Diagnosis: Primary Overt Hypothyroidism
The combination of high TSH with low T3 and low T4 definitively indicates primary overt hypothyroidism, requiring immediate levothyroxine therapy. This pattern reflects thyroid gland failure with inadequate hormone production, triggering compensatory TSH elevation 1.
Diagnostic Confirmation
Measure TSH and free T4 together to distinguish overt hypothyroidism (elevated TSH + low free T4) from subclinical disease (elevated TSH + normal free T4) 1.
Check anti-TPO antibodies to identify autoimmune thyroiditis (Hashimoto's disease), the most common cause in iodine-sufficient populations; positive antibodies predict higher progression risk and confirm autoimmune etiology 1, 2.
Rule out central hypothyroidism by confirming TSH is appropriately elevated (not low or inappropriately normal), which would indicate pituitary/hypothalamic disease rather than primary thyroid failure 2.
Exclude adrenal insufficiency before starting levothyroxine by measuring morning cortisol and ACTH, especially in patients with autoimmune hypothyroidism, suspected central disease, or those on immunotherapy—initiating thyroid hormone before adequate glucocorticoid coverage can precipitate life-threatening adrenal crisis 1, 2, 3.
Levothyroxine Dosing Strategy
Initial Dosing
For patients <70 years without cardiac disease: start levothyroxine at full replacement dose of 1.6 mcg/kg/day (typically 100-125 mcg daily for average-weight adults) to rapidly normalize thyroid function 1, 3.
For patients >70 years OR with cardiac disease/multiple comorbidities: start at 25-50 mcg/day and titrate gradually by 12.5-25 mcg every 6-8 weeks to avoid unmasking cardiac ischemia or precipitating arrhythmias 1, 2, 3.
For patients with long-standing severe hypothyroidism: use conservative dosing (25-50 mcg/day initially) regardless of age, as rapid normalization can trigger cardiac complications 2.
Dose Titration
Increase levothyroxine by 12.5-25 mcg increments every 6-8 weeks based on TSH response until target range is achieved 1.
Larger adjustments (25 mcg) are appropriate for younger patients without cardiac disease; smaller increments (12.5 mcg) are safer for elderly or cardiac patients 1.
Target TSH: 0.5-4.5 mIU/L with normal free T4 for primary hypothyroidism without thyroid cancer 1, 2, 3.
Monitoring Protocol
Recheck TSH and free T4 every 6-8 weeks during dose titration, as this interval is required to reach steady-state levothyroxine levels 1, 3.
Free T4 helps interpret ongoing abnormal TSH during therapy, as TSH may take longer to normalize than free T4 1.
Once stable, monitor TSH every 6-12 months or sooner if symptoms change 1, 3.
For patients with cardiac disease or atrial fibrillation: consider more frequent monitoring (within 2 weeks of dose adjustment) rather than waiting the full 6-8 weeks 1.
Critical Safety Considerations
Before Starting Levothyroxine
Always exclude adrenal insufficiency first in patients with suspected central hypothyroidism, autoimmune disease, or those on immunotherapy—measure morning cortisol and ACTH 1, 2, 3.
If adrenal insufficiency is present: start hydrocortisone (20 mg morning, 10 mg afternoon) at least one week before initiating levothyroxine 1, 2.
In suspected central hypothyroidism or hypophysitis: always replace cortisol before thyroxine to prevent adrenal crisis 1.
Avoiding Overtreatment
Approximately 25% of patients on levothyroxine are unintentionally overtreated with suppressed TSH, increasing risks of atrial fibrillation (3-5 fold), osteoporosis, fractures, and cardiovascular mortality 1, 2, 3.
TSH suppression <0.1 mIU/L is especially hazardous in elderly patients and postmenopausal women, dramatically increasing atrial fibrillation and fracture risk 1.
If TSH falls <0.1 mIU/L: reduce levothyroxine by 25-50 mcg immediately 1, 2.
If TSH is 0.1-0.45 mIU/L: reduce by 12.5-25 mcg, particularly in elderly or cardiac patients 1.
Special Population Considerations
Pregnant Women or Planning Pregnancy
Treat any TSH elevation immediately in women planning pregnancy or currently pregnant, targeting TSH <2.5 mIU/L in the first trimester 1, 2, 3.
Levothyroxine requirements increase 25-50% during pregnancy; increase weekly dosage by 30% (take one extra dose twice weekly) upon pregnancy confirmation, followed by monthly monitoring 1, 3.
Untreated maternal hypothyroidism increases risk of preeclampsia, low birth weight, and neurodevelopmental deficits in offspring 1, 3.
Patients on Immunotherapy
Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 16-20% with combination immunotherapy 1.
Consider treatment even for subclinical hypothyroidism if fatigue or other symptoms are present in patients on checkpoint inhibitors 1.
Continue immunotherapy in most cases—thyroid dysfunction rarely requires treatment interruption 1.
Common Pitfalls to Avoid
Never treat based on a single elevated TSH value—30-60% of elevated TSH levels normalize spontaneously on repeat testing after 3-6 weeks 1, 2.
Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism—this can precipitate adrenal crisis 1, 2, 3.
Avoid excessive dose increases that could lead to iatrogenic hyperthyroidism, especially in elderly patients or those with cardiac disease 1.
Do not adjust doses too frequently—wait 6-8 weeks between adjustments to allow steady-state levels to be reached 1.
Recognize transient causes of TSH elevation: acute illness, recent iodine exposure, recovery from thyroiditis, or certain medications can temporarily elevate TSH 1, 2.
Expected Treatment Outcomes
Symptom improvement typically occurs within 6-8 weeks of adequate levothyroxine replacement 1.
Treatment prevents progression to severe hypothyroidism and reduces cardiovascular risk, improves lipid profiles (lowers LDL cholesterol), and enhances quality of life 1, 2.
Cardiac function improves with treatment, as hypothyroidism causes delayed myocardial relaxation, reduced cardiac output, and increased systemic vascular resistance 1, 2.