Levothyroxine: Synthetic T4 for Hypothyroidism and Thyroid Cancer
Levothyroxine (L-thyroxine, T4) is the synthetic form of the thyroid hormone thyroxine, produced naturally by the thyroid gland. It is the most commonly prescribed hormone replacement worldwide and has been in clinical use since the 1960s. Levothyroxine is used both for replacement therapy in hypothyroidism and for TSH suppression in differentiated thyroid cancer.
The drug has a narrow therapeutic index, meaning small differences in dose can result in under- or over-treatment. The numerous drug and food interactions affecting its absorption make consistent administration practices critical. Despite its widespread use, dosing requires individualisation based on regular TSH monitoring.
Mechanism of Action
Thyroxine (T4) is the primary secretory product of the thyroid gland and serves as a prohormone. Most T4 is converted to the biologically active triiodothyronine (T3) in peripheral tissues, primarily the liver and kidneys, by deiodinase enzymes. T3 binds to nuclear thyroid hormone receptors, regulating the transcription of genes involved in metabolism, thermogenesis, cardiovascular function, growth, and neurological development. Levothyroxine provides a stable and consistent source of T4, allowing the body's own peripheral conversion mechanisms to regulate T3 levels according to tissue needs, which is physiologically more natural than providing T3 directly.
Indications
Levothyroxine is the treatment of choice for all forms of primary, secondary, and tertiary hypothyroidism, including Hashimoto's thyroiditis, post-thyroidectomy, post-radioiodine treatment, and congenital hypothyroidism. In differentiated thyroid cancer (papillary and follicular), supraphysiological doses are used to suppress TSH below the normal range, thereby reducing the growth stimulus for residual thyroid cancer cells. Levothyroxine is used during pregnancy in women with hypothyroidism, where adequate thyroid hormone levels are critical for foetal neurological development.
Dosage and Administration
Full replacement doses for adults typically range from 1.6 to 1.8 micrograms per kilogram body weight per day. Starting doses in elderly patients, those with heart disease, or those with long-standing severe hypothyroidism should be lower (25 to 50 micrograms per day) and titrated upward slowly. For TSH suppression in thyroid cancer, doses achieving TSH below 0.1 mIU/L are typically required for high-risk patients. Levothyroxine must be taken on an empty stomach, 30 to 60 minutes before breakfast or any food, calcium, iron, or other medications, to ensure maximal consistent absorption. The tablet should be taken with a glass of water and not crushed or chewed (liquid formulations are available for those who cannot swallow tablets).
Side Effects
Side effects of levothyroxine result almost entirely from over-replacement (iatrogenic hyperthyroidism): palpitations, tachycardia, atrial fibrillation, heat intolerance, excessive sweating, weight loss, anxiety, insomnia, tremor, and diarrhoea. These resolve with dose reduction. Long-term TSH suppression increases the risk of osteoporosis and atrial fibrillation, particularly in postmenopausal women. Correctly dosed levothyroxine replacement has no intrinsic side effects. Rarely, allergy to excipients in the tablet (lactose, acacia) can cause gastrointestinal symptoms.
Interactions
Calcium carbonate, iron supplements, magnesium, antacids, sucralfate, and sevelamer significantly reduce levothyroxine absorption when taken simultaneously; a minimum four-hour separation is required. Cholestyramine, colestipol, and orlistat bind T4 in the gut and reduce absorption. Rifampicin, phenytoin, carbamazepine, and phenobarbital accelerate T4 metabolism and may require increased doses. Sertraline and other antidepressants, as well as oestrogens (oral contraceptives, HRT), increase thyroid-binding globulin and may require dose adjustment. Proton pump inhibitors and achlorhydria reduce absorption from solid tablets.
Special Notes
Brand and generic levothyroxine formulations differ in their pharmacokinetics and should not be switched without retesting TSH. TSH should be measured six to eight weeks after any dose change. During pregnancy, TSH targets are lower than in non-pregnant adults and the levothyroxine dose typically needs to increase by 25 to 50 percent; dosing should be guided by trimester-specific TSH reference ranges. Levothyroxine is safe during breastfeeding. Patients should take it at the same time each day and be consistent with the fasting period before ingestion.
Related Topics
Frequently Asked Questions
Why must levothyroxine be taken on an empty stomach?
Levothyroxine absorption from the gut is highly variable and significantly reduced by food, beverages other than water, calcium, iron, and many medications. Taking it 30 to 60 minutes before breakfast on an empty stomach with a glass of water maximises and standardises absorption, which is essential for consistent TSH control with a narrow therapeutic index drug.
Why does the dose need to increase during pregnancy?
Pregnancy increases oestrogen levels, which raise thyroid-binding globulin (TBG) concentrations. More TBG means more T4 is bound and less is free (active). Additionally, the foetus depends entirely on maternal T4 during the first trimester. These factors together increase the demand for levothyroxine by approximately 25 to 50 percent, with individual variation.
Can I switch between different levothyroxine brands?
Switching brands should be done cautiously and followed by TSH retesting after six to eight weeks. Different formulations (tablets, capsules, liquids, different tablet excipients) have different pharmacokinetic profiles, and even small differences in bioavailability can cause clinically significant changes in TSH in patients with fine dose requirements. Consistency with one formulation is generally preferred.
Sources
- ETA Guideline: Management of Hypothyroidism 2022
- Jonklaas J et al: ATA Guidelines Hypothyroidism. Thyroid 2023
- Fachinformation Euthyrox, Henning Berlin, aktueller Stand