Hyperthyroidism, Thyroid Storm, and Graves Disease

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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 refers to an excessive amount of circulating thyroid hormone, is not synonymous with hyperthyroidism. Increased levels of hormone can occur despite otherwise 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.[1] 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 synthesize 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.

Epidemiology

Frequency

The overall incidence of hyperthyroidism is estimated between 0.05% and 1.3%, with the majority consisting of subclinical disease. A population-based study in the United Kingdom and Ireland found an incidence of 0.9 cases per 100,000 children younger than 15 years, showing that the disease incidence increases with age.[2] 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. In Japan, the estimated incidence of thyroid storm in hospitalized patients is 0.20 per 100,000 annually, according to a study by Akamizu, with the rate being 0.22% of all thyrotoxic patients.[3]

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.

A study by Ono et al of 1324 patients indicated that the following factors are associated with increased mortality risk in thyroid storm[4] :

In addition, a study by Swee et al of 28 patients with thyroid storm reported that CNS dysfunction of greater than mild severity appeared to be a risk factor for mortality.[5]

A study by Mohananey et al found that among patients hospitalized in the United States with thyroid storm, the incidence of cardiogenic shock increased from 0.5% in 2003 to 3% in 2011. However, the mortality rate among the cardiogenic shock patients fell from 60.5% in 2003 to 20.9% in 2011. The investigators also reported that a history of atrial fibrillation, alcohol abuse, preexisting congestive heart failure, coagulopathy, drug use, liver disease, pulmonary circulatory disease, valvular disease, weight loss, renal failure, and fluid and electrolyte disease was more likely in thyroid storm patients with cardiogenic shock than in other thyroid storm patients.[6]

Race

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Sex

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Age

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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.

Physical

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Causes

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

Laboratory Studies

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Imaging Studies

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Other Tests

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Emergency Department Care

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Consultations

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Guidelines Summary

ATA and AACE (2011)

In 2011, a task force of expert clinicians assembled by the American Thyroid Association and the American Association of Clinical Endocrinologists released a set of 100 evidence-based recommendations on the management of thyrotoxicosis. These guidelines addressed the following[13] :

ATA (2016)

In 2016, the American Thyroid Association updated the 2011 guidelines. The following are a sampling of the 124 evidence-based recommendations included in the guideline update[14] :

Japanese guidelines (2016)

Also in 2016, the Japan Thyroid Association and Japan Endocrine Society released guidelines for the management of thyroid storm. Recommendations include the following[15] :

ATA (2017)

In 2017, the American Thyroid Association released guidelines pertaining to the diagnosis and management of thyroid disease in women during pregnancy and the postpartum period, as well as prior to conception. Recommendations regarding Graves disease and hyperthyroidism in pregnancy included the following[16] :

Medication Summary

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. A study by Tun et al indicated that in patients with Graves disease receiving thionamide therapy, high thyrotropin receptor–stimulating antibody (TRab) levels at diagnosis of the disease and/or high TRab levels at treatment cessation are risk factors for relapse, particularly within the first two years. The study included 266 patients.[17]

A retrospective study by Rabon et al indicated that in children with Graves disease, antithyroid drugs usually do not induce remission, although most children who do achieve remission through these agents do not relapse. Of 268 children who were started on an antithyroid drug, 57 (21%) experienced remission, with 16 of them (28%) relapsing.[18]

Propylthiouracil (PTU)

Clinical Context:  DOC; effects may be seen soon after drug is started, but therapy may need to be continued for 4-12 wk. Laboratory monitoring of T4 and T3 levels may be required to adjust therapy. Although classified as pregnancy category D, recommended as DOC for women who are pregnant or breastfeeding.

Methimazole (Tapazole)

Clinical Context:  An effective inhibitor of thyroid synthesis; however, it does not inhibit peripheral conversion of thyroid hormone

Class Summary

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.

Iopanoic acid

Clinical Context:  Absorption from GI tract is rapid and complete. Iodine equilibrates in extracellular fluids and is concentrated specifically by thyroid gland. For treatment of thyrotoxicosis, parenteral iodine may be used.

Saturated solution of potassium iodide (SSKI, PIMA)

Clinical Context:  Inhibits thyroid hormone secretion. Solution contains 50 mg of iodide per drop and may be mixed with juice or water.

Lugol solution

Clinical Context:  Inhibits thyroid hormone secretion. Contains 8 mg of iodide per drop. May be mixed with juice or water for intake.

