AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

A toxic nodular goiter (TNG) is a thyroid gland that contains autonomously functioning thyroid nodules that secrete excess thyroid hormone. Henry Plummer, MD, first described TNG in 1913; thus, TNG is also known as Plummer disease. TNG is the second most common cause of hyperthyroidism in the western world, after Graves disease. In elderly individuals and in areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Pathophysiology

TNG represents a spectrum that ranges from a single hyperfunctioning nodule within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG are similar to those of other types of hyperthyroidism.

Frequency

United States

TNG accounts for approximately 15-30% of cases of hyperthyroidism in the United States.

International

In areas of endemic iodine deficiency, TNG accounts for approximately 58% of cases of hyperthyroidism, 10% of which are from solitary toxic nodules. Graves disease accounts for 40% of cases of hyperthyroidism. In patients with underlying nontoxic multinodular goiter, initial iodine supplementation (or iodinated contrast agents) can lead to hyperthyroidism (Jod-Basedow effect). Iodinated drugs, such as amiodarone, may also induce hyperthyroidism in patients with underlying nontoxic multinodular goiter. Roughly 3% of patients treated with amiodarone in the United States (more in areas of iodine deficiency) develop amiodarone-induced hyperthyroidism.

Mortality/Morbidity

Morbidity and mortality from TNG may be divided into problems related to hyperthyroidism and problems related to growth of the nodules and gland.

• TNG is more common in elderly adults; therefore, complications due to comorbidities, such as coronary artery disease, are significant in the management of hyperthyroidism.
• Local compression problems due to nodule growth are unusual and include dyspnea, hoarseness, and dysphagia.

Sex

TNG occurs more commonly in women than in men. In persons older than 40 years, the prevalence rate of palpable nodules is 5-7% in women and 1-2% in men.

Age

Most patients with TNG are older than 50 years.

Thyrotoxicosis often occurs in patients with a history of longstanding goiter. Toxicity occurs in a subset of patients who develop autonomous function. This toxicity usually peaks in the sixth and seventh decades of life, especially in those with a family history of multinodular goiter or TNG, suggesting a genetic component.

CLINICAL

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History

• Thyrotoxic symptoms: Most patients with toxic nodular goiter (TNG) present with symptoms typical of hyperthyroidism. Symptoms include heat intolerance, palpitations, tremor, weight loss, hunger, and frequent bowel movements.
• • Elderly patients may have atypical symptoms that include the following:
    • Weight loss is the most common complaint in elderly patients with hyperthyroidism.

    • Anorexia and constipation may occur, in contrast to frequent bowel movements often reported by younger patients.

    • Dyspnea or palpitations may be a common occurrence.

    • Tremor also occurs but can be confused with essential senile tremor.

    • Cardiovascular complications occur commonly in elderly patients, and a history of atrial fibrillation, congestive heart failure, or angina may be present.

  • F. Lahey, MD, first described apathetic hyperthyroidism in 1931; this is characterized by blunted affect, lack of hyperkinetic motor activity, and slowed mentation in a patient who is thyrotoxic.

• Obstructive symptoms: A significantly enlarged goiter can cause symptoms related to mechanical obstruction.
• • A large substernal goiter may cause dysphagia, dyspnea, or frank stridor. Rarely, this goiter results in a surgical emergency.

  • Involvement of the recurrent or superior laryngeal nerve may result in complaints of hoarseness or voice change.

• Asymptomatic: Many patients are asymptomatic or have minimal symptoms and are incidentally found to have hyperthyroidism during routine screening. The most common laboratory finding is a suppressed thyroid-stimulating hormone (TSH) with normal free thyroxine (T4) levels.

