Levothyroxine Side Effects
Primary Side Effects from Overtreatment (Iatrogenic Hyperthyroidism)
The most clinically significant side effects of levothyroxine result from overtreatment, not from the medication itself at appropriate replacement doses. Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, which dramatically increases the risk of serious complications 1.
Cardiovascular Complications
- Atrial fibrillation risk increases 3-5 fold when TSH is suppressed below 0.4 mIU/L, particularly in patients over 60 years of age 1.
- Palpitations, tachycardia, arrhythmias, increased pulse and blood pressure can occur with excessive dosing 2.
- Heart failure, angina, myocardial infarction, and cardiac arrest represent the most severe cardiovascular complications 2.
- All-cause and cardiovascular mortality increase up to 2.2-fold and 3-fold respectively in individuals older than 60 years with TSH below 0.5 mIU/L 1.
- Even therapeutic doses can unmask or worsen cardiac ischemia in elderly patients with underlying coronary disease 1.
Bone and Metabolic Effects
- Decreased bone mineral density occurs with TSH suppression, particularly in postmenopausal women, due to increased bone resorption 2.
- Meta-analyses demonstrate significant bone mineral density loss even with TSH levels between 0.1-0.45 mIU/L 1.
- Women over 65 years with TSH ≤0.1 mIU/L have increased risk of hip and spine fractures 1.
- Increased serum calcium and phosphorous levels, elevated bone alkaline phosphatase, and suppressed parathyroid hormone levels accompany the bone loss 2.
Neurological and Psychiatric Symptoms
- Headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, and insomnia are common with overtreatment 2.
- Seizures have been reported rarely with institution of levothyroxine therapy 2.
- Tremors and muscle weakness occur with excessive thyroid hormone 2.
Gastrointestinal and General Symptoms
- Diarrhea, vomiting, abdominal cramps, and elevations in liver function tests can occur 2.
- Fatigue (paradoxically), increased appetite, weight loss, heat intolerance, fever, and excessive sweating represent hypermetabolic symptoms 2.
- Hair loss, flushing, and rash may develop 2.
Pediatric-Specific Adverse Effects
- Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine 2.
- Craniosynostosis can occur in infants with incomplete fontanelle closure if overtreated 2.
- Premature epiphyseal closure compromises adult height in growing children who are overtreated 2.
Hypersensitivity Reactions to Inactive Ingredients
- Urticaria, pruritus, skin rash, flushing, and angioedema can occur as reactions to inactive ingredients 2.
- Gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), fever, arthralgia, serum sickness, and wheezing have been reported 2.
- FD&C Yellow No. 5 (tartrazine) in certain formulations may cause allergic-type reactions including bronchial asthma in susceptible persons, particularly those with aspirin hypersensitivity 2.
- Hypersensitivity to levothyroxine itself is not known to occur 2.
Critical Safety Considerations
Risk of Adrenal Crisis
- In patients with concurrent adrenal insufficiency or central hypothyroidism, starting levothyroxine before corticosteroids can precipitate life-threatening adrenal crisis 1, 3.
- Always rule out adrenal insufficiency before initiating or increasing levothyroxine, particularly in suspected central hypothyroidism or hypophysitis 1.
Drug Interactions Affecting Efficacy
- Phosphate binders (calcium carbonate, ferrous sulfate), bile acid sequestrants, proton pump inhibitors, sucralfate, and antacids can reduce levothyroxine absorption 2.
- Phenobarbital and rifampin increase hepatic metabolism of levothyroxine, potentially causing hypothyroidism despite treatment 2.
- Administer levothyroxine at least 4 hours apart from binding agents 2.
Side Effects at Appropriate Replacement Doses
When properly dosed and monitored, levothyroxine is generally safe for long-term use 1. The medication itself at replacement doses does not cause significant adverse effects 4. Most safety data comes from post-marketing surveillance rather than controlled trials, as the FDA approval process in 2000 did not include studies evaluating long-term adverse effects 1.