What are the differences between T3 (triiodothyronine) and T4 (thyroxine) in thyroid function and their respective medications?

T3 and T4 in Thyroid Function: Key Differences and Medications

Fundamental Physiological Differences

T4 (thyroxine) is the primary hormone secreted by the thyroid gland, comprising 80% of thyroid hormone production, while T3 (triiodothyronine) represents only 20% of direct thyroid secretion. 1, 2, 3

Hormone Production and Conversion

• T4 functions essentially as a "prodrug" that must be converted to T3 in peripheral tissues (liver, kidneys, and other organs) through a process called deiodination 1, 4, 3
• Approximately 80% of circulating T3 is derived from peripheral conversion of T4, not from direct thyroid secretion 1, 3
• Only about 20% of circulating T3 comes directly from the thyroid gland itself 3

Biological Activity and Potency

• T3 is the metabolically active form that actually binds to nuclear receptors and controls DNA transcription and protein synthesis 1
• T3 is approximately 4 times more biologically potent than T4 2
• T4 contains four iodine atoms, while T3 contains three iodine atoms (hence their names) 1, 2

Protein Binding and Half-Life

• T4 is more extensively protein-bound (99.96%) compared to T3 (99.5%), meaning less free hormone is available 1
• T4 has a much longer half-life of 6-7 days, while T3 has a half-life of only 2 days or less 1
• The higher protein binding and longer half-life of T4 make it more stable in the bloodstream 1

Medications for Thyroid Hormone Replacement

Levothyroxine (T4 Replacement)

Levothyroxine is the standard first-line medication for hypothyroidism and remains the drug of choice for thyroid hormone replacement. 5, 6

Key Characteristics of Levothyroxine

• Levothyroxine is synthetic T4 that is chemically identical to naturally produced thyroxine 1
• Available in multiple strengths: 25,50,75,88,100,112,125,137,150,175,200, and 300 mcg tablets 1
• Absorption ranges from 40-80% and occurs primarily in the jejunum and upper ileum 1
• The relative bioavailability of levothyroxine tablets compared to oral solution is approximately 93% 1

Dosing Strategy

• For patients under 70 years without cardiac disease, the full replacement dose is approximately 1.6 mcg/kg/day 5
• For elderly patients (>70 years) or those with cardiac disease, start with 25-50 mcg/day and titrate gradually 5
• Monitor TSH every 6-8 weeks during dose titration, targeting TSH within the reference range of 0.5-4.5 mIU/L 5

Why Levothyroxine Works

• Levothyroxine allows the body's own deiodinase enzymes to convert T4 to T3 as needed in peripheral tissues, maintaining physiological control 1, 4
• The long half-life of T4 (6-7 days) provides stable, consistent hormone levels throughout the day 1
• Once-daily dosing is sufficient due to the extended half-life 1

Liothyronine (T3 Replacement)

Liothyronine is synthetic T3 used in specific clinical situations, but is NOT recommended as monotherapy for routine hypothyroidism treatment. 2, 4

Key Characteristics of Liothyronine

• Liothyronine is synthetic triiodothyronine (L-T3) available as the sodium salt 2
• Available in 5 mcg, 25 mcg, and 50 mcg tablets 2
• 25 mcg of liothyronine is equivalent to approximately 1 grain of desiccated thyroid or 0.1 mg (100 mcg) of levothyroxine 2
• The short half-life (≤2 days) requires multiple daily doses for stable levels 1

Limited Role in Treatment

• Combination T4 + T3 therapy does not improve well-being, cognitive function, or quality of life compared with T4 alone in most patients 6
• Multiple randomized controlled trials have failed to demonstrate superiority of combination therapy over levothyroxine monotherapy 4, 6
• The pharmacokinetic differences between T4 and T3 create barriers to effective co-administration 4

Clinical Implications of T3/T4 Differences

Why T4 Monotherapy is Preferred

Levothyroxine monotherapy successfully treats the vast majority of hypothyroid patients and should remain the standard treatment. 5, 6

• T4 replacement allows physiological tissue-specific conversion to T3 based on local metabolic needs 4, 3
• The stable pharmacokinetics of T4 avoid the peaks and troughs seen with T3 supplementation 1, 4
• TSH normalization with levothyroxine indicates adequate thyroid hormone replacement in most cases 5

Monitoring Considerations

• TSH is the primary test for monitoring levothyroxine therapy, with a target range of 0.5-4.5 mIU/L 5
• Free T4 helps interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 5
• In levothyroxine-treated patients with elevated T4 but normal T3 levels, patients typically remain clinically euthyroid 7
• Serum T3 determination may be more useful than T4 for evaluating clinical status in levothyroxine-treated individuals 7

The Persistent Symptom Dilemma

• A substantial minority of patients report persistent hypothyroid symptoms despite TSH-optimized levothyroxine therapy 4
• Some studies suggest lower T3/T4 ratios correlate with persistent symptoms like weight gain, cold intolerance, and skin problems 8
• However, pooled analyses show T4 alone provides significant benefits for psychological and physical well-being compared to combination therapy 6

Common Pitfalls to Avoid

• Never use T3 monotherapy for routine hypothyroidism treatment, as it does not provide the stable hormone levels needed 1, 2
• Avoid assuming that elevated T4 levels in levothyroxine-treated patients indicate overtreatment if T3 and TSH are normal 7
• Do not initiate combination T4 + T3 therapy based solely on persistent symptoms without considering other causes 4, 6
• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications 5