AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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

INTRODUCTION

Section 2 of 11  

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

Background

Hyperthyroidism, thyroid storm, and Graves disease are conditions of excess thyroid hormone. The elevated level of thyroid hormones can result in clinical manifestations ranging from mild to severely toxic with resultant morbidity and mortality for affected patients.

Hyperthyroidism

Hyperthyroidism presents as a constellation of symptoms due to elevated levels of circulating thyroid hormones. Because of the many actions of thyroid hormone on various organ systems in the body, the spectrum of clinical signs produced by the condition is broad. The presenting symptoms can be subtle and nonspecific, making hyperthyroidism difficult to diagnose in its early stages without the aid of laboratory data.

The term hyperthyroidism refers to inappropriately elevated thyroid function. Though often used interchangeably, the term thyrotoxicosis, which is an excessive amount of circulating thyroid hormone, is not synonymous with hyperthyroidism. Increased levels of hormone can occur despite normal thyroid function, such as in instances of inappropriate exogenous thyroid hormone or excessive release of stored hormone from an inflamed thyroid gland.

Graves disease

Graves disease (diffuse toxic goiter), the most common form of overt hyperthyroidism, is an autoimmune condition in which autoantibodies are directed against the thyroid-stimulating hormone (TSH) receptor. As a result, the thyroid gland is inappropriately stimulated with ensuing gland enlargement and increase of thyroid hormone production. Risk factors for Graves disease include family history of hyperthyroidism or various other autoimmune disorders, high iodine intake, stress, use of sex steroids, and smoking. The disease is classically characterized by the triad of goiter, exophthalmos, and pretibial myxedema.

Thyroid storm

Thyroid storm is a rare and potentially fatal complication of hyperthyroidism. It typically occurs in patients with untreated or partially treated thyrotoxicosis who experience a precipitating event such as surgery, infection, or trauma. Thyroid storm must be recognized and treated on clinical grounds alone, as laboratory confirmation often cannot be obtained in a timely manner. Patients typically appear markedly hypermetabolic with high fevers, tachycardia, nausea and vomiting, tremulousness, agitation, and psychosis. Late in the progression of disease patients may become stuporous or comatose with hypotension.

For more information, see Medscape's Thyroid Disease Resource Center.

Pathophysiology

In healthy patients, the hypothalamus produces thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH); this in turn triggers the thyroid gland to release thyroid hormone.

Thyroid hormone concentration is regulated by negative feedback by circulating free hormone primarily on the anterior pituitary gland and to a lesser extent on the hypothalamus. The secretion of TRH is also partially regulated by higher cortical centers.

The thyroid gland produces the prohormone thyroxine (T4), which is deiodinated primarily by the liver and kidneys to its active form, triiodothyronine (T3). The thyroid gland also produces a small amount of T3 directly. T4 and T3 exist in 2 forms: a free, unbound portion that is biologically active and a portion that is protein bound to thyroid-binding globulin (TBG). Despite consisting of less than 0.5% of total circulating hormone, free or unbound T4 and T3 levels best correlate with the patient's clinical status.

Frequency

United States

The overall incidence of hyperthyroidism is estimated between 0.05 to 1.3%, with the majority consisting of subclinical disease. The prevalence of hyperthyroidism is approximately 5-10 times less than hypothyroidism.

Thyroid storm is a rare disorder. Approximately 1-2% of patients with hyperthyroidism progress to thyroid storm.

Mortality/Morbidity

• Thyroid storm, if unrecognized and untreated, is often fatal.
• Adult mortality rate from thyroid storm is approximately 10-20%, but it has been reported to be as high as 75% in hospitalized populations. Underlying precipitating illness may contribute to high mortality.

Race

• White and Hispanic populations in the United States have a slightly higher prevalence of hyperthyroidism in comparison with black populations.

Sex

• A slight predominance of hyperthyroidism exists among females.

Age

• Thyroid storm may occur at any age but is most common in those in their third through sixth decades of life.
• Graves disease predominantly affects those aged 20-40 years.
• The prevalence of toxic multinodular goiter increases with age and becomes the primary cause of hyperthyroidism in elderly persons.

CLINICAL

Section 3 of 11  

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

History

The clinical presentation of hyperthyroidism ranges from an array of nonspecific historical features to an acute life-threatening event. Historical features common to hyperthyroidism and thyroid storm are numerous and represent a hypermetabolic state with increased beta-adrenergic activity.