Physical

• Findings of hyperthyroidism may be more subtle than findings of Graves disease. Features may include widened palpebral fissures, tachycardia, hyperkinesis, moist smooth skin, tremor, proximal muscle weakness, and brisk deep tendon reflexes.
• The size of the thyroid gland is variable. Large substernal glands may not be appreciable upon physical examination.
• A dominant nodule or multiple irregular, variably sized nodules are typically present. In a small gland, multinodularity may be apparent only on a sonogram. Chronic Graves disease may present with some nodularity; therefore, establishing the diagnosis is sometimes difficult.
• Hoarseness or tracheal deviation may be present upon examination.
• Mechanical obstruction may result in superior vena cava syndrome, with engorgement of facial and neck veins (Pemberton sign) (Basaria, 2004).
• Stigmata of Graves disease (eg, orbitopathy, pretibial myxedema, acropachy) are not observed.

Causes

Functional autonomy of the thyroid gland appears to be related to iodine deficiency. Various mechanisms have been implicated but the molecular pathogenesis is poorly understood.

• The sequence of events leading to toxic multinodular goiter is as follows:
• • Iodine deficiency leads to low levels of T4; this induces thyroid cell hyperplasia to compensate for the low levels of T4.

  • Increased thyroid cell replication predisposes single cells to somatic mutations of the TSH receptor. Constitutive activation of the TSH receptor may generate autocrine factors that promote further growth, resulting in clonal proliferation. Cell clones then produce multiple nodules.

• Somatic mutations of the TSH receptors and Ga protein confer constitutive activation to the cyclic adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways. These mutations may be responsible for functional autonomy of the thyroid in 20-80% of cases.
• • These mutations are found in autonomously functioning thyroid nodules, both solitary and within a multinodular gland. Nonfunctioning thyroid nodules within the same gland lack these mutations.

  • The reported frequency of these mutations varies widely, ranging from 10-80%. Higher incidence is reported in patients with iodine deficiency.

• In addition to somatic mutations, polymorphisms of the TSH receptor have been studied in patients with TNG; notably, polymorphisms involving the carboxyl-terminal tail of the human TSH receptor have been found in both nodular and genomic DNA.
• • Unlike the somatic mutations found in autonomously functioning nodules, these mutations have also been found in other cell lines, indicating a germline mutation. One of these, D727E, was present with greater frequency in patients with TNG than in healthy individuals; this suggests that this polymorphism may be associated with the disease.

  • The presence of the heterozygous state for the D727E variant of the human TSH receptor alone is not sufficient for the development of the TNG. Approximately 10% of healthy individuals have this polymorphism.

• Possible mediators in growth include the following:
• • Endothelin-1 (ET-1) production is increased in rat thyroid glands that have undergone hyperplasia; this suggests that ET-1 production may be involved in thyroid gland growth and vascularity. In contrast to normal thyroid tissue and papillary thyroid cancer, thyroid tissue in patients with TNG shows markedly positive staining of the stroma but absent staining of the follicular cells. The significance of this finding is unclear, but ET-1 is, in addition to being a vasoconstrictor, a mitogen for vascular endothelium, smooth muscle cells, and thyroid follicular cells.

  • In vitro systems have shown stimulation of thyroid follicular cell proliferation with insulinlike growth factor-1, epidermal growth factor, and fibroblast growth factor. Reduced concentrations of transforming growth factor-b1 or resistance to transforming growth factor-b have also been associated with follicular cell growth. The role of these multiple factors in the growth and secretory function of TNG needs further investigation.

DIFFERENTIALS

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Other Problems to be Considered

Subclinical hyperthyroidism
Reidel thyroiditis
Substernal goiter
Amiodarone associated thyroid disease

WORKUP

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Lab Studies

• Thyroid function tests: Evidence of hyperthyroidism must be present in order to consider a diagnosis of toxic nodular goiter (TNG).
• • Third-generation TSH assays are generally the best initial screening tool for hyperthyroidism. Patients with TNG will have suppressed TSH levels.

  • Free T4 levels or surrogates of free T4 levels (ie, free T4 index) may be elevated or within the reference range. An isolated increase in T4 is observed in iodine-induced hyperthyroidism or in the presence of agents that reduce peripheral conversion of T4 to triiodothyronine (T3) (eg, propranolol, corticosteroids, radiocontrast agents, amiodarone).

