AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Thyroid-stimulating hormone (TSH), secreted by the anterior pituitary, causes release of T3 and T4. Thyrotropin-releasing hormone (TRH), produced by the pituitary, works via a negative feedback mechanism to regulate the release of TSH.

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 is erratic (40-80%) 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 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.

Frequency

United States

According to the Annual Report of the American Association of Poison Control Centers’ National Poisoning and Exposure Database in 2005, 11,149 exposures to thyroid hormone preparations were documented; of those exposures, 5300 were associated with children younger than 6 years; 761 were associated with persons aged 6-19 years; and 5037 were associated with those aged older than 19 years. Overall, 107 people had major adverse outcomes, and 11 deaths were reported.¹

Mortality/Morbidity

One large retrospective study reported 27,680 cases of thyroid hormone ingestion. Of these cases, 2516 (9.1%) were secondary to suicidal intentions, with only 3 (0.01%) being fatal. Co-ingestants were believed to be the major cause of these fatalities. Among all groups, incidence of a major outcome (described as symptoms that are life threatening or resulting in significant residual disability) was 0.02%.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood count
• Electrolytes (eg, calcium, magnesium, phosphorous)
• Urinalysis
• Urine drug screen
• 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

• ECG is indicated to evaluate for myocardial ischemia, infarction, and cardiac dysrhythmias (eg, atrial fibrillation, SVT).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital management includes gathering evidence of ingestion, a full initial assessment, oxygen, and IV access as necessary.

Emergency Department Care

Litovitz and White developed the following approach to acute levothyroxine ingestion²:

• If the ingestion is 0.5 mg or less, discharge the patient home because no gastric decontamination is indicated.
• Ipecac syrup–induced emesis at home is recommended for ingestions occurring within 30 minutes if the amount was between 0.5 and 3 mg. Telephone follow-up daily for the next 5 days.
• Administer activated charcoal in the ED for ingestions more than 3 mg.
• Admit all symptomatic patients and place them on cardiac monitoring.
• Thyroid hormones undergo enterohepatic recycling and significant overdoses have been treated with cholestyramine, a bile sequestrant.

Important treatment points

• Ipecac syrup is no longer recommended for home or hospital treatment.
• 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: GI decontaminant

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

Drug Category: Cardiovascular agents

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

Drug Name	Esmolol (Brevibloc)
Description	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.
Adult Dose	50-200 mcg/kg/min IV; titrate to effect
Pediatric Dose	300 mcg/kg/min IV with continuous heart rate and blood pressure monitoring to determine onset of beta-blockade (>10% reductions); titrate upward in 50-100 mcg/kg/min increments q10min prn
Contraindications	Documented hypersensitivity; asthma; COPD; CHF; moderate-to-severe left ventricular dysfunction; hypotension <90 mm Hg; bradycardia <60/min; second- and third-degree AV block
Interactions	Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effect; cardiotoxicity may increase when administered concurrently with sparfloxacin, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity increases when administered concurrently with digoxin, flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Beta-adrenergic blockers may mask signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; symptoms of hyperthyroidism, including thyroid storm may worsen when medication is abruptly withdrawn; withdraw drug slowly and monitor patient closely; because of small doses and rapid onset of effects, use volumetric infusion pump when available

Drug Category: Thyroid agents

Thyroid agents are administered to prevent peripheral conversion of T4 to T3.

Drug Category: Bile acid sequestrants

These agents are utilized to bind thyroid hormone agents, which undergo enterohepatic recycling and reabsorption.

Drug Category: Antipyretics

Used to treat hyperthermia.

Drug Category: Antihypertensive agents

Used to treat hypertension caused by thyroid hormone toxicity.

Drug Name	Guanethidine (Ismelin)
Description	Blocks the adrenergic actions of norepinephrine by interfering with either its release or distribution. These effects produce a reduction in total peripheral resistance that result in lower blood pressure.
Adult Dose	10 mg/d PO initial; can increase gradually to an average of 25-50 mg/d
Pediatric Dose	0.2 mg/kg/d PO initially and increase by 0.2 mg/kg/d at 7- to 10-d intervals to 3 mg/kg/d
Contraindications	Documented hypersensitivity; pheochromocytoma or have taken MAO inhibitors within the last 14 d
Interactions	Tricyclic antidepressants, methylphenidate, thioxanthenes, phenothiazines, sympathomimetics, anorexiants, haloperidol may reduce effects of guanethidine; minoxidil, epinephrine, and norepinephrine may increase the toxicity of guanethidine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in congestive heart failure, asthma, peptic ulcer disease, and regional vascular disease

Drug Category: Corticosteroids

Used when adrenal crisis suspected.

Drug Name	Dexamethasone (AK-Dex, Alba-Dex, Baldex, Decadron, Dexone)
Description	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.
Adult Dose	4-8 mg IV, followed by 16-24 mg/d as IV injection q4-6h or as continuous infusion
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient admission is warranted for symptomatic patients. Because symptoms generally revolve around cardiovascular problems, admit to a cardiac monitored bed while appropriate beta-blockade is achieved.

In/Out Patient Meds

• 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

• 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center, Poisoning - First Aid and Emergency Center, and Endocrine System Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, Poison Proofing Your Home, and Thyroid Problems.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider co-ingestion, as in other toxic ingestions
• Failure to provide corresponding appropriate emergency medical and psychiatric care and disposition if ingestion may have been a suicide attempt
• Failure to acknowledge the possibility of suicide attempts in older children
• Failure to diagnose ingestion in obese or anorexic patients who have been surreptitiously ingesting thyroid supplements as a means to achieve weight-loss goals

Special Concerns

Because of the delayed effects of thyroid hormone, longer periods of observation and treatment may be required.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932. [Medline]. [Full Text].
2. Litovitz TL, White JD. Levothyroxine ingestions in children: an analysis of 78 cases. Am J Emerg Med. Jul 1985;3(4):297-300. [Medline].
3. Bauer LA. Simulations of Levothyroxine Bioavailability Using a Single-Dose Study Protocol. Am J Ther. Jun 1995;2(6):414-416. [Medline].
4. Berkner PD, Starkman H, Person N. Acute L-thyroxine overdose; therapy with sodium ipodate: evaluation of clinical and physiologic parameters. J Emerg Med. May-Jun 1991;9(3):129-31. [Medline].
5. Bosse GM, Matyunas NJ. Delayed toxidromes. J Emerg Med. Jul-Aug 1999;17(4):679-90. [Medline].
6. Golightly LK, Smolinske SC, Kulig KW, Wruk KM, Gelman CJ, Rumack BH. Clinical effects of accidental levothyroxine ingestion in children. Am J Dis Child. Sep 1987;141(9):1025-7. [Medline].
7. Lehrner LM, Weir MR. Acute ingestions of thyroid hormones. Pediatrics. Mar 1984;73(3):313-7. [Medline].
8. Seger D. Endocrine principles. In: Goldfrank L, ed. Goldfrank's Toxicologic Emergencies. 5^th ed. New York, NY: McGraw-Hill; 1994:338-90.
9. Singh GK, Winterborn MH. Massive overdose with thyroxine,--toxicity and treatment. Eur J Pediatr. Jan 1991;150(3):217. [Medline].
10. Tunget CL, Clark RF, Turchen SG, Manoguerra AS. Raising the decontamination level for thyroid hormone ingestions. Am J Emerg Med. Jan 1995;13(1):9-13. [Medline].
11. Veltri JC, Litovitz TL. 1983 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. Sep 1984;2(5):420-43. [Medline].

Article Last Updated: Mar 11, 2008