Liothyronine (T3) in Hypothyroidism
Liothyronine is NOT a first-line therapy for hypothyroidism and should only be considered as a trial in select patients with persistent symptoms despite optimized levothyroxine monotherapy.
Levothyroxine (T4) monotherapy remains the standard of care for all newly diagnosed hypothyroid patients, as it is the only treatment with decades of safety data and FDA approval for this indication 1.
Indications for Liothyronine Trial
Primary Indication
- A trial of LT4+LT3 combination therapy may be warranted only in patients with confirmed overt hypothyroidism who have persistent symptoms after 3-6 months of optimized levothyroxine monotherapy (TSH 0.3-2.0 mIU/L), and in whom other comorbidities have been excluded 2.
Prerequisites Before Considering LT3
- Confirm diagnosis of overt hypothyroidism with documented low free T4 and elevated TSH prior to any treatment 2.
- Optimize levothyroxine dosing to achieve TSH 0.3-2.0 mIU/L for at least 3-6 months before assessing therapeutic response 2.
- Rule out other causes of persistent symptoms including depression, sleep disorders, anemia, vitamin B12 deficiency, celiac disease, and adrenal insufficiency 1.
- In some patients, it may be acceptable to target TSH 0.1-0.3 mIU/L (below reference range but not fully suppressed) before concluding levothyroxine has failed 2.
Patients Who Should NOT Receive LT3
- Patients with subclinical hypothyroidism (normal free T4, elevated TSH) who have not had a trial without thyroid hormone replacement 2.
- Patients without clear biochemical evidence of overt hypothyroidism should first undergo a trial off thyroid hormone replacement entirely 2.
- Newly diagnosed hypothyroid patients—these should always start with levothyroxine monotherapy 3.
Starting Dose and Titration
Initial Dosing Strategy
- Reduce the levothyroxine dose by 25 mcg/day and add liothyronine 2.5-7.5 mcg once or twice daily 3.
- The typical LT4/LT3 ratio used in clinical trials is approximately 17:1 4.
Titration Schedule
- Recheck TSH and free T4 (and free T3 if available) 6-8 weeks after initiating combination therapy 1.
- Adjust doses in small increments to maintain TSH in the target range of 0.3-2.0 mIU/L 2.
- Continue monitoring every 6-8 weeks during dose adjustments until stable 1.
- Once stable, monitor TSH every 6-12 months 1.
Dosing Considerations
- Transient episodes of elevated T3 with these doses are unlikely to exceed the reference range and have not been associated with adverse drug reactions 3.
- Some patients may require higher doses; desiccated thyroid extract (DTE) contains approximately 11 mcg T3 per typical daily dose, though individual requirements vary 3.
Contraindications and Precautions
Absolute Contraindications
- Adrenal insufficiency must be ruled out before starting or increasing any thyroid hormone therapy, as thyroid hormone can precipitate life-threatening adrenal crisis 1.
- Measure morning cortisol and ACTH before initiating therapy in patients with suspected central hypothyroidism or hypophysitis 1.
Relative Contraindications and High-Risk Groups
- Elderly patients (>70 years) or those with cardiac disease should start with lower doses (25-50 mcg levothyroxine daily) and titrate slowly to avoid precipitating myocardial infarction, heart failure, or arrhythmias 1.
- Patients with atrial fibrillation, recent acute coronary syndrome, or severe cardiac disease require careful cardiac monitoring during any thyroid hormone adjustment 1.
- Pregnant women should receive levothyroxine monotherapy only, as T3 supplementation provides inadequate fetal thyroid hormone delivery 1.
Cardiovascular Risks
- Prolonged TSH suppression (<0.1 mIU/L) increases risk of atrial fibrillation 3-5 fold, especially in patients >60 years 1.
- TSH suppression is associated with increased cardiovascular mortality and left ventricular hypertrophy 1.
Bone Health Risks
- TSH suppression increases risk of osteoporosis and fractures, particularly in postmenopausal women 1.
- Patients with chronic TSH suppression should ensure adequate calcium (1200 mg/day) and vitamin D (1000 units/day) intake 1.
Monitoring Recommendations
Laboratory Monitoring
- TSH and free T4 should be measured 6-8 weeks after any dose adjustment 1.
- Free T3 measurements are not useful for predicting treatment response or monitoring combination therapy 4.
- Neither baseline T3 levels nor changes in T3 during combination therapy predict which patients will benefit from LT4+LT3 treatment 4.
Target Ranges
- Target TSH: 0.3-2.0 mIU/L for most patients 2.
- In select cases, TSH 0.1-0.3 mIU/L may be acceptable long-term, but TSH should never be fully suppressed (<0.1 mIU/L) in patients treated for primary hypothyroidism 2.
- Free T4 should remain within the reference range 1.
Long-Term Monitoring
- Once stable, check TSH every 6-12 months 1.
- Monitor for symptoms of overtreatment: palpitations, tremor, heat intolerance, weight loss, anxiety 1.
- Screen for atrial fibrillation with ECG in elderly patients or those with cardiac risk factors 1.
- Consider bone density assessment in postmenopausal women with prolonged therapy 1.
Evidence Quality and Clinical Outcomes
Trial Evidence
- Multiple randomized controlled trials have failed to demonstrate superiority of LT4+LT3 combination therapy over levothyroxine monotherapy for symptom improvement or quality of life 2, 5.
- These trials may have failed due to non-physiological T3 doses and heterogeneity in patient phenotypes 5.
- Trials following almost 1000 patients for nearly 1 year show that LT4+LT3 can restore euthyroidism while maintaining normal TSH, similar to LT4 monotherapy 3.
Long-Term Safety
- An observational study of 400 patients with mean follow-up of ~9 years showed no increased mortality or morbidity from cardiovascular disease, atrial fibrillation, or fractures after adjusting for age, compared to patients taking only LT4 3.
Patient Selection
- Approximately 65% of patients report subjective improvement with combination therapy at 12 months, while 35% remain nonresponders 4.
- There are no reliable predictors (including baseline or follow-up T3 levels) to identify which patients will benefit from combination therapy before starting treatment 4.
Critical Pitfalls to Avoid
- Never start liothyronine in newly diagnosed hypothyroid patients—always begin with levothyroxine monotherapy 3.
- Do not initiate combination therapy without first optimizing levothyroxine monotherapy for 3-6 months with TSH 0.3-2.0 mIU/L 2.
- Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism—this can precipitate adrenal crisis 1.
- Avoid measuring T3 levels to guide treatment decisions, as they do not predict response or guide monitoring 4.
- Do not allow TSH to become fully suppressed (<0.1 mIU/L) in patients treated for primary hypothyroidism, as this significantly increases cardiovascular and bone risks 1.
- Approximately 25% of patients on thyroid hormone are unintentionally overtreated with suppressed TSH, increasing serious complication risks 1.
- Individual clinicians should not feel obliged to continue liothyronine prescribed by others if they judge it not to be in the patient's best interest 2.
Shared Decision-Making
The decision to start liothyronine should be a shared decision between patient and clinician, with clear discussion of the lack of robust evidence for benefit, the need for ongoing monitoring, and the potential for adverse effects 2. Patients should understand that combination therapy remains controversial and that most will not experience additional benefit beyond optimized levothyroxine monotherapy 2, 5.