AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Differentials
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Differentials
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

Background

The term thyrotoxicosis refers to the hypermetabolic clinical syndrome resulting from serum elevations in thyroid hormone levels, specifically free thyroxine (T4), triiodothyronine (T3), or both. Hyperthyroidism is a type of thyrotoxicosis in which accelerated thyroid hormone biosynthesis and secretion by the thyroid gland produce thyrotoxicosis. However, hyperthyroidism and thyrotoxicosis are not synonymous.

Although many patients have thyrotoxicosis caused by hyperthyroidism, other patients may have thyrotoxicosis caused by inflammation of the thyroid gland, which causes release of stored thyroid hormone but not accelerated synthesis, or thyrotoxicosis, which is caused by ingestion of exogenous thyroid hormone. Differentiating between thyrotoxicosis caused by hyperthyroidism and thyrotoxicosis not caused by hyperthyroidism is important because disease management and therapy differ for each form. Thyroid imaging and radiotracer thyroid uptake measurements combined with serologic data enable specific diagnosis and appropriate patient treatment.

Pathophysiology

The thyroid gland actively transports iodide from circulating blood into the thyroid follicular cells. Subsequently, iodide is organified into tyrosyl residues of thyroglobulin and stored within the thyroid follicles. When required, thyroglobulin undergoes proteolysis with the release of T3 and T4 as the principle active forms of thyroid hormone. In extrathyroidal tissues, some of the T4 is deiodinated to the more metabolically potent T3 hormone.

The process of synthesis, storage, and release of T3 and T4 by the thyroid is normally controlled by the pituitary gland through its release of thyrotropin. This process involves a negative feedback loop wherein increasing blood levels of T3 and/or T4 inhibit release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyrotropin from the pituitary (see Image 1). In thyrotoxicosis, the high blood levels of T3 and/or T4 inhibit the hypothalamic-pituitary release of thyrotropin; therefore, serum levels of thyrotropin are markedly reduced or undetectable. Therefore, the measurement of thyrotropin serum levels is the primary test in the diagnosis of thyrotoxicosis.

Causes

The common causes of thyrotoxicosis have different pathophysiologic features, which include autoimmune disease, functioning thyroid adenoma, and infection. Common causes of thyrotoxicosis include (1) autoimmune disease; Graves disease, lymphocytic thyroiditis with hyperthyroidism (ie, silent thyroiditis), and postpartum thyrotoxicosis (PPT); (2) neoplasm, toxic nodule, and toxic multinodular goiter (autonomously functioning nodules); and (3) infection, subacute thyroiditis (SAT), and, very rarely, acute suppurative thyroiditis.

Graves disease

Named for the Irish physician, Robert Graves, who described the disease in 1835, Graves disease is caused by circulating thyroid receptor autoantibodies (TRab). The antibodies not only displace thyrotropin from the thyroid receptors but also mimic thyrotropin by activating the receptor to stimulate the synthesis and release T3 and T4. Because autoantibody production is not linked to the normal pituitary negative feedback loop, thyroid gland function becomes autonomous, and serum T4 and T3 levels become abnormally high and lead to clinical thyrotoxicosis.

Because hormone synthesis is accelerated and thyroid gland radioiodine uptake is elevated, radionuclide scans demonstrate a diffuse increase in iodine uptake by the gland (see Images 2-4). The natural clinical course of Graves disease usually is interrupted by specific therapy; left untreated, Graves disease may be lethal.

Graves disease is closely associated with Hashimoto disease (chronic lymphocytic thyroiditis) in which thyrotoxic/cytotoxic antithyroid antibodies attack the gland. Hashimoto disease is the leading natural cause of thyroid failure and hypothyroidism. The 2 diseases may coexist, and their clinical features may overlap. Graves ophthalmopathy also appears to share a similar immune basis and may occur with or without associated thyroid disease.

