What is the appropriate management for an adult on levothyroxine for three months who now has a free thyroxine of 0.11 ng/dL and a thyroid‑stimulating hormone exceeding 150 IU/mL (previously 91 IU/mL)?

Immediate Investigation for Medication Non-Adherence and Malabsorption

This patient's worsening thyroid function after three months of levothyroxine—with free T4 dropping from 0.8 to 0.11 ng/dL and TSH rising from 91.42 to >150 IU/mL—indicates either complete non-adherence to therapy or severe malabsorption, and requires urgent investigation before any dose adjustment. 1

Critical First Steps: Rule Out Non-Adherence and Malabsorption

Assess Medication Adherence

• Directly observe the patient taking levothyroxine to confirm they are actually swallowing the medication, as patients may hide or spit out tablets even when claiming compliance 2
• Question the patient about their dosing schedule, timing relative to meals, and any missed doses 1
• Verify the patient is taking levothyroxine on an empty stomach, at least 30-60 minutes before food, as food significantly impairs absorption 1
• Confirm the patient is not taking levothyroxine within 4 hours of iron supplements, calcium supplements, or antacids, which dramatically reduce absorption 1

Investigate Malabsorption

• Review for gastrointestinal conditions that impair levothyroxine absorption, including celiac disease, inflammatory bowel disease, atrophic gastritis, or prior gastric bypass surgery 3
• Check for interfering medications such as proton pump inhibitors, sucralfate, bile acid sequestrants, or enzyme inducers that reduce levothyroxine efficacy 3
• Consider measuring anti-tissue transglutaminase antibodies to screen for celiac disease, which is more common in patients with autoimmune thyroid disease 4

Alternative Route if Oral Therapy Fails

Intramuscular Levothyroxine Administration

• If non-adherence or malabsorption is confirmed and cannot be corrected, switch to intramuscular levothyroxine 200-500 mcg once weekly 2
• This route bypasses gastrointestinal absorption and ensures reliable drug delivery 2
• Monitor TSH and free T4 every 6-8 weeks after initiating intramuscular therapy to titrate the dose 2

Exclude Life-Threatening Myxedema Coma

Clinical Assessment for Severe Decompensation

• Immediately assess for signs of myxedema coma: hypothermia, hypotension, bradycardia, hypoventilation, altered mental status, or decreased level of consciousness 4
• If myxedema coma is present, this is a medical emergency requiring intensive care unit admission with mortality rates up to 30% 4
• In myxedema coma, initiate intravenous levothyroxine 200-400 mcg loading dose, followed by 50-100 mcg daily, plus intravenous hydrocortisone 100 mg every 8 hours to prevent adrenal crisis 2, 4

Rule Out Concurrent Adrenal Insufficiency

Critical Safety Consideration

• Before increasing or restarting levothyroxine, rule out adrenal insufficiency by checking morning cortisol and ACTH levels 5
• If adrenal insufficiency is present, start hydrocortisone 20 mg in the morning and 10 mg in the afternoon for at least one week before initiating thyroid hormone replacement 5
• Starting or increasing levothyroxine before treating adrenal insufficiency can precipitate life-threatening adrenal crisis 5

Dose Adjustment Strategy Once Adherence/Absorption Confirmed

For Patients <70 Years Without Cardiac Disease

• If adherence and absorption are confirmed adequate, increase levothyroxine by 25-50 mcg based on current dose 5
• Recheck TSH and free T4 in 6-8 weeks after dose adjustment 1
• Target TSH within the reference range of 0.5-4.5 mIU/L with normal free T4 5

For Patients >70 Years or With Cardiac Disease

• Use smaller increments of 12.5-25 mcg to avoid precipitating cardiac ischemia or arrhythmias 5
• Monitor closely for angina, palpitations, dyspnea, or signs of heart failure 5

Common Pitfalls to Avoid

• Never assume the patient is taking their medication correctly without direct verification, as up to 25% of apparent treatment failures are due to non-adherence 2
• Never increase the levothyroxine dose without first investigating why the initial therapy failed, as this perpetuates the underlying problem 3
• Never start or increase thyroid hormone without ruling out adrenal insufficiency, especially in patients with severe hypothyroidism, as this can be fatal 5
• Never overlook celiac disease or other malabsorption syndromes in patients with autoimmune thyroid disease who fail to respond to adequate levothyroxine doses 4