How should I confirm primary hypothyroidism and start levothyroxine therapy, including appropriate dosing, monitoring schedule, and steps if the patient does not achieve euthyroidism?

Confirming Primary Hypothyroidism and Initiating Levothyroxine Therapy

Diagnostic Confirmation

Measure TSH as the first-line screening test, followed by free T4 to distinguish subclinical from overt hypothyroidism. 1

• TSH has >98% sensitivity and >92% specificity for detecting thyroid dysfunction, making it the most reliable initial test 1, 2
• If TSH is elevated, measure free T4 to categorize the severity:
  • Overt hypothyroidism: Elevated TSH + Low free T4 1
  • Subclinical hypothyroidism: Elevated TSH + Normal free T4 1
• Confirm with repeat testing after 3-6 weeks before initiating treatment, as 30-60% of elevated TSH values normalize spontaneously 1
• Consider measuring anti-TPO antibodies to identify autoimmune etiology (Hashimoto's thyroiditis), which predicts higher progression risk (4.3% vs 2.6% annually in antibody-negative patients) 1

Critical Safety Step Before Treatment

Always rule out concurrent adrenal insufficiency before starting levothyroxine, especially in patients with suspected central hypothyroidism or multiple pituitary hormone deficiencies. 1, 3

• Check morning cortisol (≈8 AM) and ACTH if adrenal insufficiency is suspected 3
• If adrenal insufficiency is present, start hydrocortisone (15 mg morning, 5 mg afternoon) at least 1 week before levothyroxine to prevent life-threatening adrenal crisis 1, 3
• This is the most critical pitfall to avoid—starting thyroid hormone before corticosteroids can precipitate adrenal crisis 1, 3

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When to Initiate Levothyroxine

Immediate Treatment Indications

Initiate levothyroxine immediately for: 1

1. TSH >10 mIU/L regardless of symptoms (carries ~5% annual progression risk to overt hypothyroidism) 1
2. Any TSH elevation with low free T4 (overt hypothyroidism) 1
3. Symptomatic patients with any degree of TSH elevation (fatigue, weight gain, cold intolerance, constipation) 1
4. Pregnant women or those planning pregnancy with any TSH elevation (target TSH <2.5 mIU/L in first trimester) 1, 4

Individualized Treatment Decisions (TSH 4.5-10 mIU/L with Normal Free T4)

For TSH 4.5-10 mIU/L with normal free T4, routine treatment is NOT recommended, but consider a 3-4 month trial in: 1

• Symptomatic patients with clear evaluation of benefit 1
• Patients with positive anti-TPO antibodies (higher progression risk) 1
• Patients with goiter or infertility 1

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Levothyroxine Dosing

Initial Dosing Strategy

For patients <70 years without cardiac disease or multiple comorbidities: 1, 4

• Start with full replacement dose of 1.6 mcg/kg/day (based on ideal body weight) 1, 4, 5
• This approach is safe and reaches euthyroidism faster than low-dose titration 5

For patients >70 years OR with cardiac disease/multiple comorbidities: 1, 4

• Start with 25-50 mcg/day and titrate gradually by 12.5-25 mcg every 6-8 weeks 1, 4
• This conservative approach prevents unmasking cardiac ischemia or precipitating arrhythmias 1

For pregnant patients with new-onset hypothyroidism: 4

• TSH ≥10 mIU/L: Start 1.6 mcg/kg/day 4
• TSH <10 mIU/L: Start 1.0 mcg/kg/day 4

For pregnant patients with pre-existing hypothyroidism: 4

• Increase pre-pregnancy dose by 25-50% immediately upon pregnancy confirmation 4
• Levothyroxine requirements typically increase during pregnancy 1

Administration Instructions

• Take on an empty stomach, 30-60 minutes before breakfast 1
• Separate from iron, calcium supplements, or antacids by at least 4 hours 1

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Monitoring Schedule

During Dose Titration

Recheck TSH and free T4 every 6-8 weeks after any dose adjustment until target TSH is achieved. 1, 4

• This 6-8 week interval represents the time needed to reach steady-state concentrations 1
• Target TSH: 0.5-4.5 mIU/L with normal free T4 for primary hypothyroidism 1
• Free T4 helps interpret ongoing abnormal TSH levels, as TSH may take longer to normalize 1

After Achieving Stable Dose

Once adequately treated, repeat TSH testing every 6-12 months or sooner if symptoms change. 1, 4

Special Monitoring for Pregnant Patients

Check TSH every 4 weeks until stable, then at minimum once per trimester. 4

• Adjust levothyroxine by 12.5-25 mcg increments based on TSH results 4
• Reduce to pre-pregnancy dose immediately after delivery and monitor TSH 4-8 weeks postpartum 4

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Dose Adjustments When Euthyroidism Is Not Achieved

If TSH Remains Elevated

Increase levothyroxine by 12.5-25 mcg increments based on current dose and patient characteristics: 1

• Use 25 mcg increments for patients <70 years without cardiac disease 1
• Use 12.5 mcg increments for patients >70 years or with cardiac disease 1
• Recheck TSH and free T4 in 6-8 weeks after each adjustment 1

If TSH Becomes Suppressed (Overtreatment)

Development of low TSH on therapy suggests overtreatment or recovery of thyroid function: 1

• TSH <0.1 mIU/L: Decrease levothyroxine by 25-50 mcg immediately 1
• TSH 0.1-0.45 mIU/L: Decrease by 12.5-25 mcg, particularly in elderly or cardiac patients 1
• Prolonged TSH suppression increases risk for atrial fibrillation (3-5 fold), osteoporosis, fractures, and cardiovascular mortality 1

Common Reasons for Inadequate Response

If TSH remains elevated despite apparent adequate dosing, consider: 1, 4

• Poor compliance (most common) 4
• Inadequate absorption (taking with food, coffee, or interfering medications) 1
• Drug interactions (iron, calcium, proton pump inhibitors, bile acid sequestrants) 1
• Malabsorption disorders (celiac disease, atrophic gastritis) 1

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Critical Pitfalls to Avoid

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

2. Do not treat based on a single elevated TSH value—confirm with repeat testing, as 30-60% normalize spontaneously 1

3. Avoid adjusting doses too frequently—wait 6-8 weeks between adjustments to reach steady state 1

4. Do not ignore suppressed TSH in treated patients—approximately 25% of patients are unintentionally overtreated, increasing serious complication risks 1

5. Never use TSH to monitor central hypothyroidism—TSH remains low/normal even when adequately treated; use free T4 instead 3, 2

6. Avoid full replacement doses in elderly patients with cardiac disease—start low (25-50 mcg/day) and titrate slowly to prevent cardiac complications 1, 4