I am taking levothyroxine 100 µg daily and my labs show a markedly elevated TSH (~31.5 uIU/mL) and low free T4 (~0.65 ng/dL); what is the appropriate next step in management?

Increase Levothyroxine Dose Immediately

Your current levothyroxine dose of 100 µg is clearly insufficient, as evidenced by a markedly elevated TSH of 31.5 uIU/mL and low free T4 of 0.65 ng/dL, indicating severe undertreatment that requires prompt dose escalation to prevent cardiovascular complications, metabolic dysfunction, and quality of life deterioration. 1

Immediate Dose Adjustment Strategy

Increase your levothyroxine dose by 25–50 µg immediately (to 125–150 µg daily), depending on your age and cardiac status 1:

• If you are under 70 years without cardiac disease: Increase to 150 µg daily (50 µg increment) 1
• If you are over 70 years or have cardiac disease: Increase to 125 µg daily (25 µg increment) to avoid unmasking cardiac ischemia or precipitating arrhythmias 1

The magnitude of your TSH elevation (31.5 uIU/mL) indicates profound thyroid hormone deficiency that warrants more aggressive correction than typical dose adjustments 1.

Critical Safety Assessment Before Dose Increase

Before increasing levothyroxine, you must exclude concurrent adrenal insufficiency by measuring morning (8 AM) serum cortisol and ACTH 1. Starting or increasing thyroid hormone in the presence of undiagnosed adrenal insufficiency can precipitate life-threatening adrenal crisis 1. If cortisol is low or you have symptoms such as hypotension, hyponatremia, or unexplained fatigue beyond what hypothyroidism explains, initiate hydrocortisone 20 mg in the morning and 10 mg in the afternoon for at least one week before increasing levothyroxine 1.

Monitoring Protocol

Recheck TSH and free T4 in 6–8 weeks after the dose increase, as this interval is required to reach steady-state hormone levels 1, 2. Your target is:

• TSH: 0.5–4.5 mIU/L 1
• Free T4: upper half of normal range (approximately 1.2–1.77 ng/dL in your lab's reference range) 1

Continue adjusting the dose by 12.5–25 µg increments every 6–8 weeks until TSH normalizes 1. Once stable, monitor TSH every 6–12 months or sooner if symptoms change 1, 2.

Why This Degree of Undertreatment Occurred

Several factors may explain persistent elevation of TSH despite levothyroxine therapy 1:

Medication Adherence Issues

• Non-adherence is the most common cause of elevated TSH on levothyroxine 1
• Taking levothyroxine inconsistently or missing doses frequently results in this pattern 1

Absorption Problems

• Timing of administration: Levothyroxine must be taken on an empty stomach, 30–60 minutes before breakfast, and at least 4 hours apart from iron, calcium supplements, proton-pump inhibitors, or antacids 1
• Gastrointestinal disorders: Conditions like celiac disease, inflammatory bowel disease, or atrophic gastritis can impair absorption 1
• Consider switching to liquid levothyroxine formulation if malabsorption is suspected, as it achieves better TSH control than tablets in patients with absorption issues 3

Drug Interactions

Common medications that interfere with levothyroxine absorption or metabolism include 1:

• Iron supplements
• Calcium carbonate
• Proton-pump inhibitors (omeprazole, lansoprazole)
• Bile acid sequestrants (cholestyramine)
• Soy products
• High-fiber supplements

Increased Levothyroxine Requirements

• Weight gain increases levothyroxine requirements (dose is approximately 1.6 mcg/kg/day) 1
• Pregnancy increases requirements by 25–50% 2
• Certain medications (estrogen, rifampin, phenytoin, carbamazepine) increase levothyroxine metabolism 1

Consequences of Continued Undertreatment

Persistent TSH elevation >10 mIU/L carries significant health risks 1:

• Cardiovascular dysfunction: Delayed myocardial relaxation, reduced cardiac output, increased systemic vascular resistance, and potential heart failure 1
• Adverse lipid profile: Elevated total cholesterol and LDL cholesterol, increasing cardiovascular risk 1
• Progression risk: Approximately 5% annual risk of worsening to more severe hypothyroidism 1
• Quality of life impairment: Persistent fatigue, weight gain, cold intolerance, constipation, cognitive slowing, and mood disturbances 1

Common Pitfalls to Avoid

• Never adjust levothyroxine dose more frequently than every 6–8 weeks before steady state is reached, as this leads to inappropriate dose changes 1
• Do not assume the current dose is adequate simply because you have been taking it for a prolonged period—absorption, adherence, or metabolic changes may have occurred 1
• Avoid excessive dose increases that could lead to iatrogenic hyperthyroidism (TSH <0.1 mIU/L), which increases risk for atrial fibrillation, osteoporosis, and cardiovascular complications 1
• Do not ignore the possibility of pseudomalabsorption (non-adherence masquerading as malabsorption)—a levothyroxine absorption test can differentiate true malabsorption from non-adherence if needed 4

Special Considerations

If you have cardiac disease, are elderly, or have multiple comorbidities, use the more conservative 25 µg increment (to 125 µg daily) and monitor closely for angina, palpitations, or worsening heart failure 1. Obtain an ECG to screen for baseline arrhythmias before dose escalation 1.

If pregnancy is confirmed or planned, more aggressive TSH normalization is warranted, targeting TSH <2.5 mIU/L in the first trimester, as maternal hypothyroidism is associated with preeclampsia, low birth weight, and neurodevelopmental effects in offspring 1, 2.