Disseminated autonomy

Disseminated autonomy (DISA) is a disease that is addressed less frequently. DISA can be established only by the exclusion of Graves disease. DISA and Graves disease can be distinguished from each other only with clinical findings, such as the presence of endocrine ophthalmopathy or thyrotropin-binding immunoglobulins. (See further discussion of thyroid autonomy under nodular disease below.)

Lymphocytic thyroiditis

In the spectrum of autoimmune thyroid diseases, variants that cause thyrotoxicosis exist. These diseases occur by mean of an inflammatory process unassociated with thyroid pain or tenderness, not the production of stimulating antibodies. This process has been termed painless thyroiditis with hyperthyroidism to distinguish it from subacute or "viral" thyroiditis in which the thyroid is painful or tender (see Subacute thyroiditis, below).

Lymphocytic thyroiditis more commonly is termed silent thyroiditis. A similar condition that occurs in 5-10% of postpartum women is called postpartum thyroiditis (PPT). During the acute phase, silent thyroiditis may be clinically indistinguishable from Graves disease. However, because iodine clearance and hormone synthesis by the thyroid is turned off by the decrease in serum thyrotropin levels, radioiodine uptake is low, generally less than 3%, which allows its differentiation from Graves disease. The low uptake usually precludes diagnostic radionuclide scanning of the thyroid.

The natural course of silent thyroiditis most frequently is spontaneous resolution; therefore, symptomatic treatment usually suffices. Acute flares may be followed by a period of hypofunctionality. The hypothyroid phase is usually transient; therefore, the physician should time for spontaneous recovery before initiating lifelong hormone replacement therapy.

Occasionally, silent thyroiditis is a recurring process, and patients may benefit from anti-inflammatory drugs, surgery, or iodine 131, which is administered in the asymptomatic phase when iodine uptake is adequate. PPT occurs at a time of great physiologic and emotional challenge to the patient. Symptoms can be mistaken for anxiety or depression; therefore, clinical awareness of the potential for thyroiditis is important at this time.

Toxic nodules and thyroid autonomy

Thyroid autonomy is the state wherein a single nodule, several nodules, or the entire gland function autonomously in the absence of circulating thyrotropin or thyroid-stimulating immunoglobulins (TSIs). Somatic thyrotropin receptor mutation is the most prevalent etiology of autonomously functioning thyroid nodules.

Thyroid autonomy is most frequently found in toxic multinodular goiters, a group of clinical presentations in which autonomously functioning nodules are present in a goiter with or without additional nodules. The nonautonomous nodules may show normal or suppressed radioiodine uptake on scintigraphy.

The 3 distinct categories of thyroid autonomy are (1) benign adenomas (encapsulated tumor) and adenomatous nodules (not encapsulated but circumscribed), (2) malignant thyroid tumors with hyperthyroidism, and (3) microscopic areas in euthyroid goiters, perhaps the histological equivalent of disseminated autonomy.

An autonomously functioning thyroid nodule (AFTN) is a focus of functioning thyroid cells wherein thyroid hormone production has been uncoupled from the normal pituitary-thyroid negative feedback loop. When the nodule's level of thyroid hormone production has reached a level at which serum thyrotropin levels are depressed, the nodule is termed toxic. In one US study, 94% of AFTNs treated with surgical excision were adenomas and the remainder were more heterogeneous lesions. Functioning thyroid carcinomas that cause thyrotoxicosis are exceedingly rare. Usually, they should not be included in the differential diagnosis.

Thyroid iodine uptake is normal or high, and thyroid scans reveal a hyperfunctional (ie, hot) nodule with depressed or absent tracer uptake in the remainder of the gland (see Image 5). A toxic nodule rarely resolves spontaneously, and the use of antithyroid drugs is a commitment to lifelong therapy. Therefore, specific curative treatment with ¹³¹I treatment or surgical excision is performed. Ablation of the nodule with percutaneous alcohol injection is proven effective, but it has not become commonplace therapy in most practices.

