What are the usual side effects of levothyroxine (thyroid hormone replacement) therapy?

Side Effects of Levothyroxine Therapy

The most common side effects of levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage, including cardiovascular effects (palpitations, tachycardia, arrhythmias), central nervous system effects (anxiety, irritability, insomnia), and gastrointestinal disturbances. 1

Common Side Effects

Levothyroxine side effects typically manifest as symptoms of excessive thyroid hormone and can include:

General/Systemic

• Fatigue
• Increased appetite
• Weight loss
• Heat intolerance
• Excessive sweating
• Fever

Central Nervous System

• Headache
• Hyperactivity
• Nervousness and anxiety
• Irritability
• Emotional lability
• Insomnia

Musculoskeletal

• Tremors
• Muscle weakness
• Muscle spasms

Cardiovascular

• Palpitations
• Tachycardia
• Arrhythmias
• Increased pulse and blood pressure
• Heart failure (in severe cases)
• Angina
• Myocardial infarction (in severe cases)
• Cardiac arrest (rare)

Gastrointestinal

• Diarrhea
• Vomiting
• Abdominal cramps
• Elevated liver function tests

Other

• Hair loss
• Skin rash
• Decreased bone mineral density
• Menstrual irregularities
• Impaired fertility 1

Serious Long-Term Risks of Overtreatment

Overtreatment with levothyroxine is particularly concerning and can lead to:

• Osteoporosis and fractures: Increased bone resorption and decreased bone mineral density, especially in postmenopausal women 2, 1
• Cardiac complications: Atrial fibrillation, abnormal cardiac output, ventricular hypertrophy 2, 1
• Subclinical hyperthyroidism: Approximately 25% of patients on levothyroxine are inadvertently maintained on doses high enough to make TSH levels undetectable 2

Special Population Considerations

Elderly Patients

• More susceptible to cardiac adverse reactions
• Should start at lower doses (12.5-50 mcg/day) 1
• Higher risk of atrial fibrillation and osteoporotic fractures even with slight overdose 3

Patients with Diabetes

• Levothyroxine may worsen glycemic control
• May require adjustment of antidiabetic medications or insulin 1

Patients with Adrenal Insufficiency

• Risk of precipitating acute adrenal crisis if levothyroxine is started before glucocorticoid replacement
• Thyroid hormone increases metabolic clearance of glucocorticoids 1

Oxidative Stress and Daily Discomfort

Research indicates that levothyroxine therapy can cause oxidative stress, which may contribute to side effects:

• Studies have shown increased plasma hydroperoxides and hs-CRP (markers of oxidative stress and inflammation) following levothyroxine administration 4
• Common daily discomforts reported include anxiety/agitation, sweating, palpitations, and headache 5, 4
• These side effects have been found to correlate with oxidative stress markers 4

Monitoring and Prevention of Side Effects

To minimize side effects:

1. Proper dosing: Start with appropriate dose based on age, weight, and cardiovascular status

   • Young adults: ~1.5 mcg/kg/day
   • Elderly or those with coronary disease: 12.5-50 mcg/day 3

2. Proper administration: Take on an empty stomach, 30-60 minutes before breakfast with a full glass of water 6

3. Regular monitoring: Check TSH levels every 4-6 weeks until stable, then every 3-6 months 6

4. Avoid overtreatment: Administer the minimum dose needed to achieve desired clinical and biochemical response 1

5. Be aware of drug interactions: Certain medications can affect levothyroxine absorption or metabolism 1

Hypersensitivity Reactions

Although rare, hypersensitivity reactions to inactive ingredients in levothyroxine formulations can occur:

• Urticaria
• Pruritus
• Skin rash
• Flushing
• Angioedema
• Gastrointestinal symptoms
• Fever
• Arthralgia
• Serum sickness
• Wheezing 1

Pitfalls to Avoid

1. Overlooking subtle signs of overtreatment: Monitor for early signs of excessive dosing before more serious complications develop

2. Ignoring drug interactions: Be aware that iron supplements, calcium supplements, and certain antacids can reduce levothyroxine absorption 1

3. Inadequate monitoring: Failure to check TSH levels regularly can lead to undetected overtreatment

4. Attributing non-specific symptoms to hypothyroidism: This can lead to unnecessary treatment or dose increases when TSH is only slightly elevated 3

5. Ignoring patient-reported side effects: These may indicate need for dose adjustment even when lab values appear acceptable

By understanding these common side effects and implementing appropriate monitoring strategies, clinicians can optimize levothyroxine therapy while minimizing adverse effects and improving patient quality of life.