Hyperthyroidism
The term hyperthyroidism refers to an overproduction of hormone by the thyroid gland. The resulting physiologic syndrome of excess thyroid hormone is termed thyrotoxicosis, although the two terms should not be used synonymously. Hyperthyroidism should be used to describe conditions associated with a sustained overproduction of thyroid hormone, such as Graves' disease or toxic multinodular goiter (TMNG). Several other conditions or situations result in transient increases in circulating thyroid hormone, which may result in thyrotoxicosis, but they do not cause hyperthyroidism in the strict sense of the term (Table 3-1). This chapter reviews the epidemiology, clinical presentation, evaluation, and management of patients with hyperthyroidism, focusing on surgical management.
Causes of Thyrotoxicosis
HCG = human chorionic gonadotropin; TSH = thyroid-stimulating hormone.
| Hyperthyroidism (sustained hormone excess) |
| Graves' disease |
| Toxic multinodular goiter |
| Toxic adenoma |
| HCG induced |
| Gestational hyperthyroidism |
| Trophoblastic tumors |
| Iodine-induced hyperthyroidism (Jod-Basedow effect) |
| Drug induced |
| Struma ovarii |
| TSH-secreting pituitary tumors |
| Metastatic functioning thyroid carcinoma |
| Thyrotoxicosis (transient hormone excess) |
| Thyroiditis |
| Infectious |
| Autoimmune |
| Drug induced |
| Iatrogenic: hormone overreplacement |
| Thyrotoxicosis factitia |
Hyperthyroidism is present in approximately 0.5% of the population. An additional 0.8% of the population has mildly suppressed or undetectable serum thyroid-stimulating hormone (TSH) levels but circulating thyroid hormone levels in the normal range.Additionally, the rate of development of the various causes of hyperthyroidism varies according to geographic location and is believed to be related to the iodine intake of the population. For example, an epidemiologic survey comparing an area of normal iodine intake to one with insufficient iodine intake found that Graves' disease accounted for 80% of cases of hyperthyroidism in the iodine-sufficient population but toxic uninodular and multinodular goiter accounted for the majority of cases in the iodine-deficient population.3
The clinical presentation of this disorder involves multiple symptoms that vary depending on the degree of hormone excess, the duration of illness, and the presence of other medical comorbidities. Additionally, the patient's age may affect the clinical presentation because elderly patients with thyrotoxicosis often have minimal clinical symptoms, a phenomenon termed apathetic hyperthyroidism.4 Thyroid hormones, namely thyroxine (T4) and triiodothyronine (T3), are involved in the production of heat and energy; the development of the nervous system; the regulation of somatic growth and puberty; and the coordination of the synthesis of proteins involved in normal hepatic, cardiovascular, neurologic, and muscular functions. The wide range of actions of T3 and T4 on multiple organ systems accounts for the number and variability of symptoms that may accompany thyrotoxicosis (Table 3-2). Typically, patients complain of nervousness or anxiety, restlessness, palpitations, weight loss, and sensitivity to heat. Women may have irregular menses or problems with decreased fertility, and men may develop painful gynecomastia or reduced libido.5,6
Table 3-2. Common Signs and Symptoms of Thyrotoxicosis
| System | Signs and Symptoms |
|---|---|
| Constitutional | Weight loss or gain |
| Fatigue | |
| Heat intolerance | |
| Psychological | Anxiety |
| Emotional lability | |
| Insomnia | |
| Cardiovascular | Palpitations |
| Tachycardia | |
| Arrhythmia | |
| Widened pulse pressure | |
| Gastrointestinal | Diarrhea |
| Dysphagia | |
| Increased appetite | |
| Musculoskeletal | Proximal muscle weakness |
| Osteopenia, osteoporosis | |
| Respiratory | Air hunger |
| Integumentary | Warm, moist skin |
| Onycholysis | |
| Pretibial myxedema | |
| Ophthalmologic | Eyelid retraction, stare |
| "Lid lag" | |
| Infiltrative ophthalmopathy (Graves' disease) | |
| Reproductive | Oligomenorhea, decreased fertility (women) |
| Gynecomastia (men |
Clinical findings frequently include tachycardia; warm, moist skin; and mild tremor. An enlarged thyroid gland is variably present. Other physical examination findings include "lid lag," which refers to a slight delay of the eyelid in following the eye itself when having a patient look down; it is caused by increased sympathetic activity. Exophthalmos (protrusion of the eye), pretibial myxedema, and acropachy (clubbing of the fingers and toes) are specific physical examination findings in patients with hyperthyroidism caused by Graves' disease and are discussed in more detail in subsequent sections.