Toxic multinodular goiter

Usually, toxic multinodular goiter (TMNG) is the end result of a slow process that occurs over many years, and patients often are older than those with other conditions. In contrast to most cases of Graves disease, TMNG is subtler and/or more likely to be overlooked because of its insidious onset. TMNG occurs in a patient with multinodular goiter whenever newly generated follicles with some degree of autonomous capability reach sufficient size and functionality to cause thyrotoxicosis (ie, Plummer disease).

Similar to toxic adenomas and adenomatous nodules, toxic multinodular goiters may have somatic mutations of the thyrotropin receptor, but this is not uniform and different or overlapping pathophysiologic processes may be present. This is a clinical disorder rather than a specific disease entity.

Iodine uptake is normal or elevated, and radionuclide scans demonstrate multiple nodules or a markedly heterogeneous distribution of tracer (see Image 6).

As in AFTN, successful treatment of TMNG with ¹³¹I may require a dose that is larger than the usual effective dose for Graves disease. The use of ¹³¹I may be somewhat more hazardous in an elderly patient with coexisting cardiovascular disease, and pretreatment with antithyroid drugs may reduce the risk. Surgery can be effective immediately. Treatment with antithyroid drugs is effective in the short term, but it is not recommended as definitive therapy because it must be lifelong.

Subacute thyroiditis

The cause of subacute thyroiditis (de Quervain thyroiditis, granulomatous giant cell thyroiditis) may be multifactorial; however, indirect but strong evidence suggests that viral infection is the precipitating event. Half the patients have a history of antecedent viral upper respiratory tract illness. When a patient with clinical signs and symptoms of thyrotoxicosis also has substantial thyroid pain and tenderness, a diagnosis of SAT is almost always correct. The diagnosis is confirmed with elevated T3 and/or T4 levels, low thyrotropin levels, and low ( <3%) thyroid radioiodine uptake. The sedimentation rate is consistently elevated. However, if the patient presents late in the course of the illness, the clinical and laboratory findings may be confusing.

SAT seldom is occurs very young or elderly patients. The hyperthyroid phase usually lasts 4-10 weeks; frequently, this phase is followed by a hypothyroid phase of similar duration. The illness may last for 1 year or longer, but ultimately, the patient almost always returns to a euthyroid state; therefore, treatment is aimed at the symptoms. Beta-blocking drugs and nonsteroidal anti-inflammatory agents often are beneficial. Occasionally, steroid anti-inflammatory therapy is necessary. Correct diagnosis minimizes inappropriate therapeutic attempts with antithyroid drugs, ¹³¹I, or surgery. In addition, care must be taken not to initiate long-term thyroid hormone replacement therapy in the hypothyroid phase of the illness because thyroid function returns to normal in more than 90% of patients.

Uncommon causes of thyrotoxicosis include the following: acute or suppurative thyroiditis, factitious or iatrogenic thyrotoxicosis, struma ovarii, follicular carcinoma, thyrotoxicosis induced by excess pituitary production of thyrotropin, and thyrotoxicosis secondary to high circulating levels of human chorionic gonadotropin.

Frequency

United States

On a survey, as many as 27 women per 1000 provide a history of current or past hyperthyroidism. At any time, the risk for Graves disease is approximately 1.4 cases per 1000 persons. The rate of SAT is approximately 20% of the rate for Graves disease. AFTN and TMNG are somewhat less common than SAT, but the incidence varies considerably in separate series. Silent thyroiditis is less common than Graves disease or SAT, but PPT may affect 5-10% of new mothers.

International

Graves disease appears to be distributed equally worldwide. Also, nodular thyrotoxicosis and silent or PPT also are commonly reported commonly. SAT is rare in the tropics.

Mortality/Morbidity

Thyroid storm occurs only rarely, but it is potentially lethal and must be recognized and treated with urgency (see Hyperthyroidism, Thyroid Storm, and Graves Disease).

Untreated chronic hyperthyroidism that results from cardiac decompensation or metabolic complications is rarely fatal, but permanent or long-term states of hyperthyroidism require specific treatment to control or cure the disease. Usually, associated complications, such as muscle deterioration and infertility, fully resolve after successful treatment.

