What are the indications, starting dose, titration, contraindications, and monitoring recommendations for liothyronine (synthetic triiodothyronine, T3) in adult hypothyroidism, particularly in patients with cardiac disease or the elderly?

Liothyronine (T3) in Adult Hypothyroidism

Indications for Liothyronine

Liothyronine should be reserved exclusively for hypothyroid patients who remain symptomatic despite adequate levothyroxine (LT4) monotherapy with normalized TSH, and only after excluding other causes of persistent symptoms. 1, 2

When to Consider LT4+LT3 Combination Therapy:

• Patients with persistent fatigue, cognitive impairment, or mood disturbances despite TSH 0.5-4.5 mIU/L on LT4 alone 1, 2
• Only after confirming medication adherence and excluding associated autoimmune diseases 2
• Treatment must be instituted by endocrinologists and discontinued if no improvement after 3 months 2
• This remains an experimental approach with insufficient evidence that combination therapy is superior to LT4 monotherapy 2

Contraindications:

• Newly diagnosed hypothyroidism (LT4 monotherapy is standard first-line) 3, 2
• Cardiac disease without careful dose titration (see below) 1
• Patients who have not received adequate trial of LT4 optimization 2

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Starting Dose and Titration

Begin by reducing the LT4 dose by 25 mcg/day and adding liothyronine 2.5-7.5 mcg once or twice daily. 3

Specific Dosing Algorithm:

• Initial LT4/LT3 ratio: 13:1 to 20:1 by weight 2
• LT4 administration: Once daily 2
• LT3 administration: Split the daily dose into two divided doses (e.g., morning and early afternoon) 2
• Example regimen: If patient on 100 mcg LT4, reduce to 75 mcg LT4 and add 2.5-5 mcg LT3 twice daily 3, 2

Titration Strategy:

• Recheck TSH, free T4, and free T3 after 6-8 weeks 1, 2
• Target TSH 0.5-4.5 mIU/L with normal free T4 and free T3 levels 1, 2
• Adjust doses in small increments (2.5 mcg LT3 or 12.5-25 mcg LT4) 1
• Critical: Aim for normal free T4/free T3 ratios, not just TSH normalization 2

Pharmacokinetic Considerations:

• LT3 has a time to peak of 1.8 hours and biphasic elimination with half-lives of 2.3 hours (distribution) and 22.9 hours (elimination) 4
• Twice-daily dosing at 0.07 mcg/kg prevents supraphysiologic T3 peaks while maintaining stable levels 4
• Transient T3 elevations with doses of 2.5-7.5 mcg are unlikely to exceed reference range 3

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Special Populations: Cardiac Disease and Elderly

For patients >70 years or with any cardiac disease, start with the lowest LT3 dose (2.5 mcg twice daily) and titrate extremely slowly. 1

Cardiac Disease Protocol:

• Begin LT4 at 25-50 mcg/day if initiating thyroid replacement 1
• Add LT3 only after stable on LT4 for 6-8 weeks 1
• Start LT3 at 2.5 mcg twice daily (total 5 mcg/day) 3, 4
• Increase by 2.5 mcg increments every 6-8 weeks maximum 1
• Monitor for angina, palpitations, arrhythmias at each visit 1
• Obtain ECG to screen for atrial fibrillation before and during titration 1

Elderly Patients (>70 years):

• Use 12.5 mcg LT4 dose reductions (not 25 mcg) when adding LT3 1
• Target TSH may be slightly higher (up to 5-6 mIU/L acceptable) to avoid overtreatment 1
• More frequent monitoring (every 4-6 weeks during titration) 1

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Monitoring Recommendations

Monitor TSH, free T4, AND free T3 every 6-8 weeks during dose adjustments, then every 6-12 months once stable. 1, 2

Monitoring Protocol:

• During titration: TSH, free T4, free T3 every 6-8 weeks 1, 2
• Once stable: Every 6-12 months or with symptom changes 1
• Cardiac patients: Consider more frequent monitoring (every 4-6 weeks initially) 1
• Critical: Free T3 measurements alone do NOT predict treatment response or guide dosing 5

Target Laboratory Values:

• TSH: 0.5-4.5 mIU/L 1, 2
• Free T4: Within reference range 2
• Free T3: Within reference range (not supraphysiologic) 2
• Normal free T4/free T3 ratio 2

Clinical Assessment:

• Evaluate symptom improvement at 3 months—discontinue if no benefit 2
• Assess for hyperthyroid symptoms: tremor, palpitations, heat intolerance, weight loss 1
• Monitor for cardiac complications: atrial fibrillation, angina 1

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Critical Safety Considerations

Adrenal Insufficiency Screening:

Before initiating or increasing any thyroid hormone (including LT3), measure morning cortisol and ACTH to exclude adrenal insufficiency—starting thyroid hormone before corticosteroids can precipitate adrenal crisis. 1

Risks of Overtreatment:

• TSH suppression <0.1 mIU/L increases atrial fibrillation risk 3-5 fold 1
• Prolonged suppression increases osteoporosis and fracture risk, especially in postmenopausal women 1
• Approximately 25% of patients on thyroid replacement are unintentionally overtreated 1

Dose Reduction Triggers:

• If TSH <0.1 mIU/L: Reduce total thyroid hormone dose by 25-50 mcg LT4 equivalent immediately 1
• If TSH 0.1-0.45 mIU/L: Reduce by 12.5-25 mcg, especially in elderly or cardiac patients 1

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Common Pitfalls

• Using commercially available combination preparations: All have LT4/LT3 ratios <13:1 and are NOT recommended 2
• Relying on T3 measurements to predict response: Neither baseline nor changes in serum T3 predict who will benefit from combination therapy 5
• Failing to discontinue after 3 months if no improvement: This is experimental therapy and should not continue indefinitely without clear benefit 2
• Starting combination therapy in newly diagnosed patients: LT4 monotherapy remains standard first-line treatment 3, 2
• Adjusting doses too frequently: Wait 6-8 weeks between adjustments to reach steady state 1

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Evidence Quality

The evidence supporting LT4+LT3 combination therapy is limited, with observational data showing no increased mortality or cardiovascular morbidity over ~9 years compared to LT4 alone 3, but randomized trials have not definitively proven superiority 2. This therapy should be considered experimental and reserved for carefully selected patients who have failed optimized LT4 monotherapy 2.