• Weight loss
• • Patients typically report an average loss of approximately 15% of their prior weight.
  • Basal metabolic rate is increased with a stimulation of lipolysis and lipogenesis.
• Palpitations
• Chest pain - Often occurs in the absence of cardiovascular disease
• Psychosis
• Menstrual irregularity
• Disorientation
• Tremor
• Nervousness, anxiety, or emotional lability
• Heat intolerance
• Increased perspiration
• Fatigue
• Weakness - Typically affects proximal muscle groups
• Edema
• Dyspnea
• Frequent bowel movements

Physical

• Fever
• Tachycardia (often out of proportion to the fever)
• Diaphoresis (often profuse)
• Dehydration secondary to GI losses and diaphoresis
• Warm, moist skin
• Widened pulse pressure
• Congestive heart failure (may be a high output failure)
• Thyromegaly
• • Nontender, diffuse enlargement in Graves disease
  • Tender, diffusely enlarged gland in thyroiditis
  • Thyroid nodules, either single or multinodular goiter
• Exophthalmos
• Shock
• Atrial fibrillation
• • Typically in elderly patients
  • May be refractory to attempted rate control with digitalis
  • Converts after antithyroid therapy in 20-50% of patients
• Myopathy
• Thyroid bruit - Relatively specific for thyrotoxicosis
• Fine, resting tremor

Causes

Hyperthyroidism results from numerous etiologies, including autoimmune, drug-induced, infectious, idiopathic, iatrogenic, and malignancy.

• Autoimmune
• • Graves disease
  • Chronic thyroiditis (Hashimoto thyroiditis) - Although the primary cause of hypothyroidism, the disease process occasionally presents initially with thyrotoxicosis
  • Subacute thyroiditis (de Quervain thyroiditis) - Diffuse, painful inflammation of the thyroid producing a transient state leakage of stored hormone
  • Postpartum thyroiditis - Presents similarly to subacute thyroiditis 2-6 months postpartum but typically painless with mild symptoms
• Drug-induced
• • Iodine-induced - Occurs after administration of either supplemental iodine to those with prior iodine deficiency or pharmacologic doses of iodine (contrast media, medications) in those with underlying nodular goiter
  • Amiodarone - Its high iodine content is primarily responsible for producing a hyperthyroid state, though the medication may itself induce autoimmune thyroid disease.
• Infectious
• • Suppurative thyroiditis - Often bacterial, results in a painful gland commonly in those with underlying thyroid disease or in immunocompromised individuals
  • Postviral thyroiditis
• Idiopathic
• • Toxic multinodular goiter - The second most common cause of hyperthyroidism, characterized by functionally autonomous nodules, typically after age 50 years
• Iatrogenic
• • Thyrotoxicosis factitia - A psychiatric condition in which high quantities of exogenous thyroid hormone are consumed
  • Surgery - Now uncommon secondary to preventative measures, manipulation of the thyroid gland during thyroidectomy historically caused a flood of hormone release, often resulting in highly toxic blood levels
• Malignancy
• • Toxic adenoma - A single, hyperfunctioning nodule within a normally functioning thyroid gland commonly among patients in their 30s and 40s
  • Thyrotropin-producing pituitary tumors
  • Struma ovarii - Ovarian teratoma with ectopic thyroid tissue
• Thyroid storm can be triggered by many different events, classically in patients with underlying Graves disease or toxic multinodular goiter.
• • Infection
  • Surgery
  • Cardiovascular events
  • Toxemia of pregnancy
  • Diabetic ketoacidosis, hyperosmolar coma, and insulin-induced hypoglycemia
  • Thyroidectomy
  • Discontinuation of antithyroid medication
  • Radioactive iodine
  • Vigorous palpation of the thyroid gland in hyperthyroid patients

DIFFERENTIALS

Section 4 of 11  

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

Other Problems to be Considered

Psychosis
Anxiety
Malignancy
Pregnancy
Pheochromocytoma

WORKUP

Section 5 of 11  

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

Lab Studies

• Thyroid function studies confirm the diagnosis in the appropriate clinical setting.
• • Elevation of free T4 and low to undetectable TSH levels are diagnostic of thyrotoxicosis.
  • Excessive TSH levels in the setting of elevated free T4 indicate hyperthyroidism of pituitary origin.
  • There is little utility in obtaining total T4 levels, as variations in serum thyroid-binding proteins alter the ability to interpret results.
  • Particularly in thyroid storm, the diagnosis must be made on the basis of the clinical examination as rapid assays are not universally available.
  • Thyroid function studies do not distinguish thyrotoxicosis from thyroid storm; however, several laboratory abnormalities may be encountered in thyroid storm.
• Hyperglycemia
• Hypercalcemia
• Hepatic function abnormalities
• Low serum cortisol
• Leukocytosis
• Hypokalemia (in thyrotoxic periodic paralysis)