As previously mentioned, these clinical findings are frequently much more subtle in elderly individuals. These patients may present with congestive heart failure with an arrhythmia. Approximately 25% to 35% of these elderly patients with thyrotoxicosis develop atrial fibrillation, which is resistant to treatment until the thyroid disorder has been treated.7Additionally, 15% of elderly individuals with atrial fibrillation have underlying thyrotoxicosis.8 Another common clinical presentation of elderly patients with thyrotoxicosis is unexplained weight loss, which is commonly associated with anorexia, rather than the corresponding increase in appetite seen in younger individuals. These findings frequently initiate an exhaustive search for an underlying malignancy before thyrotoxicosis is diagnosed.9
Patients with thyrotoxicosis may also present with a potentially life-threatening constellation of signs and symptoms referred to as thyroid storm. This condition typically occurs in patients with known or undiagnosed thyrotoxicosis after a precipitating event such as surgery, trauma, childbirth, or infection. Signs and symptoms include severe tachycardia, fever, arrhythmias, congestive heart failure, agitation, psychosis, and coma.10
The laboratory diagnosis is relatively unambiguous and typically includes elevated serum concentrations of unbound T3 and T4 with a suppressed TSH hormone level. Measuring levels of the unbound or free fractions of T3 and T4 is preferable to measuring total serum levels because using T3 and T4 levels avoids diagnostic confusion in the setting of changing levels of thyroid-binding proteins. A minority of patients (~1%) have normal serum concentrations of T4 and elevated T3 concentrations known as T3 toxicosis.11Elevated T3 and T4 levels in the setting of elevated TSH levels may be seen in patients with an inappropriate TSH syndrome, such as a thyrotropin-secreting pituitary tumor or thyroid hormone resistance.12,13
Measurement of thyroid autoantibodies may play a role in elucidating the cause of hyperthyroidism or thyrotoxicosis. Antithyroid microsomal antibodies are antibodies to microsomes that may be released into the circulation with thyroid cell destruction (also known as antimicrosomal or antithyroid peroxidase antibodies). Increased serum levels are usually associated with Hashimoto's (chronic lymphocytic) thyroiditis but may also be seen in patients with other autoimmune conditions such as hemolytic anemia and Sjögren's syndrome.14 Antibodies to the TSH receptor (also known as thyroid-stimulating immunoglobulins) are elevated in the majority (80%) of patients with Graves' disease.15,16
All patients with evidence of thyrotoxicosis should undergo thyroid ultrasonography. This simple, noninvasive test may reveal the presence of diffuse thyromegaly, a multinodular goiter, or a solitary nodule. It may also show the characteristic ultrasound findings of thyroiditis, all of which may provide a great deal of information to the clinician concerning the cause of the patient's thyrotoxicosis. Ultrasonography may be performed in the office and is an extremely useful aspect of the physical examination of patients presenting with symptoms of hyperthyroidism.
With proven biochemical evidence of hyperthyroidism, thyroid scintigraphy with radioactive iodine (RAI) uptake measurement provides useful information that may direct clinical management. This nuclear medicine test typically uses iodine 123 or technetium-99m pertechnetate as radiopharmaceuticals and is a measure of the iodine avidity of the thyroid gland. Diffusely elevated uptake throughout the thyroid gland suggests Graves' disease, although focal areas of increased uptake with relative suppression of the remaining thyroid gland are indicative of toxic solitary nodule or TMNG. A diffusely low pattern of uptake is seen in thyrotoxicosis caused by thyroiditis, with excess release of preformed hormone because of cellular destruction. This is different from thyrotoxicosis caused by the excess formation of new hormone, as is the case with hyperthyroidism caused by Graves' disease, toxic adenoma, and TMNG. Thyroid scintigraphy may also reveal the presence of discrete nodules with low uptake, or "cold" nodules, necessitating additional investigation to rule out malignancy.