Graves ophthalmopathy is a chronic orbital inflammatory process that occurs with or without associated autoimmune thyroid disease. Its pathogenesis remains controversial, but a theory states the thyroid and orbit share antigens. The course of the disease may be innocuous or aggressive, with a loss of vision.

TSI levels correlate with activity and the severity of ophthalmopathy, and high TSI levels in combination with low thyroid peroxidase antibodies (TSO) are associated with a marked increase in the occurrence of ophthalmopathy.

Reports state that Graves ophthalmopathy may be exacerbated by ¹³¹I treatment of Graves thyrotoxicosis. At least 1 report suggests that concurrent corticosteroid treatment with ¹³¹I prevents exacerbation of the ophthalmopathy. Prednisone with ¹³¹I has been shown to prevent an exacerbation of exophthalmos at a dose of 30 mg/d for 1 month, with tapering over 2-3 months. Individual risk-benefit assessment is necessary before such treatment.

Race

Thyrotoxicosis affects all races. Differences in the reported rates appear to be based on geographic factors rather than ethnicity; they may partly result from dietary influences.

Sex

With most forms of thyrotoxicosis, women are affected approximately 4 times as frequently as men. This difference is true even for SAT, which is believed to be viral induced. X-linked genetic transmission is probably a factor, and it may responsible for sex and familial prevalences.

Age

In Graves disease, the incidence is fairly consistent in persons aged 20 years and older. Increasing incidence is noted in TMNG in those older than 30 years. In AFTN, silent thyroiditis, and SAT, disease predominately occurs in patients aged 20-60 years.

Anatomy

The normal location of the thyroid in the superficial anterior neck facilitates clinical examination and evaluation with ultrasonography (US) and scintigraphy. The normal thyroid is bilobed, with a connecting isthmus. The shape often is described as that of the H of the Honda car symbol. Commonly, the right lobe is larger than the left; occasionally, the extreme of the absence or agenesis of the left lobe is observed. A pyramidal lobe of variable size projects cephalad from the isthmus in many people. Neoplastic or hyperplastic growth may extend inferiorly (retrosternal), and adjustments in the imaging technique may be required. The adjacent anatomy of the laryngeal nerves and parathyroid glands is an important surgical consideration.

Clinical Details

Clinical features of thyrotoxicosis are largely independent of its cause, although clues (eg, tender thyroid gland or palpable nodule) may suggest SAT or AFTN. The presence of a fast pulse, tremor, eyelid lag, and warm moist skin in a patient with weight loss, difficulty climbing stairs, palpitations, and intolerance for warm rooms or weather is the pathognomonic clinical presentation of thyrotoxicosis. However, the clinical features are variable. Elderly patients may have few symptoms and limited signs of disease; they may have only atrial fibrillation, lethargy, or weight loss. A profound acute presentation or exacerbation of the signs or symptoms may herald the onset of thyroid storm, a potentially fatal state that requires immediate recognition and treatment see Hyperthyroidism, Thyroid Storm, and Graves Disease).

Subclinical thyroid disease

In countries in which screening thyrotropin assays are commonly used, patients with only a low thyrotropin level but no other signs or symptoms of thyrotoxicosis are identified with greater frequency. The causes include excess thyroid hormone therapy, early or mild Graves disease, autonomous nodule(s), or mild cases of silent, postpartum or viral thyroiditis.

A few patients will be encountered who (1) have persistently low thyrotropin levels but are otherwise clinically normal and have normal T3 and T4 levels and are negative for TRab, (2) have normal responses to thyroid feedback homeostasis tests (eg, T3 suppression), and (3) do not become hyperthyroid during many years of monitoring.

Many of these patients have preclinical or asymptomatic early Graves disease, and they must be distinguished from those without disease but just a low thyrotropin level because the former are at risk for complications such as atrial fibrillation and left ventricular dysfunction. Such patients usually have elevated TRab and/or TSI values.

