Table 3.
Factors that modulate the distribution, metabolism, and excretion of LT4 (↓ = decrease, ↑ = increase)
| Distribution | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Factor | Category | Subcategory | Observations/putative mechanism | Suggested action | References | |||||
| Postmenopausal treatment with estrogen | Behavioral | medications | ↑ in serum TT4, TBG and TSH. ↓ in serum FT4, possibly due to an increase in serum TBG levels | Increase the LT4 dose if estrogen therapy is initiated | [89] | |||||
| Activity of the drug transporter OATP2B1 | Pathophysiological | physiological | ↑ in OATP2B1 gene expression levels in an in vitro (cell culture) study upon exposure to thyroid hormones | Systematic OATP2B1 genotyping is not recommended. Treat the patient on the basis of other data | [85] | |||||
| Metabolism | ||||||||||
| Factor | Category | Subcategory | Observations/putative mechanism | Suggested action | References | |||||
| Selenium deficiency | Pathophysiological | pathological | ↓ in FT3, ↑ in glutathione peroxidase, which competes with deiodinases for selenium | Screen for oxidative stress | [109] | |||||
| Oxidative stress | Pathophysiological | pathological | ↓ in serum malondialdehyde levels upon treatment with LT4 | Screen for oxidative stress | [111] | |||||
| Pregnancy | Pathophysiological | physiological | ↑ in FT4 during pregnancy in women with hypothyroidism. The main determinants of FT4 were weight and age | Adjust LT4 dose for bodyweight changes during pregnancy | [138] | |||||
| Excretion | ||||||||||
| Factor | Category | Subcategory | Observations/putative mechanism | Suggested action | References | |||||
| Nephrotic syndrome | Pathophysiological | pathological | ↑ in proteinuria and the renal excretion of T4 bound to transport proteins | Screen for nephrotic syndrome | [118, 119] | |||||
| Bile acid sequestrants (cholestyramine, colestipol and colesevelam) | Behavioral | medications | ↑ enterohepatic recycling of T4 | Screen for the use of bile acid sequestrants | [120, 121] | |||||
| Colesevelam | Behavioral | medications | Formation of a colesevelam-T4 complex in the stomach, with ↑ excretion in the feces | Screen for the use of colesevelam | [122] | |||||
| Phenobarbital, phenytoin, carbamazepine, and rifampin | Behavioral | medications | ↑ in the levels of the enzyme responsible for the glucuronidation of LT4 | Screen for the use of phenobarbital, phenytoin, carbamazepine, and rifampin | [116, 117] | |||||
TT4 total thyroxine, TBG thyroxine-binding globulin, TSH thyroid-stimulating hormone, FT4 free thyroxine, LT4 levothyroxine, OATP2B1 organic anion transporting polypeptide 2B1, FT3 free liothyronine, FT4 free thyroxine, T4 thyroxine