Over 99 per cent is protein bound, so only the free fraction is active
Expansion
- 99.97 per cent of T4 and 99.7 per cent of T3 circulate bound
- Main carrier is thyroxine-binding globulin, with transthyretin and albumin
- Only the free fraction enters cells and exerts effect, and only the free fraction is sensed by the feedback loop
Binding globulin raised: pregnancy, oestrogen and the combined pill, tamoxifen, acute hepatitis, and hereditary excess. Total T4 rises, free T4 and TSH remain normal.
Binding globulin lowered: nephrotic syndrome, malnutrition, cirrhosis, androgens, glucocorticoids, severe illness. Total T4 falls with normal free hormone.
This is why free T4 rather than total T4 is measured in modern practice.
The binding also explains the long half-life of T4 (about 7 days) compared with T3 (about 1 day), which is why levothyroxine is given once daily, why dose changes take 6 weeks to assess, and why a missed dose matters little.
Drugs displacing thyroid hormone from binding proteins, such as phenytoin, salicylates and furosemide in high dose, cause transient changes that quickly re-equilibrate.