Other than proper adjustment of dose in those patients on thyroid hormone therapy, no uniform recommendations for management of subclinical hyperthyroidism have been established. Fifty percent of patients with an isolated suppressed (but measurable) sensitive thyrotropin level return to normal levels without intervention, and observation and repeat testing is appropriate in those without symptoms.

Those with an undetectable sensitive thyrotropin or those who are symptomatic should be considered for intervention after the cause has been determined.

Preferred Examination

The diagnosis of thyrotoxicosis is predominately based on laboratory results, including an elevated free T3/T4 level and suppressed thyrotropin level; however, the clinical examination may reveal the etiology. If the thyroid gland is normal or diffusely enlarged on physical examination, the most likely diagnosis is Graves disease. If one or more thyroid nodules are palpated, the patient probably has AFTN or TMNG. If the thyroid gland is markedly tender, subacute thyroiditis is likely. However, silent thyroiditis is almost always in the differential diagnosis with Graves disease. In addition, some patients with silent thyroiditis may have a tender thyroid gland, and some patients with subacute thyroiditis have only mild thyroid tenderness.

As a result of the clinical overlap, knowledge of thyroid iodine uptake is necessary for specific diagnosis and appropriate therapy in most patients. Also, thyroid radionuclide scintigraphy can help distinguish Graves disease from a toxic nodule and toxic multinodular goiter. The Table contains a summary of the laboratory, thyroid uptake, and scanning findings in the various common forms of thyrotoxicosis.

Summary of Laboratory, Thyroid Uptake, and Scanning Findings

Limitations of Techniques

Thyroid uptake testing, thyroid scintigraphy, and thyroid US are not the primary testing modalities for diagnosis of thyrotoxicosis, but their findings can be critical in the differential diagnosis and in selecting treatment once thyrotoxicosis is established with serologic test results.

Scintigraphy

Graves disease	Elevated to highly elevated	Elevated	Low to absent	Normal to very high	Diffuse increased uptake
Autonomous nodule	Elevated to highly elevated	Normal	Low to absent	Normal to very high	Hot nodule
Toxic mulitnodular goiter	Elevated to highly elevated	Normal	Low to absent	Normal to very high	Hot nodules
Subacute thyroiditis	Elevated to highly elevated	Normal	Low to absent	Very low (0-2%)	Depressed uptake
Silent thyroiditis or PPT	Elevated to highly elevated	Normal	Elevated	Very low (0-2%)	Depressed uptake

Establishing the presence of thyrotoxicosis

Currently, the measurement of free thyroid hormone is considered the appropriate test. A total T3 or T4 level has less diagnostic accuracy compared with other measure because of the variability of binding protein levels.

At present, most thyrotropin assays are performed with sensitive methods. The measurement of thyrotropin levels is unique as a screening test for hyperthyroidism.

Regarding other laboratory tests, T3-suppression and TRH-stimulation tests are seldom needed to establish the autonomy of the gland or nodule. The measurement of free T3 and T4 levels and the sensitive thyrotropin assay usually suffice for diagnosis and therapeutic decision making. In truly borderline cases, short-term observation and repeat testing may be helpful. TRab and TSI measurement may be helpful in borderline or confusing cases.

Establishing the cause of thyrotoxicosis

In the thyroid radioiodine tracer uptake test, a measured dose of radiotracer, usually iodine 123 or ¹³¹I is administered to the patient. After 4-24 hours, activity in the thyroid (ie, neck activity corrected for background levels) is imaged, and the percentage of the administered dose within the thyroid is calculated. Each laboratory should establish their normal values, but generally, normal values are in the range of 5-25%. Thyrotoxicosis (ie, Graves disease, AFTN, TMNG) caused by hyperfunctional thyroid tissue is associated with normal-to–markedly increased uptake.

Thyrotoxicosis (ie, SAT, silent thyroiditis) caused by inflammation of the thyroid gland has low-to-absent uptake. Thyroid scintigraphy after the oral administration of ¹²³I or intravenous administration of technetium 99m is helpful in demonstrating diffuse tracer uptake (Graves disease) versus nodular tracer concentration (AFTN, TMNG). The image can also be used distinguish low thyroid uptake from a high thyroid uptake, but the findings are not as quantitative as those of the thyroid uptake test.

