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.
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.
According to the Annual Report of the American Association of Poison Control Centers’ National Poison Data System, in 2014, 13,623 exposures to thyroid hormone preparations were documented; of the total listed, 9,301 were single substance exposures. The breakdown by age for single substance exposures is as follows; 4,444 were associated with children younger than 5 years; 427 were associated with persons aged 6-12 years; 295 were associated with those aged 13-19 years; and 3,597 were associated with those greater than 20 years old. Overall, 53 moderate adverse outcomes, 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.
ECG is indicated to evaluate symptomatic patients for myocardial ischemia, myocardial infarction, and cardiac dysrhythmias (eg, atrial fibrillation, SVT).
Prehospital management includes gathering evidence of ingestion, administration of charcoal in alert patients with an exposure of more than 5 mg of thyroxine, a full initial assessment, oxygen, and intravenous access as necessary.
If the ingestion is 0.5 mg (500 mcg) or less, discharge the patient home because no gastric decontamination is indicated.[3]
Most unintentional exposures could be treated with no decontamination, prudent follow up and observation at home, especially if calculated dose is below 4 mg (4,000 mcg).[4]
Phone follow up should be conducted up to 10 days after exposure.
Unintentional exposures in excess of 5 mg (5,000 mcg) of thyroxine may benefit from administration of activated charcoal.
Intentional massive exposures in excess of 10 mg (10,000 mcg) that present early (within an hour) may benefit from more aggressive decontamination, including gastric lavage, and subsequent administration of activated charcoal.
Patients with massive exposures or ingestion of T3-containing preparations should be admitted in anticipation of pending toxicity.
Admit all symptomatic patients and place them on cardiac monitoring.
Symptomatic patients require correction of dehydration and control of hyperthermia.
Important treatment points:
Ipecac syrup is no longer recommended for home or hospital treatment.
Asymptomatic patients should not be treated empirically with beta-blockers.
Chronic overdose—withdraw drug.
Use acetaminophen for fever control; aspirin is contraindicated because it displaces T4 from thyroid-binding globulin (TBG), increasing free T4.
Because of the delayed conversion to T3 and distribution to tissues, patients must be observed and managed for a longer period of time, especially with large overdoses.
The hypothalamic-pituitary-thyroid axis will return to normal in 6-8 weeks.
Consult the regional poison control center or local medical toxicologist (certified through the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.
Clinical Context:
Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
Most useful if used within 4 h of ingestion. Repeated doses may be used, particularly with ingestions of sustained-released agents. May repeat dose q4h at 0.5 g/kg. Alternate with and without cathartic, if used.
Clinical Context:
A short-acting IV cardioselective beta-adrenergic blocker with no membrane depressant activity. Intravenous agent with half-life of 8 min, which allows for titration to effect and quick discontinuation prn.
Clinical Context:
Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby, inhibiting thyroid hormone synthesis; inhibits T4 to T3 conversion.
Thyroid agents are administered to prevent peripheral conversion of T4 to T3.
The US Food and Drug Administration (FDA) had added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that propylthiouracil should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.
The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.
The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil (PTU). Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).
PTU is considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU.
For more information, see the FDA Safety Alert.[5]
- Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.
- Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
- For suspected liver injury, promptly discontinue PTU therapy and evaluate for evidence of liver injury and provide supportive care.
- PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.
- Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.
Clinical Context:
Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.
These agents used to be utilized to bind thyroid hormone agents, which undergo enterohepatic recycling and reabsorption. There is no current strong recommendation supporting use of cholestyramine.
Clinical Context:
Inhibits action of endogenous pyrogens on heat-regulating centers; reduces fever by a direct action on the hypothalamic heat-regulating centers, which, in turn, increase the dissipation of body heat via sweating and vasodilation.
Clinical Context:
Used as empiric treatment of shock in suspected adrenal crisis or insufficiency until serum cortisol levels are drawn.
Adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose-dependent or duration-dependent.
Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.
Patients can be switched from an IV to PO regimen in a 1:1 ratio.
Inpatient admission is warranted for symptomatic patients. Because symptoms generally revolve around cardiovascular problems, admit to a cardiac monitored bed while appropriate beta-blockade, IV hydration, and control of agitation and hyperthermia are achieved.
Patients most frequently are treated on an outpatient basis if good follow-up can be guaranteed and psychiatric evaluation is not required. When symptoms develop, beta-blockade may be initiated and titrated to response.
For patient education resources, see the Drug Overdose Center, Poisoning - First Aid and Emergency Center, and Endocrine System Center, as well as Poisoning, Drug Overdose, Activated Charcoal, Poison Proofing Your Home, and Thyroid Problems.
Lisandro Irizarry, MD, MPH, FACEP, Chair, Department of Emergency Medicine, Wyckoff Heights Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Anton A Wray, MD, FACEP, Assistant Professor of Clinical Emergency Medicine, New York Medical College; Program Director Department of Emergency Medicine, Wyckoff Heights Medical Center
Disclosure: Nothing to disclose.
Nadine A Youssef, MD, Assistant Professor of Emergency Medicine, Tufts University, Department of Emergency Medicine
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Attending Physician in Emergency Medicine and Medical Toxicology, Excela Health System
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