  • Some patients may have normal free T4 levels (or free T4 index) with an elevated T3 level (T3 toxicosis); this may occur in 5-46% of patients with toxic nodules. Note that the total T3 and T4 levels may often be within the reference range but may be higher than the normal range for a particular individual; this is especially true in patients with nonthyroidal illness in which T3 levels are decreased.

• Subclinical hyperthyroidism: Some patients may have suppressed TSH levels with normal free T4 and total T3 levels.

Imaging Studies

• Sonography
• • Sonography is a highly sensitive procedure for delineating discrete nodules not palpable during thyroid examination. Sonography is helpful when correlated with nuclear scans to determine functionality of nodules.

  • This technique may be used to serially examine the size of thyroid nodules.

• Nuclear scintigraphy
• • Nuclear medicine scans can be performed with radioactive iodine I 123 or technetium Tc 99m. These isotopes are chosen for their shorter half-life and because they provide lower radiation exposure to the patient when compared to sodium iodide I 131.

  • Technetium is trapped in the thyroid but not organified. Although convenient, technetium scanning may provide misleading results. Some nodules that appear hot or warm on technetium scan results may be cold on iodine scan results. Nodules with discordant technetium and iodine scan results may be malignant; therefore, iodine I 123 scanning is preferred.

  • By determining the amount of thyroid uptake, nuclear scans allow determination of the cause of hyperthyroidism. Patients with Graves disease usually have homogeneous diffuse uptake. Glands with thyroiditis have low uptake.

  • In patients with TNG, the scan results usually reveal patchy uptake, with areas of both increased and decreased uptake. The uptake rate of radioiodine in 24 hours averages approximately 20-30%. Radioactive sodium iodide I 131 ablation of the thyroid gland may be considered if thyroid uptake value is elevated. Several therapeutic modalities have been suggested to increase uptake (eg, low iodine diet, lithium, recombinant TSH, propylthiouracil).

  • Thyroid scanning is also useful for helping to determine the presence of substernal extension of the thyroid gland, which may contain toxic nodules.

• Other imaging modalities
• • In the workup for patients with compressive or obstructive symptoms, CT scan of the neck may help establish whether the trachea is patent and if tracheal deviation or impingement of other structures is caused by a nodular goiter.

  • Multinodular goiters, especially those with a substernal component, are often incidental findings on chest radiographs, CT scans, or MRI. CT scans with iodinated contrast may induce thyrotoxicosis in individuals with an underlying nontoxic multinodular goiter by supplying an iodine load (Jod-Basedow effect). This type of thyrotoxicosis is self-limited but may last longer if areas of autonomy already exist within the goiter.

Procedures

• Fine-needle aspiration
• • Fine-needle aspiration is not usually indicated in an autonomously functioning (ie, hot) thyroid nodule. The risk of malignancy is quite low. Interpretation of the cytology specimen is difficult because it is likely to demonstrate a follicular neoplasm (ie, sheets of follicular cells with little or no colloid), and distinguishing between a benign lesion and a malignant lesion is not possible without histologic sectioning to examine for the presence of vascular or capsular invasion.

  • Perform a fine-needle aspiration biopsy if a dominant cold nodule is present in a multinodular goiter. A clinically significant nodule is larger than 1 cm in maximum diameter, based on either palpation or ultrasound images, unless there is an increased risk of malignancy. Nonpalpable nodules may be biopsied with the assistance of sonography.

  • A history of head or neck irradiation during childhood increases the risk of malignancy. Head or neck irradiation in an adult increases the frequency of TNG and carcinoma of the thyroid. Patients from iodine-replete areas have the same risk of malignancy as those from iodine-deficient areas.

Histologic Findings

Autonomous nodules may be monoclonal or polyclonal. Many nodules studied in multinodular goiters may actually be monoclonal, even in the setting of histologically marked phenotypic variation.