Imaging Studies

• Chest radiography may identify congestive heart failure or pulmonary infections, often associated with progression to thyroid storm.
• Nuclear thyroid scan
• • Diffuse uptake in Graves disease
  • Focal uptake in toxic nodular thyroiditis

Other Tests

• Electrocardiogram
• • Sinus tachycardia most common
  • Atrial fibrillation (often in elderly patients)
  • Complete heart block (rare)

TREATMENT

Section 6 of 11  

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

Emergency Department Care

• Do not delay treatment once thyroid storm is suspected.
• Patients with severe thyrotoxicosis must be placed on a cardiac monitor. The patient should be intubated if profoundly altered. Supplemental oxygen may be required. Aggressive fluid resuscitation may be indicated.
• Fevers are treated with cooling measures and antipyretics. However, aspirin should be avoided to prevent decreased protein binding and subsequent increases in free T3 and T4 levels. Only in the setting of subacute thyroiditis is aspirin indicated.
• Aggressive hydration of up to 3-5 L/d of crystalloid compensates for potentially profound GI and insensible losses.
• Appropriate electrolyte replacement should be directed by laboratory values.
• Atrial fibrillation due to thyroid storm may be refractory to rate control, and conversion to sinus rhythm may be impossible until after antithyroid therapy has been initiated.
• Intravenous glucocorticoids are indicated if adrenal insufficiency is suspected. Large doses of dexamethasone (2 mg q6h) inhibit hormone production and decrease peripheral conversion from T4 to T3.
• Antithyroid medications such as propylthiouracil (PTU) and methimazole (MMI) oppose synthesis of T4 by inhibiting the organification of tyrosine residues.
• • PTU also inhibits the conversion of T4 to active T3, although this effect is minimal and not usually clinically significant.
  • Clinical effects may be seen as soon as 1 hour after administration. Both agents are administered orally or via a nasogastric tube.
  • PTU and MMI inhibit the synthesis of new thyroid hormone but are ineffective in blocking the release of preformed thyroid hormone. Iodide administration serves this purpose well; however, it should be delayed until 1 hour after the loading dose of antithyroid medication to prevent the utilization of iodine in the synthesis of new thyroid hormone. Lithium may be used as an alternative in those with iodine allergy.
  • Antithyroid medications appear to also have an immunosuppressive effect, evidenced by decreased serum concentrations of antithyrotropin-receptor antibodies.
  • Primary antithyroid treatment (as an alternative to surgery) is often suggested  for Graves disease, as remission after cessation of medical management is possible. In those with toxic multinodular goiters and solitary autonomous nodules, first-line treatment with antithyroid drugs is not recommended since spontaneous remission is rare. 
• Beta-adrenergic blocking agents are the mainstays of symptomatic therapy for thyrotoxicosis. Propranolol has been used with the greatest success due to the additional benefit of inhibition of peripheral conversion of T4 to T3.

Consultations

• An intensivist should be consulted for admission to an ICU when thyroid storm is the presumptive diagnosis.
• An endocrinologist or internist may be helpful in confirming the diagnosis and in assisting in patient management.

MEDICATION

Section 7 of 11  

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

The goals of medical therapy are blockade of peripheral effects, inhibition of hormone synthesis, blockade of hormone release, and prevention of peripheral conversion of T4 to T3. Restoration of a clinical euthyroid state may take up to 8 weeks.

Blocking agents such as beta-blockers reduce sympathetic hyperactivity and decrease peripheral conversion of T4 to T3.

Guanethidine and reserpine have been used to provide sympathetic blockade and may be effective agents if beta-blockers are contraindicated or not tolerated.

Iodides and lithium work to block release of preformed thyroid hormone.

Thionamides prevent synthesis of new thyroid hormone.

Drug Category: Inhibitors of hormone synthesis

Thionamides (eg, propylthiouracil, methimazole) prevent hormone synthesis by inhibiting both the organification of iodine to tyrosine residues and the coupling of iodotyrosines. The drug must be given orally or via a nasogastric tube. PTU has the added benefit of inhibiting peripheral conversion of T4 to T3.

Drug Category: Blockade of hormone release

Iodides and lithium are used effectively to block the release of thyroid hormone. Effects are exerted directly on the thyroid gland. Lithium is used only as a secondary agent due to difficulty in titrating to an effective dose and its narrow therapeutic window. These agents should be administered at least 1 hour after PTU is given to ensure the advance blockade of thyroid hormone formation; otherwise, administering iodides could worsen symptoms. Iodide preparations are known to cause serum sickness–type reactions. Iodides should not be used for long-term therapy in thyrotoxicosis. Preparations include saturated solution of potassium iodide (SSKI), iopanoic acid, and Lugol iodine.

