Thyroid Hormone Toxicity

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 at a rate that 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, gastrointestinal, 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.

Etiology

The abuse of thyroid hormone has been reported in patients as a method of weight reduction, with many over-the-counter thyroid supplements containing clinically relevant levels of T3 and T4, sometimes even exceeding doses of levothyroxine prescribed for hypothyroidism. It is important to recognize the potential for unintended ingestions of thyroid hormone from over-the-counter weight loss supplements with unknown ingredients in addition to intentional abuse of thyroid supplements.[2]

United States statistics

According to the Annual Report of the American Association of Poison Control Centers’ National Poison Data System, in 2020, 13,118 exposures to thyroid hormone preparations were documented; of the total listed, 8,663 were single substance exposures. The breakdown by age for single substance exposures is as follows; 4,081 were associated with children younger than 5 years; 339 were associated with persons aged 6-12 years; 260 were associated with those aged 13-19 years; and 3,500 were associated with those greater than 20 years old. Overall, 61 moderate adverse outcomes, 2 major adverse outcomes, and 1 death were reported.[3]

International statistics

In a study by Ergul et al conducted in Turkey, the incidence of acute L-thyroxine ingestion in children was 0.07-1.2% per year. No serious complications or deaths were reported.[4]

Race-, sex-, and age-related demographics

No scientific data demonstrate that outcomes following a toxic thyroid hormone ingestion are based on race.

No scientific data demonstrate that outcomes following a toxic thyroid hormone ingestion are based on sex.

Inadvertent excessive thyroid hormone ingestion occurs primarily in pediatric patients.

Significant toxicity with acute ingestions is rare. Serious toxicity is more commonly observed with chronic ingestions of large amounts of T4 than with other thyroid hormone ingestions. 

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.

History

Access to thyroid hormone or other pharmaceuticals, especially in pediatric or unknown ingestions, is important to diagnosis and management. Reported symptoms may include:

• Abdominal pain
• Nausea or vomiting
• Diarrhea
• Increased appetite
• Insomnia
• Anxiousness
• Agitation
• Tremor
• Weakness

Physical examination

Focus the physical examination on findings consistent with symptoms of increased adrenergic activity as below.

Acute signs include:

• Tachycardia

• Palpitations or Arrhythmia

• Hypertension or hypotension

• Hyperpyrexia/heat intolerance

• Tremor

• Seizures

• Weakness

• Diaphoresis

• Confusion

• Psychosis

• Hypoglycemia

• Skin flushing

• Transient systolic ejection murmurs

• Pulmonary edema

• Adrenal insufficiency

Chronic signs are as follows:

• Weight loss

• Menstrual irregularities

• Supraventricular tachycardia (SVT)

• High-output left ventricular failure

• Hypotension

• Hemiparesis

• Delirium

• Coma

• Pneumonia

• Sepsis

• Hyperthermia

• Acute renal failure

• Myopathy

• Palmar and plantar desquamation

• Premature epiphyseal closure in children

• Craniosynostosis (infants)

Most asymptomatic patients do not require diagnostic testing, especially very early after exposure.

The following tests are indicated in symptomatic patients:

• Complete blood cell count

• Electrolytes (eg, calcium, magnesium, phosphorous)

• Urinalysis

• Serum acetaminophen level (in patients with intentional exposures and suicidal ideations)

• Arterial blood gas (ABG)

• T3, T4, and T3 resin uptake (RU) levels may be sent 2-6 hours postingestion; however, remember the following:

  • These levels offer no aid in the acute phase of clinical management.

  • These levels are of no value in determining prognosis.

Other tests

Electrocardiography is indicated to evaluate symptomatic patients for myocardial ischemia, myocardial infarction, and cardiac dysrhythmias (eg, atrial fibrillation, supraventricular tachycardia).

Procedures

Lumbar puncture (LP) should be considered in patients with hyperthermia and change of mental status to rule out CNS infection.

Prehospital care

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.

Emergency department care

If the ingestion is 0.5 mg (500 mcg) or less, discharge the patient home because no gastric decontamination is indicated.[5]

Most unintentional exposures can be treated with no decontamination, prudent follow up and observation at home, especially if calculated dose is below 4 mg (4,000 mcg).[6]  Virtual or telephonic 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 include the following:

• 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.

Consultations

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.

Further inpatient care

Inpatient admission is warranted for symptomatic patients. Because symptoms generally revolve around cardiovascular manifestations of thyrotoxicosis, admit to a cardiac monitored bed while appropriate beta-blockade, IV hydration, and control of agitation and hyperthermia are achieved.

Inpatient and outpatient medications

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.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Empirically used to minimize systemic absorption of the toxin. May only benefit if administered within 1-2 h of ingestion.

Activated charcoal (Liqui-Char)

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.

Class Summary

Beta-blockers are administered to counteract the increase in adrenergic activity and treat serious tachyarrhythmias.

Propranolol (Inderal)

Noncardioselective beta-blocker, widely available. DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.

Important added benefit is the inhibition of peripheral conversion of T4 to T3.

Esmolol (Brevibloc)

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.

Class Summary

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.[7]

- 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.

Propylthiouracil (Propyl-Thyracil)

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.

Class Summary

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.

Cholestyramine (Questran)

Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Class Summary

Used to treat hyperthermia.

Acetaminophen (Tylenol, Aspirin Free Anacin)

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.

Class Summary

Used when adrenal crisis suspected.

Hydrocortisone (Cortef, Hydrocort, Hydrocortone, HydroTex, Solu-Cortef)

Can be used to treat the potential adrenal insufficiency occurring secondary to the hypermetabolic hyperthyroid state.

DOC because of mineralocorticoid activity and glucocorticoid effects.

Dexamethasone (AK-Dex, Alba-Dex, Baldex, Decadron, Dexone)

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.