The histologic appearance of a multinodular goiter can be highly variable and may involve the presence of normal-sized follicles, microfollicles, or macrofollicles all coexisting within the same gland. Early goiters display micronodular growth patterns. Actively proliferating follicular cells can be observed within some thyroid follicles, resulting in budding intraluminal projections, while other cells within the same follicle appear to be in the resting phase. Conversely, some follicles show a more uniform appearance of cells. Periods of alternating active and quiescent growth appear to occur within the goiter. Areas of fresh and old hemorrhage with calcification are also occasionally present.

TREATMENT

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Medical Care

The optimal therapy for treatment of toxic nodular goiter (TNG) remains controversial. Unlike Graves disease, TNG is not an autoimmune disease and rarely, if ever, remits. Therefore, patients who have autonomously functioning nodules should be treated definitely with radioactive iodine or surgery. Patients with subclinical hyperthyroidism should be monitored closely for overt disease. Some suggest that elderly patients, women with osteopenia, and patients with risk factors for atrial fibrillation should be treated, even those who have subclinical disease.

• Sodium iodide I 131 treatment: In the United States and Europe, radioactive iodine is considered the treatment of choice for TNG. Except for pregnancy, there are no absolute contraindications to radioiodine therapy.
• • Much debate exists regarding optimal dosing of radioactive iodine. Patients with TNG tend to have less uptake than patients with Graves disease; therefore, they are generally considered to need higher doses of sodium iodide I 131. However, recent studies by Allahabadia et al suggest that fixed doses of radioiodine do not demonstrate any difference in response in these two groups of patients (using a fixed dose of 370 megabequerels).

  • A single dose of radioiodine therapy has a success rate of 85-100% in patients with TNG. Radioiodine therapy may reduce the size of the goiter by up to 40%.

  • Failure of initial treatment with radioactive iodine has been associated with increased goiter size and higher T3 and free T4 levels, which suggests that these factors may present a need for higher doses of sodium iodide I 131.

  • In patients with uptakes of less than 20%, pretreatment with lithium, propylthiouracil, or recombinant TSH can increase the effectiveness of iodine uptake and treatment. This treatment may be valuable in elderly patients in whom surgery is considered high risk.

  • Complications
    • Hypothyroidism occurs in 10-20% of patients; this is similar to the incidence rate after surgery and is substantially less than in the treatment of Graves disease.

    • Tracheal compression due to thyroid swelling after radiation therapy is no longer thought to be a risk.

    • Elderly patients may have exacerbation of congestive heart failure and atrial fibrillation. Pretreat elderly patients with antithyroid drugs.

    • Thyroid storm is a rare complication, particularly in patients with rapidly enlarging goiters or high total T3 levels. Patients with these conditions should receive pretreatment with antithyroid drugs.

• Pharmacotherapy: Antithyroid drugs and beta-blockers are used for short courses in the treatment of TNG; they are important in rendering patients euthyroid in preparation for radioiodine or surgery and treating hyperthyroidism while awaiting full clinical response to radioiodine. Patients with subclinical disease at high risk of complications (eg, atrial fibrillation, osteopenia) may be given a trial of low dose methimazole (5-15 mg/d) or beta-blockers and monitored for a change in symptoms or for progression of disease that requires definitive treatment.
• • Thioamides: The role of therapy with thioamides (eg, propylthiouracil, methimazole) is to achieve euthyroidism prior to definitive treatment with either surgery or radioiodine therapy. Data suggest that pretreated patients have decreased response to radioiodine. The general recommendation is to stop antithyroid agents at least 4 days prior to radioiodine therapy to maximize the radioiodine effect.
    • Antithyroid drugs are often administered for 2-8 weeks before radioiodine therapy to avoid the risk of precipitating thyroid storm. Although many physicians no longer consider this treatment necessary, general consensus is that elderly patients or patients with high risk of cardiac complications should receive this treatment.