The common antithyroid antibody (ie, antimicrosomal/peroxidase, antithyroglobulin) levels are somewhat variable and inconsistent but are elevated in most cases. High levels are usually seen in persons with Hashimoto disease. Antibody assays are not required for the clinical diagnosis and treatment of thyroid disease in most patients.

DIFFERENTIALS

Section 3 of 8  

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• Introduction
• Differentials
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

ULTRASOUND

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Findings

Thyroid US is not necessary for the differential diagnosis of thyrotoxicosis, although certain findings are important.

In Graves disease, the thyroid appears normal or moderately enlarged. Color flow imaging demonstrates a general mild-to-marked increased in the blood flow through the parenchyma (see Image 7). With AFTN and TMNG, sonograms demonstrate 1 or more nodules, but they do not indicate the functional status of any nodule.

In silent and PPT, the gland may be normal, or it may be generally large or plump. The pyramidal lobe may be prominent. The parenchyma may be heterogeneously hyperechoic. With SAT, the gland is edematous; the edema is reflected as hypoechogenicity. This finding can be regional because the gland may not be affected uniformly.

Degree of Confidence

US is generally not used as a diagnostic test for hyperthyroidism. Nevertheless, generalized hypervascularity on color Doppler US is characteristic of diffuse thyrotoxicosis (Graves disease).

NUCLEAR MEDICINE

Section 5 of 8  

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Findings

Nuclear medicine examinations are used to differentiate the causes of thyrotoxicosis after the diagnosis is made clinically and confirmed by using appropriate laboratory tests. At that point, measurements of thyroid radiotracer uptake with ¹²³I or ¹³¹I and findings on a thyroid scan obtained with ¹²³I or ^99mTc confirm the diagnosis, and treatment can be initiated.

The Table summarizes the laboratory, thyroid uptake, and radionuclide scanning findings in the various common forms of thyrotoxicosis.

Degree of Confidence

With concordant clinical, laboratory, and imaging findings, confidence in a specific diagnosis is high.

False Positives/Negatives

Normal results on 4- to 24-hour thyroid uptake scans do not preclude a diagnosis of hyperthyroidism. Many multivitamins and other food supplements contain large amounts of iodine, and the extra iodine competes with radioiodine for thyroid clearance. Other sources of iodine ingestion also may be present.

INTERVENTION

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The treatment of thyrotoxicosis depends on the cause of the disease. In PPT, SAT, and silent thyroiditis, the disease is self-limiting, and symptomatic medical treatment usually is sufficient. Graves disease, AFTN, and TMNG require specific therapy.

Antithyroid drugs, surgical excision, and radiation therapy with ¹³¹I are means of controlling hyperthyroidism, and each is more than 90% successful in appropriate patients. In Europe, antithyroid drugs are used in the primary therapy in most patients with Graves disease. In the United States, most clinics use ¹³¹I in the primary therapy in adult patients, unless reasons not to use radiation are present.

Some patients are concerned about the possible adverse effects of radiation associated with ¹³¹I therapy. This topic has been investigated extensively. No evidence suggests that the incidence of leukemia, thyroid cancer, or reproductive abnormalities is increased. In addition, children of patients with Graves disease who were treated with radioiodine were not found to have an increased incidence of congenital defects. Investigators in a recent study of 7417 patients did raise the possibility of a higher mortality rate (vs incidence) due to small bowel cancer and thyroid cancer, but the absolute numbers were small (Franklyn, 1999).

Pregnancy is a contraindication. ¹³¹I treatment can possibly exacerbate coexisting Graves ophthalmopathy. Large goiters may be reduced in size more quickly and reliably with surgery. In this radiology article, only therapy with ¹³¹I is addressed.

