What are the primary side effects of levothyroxine (thyroid hormone replacement medication)?

Primary Side Effects of Levothyroxine

The primary side effects of levothyroxine are manifestations of iatrogenic hyperthyroidism due to therapeutic overdosage, affecting cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. 1

Side Effects from Therapeutic Overdosage

The FDA-approved labeling clearly identifies that adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism resulting from excessive dosing 1. This is a critical distinction—when properly dosed, levothyroxine is generally safe, but approximately 25% of patients are unintentionally maintained on doses high enough to suppress TSH completely, leading to significant complications 2, 3.

Cardiovascular Effects

• Palpitations, tachycardia, and cardiac arrhythmias are among the most concerning side effects, particularly in elderly patients and those with pre-existing cardiac disease 1
• Increased pulse and blood pressure occur with overtreatment 1
• Heart failure, angina, myocardial infarction, and cardiac arrest represent severe cardiovascular complications of excessive dosing 1
• Atrial fibrillation risk increases 5-fold in individuals ≥45 years with TSH <0.4 mIU/L 2
• Left ventricular hypertrophy and abnormal cardiac output may develop with long-term TSH suppression 2

Central Nervous System Effects

• Headache, hyperactivity, nervousness, anxiety, and irritability are common neurological manifestations 1
• Emotional lability and insomnia frequently occur with overtreatment 1
• Seizures have been reported rarely with the institution of levothyroxine therapy 1

Gastrointestinal Effects

• Diarrhea, vomiting, and abdominal cramps are typical gastrointestinal side effects 1
• Elevations in liver function tests may occur 1

Musculoskeletal Effects

• Tremors, muscle weakness, and muscle spasm are characteristic musculoskeletal manifestations 1

General Systemic Effects

• Fatigue, increased appetite, and weight loss occur with overtreatment 1
• Heat intolerance, fever, and excessive sweating reflect increased metabolic rate 1

Dermatologic Effects

• Hair loss, flushing, and rash are reported dermatologic side effects 1

Endocrine and Metabolic Complications

Bone Health

• Decreased bone mineral density is a significant concern with levothyroxine over-replacement, particularly in post-menopausal women 1
• Increased bone resorption may be associated with increased serum calcium and phosphorous levels, elevations in bone alkaline phosphatase, and suppressed parathyroid hormone 1
• Increased fracture risk, particularly hip and spine fractures in women >65 years with TSH ≤0.1 mIU/L 2

Reproductive Effects

• Menstrual irregularities and impaired fertility can occur with improper dosing 1

Metabolic Effects

• Worsening of diabetic control may occur when levothyroxine is added to therapy in patients with diabetes mellitus, requiring increased antidiabetic agent or insulin requirements 1

Pediatric-Specific Adverse Reactions

• Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine 1
• Craniosynostosis in infants who have not undergone complete closure of the fontanelles may result from overtreatment 1
• Premature closure of the epiphyses in pediatric patients still experiencing growth, resulting in compromised adult height 1

Hypersensitivity Reactions

• Urticaria, pruritus, skin rash, flushing, and angioedema have occurred in patients treated with thyroid hormone products, though these are reactions to inactive ingredients rather than levothyroxine itself 1
• Gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), fever, arthralgia, serum sickness, and wheezing may occur as hypersensitivity reactions 1
• Allergic reactions due to tartrazine (FD&C Yellow No. 5) may occur in certain susceptible persons, particularly those with aspirin hypersensitivity 1

Critical Safety Considerations

Cardiac Monitoring

• Patients with coronary artery disease receiving suppressive levothyroxine therapy require monitoring for cardiac arrhythmias during surgical procedures 1
• If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and restarted at a lower dose 1

Adrenal Crisis Risk

• Thyroid hormone increases metabolic clearance of glucocorticoids, and initiation of thyroid hormone therapy prior to glucocorticoid therapy may precipitate acute adrenal crisis in patients with adrenal insufficiency 1
• Patients with adrenal insufficiency must receive replacement glucocorticoids prior to initiating levothyroxine 1

Common Pitfalls in Clinical Practice

• Approximately 25% of patients are inadvertently maintained on excessive doses that fully suppress TSH, increasing risks for osteoporosis, fractures, and cardiac complications 2, 3
• Overtreatment occurs in 14-21% of treated patients, emphasizing the critical importance of regular TSH monitoring every 6-8 weeks during dose titration and every 6-12 months once stable 2
• Elderly patients and those with cardiac disease require lower starting doses (25-50 mcg/day) with gradual titration to avoid exacerbating cardiac symptoms 2, 3