In a 48-year-old man with hypothyroidism on levothyroxine 150 µg daily who has persistently elevated thyroid-stimulating hormone despite reported adherence, what could be causing this and what should be evaluated?

Evaluation of Persistent TSH Elevation Despite Levothyroxine Therapy

Primary Assessment: Rule Out Non-Adherence First

The most common cause of persistently elevated TSH despite reported adherence is actually non-adherence or improper medication administration, which should be systematically evaluated before pursuing other causes. 1, 2, 3

Verify True Adherence with Levothyroxine Loading Test

• Administer a supervised single dose of 1000 µg levothyroxine and measure free T4 at baseline and 2 hours post-dose 1, 3
• A doubling of free T4 within 2 hours confirms adequate absorption and strongly suggests non-adherence as the underlying issue 2, 3
• This test is both diagnostic and therapeutic—scheduling it often prompts patients to resume proper adherence, with subsequent TSH normalization on lower doses 3
• If free T4 fails to rise appropriately, true malabsorption is confirmed and warrants further investigation 1, 2

Medication Administration Issues

Timing and Co-Administration Problems

• Levothyroxine must be taken on an empty stomach, 30-60 minutes before food, and separated by at least 4 hours from iron, calcium supplements, or antacids 4
• Taking levothyroxine with food, coffee, or other medications dramatically reduces absorption 5
• Question the patient specifically about: exact timing of dose relative to meals, consumption of coffee or supplements within 1 hour, and any changes in breakfast routine 5

Drug Interactions Reducing Absorption

Review the patient's medication list for agents that interfere with levothyroxine absorption 6:

• Proton pump inhibitors and H2 blockers (reduce gastric acidity needed for dissolution) 5
• Iron supplements, calcium carbonate, aluminum hydroxide antacids (chelation) 7, 5
• Bile acid sequestrants (cholestyramine, colestipol) 5
• Sucralfate, sevelamer, orlistat 5
• Statins (may interfere with absorption) 7

Gastrointestinal Causes of Malabsorption

Gastroparesis—A Frequently Missed Cause

• Gastroparesis can cause levothyroxine malabsorption and should be considered in any patient requiring >2.7 mcg/kg/day 7
• This is particularly relevant in patients with diabetes mellitus, as your patient may have 7
• Confirm with gastric emptying study if suspected 7
• Consider crushing tablets or switching to liquid formulation if gastroparesis is present 7, 5

Other Gastrointestinal Disorders

• Screen for celiac disease with tissue transglutaminase antibodies (tTG-IgA) and total IgA 7, 2
• Test for Helicobacter pylori infection (can impair absorption) 7
• Check for atrophic gastritis with anti-parietal cell antibodies 7
• Inflammatory bowel disease, short bowel syndrome, or previous gastric bypass surgery all impair absorption 5

Increased Levothyroxine Requirements

Conditions Increasing Thyroid Hormone Metabolism or Binding

• Pregnancy (if applicable—requirements increase 25-50% during pregnancy) 8
• Estrogen therapy (increases thyroxine-binding globulin) 6
• Nephrotic syndrome (urinary protein loss) 7
• Medications that increase hepatic metabolism: rifampin, carbamazepine, phenytoin, phenobarbital 5

Diagnostic Algorithm

Step 1: Perform supervised levothyroxine loading test (1000 µg with 2-hour free T4 measurement) 1, 2, 3

Step 2: If absorption is normal (free T4 doubles):

• Non-adherence confirmed 2, 3
• Counsel patient on proper administration 2
• Consider directly observed therapy or weekly dosing regimens 2

Step 3: If absorption is impaired (free T4 fails to rise appropriately):

• Screen for celiac disease (tTG-IgA, total IgA) 7, 2
• Test for H. pylori 7
• Check anti-parietal cell antibodies 7
• Consider gastric emptying study if diabetes or gastroparesis symptoms present 7
• Review all medications for interactions 7, 5

Step 4: If malabsorption confirmed, consider alternative formulations:

• Liquid levothyroxine formulation (bypasses tablet dissolution issues) 5, 2
• Crushing tablets (enhances absorption in gastroparesis) 7
• Intramuscular or intravenous levothyroxine (for severe refractory cases) 5

Critical Pitfalls to Avoid

• Never assume adherence based solely on patient report—objective testing with loading test is essential 1, 2, 3
• Do not continue escalating levothyroxine doses indefinitely without investigating the cause—doses >2.7 mcg/kg/day suggest an underlying problem 7
• Approximately 25% of patients on levothyroxine are unintentionally overtreated with suppressed TSH, so careful monitoring is essential once the issue is resolved 6, 4
• Failing to ask specifically about timing of levothyroxine relative to food, coffee, and other medications is a common oversight 5

Monitoring After Intervention

• Recheck TSH and free T4 every 6-8 weeks after any intervention until target TSH of 0.5-4.5 mIU/L is achieved 6, 4, 8
• Once stable, monitor TSH every 6-12 months 6, 4
• Target TSH should be within the reference range (0.5-4.5 mIU/L) with normal free T4 6, 4