Class Summary

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.

Propranolol (Inderal)

Clinical Context:  DOC; can control cardiac and psychomotor manifestations within minutes.

Class Summary

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.

Dexamethasone (Decadron)

Clinical Context:  Blocks conversion of T4 to T3 and does not interfere with cortisol stimulation testing.

Class Summary

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

Further Outpatient Care

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Further Inpatient Care

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Transfer

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Complications

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Prognosis

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Patient Education

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What is hyperthyroidism?What is Graves disease?What is thyroid storm?What are conditions of excess thyroid hormone?What is the pathophysiology of conditions of excess thyroid hormone?What is the incidence of hyperthyroidism?What is the incidence of thyroid storm?What is the mortality risk from thyroid storm?What is the racial predilections of hyperthyroidism?How does the incidence of hyperthyroidism vary by sex?How does the incidence of hyperthyroidism, thyroid storm, and Graves disease vary by age?What are the signs and symptoms of hyperthyroidism and thyroid storm?Which physical findings are characteristic of hyperthyroidism?What are autoimmune etiologies of hyperthyroidism?What are drug-induced etiologies of hyperthyroidism?What are infectious etiologies of hyperthyroidism?What is the role of toxic multinodular goiter in the etiology of hyperthyroidism?What are iatrogenic etiologies of hyperthyroidism?What is the role of tumors in the etiology of hyperthyroidism?What are events that may trigger thyroid storm?What are the differential diagnoses for Hyperthyroidism, Thyroid Storm, and Graves Disease?What is the role of thyroid function studies in the workup of hyperthyroidism, thyroid storm, and Graves disease?Which lab studies are performed in the workup of hyperthyroidism, thyroid storm, and Graves disease?What is the role of imaging studies in the workup of hyperthyroidism, thyroid storm, and Graves disease?Which findings on electrocardiogram suggest hyperthyroidism, thyroid storm, and Graves disease?What is included in emergency department (ED) care of hyperthyroidism, thyroid storm, and Graves disease?Which medications are used in the emergency department (ED) treatment of hyperthyroidism, thyroid storm, and Graves disease?What are the FDA warnings for the use of propylthiouracil (PTU) in the treatment of hyperthyroidism, and Graves disease?What is the role of propylthiouracil (PTU) in the emergency department (ED) treatment of hyperthyroidism, and Graves disease?How is thyrotoxicosis managed in the emergency department (ED)?What are treatment options for medication-induced thyroid storm?Which specialists should be consulted for the treatment of hyperthyroidism, thyroid storm, and Graves disease?What are the key recommendations of the Japanese guidelines (2016) on the management of thyroid storm?What do the ATA and AACE (2011) treatment guidelines for thyrotoxicosis cover?What are the key recommendations of the ATA (2016) treatment guidelines for hyperthyroidism, thyroid storm, and Graves disease?What are the ATA (2017) recommendations on the management of hyperthyroidism, thyroid storm, and Graves disease during pregnancy?What are the goals of medical therapy for hyperthyroidism, thyroid storm, and Graves disease?Which medications are used in the treatment of hyperthyroidism, thyroid storm, and Graves disease?Which medications in the drug class Corticosteroids are used in the treatment of Hyperthyroidism, Thyroid Storm, and Graves Disease?Which medications in the drug class Beta-adrenergic blockers are used in the treatment of Hyperthyroidism, Thyroid Storm, and Graves Disease?Which medications in the drug class Blockade of hormone release are used in the treatment of Hyperthyroidism, Thyroid Storm, and Graves Disease?Which medications in the drug class Inhibitors of hormone synthesis are used in the treatment of Hyperthyroidism, Thyroid Storm, and Graves Disease?What outpatient followup is needed for hyperthyroidism, thyroid storm, and Graves disease?What is included in inpatient care of hyperthyroidism, thyroid storm, and Graves disease?When is transfer indicated for patients with hyperthyroidism, thyroid storm, and Graves disease?What are the complications of hyperthyroidism, thyroid storm, and Graves disease?What is the prognosis of hyperthyroidism, thyroid storm, and Graves disease?What is included in patient education about hyperthyroidism, thyroid storm, and Graves disease?

Author

Erik D Schraga, MD, Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Howard A Bessen, MD, Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Additional Contributors

Robin R Hemphill, MD, MPH, Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine

Disclosure: Nothing to disclose.

References

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