Wait 6-8 weeks between adjustments to allow steady state to be reached 1
• Target free T4 in the upper half of the reference range (approximately 14-19 pmol/L) 1

Monitoring Strategy: TSH is Useless in Central Hypothyroidism

TSH cannot be used to monitor central hypothyroidism—you must rely on free T4 and clinical assessment. 4

Monitoring Schedule

• Recheck free T4 levels 6-8 weeks after each dose adjustment 1
• Once stable, monitor free T4 every 6-12 months 1
• Annual monitoring of other pituitary hormones may be warranted depending on etiology 1

Target Free T4 Levels

• Aim for free T4 in the upper half of normal range (14-19 pmol/L based on typical reference ranges) 1, 5
• Studies show that pituitary patients are at high risk of under-replacement, with 38.9% having free T4 ≤13 pmol/L when the median in adequately treated primary hypothyroidism is 16 pmol/L 5
• The 20-80th centile range for free T4 in well-replaced primary hypothyroidism is 14-19 pmol/L, which should guide replacement targets in central hypothyroidism 5

Special Considerations and Adjustments

Impact of Other Hormone Replacements

• Male patients on growth hormone therapy require higher levothyroxine doses to maintain euthyroid status 6
• Female patients on estrogen therapy need higher levothyroxine doses compared to non-treated patients 6
• The levothyroxine dose is positively correlated with the number of hormone deficiencies present 6

Age-Related Dosing

• Mean levothyroxine dose of 1.6±0.5 mcg/kg/day is typical for central hypothyroidism 6
• Dose requirements are negatively correlated with age—older patients generally need lower doses 6

Critical Pitfalls to Avoid

Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism—this can precipitate adrenal crisis. 3, 1

• Do not rely on TSH to diagnose or monitor central hypothyroidism—TSH is normal in the majority of cases, low in 8%, and paradoxically elevated in 8% 6
• Do not assume normal free T4 excludes central hypothyroidism—28% of central hypothyroidism patients have free T4 in the low-normal range at diagnosis, especially those with childhood-onset disease 6
• Avoid under-replacement—pituitary patients are systematically under-replaced compared to primary hypothyroidism patients, with 38.9% having inappropriately low free T4 levels on treatment 5
• Do not miss non-thyroidal illness syndrome (NTIS)—in critically ill patients, low T4 with normal TSH may represent NTIS rather than true central hypothyroidism, and treatment has not shown benefit 2

Long-Term Management Expectations

• Patients with central hypothyroidism typically require lifelong hormone replacement 1
• Treatment adequacy is best reflected by the combination of upper-normal free T4 and low-normal free T3 levels 6
• Approximately 75% of adequately treated patients will have suppressed TSH, which is expected and not a sign of overtreatment in central hypothyroidism 6
• Only 49% of treated patients achieve normal free T3 levels despite 94% achieving normal free T4, highlighting the complexity of optimal replacement 6