    • Both antithyroid drugs and beta-blockers have side effects—most commonly pruritic rash, fever, gastrointestinal upset, and arthralgias. More serious potential side effects include agranulocytosis, drug-induced lupus and other forms of vasculitis, and liver damage.

  • Beta-adrenergic receptor antagonists: These drugs remain useful in the treatment of symptoms of thyrotoxicosis; they may be used alone in patients with mild thyrotoxicosis or in conjunction with thioamides for treatment of more severe disease.
    • Propranolol, a nonselective beta-blocker, may help lower the heart rate, control tremor, reduce excessive sweating, and alleviate anxiety. Propranolol is also known to reduce the conversion of T4 to T3.

    • In patients with underlying asthma, beta-1 selective antagonists, such as atenolol or metoprolol, would be safer options.

    • In patients with contraindications to beta-blockers (eg, moderate-to-severe asthma), calcium channel antagonists (eg, diltiazem) may be used to help control the heart rate.

Surgical Care

Surgical therapy is usually reserved for young individuals, patients with a large nodule or nodules or obstructive symptoms, patients with dominant nonfunctioning or suspicious nodules, patients who are pregnant, patients in whom radioiodine therapy has failed, or patients who require a rapid resolution of the thyrotoxic state.

• Subtotal thyroidectomy results in rapid cure of hyperthyroidism in 90% of patients and allows for rapid relief of compressive symptoms.
• Restoring euthyroidism prior to surgery is preferable.

• Complications of surgery include the following:
• • Frequency of hypothyroidism is similar to that of those treated with radioiodine (15-25%).

  • Complications include permanent vocal cord paralysis (2.3%), permanent hypoparathyroidism (0.5%), temporary hypoparathyroidism (2.5%), and significant postoperative bleeding (1.4%).

  • Other postoperative complications include tracheostomy, wound infection, wound hematoma, myocardial infarction, atrial fibrillation, and stroke.

  • The mortality rate is almost zero.

Consultations

• Consult an endocrinologist for hyperthyroidism that has not responded to medical therapy or if other comorbid conditions are complicating the patient's condition. Refer patients with amiodarone-associated hyperthyroidism to an endocrinologist. In a multinodular goiter with cold and hot areas on thyroid scan findings, fine-needle aspiration may be required to determine the histologic nature of the cold lesions.
• Consult an endocrine surgeon if medical therapy fails to maintain the euthyroid state, if compromise of the trachea is noted on imaging studies, or if the patient requests surgical removal.
• Consult a thoracic surgeon in the case of a toxic substernal goiter, for which the surgeon may be helpful in further diagnostic and therapeutic measures.

Activity

• Activity should be restricted to maintain a heart rate less than 90 beats per minute.

MEDICATION

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

Drug Category: Antithyroid agents

Inhibit thyroid hormone production. Propylthiouracil and methimazole are thioamide derivatives. Propylthiouracil is a thiourea antithyroid drug that blocks the production of thyroid hormones. This drug, at high doses, also inhibits the peripheral deiodination of T4 to T3 and is used (1) in management of hyperthyroidism, including treatment of Graves disease; (2) in preparation of patients who are hyperthyroid for thyroidectomy; (3) as an adjunct to radioiodine therapy; and (4) as treatment for thyroid storm. Unlike propylthiouracil, methimazole lacks the ability to block peripheral conversion of T4 to T3.