Drug Category: Beta-adrenergic blockers

Beta-blockade is mainstay of symptomatic therapy; antiadrenergic effects block effects of excess thyroid hormone. Beta-blockade also plays a role in the prevention of peripheral conversion of T4 to T3. Propranolol is the best studied in this class, but other beta-blockers have similar effects in hyperthyroidism.

Effects are relatively dramatic, and results may be seen within 10 minutes after administration.

Use of beta-blockers improves heart failure that is due to thyrotoxic tachycardia or thyrotoxic myocardial depression but may worsen heart failure that is due to other causes. When in doubt, therapy may be begun with a short-acting titratable agent, such as esmolol.

Reserpine and guanethidine are effective autonomic blockers that may be used if beta-blockers are contraindicated.

Drug Category: Corticosteroids

These agents play a role in the prevention of peripheral conversion of T4 to T3

FOLLOW-UP

Section 8 of 11  

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

Further Inpatient Care

• Admit patients with thyroid storm to the intensive care unit.
• Severely thyrotoxic patients should be admitted to a monitored setting.
• Confirm the diagnosis with laboratory analysis.
• Clinical improvement should be evident within hours of initiating therapy.
• Monitor therapy by laboratory values and clinical assessment. Titrate medications to optimize antithyroid and antiadrenergic effects.
• Therapy may be required for 4-8 weeks.
• Aggressively treat infection and any other underlying precipitant.

Further Outpatient Care

• Patients with mild-to-moderate hyperthyroidism or Graves disease should follow up with their primary care physician or endocrinologist after a period of ED monitoring.

Transfer

• Initiate antithyroid therapy for patients with thyrotoxicosis.
• Ensure hemodynamic stability prior to transfer.
• Consider transfer if intensivist or endocrinologist is not available to assist inpatient management.

Complications

• Surgical complications
• • Hypoparathyroidism
  • Damage to recurrent laryngeal nerve
  • Hypothyroidism with subtotal thyroidectomy
• Development of hypothyroidism following radioiodine treatment
• Visual loss or diplopia due to severe ophthalmopathy
• Localized pretibial myxedema
• High-output cardiac failure
• Muscle wasting and proximal muscle weakness

Prognosis

• Thyroid storm is usually fatal if untreated.
• • Overall rate of mortality due to thyroid storm is approximately 10-20% but has been reported as high as 75%; the precipitating factor or underlying illness is often the cause of death.
  • With early diagnosis and adequate treatment, the prognosis is good.

Patient Education

• Stress the importance of medication compliance.
• Provide return precautions including symptoms suggestive of secondary hypothyroidism and undertreated hyperthyroidism.
• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education articles Thyroid Problems and Thyroid Storm.

MISCELLANEOUS

Section 9 of 11  

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

Medical/Legal Pitfalls

• Because of the variable presentation of hyperthyroidism, even severe forms may be missed initially, particularly when patients present obtunded or comatose.
• Apathetic thyrotoxicosis often is missed in the elderly (ie, aged 70-80 y). Symptoms consistent with apathetic thyrotoxicosis include prolonged duration of symptoms, increased weight loss, cardiovascular abnormalities (common), and ocular findings (less common).
• Consider the possibility of thyrotoxicosis whenever a patient with acute behavioral changes is referred for psychiatric evaluation.

Special Concerns

• Secondary hypothyroidism is a risk after thyroid surgery, radioablation, or thyroiditis.
• Symptoms of thyrotoxicosis may be overlooked in pregnancy, as they may be indistinguishable from normal physiologic changes.
• Hyperthyroidism during pregnancy warrants especially close attention and almost always should be treated with antithyroid medications.
• Although surgery has been performed successfully during pregnancy, no data show that it has any significant advantage over antithyroid drugs as treatment. Since the necessary pretreatment with radioiodine is contraindicated, surgery should only be used if medical management is unsuccessful.
• Iodide should not be used in pregnancy unless the benefits outweigh the risks, as it can lead to goiter development in the fetus.
• During pregnancy, PTU should be used preferentially over methimazole. Each of these agents crosses the placental barrier and inhibits fetal thyroid function, but PTU crosses less readily.

ACKNOWLEDGMENTS

Section 10 of 11  

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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Craig A Manifold, DO, to the development and writing of this article.

REFERENCES

Section 11 of 11

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

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Article Last Updated: Jun 4, 2008