Indications for therapy with ¹³¹I

Indications for therapy with ¹³¹I include the following: patient older than a predetermined age, patient who failed to respond to antithyroid drugs, or patient with contraindications to surgery.

General contraindications for therapy with ¹³¹I

General contraindications for therapy with ¹³¹I include the following: pregnancy or breastfeeding, low ¹³¹I uptake resulting from prior medication or disease, possibility of thyroid cancer, patient younger than a predetermined age, or patient concerned about radiation exposure.

Questionable contraindications for therapy with ¹³¹I

Questionable contraindications for therapy with ¹³¹I include the following: unusually large gland, or active Graves ophthalmopathy.

Selecting the dose of ¹³¹I

Several philosophies and schemes exist for determining the optimum therapeutic dose of ¹³¹I in each patient. The following formula can be used to arrive at a dose: Dose = (estimated gland weight in grams/24-hour uptake) x desired dose in microcurie per gram of tissue.

The desired dose may range from low (25 µCi/g) to high (160 µCi/g). These doses are generally based on calculations made by using a 24-hour iodine uptake rather than 4- or 5-hour values. The earlier uptake values in Graves are about a third lower than those at 24 hours, but the values are variable; some patients have high turnover rates and an uptake value that is actually lower at 24 hours. Individual facilities should keep track of their normal and abnormal values in radioiodine uptake because these may differ by locality and change overtime.

In general, lower doses result in more patients who are euthyroid 1 year after treatment; however, more treatment failures occur, requiring second or third treatments with ¹³¹I. Even patients who are euthyroid after 1 year are at high risk for later occurrences of hypothyroidism. A moderate dose protocol with an average total dose of 9 mCi ¹³¹I controls disease in most patients, and fewer than 10% of patients require retreatment.

Some clinicians believe that such calculations are futile, and they advocate the use of a standard dose. The average moderate-dose protocol is similar to the empiric-baseline dose of 10 mCi used by many clinics, including the author's. The 10-mCi dose is adjusted for patients with particularly large or small glands or unusually high or low thyroid uptake. In the most recent 1000 patients treated at the author's clinic, disease in 89% responded to the initial treatment.

Proponents of this approach suggest that is has several advantages, including the following: (1) Disease is brought under control rapidly. (2) The cost and patient inconvenience are minimized by reducing the need for repeat treatments. (3) Thyroid hormone replacement therapy can be started early; early treatment reduces the likelihood of delayed diagnosis, which may occur years later in a patient who was lost to follow-up monitoring. The advantages must be balanced against the general principle of avoiding unnecessary radiation exposure.

The effectiveness of the treatment of Graves disease is usually apparent in 3 months. Occasionally, patients may have a delayed response after 3-6 months. Rarely, a patient without a response at 6 months has a response after a year. At the author's institution, patients usually are examined at 6 and 12 weeks after treatment. If significant but incomplete improvement is reflect in the laboratory values, the author may wait for 18 or even 24 weeks to see if improvement continues. If no improvement occurs by 12 weeks, retreatment with a 50% increase in the dose of ¹³¹I is usually recommended.

Often, antithyroid drugs are administered before ¹³¹I treatment to deplete the gland of stored hormone and to normalize serum T3 and T4 levels before therapy. As a result, the possibility of a radiation-induced exacerbation of thyrotoxicosis is diminished, and the patient feels better sooner. The antithyroid drug is discontinued 2 days before therapy. A rebound phenomena may occur after the withdrawal of antithyroid drugs; thyroid radioiodine uptake is higher than that observed at the time of initial diagnosis. In patients with relatively low uptake who may otherwise require a large dose of ¹³¹I, pretreatment with antithyroid drugs and its withdrawal 24-72 hours prior to therapy may enhance uptake compared with therapy without pretreatment; thus, a lower effective dose of ¹³¹I can be administered.

