Thyroid Hormone Toxicity .

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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.

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.

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.

History

Access to thyroid hormone, especially in pediatric or unknown ingestions, is important.

Physical

Focus the physical examination on findings consistent with symptoms of increased adrenergic activity and on the following signs:

  • Acute

    • Abdominal pain
    • Nausea or vomiting
    • Diarrhea
    • Increased appetite
    • Insomnia
    • Anxiousness
    • Agitation
    • Tremor
    • Seizures
    • Weakness
    • Diaphoresis
    • Tachycardia
    • Palpitations
    • Hypertension or hypotension
    • Hyperpyrexia/heat intolerance
    • Confusion
    • Psychosis
    • Hypoglycemia
    • Skin flushing
    • Transient systolic ejection murmurs
    • Pulmonary edema
    • Adrenal insufficiency
  • Chronic

    • 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)

    Causes

    Long-term abuse of thyroid supplements has been reported in obese patients as a method of weight control.

    Differential Diagnoses

    Laboratory Studies

    See the list below:

    • Most asymptomatic patients do not require diagnostic testing, especially very early after exposure.
    • The following tests are indicated in symptomatic patients:

      • Complete blood 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.

      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

      See the list below:

      • 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.

        GI decontaminant

        Class Summary

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

        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.

        Cardiovascular agents

        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.

        Thyroid agents

        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.[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.

        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.

        Inpatient Care

        See the list below:

        • 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.

        Inpatient & Outpatient Medications

        See the list below:

        • 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.

        Prognosis

        See the list below:

        • 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.

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