Drug Name	Propylthiouracil
Description	Thiourea agent that blocks synthesis of thyroid hormones. In addition, inhibits peripheral deiodination of T4 to T3.
Adult Dose	Note: Only available in 50-mg size Initial: 100-150 mg PO q8h; not to exceed 900-1200 mg/d (except in treatment of thyroid storm) Maintenance: 100-300 mg/d PO Thyroid storm: 400 mg PR q6h retained over 2 h for 6 doses; similar dose may be administered NG if patient is not vomiting
Pediatric Dose	Disease not observed in children
Contraindications	Documented hypersensitivity; breastfeeding
Interactions	Monitor aPTT; hyperthyroidism increases metabolism of vitamin K–dependent clotting factors, resulting in increased sensitivity to oral anticoagulants; antithyroid drugs reduce hyperthyroidism and decrease metabolism of clotting factors, thus reducing effects of oral anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Aplasia cutis not identified with use, thus, preferred antithyroid medication during pregnancy; smallest dose to control disorder should be used because drug does cross the placenta and may result in hypothyroidism of fetus with possible goiter; fever, rash, agranulocytosis, leukopenia, aplastic anemia, hemolytic anemia, DIC, and acute myelocytic anemia; vasculitis; galactorrhea; CNS toxicity; nausea, vomiting, and dysgeusia; rarely, acute hepatitis or liver failure

Drug Category: Radioactive iodines

Radioisotopes that decay by beta and gamma emissions are used to destroy follicular cells of the thyroid gland.

Drug Category: Beta-adrenergic receptor antagonists

Inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic activity observed in hyperthyroidism.

Drug Name	Atenolol (Tenormin)
Description	Selectively blocks beta-1 receptors with little or no effect on beta-2 types. Treats cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within min.
Adult Dose	25 mg PO qd; increase to 100 mg/d as symptoms of palpitations, tremor, or pulse rate dictate
Pediatric Dose	Disease not observed in children
Contraindications	Documented hypersensitivity; low output congestive heart failure, bronchospasm, diabetes mellitus with risk of hypoglycemia unawareness, Wolff-Parkinson-White syndrome
Interactions	Coadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	May mask some clinical signs of thyrotoxicosis (withdraw slowly to avoid exacerbation of clinical symptoms or thyroid storm); caution in patients with impaired renal or hepatic function; may lower intraocular pressure and, therefore, interfere with measurements for glaucoma

Drug Name	Metoprolol, metoprolol succinate, metoprolol tartrate (Lopressor, Toprol XL)
Description	Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. Helps treat cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within min.
Adult Dose	PO: 25-50 mg bid, may need to increase to 100 mg bid or higher as symptoms of palpitations, tremor, or pulse rate dictate IV (metoprolol tartrate): 5 mg, may repeat at 3-min intervals, not to exceed 15 mg in a patient with thyroid storm; during IV administration, carefully monitor blood pressure, heart rate, and ECG
Pediatric Dose	Disease not observed in children
Contraindications	Documented hypersensitivity; low-output congestive heart failure, bronchospasm, diabetes mellitus with risk of hypoglycemia unawareness, and Wolff-Parkinson-White syndrome
Interactions	Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; toxicity may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor blood pressure, heart rate, and ECG

FOLLOW-UP

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Further Outpatient Care

• After starting propylthiouracil or methimazole in patients with toxic nodular goiter (TNG), repeat free T4 or free T4 index measurements at 4-6 weeks. TSH levels rise slower because of suppression by elevated thyroid hormone levels and may take several months to normalize.
• Radioiodine ablation may take 10 weeks to achieve clinical response. Patients may require treatment with antithyroid drugs and beta-blockers in the interim period. Check biochemical evaluation of thyroid function approximately 4 weeks after initial treatment.
• Patients who undergo total thyroidectomy should be started on levothyroxine at time of discharge, unless they are clinically hyperthyroid. Evaluate thyroid function 4-6 weeks after surgery. In the case of subtotal thyroidectomy, thyroid hormone replacement is not required; evaluate thyroid function approximately 1 month after surgery.
• Monitor patients with subclinical hyperthyroidism on initial biochemical evaluation every 6 months for the development of overt hyperthyroidism.

Complications

• Hyperthyroid complications
• • The most important complications are related to the heart.

  • Cardiomyopathy resulting in severely depressed function may be observed with hyperthyroidism, possibly related to persistent tachycardia. Fortunately, cardiomyopathy resolves remarkably with resolution of the hyperthyroid state.