¹³¹I doses larger than those administered in Graves disease usually are administered to patients with 1 or more toxic nodules. Many physicians increase the dose by 20-100% in patients with nodular disease. Many clinics increase the prescribed dose of ¹³¹I to reduce the number of patients who require a second or third treatment. Hamburger's statement regarding larger doses is often quoted: "Those who prefer to avoid, rather than relive, the disasters that can result from inadequate ¹³¹I therapy for toxic nodules should heed the advice of the older workers who advise larger ablative doses" (Hamburger, 1985).

Radiation exposure and contamination

In general, radiation safety issues associated with ¹³¹I treatment for hyperthyroidism are easily managed. Most often, treatment doses are prepared by a nuclear pharmacist and delivered as a precalibrated capsule. In facilities that prepare ¹³¹I as a liquid solution for drinking, the solution should be administered to the patient from a closed system in a negative-pressure vented environment.

The risk of direct contamination from a treated patient is essentially limited to those who have contact with the patient's urine, saliva, or feces. Patients are instructed in double flush the toilet after use and wash their hands frequently.

Exposure to persons in the patient's home and work environments can be limited to a low level by generally instructing the patient and involved persons to limit their time together and to maintain a reasonable distance. In a chair across the room from a patient treated with 10 mCi ¹³¹I, the exposure averages less than 1 mR/h during the week after treatment. Those who help this patient with personal hygiene would incur a dose rate of about 25 mR per hour of care.

Educating members of the patient's about the importance of maintaining a reasonable distance between themselves and the patient, especially during the first 24-72 hours after treatment and of avoiding contact with bodily secretions for several weeks are practical means of their minimizing exposure. For working patients, the author tends to treat patients on Friday or any day preceding a break in his or her work schedule. This schedule minimizes the patient's exposure to coworkers.

Medical/Legal Pitfalls

• Liability concerns are primarily related to ¹³¹I administration.
• • The therapist must verify the delivery and preparation of the correct dose.
  • The patient's identity must be confirmed with absolute certainty.
  • Pregnancy and breastfeeding must be excluded before treatment.

Special Concerns

• ¹³¹I therapy is contraindicated in a patient who is pregnant or breastfeeding.
• Because ¹³¹I treatment is irreversible after the dose is administered, absolute confirmation of the patient's identity and the correctness of the dose are mandatory.

MULTIMEDIA

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Media file 1:  Illustration of the negative feedback loop of the homeostasis of thyroid hormone levels. A decrease in blood thyroid hormone triiodothyronine (T3)/thyroxine (T4) levels results in the inhibition of thyrotropin-releasing hormone and thyrotropin production. The released thyrotropin stimulates synthesis and release of T3/T4 by the thyroid, which, in turn, tends to inhibit further thyrotropin release. THS is thyrotropin. TRH is thyrotropin-releasing hormone.
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Media file 2:  Iodine I 123 thyroid scan in a patient with Graves disease: Tracer uptake is uniform throughout the gland. The 5-hour iodine uptake was high at 53%.
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Media file 3:  Iodine I 123 thyroid scan in a patient with Graves disease. The 5-hour iodine uptake was elevated at 29%. Note the high level of iodine concentration near the thyroid. Also note the pyramidal lobe, which often is visualized in a hyperstimulated gland. The cold nodule in the right lobe must be addressed in the same way a solitary cold nodule in a patient without Graves disease is evaluated.
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Media file 4:  Ultrasonogram of the right lobe of the thyroid in the same patient as in Image 3. Fine-needle aspiration of the nodule prior to iodine I 131 treatment did not reveal a carcinoma.
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Media file 5:  Iodine I 123 scan in a patient with a palpable nodule in the right neck, a low serum level for thyrotropin, and a slightly elevated serum level of free triiodothyronine. The autonomously functioning nodule only partially suppresses uptake in the remainder of the gland. The 5-hour iodine uptake was mildly elevated at 22%.
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Media file 6:  Scan in a patient with a toxic multinodular goiter: The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.
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Media file 7:  Color flow ultrasonogram in the same patient as in Image 2. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope.
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REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Differentials
• Ultrasound
• Nuclear Medicine
• Intervention
• Multimedia
• References

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Article Last Updated: Mar 29, 2006