Thyroid Hormone Toxicity
- Author: Lisandro Irizarry, MD, MPH, FAAEM; Chief Editor: Asim Tarabar, MD more...
Background
Iodine is absorbed from the GI tract and is transferred to the thyroid gland where oxidization and incorporation into tyrosyl residues of thyroglobulin occurs. Tyrosine is further oxidized to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). The combination of 2 molecules of DIT forms thyroxine (T4). Triiodothyronine (T3) is made by the combination of MIT and DIT and by the monodeiodination of T4 in the periphery.
T3 is 4 times more active than the more abundant T4. The half-life of T4 is 5-7 days; the half-life of T3 is only 1 day. Approximately 99% of the circulating thyroid hormone is bound to plasma protein and is metabolized primarily by the liver.
Levels of thyroid hormones in the serum are tightly regulated by the hypothalamic-pituitary-thyroid axis. Thyroid-releasing hormone (TRH) is secreted by the hypothalamus, and stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary gland. Mature TSH reaches the thyroid gland and stimulates thyroid hormone production and release. The main hormone secreted from the thyroid gland is T4, which is converted to T3 by deiodinase in the peripheral organs. Secreted thyroid hormone reaches the hypothalamus and the pituitary, where it inhibits production and secretion of TRH and TSH, thereby establishing the hypothalamic-pituitary-thyroid axis.[1]
The most common thyroid hormone used clinically is levothyroxine (LT4), which is available in intravenously and orally administered forms to treat hypothyroidism and myxedema coma. Usual dosage ranges from 25-500 mcg/d. The higher doses can be used intravenously to treat myxedema coma.
For related information, see Medscape's Hypothyroidism Resource Center.
Pathophysiology
Pharmacokinetics
Oral absorption of thyroid hormone can be erratic (T4 up to 80%; T3 up to 95%) and decreases with age. The time for peak serum levels is 2-4 hours. The onset of action for oral administration is 3-5 days and 6-8 hours for IV administration. Thyroid hormone is more than 99% protein-bound, and it is hepatically metabolized to triiodothyronine (the active form). Half-life elimination varies from 6-7 days for euthyroid, 9-10 days for hypothyroid, and 3-4 days for hyperthyroid states. It is excreted in both urine and feces, and this also decreases with age.
Mechanism
Levothyroxine's delayed onset of toxicity is thought to be secondary to the delay in conversion of T4 to T3 and the distribution of T3 into tissues. As a result, symptoms may be delayed, developing anyway from 6 hours to 11 days after ingestion. If the ingested preparation contains T3, clinical symptoms may begin within 24 hours of ingestion. Mixtures of T4 and T3 can have immediate and delayed clinical effects. Thus, symptoms can occur anywhere from 6 hours to 11 days after ingestion.
Mechanism of toxicity involves stimulation of the cardiovascular (CV), GI, and neurologic systems through presumed activation of the adrenergic system. Although the exact mechanism of action is unknown, the metabolic effects of thyroid hormone are thought to be mediated by the control of DNA transcription and protein synthesis. Thyroid hormone is integral to the regulation of normal metabolism, growth, and development. It promotes gluconeogenesis, controls the mobilization and utilization of glycogen stores, increases the basal metabolic rate, and increases protein synthesis at a cellular level.
Epidemiology
Frequency
United States
According to the Annual Report of the American Association of Poison Control Centers’ National Poison Data System, in 2008, 13,005 exposures to thyroid hormone preparations were documented; of the total listed, 9,006 were single substance exposures. The breakdown by age for single substance exposures is as follows; 5,026 were associated with children younger than 6 years; 554 were associated with persons aged 6-19 years; and 2,957 were associated with those aged older than 19 years. Overall, 3 major adverse outcomes and no deaths were reported.[2]
Race
No scientific data demonstrate that outcomes following a toxic thyroid hormone ingestion are based on race.
Sex
No scientific data demonstrate that outcomes following a toxic thyroid hormone ingestion are based on sex.
Age
Inadvertent excessive thyroid hormone ingestion occurs primarily in pediatric patients.
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