  • The treatment of patients exhibiting atrial fibrillation using anticoagulants remains controversial, although it is recommended by many authorities. Atrial fibrillation of long duration associated with other anatomical defects of the heart should be treated with warfarin or another suitable anticoagulant.

Prognosis

• Most treated patients have a good prognosis. A worse prognosis is related to untreated hyperthyroidism. Patients should understand the gravity of hyperthyroidism. If left untreated, hyperthyroidism may lead to osteoporosis, arrhythmia, heart failure, coma, and death. Regular assessment of thyroid function is important in monitoring disease.
• Sodium iodide I 131 ablation may result in continued hyperthyroidism, with some patients (up to 73% in some studies, depending on size of goiter and dosing of radioiodine) requiring repeated treatment or surgical removal of the gland. Hypothyroidism after radioiodine ablation has been reported in 0-35% of individuals.
• Iodine-131 ablation may result in continued hyperthyroidism, with some patients (up to 73% in some studies depending on size of goiter and dosing of radioiodine) requiring repeated treatment or surgical removal of the gland. Hypothyroidism after radioiodine ablation has been reported in 0-35% of individuals.
• Surgical treatment usually consists of a lobectomy of the hyperfunctioning nodule. The rate of hypothyroidism associated with this procedure is very low. Rates of hyperthyroidism recurrence with surgery have been reported to be as low as 0-9%. Larger multinodular goiters may require total thyroidectomy.

Patient Education

• Many patients fear abnormal weight gain with the attainment of the euthyroid state. Provide patients with education regarding the role of thyroid hormone in metabolism, as well as the cardiovascular and thromboembolic risks of hyperthyroidism. Also provide guidelines for lifestyle modification to avoid weight gain.
• Appraise patients treated with propylthiouracil or methimazole of the risk of agranulocytosis and instruct them to contact a physician if they develop a fever, rash, or sore throat, so that a CBC count with differential can be urgently performed.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Pregnancy and lactation
• • Radioactive iodine is contraindicated in pregnancy. Thionamides may be used in pregnancy if the mother is clinically thyrotoxic. Untreated thyrotoxicosis is associated with increased maternal mortality and miscarriage rates. Conversely, overly aggressive treatment may result in maternal and neonatal hypothyroidism. Maintain the free T4 level on the higher end of the reference range. TSH may remain suppressed when following this course of treatment.

  • Both propylthiouracil and methimazole transfer across the placenta. The thionamide of choice during pregnancy is propylthiouracil because it appears to have more limited transfer. Cases of cutis aplasia in newborns have been reported with the use of methimazole.

  • Small amounts of both propylthiouracil and methimazole are secreted in breast milk. The use of these drugs while breastfeeding was previously considered a contraindication. However, more recently, up to 750 mg daily of propylthiouracil and up to 20 mg daily of methimazole have not been demonstrated to effect neonatal thyroid function or intellectual development.

• Although rare, follicular carcinoma of the thyroid may present as a toxic nodule.

MULTIMEDIA

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Media file 1:  Patchy uptake of iodine I 123 in a toxic multinodular goiter.
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Media type:  Image

REFERENCES

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• Aeschimann S, Kopp PA, Kimura ET, et al. Morphological and functional polymorphism within clonal thyroid nodules. J Clin Endocrinol Metab. Sep 1993;77(3):846-51. [Medline].
• Aghini-Lombardi F, Antonangeli L, Martino E, et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. J Clin Endocrinol Metab. Feb 1999;84(2):561-6. [Medline]. [Full Text].
• Allahabadia A, Daykin J, Sheppard MC, et al. Radioiodine treatment of hyperthyroidism-prognostic factors for outcome. J Clin Endocrinol Metab. Aug 2001;86(8):3611-7. [Medline]. [Full Text].
• Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab. Sep 2000;85(9):3233-8. [Medline]. [Full Text].
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Article Last Updated: Nov 18, 2005