Side Effects of Levothyroxine
Levothyroxine itself, when properly dosed, causes minimal side effects—the primary risks stem from overtreatment (iatrogenic hyperthyroidism) or undertreatment, not from the medication at replacement doses. 1
Dose-Related Adverse Effects from Overtreatment
Cardiovascular Complications
- TSH suppression below 0.1 mIU/L dramatically increases atrial fibrillation risk, with a 3-5 fold elevation, particularly in patients over 60 years 1
- Prolonged TSH suppression is associated with increased cardiovascular mortality, abnormal cardiac output, and ventricular hypertrophy 1, 2
- Even mild TSH suppression (0.1-0.45 mIU/L) carries intermediate cardiovascular risk, especially in elderly patients 1
Bone Health Deterioration
- Excessive levothyroxine causes significant bone mineral density loss, particularly in postmenopausal women 1
- Women over 65 years with TSH ≤0.1 mIU/L face markedly increased risk of hip and spine fractures 1
- Even slight overdosing sufficient to suppress TSH carries substantial osteoporotic fracture risk 1, 3
Classic Hyperthyroid Symptoms (Overdose)
- Tachycardia, tremor, sweating, heat intolerance, and weight loss indicate excessive dosing 1, 3
- These symptoms reflect a hypermetabolic state from thyroid hormone excess 1
Critical Safety Concern: Prevalence of Overtreatment
Approximately 25% of patients on levothyroxine are unintentionally maintained on doses high enough to fully suppress TSH, dramatically increasing risks for atrial fibrillation, osteoporosis, fractures, and cardiac complications 1, 2, 4. This represents a major quality-of-care issue requiring vigilant monitoring.
Risks in Older Adults
Age-Specific Vulnerabilities
- Elderly patients with cardiac disease face increased risk of cardiac decompensation, angina, or arrhythmias even with therapeutic levothyroxine doses 1
- Starting at full replacement doses in older adults can precipitate myocardial infarction, heart failure, or fatal arrhythmias 1
- Older patients require lower weight-based dosing (approximately 1.09 μg/kg actual body weight vs 1.6 μg/kg in younger adults) 5
Recommended Approach for Elderly
- For patients over 70 years or with cardiac disease, start at 25-50 mcg/day and titrate gradually by 12.5-25 mcg increments every 6-8 weeks 1, 2, 3
- More conservative dosing prevents unmasking cardiac ischemia or precipitating arrhythmias 1
Undertreatment Consequences
While not traditional "side effects," inadequate dosing causes:
- Persistent hypothyroid symptoms (fatigue, weight gain, cold intolerance, constipation) 1
- Adverse cardiovascular effects including delayed myocardial relaxation and abnormal cardiac output 1
- Unfavorable lipid profiles with elevated LDL cholesterol 1
- Reduced quality of life 1
Drug Interactions and Absorption Issues
- Iron, calcium supplements, and antacids reduce levothyroxine absorption when taken within 4 hours 1
- Enzyme inducers reduce levothyroxine efficacy 3
- Must be taken on empty stomach, 30-60 minutes before food for optimal absorption 1
Life-Threatening Risk: Adrenal Crisis
In patients with concurrent adrenal insufficiency or central hypothyroidism, starting levothyroxine before corticosteroid replacement can precipitate life-threatening adrenal crisis 1, 2. Always exclude adrenal insufficiency before initiating therapy in suspected central hypothyroidism or hypophysitis 1.
Evidence Quality Note
The FDA approval process for levothyroxine in 2000 did not include studies evaluating short- or long-term adverse effects, despite widespread prior use 1. Most safety data derives from post-marketing surveillance and observational studies rather than controlled trials designed to assess long-term harms 1.
Monitoring to Prevent Adverse Effects
- Check TSH every 6-8 weeks during dose titration 1, 2
- Once stable, monitor TSH every 6-12 months 1, 2
- Target TSH range: 0.5-4.5 mIU/L for primary hypothyroidism 1
- If TSH falls below 0.1 mIU/L, reduce dose by 25-50 mcg immediately 1
- For TSH 0.1-0.45 mIU/L, reduce by 12.5-25 mcg, especially in elderly or cardiac patients 1