The role of fine-needle aspiration biopsy (FNA) in the setting of hyperthyroidism is useful when "cold" nodules, or nodules that do not show any uptake on RAI uptake scans, are present in a patient with Graves' disease or TMNG who prefers treatment with RAI ablation rather than surgery. Ruling out malignancy in cold nodules in these instances is important before proceeding with ablation therapy. In the absence of cold nodules, FNA is less important because the incidence of malignant nodules that are hyperfunctioning is extremely rare.
A thorough history and physical examination in addition to the previously mentioned biochemical and imaging studies should lead the clinician to the cause of thyrotoxicosis. The following sections go into additional detail about the causes of hyperthyroidism in which surgical resection has a role in treatment.
Graves' disease is hyperthyroidism caused by the presence of circulating IgG autoantibodies that bind to and stimulate the G-protein–coupled TSH receptor. Graves' disease affects approximately 0.5% of the population and is responsible for the majority (50% to 80%) of cases of hyperthyroidism. There is a 5:1 to 10:1 female predominance, and the peak incidence is between 40 and 60 years of age.16,17
A hereditary component appears to confer susceptibility to Graves' disease; its presence in a maternal relative is associated with an increased incidence of the disease and younger age at onset.18,19 Environmental factors remain important, however, with only a 35% concordance rate between monozygotic twins.19 Events believed to be associated with triggering Graves' disease in susceptible individuals include the use of sex steroids or immune-modulating drugs such as interferon-α, life stresses, smoking, and dietary iodine intake.20–22
Hyperthyroidism caused by Graves' disease is attributable to an autoimmune process, whereby constitutive stimulation of the TSH receptor by autoantibodies leads to follicular hypertrophy and hyperplasia with enlargement of the thyroid gland. This also leads to thyroid hormone overproduction with a relative increase in the production and secretion of T3 relative to T4 and consequently a suppression of TSH.23 Iodine uptake and clearance are greatly enhanced, and the vascularity of the thyroid gland is significantly increased.
It is not entirely clear what mechanism is responsible for the autoimmune process in individuals with Graves' disease. Theories include the presence of abnormal clones of autoreactive T cells and abnormal antigen presentation by follicular cells independently or in response to cytokines released by infiltrating T-cell populations, but there is no concrete evidence that clearly delineates the exact mechanism.16
The clinical presentation of patients with Graves' disease is similar in most respects to those with other forms of hyperthyroidism as previously outlined. However, several clinical features are unique to these patients. The most common of these, occurring in approximately 30% of patients, is ophthalmopathy, which presents as exophthalmos, or proptosis of the eye because of enlargement of the extraocular musculature and retrobulbar tissues caused by lymphocyte infiltration with resultant increases in connective tissue and edema. This is present variably, and the degree of protrusion as well as progression of disease can be measured with an exophthalmometer. More serious cases can be cosmetically significant and may lead to chronic desiccation of the cornea because of constant exposure, sometimes requiring orbital decompression or radiotherapy.24
The pathogenesis of Graves' ophthalmopathy is incompletely understood, but current hypotheses include the idea that it is another manifestation of the autoimmune process whereby autoreactive T lymphocytes react with one or more antigens shared by thyroid cells and orbital tissues.25 Although the identity of this antigen is not known with certainty, the TSH receptor is a logical candidate because autoantibodies to this receptor are known to be responsible for the hyperthyroidism associated with this disorder and because the TSH receptor is known to be expressed in orbital connective tissues.26,27 After antigen recognition, a cascade of events occurs, including cytokine release, adipocyte differentiation, and fibroblast proliferation. These fibroblasts secrete glycosaminoglycans, whose hydrophilic properties attract water into these tissues, leading to edema. The resulting increase in orbital content leads to the clinical manifestations observed.28
Another clinical feature unique to Graves' disease is dermopathy, also known as pretibial myxedema. This is not seen as commonly as ophthalmopathy, only occurring in around 1% of these patients. Dermopathy presents as areas of nonpitting edema and thickening of the skin, typically on the anterior surfaces of the lower extremities, although it may occur in other areas of the body in advanced cases. The pathophysiology is thought to be similar to the mechanism responsible for ophthalmopathy, with antigen recognition and activation of fibroblasts and differentiation of adipocytes, leading to compression of the dermal lymphatics. TSH receptor expression has also been show to occur in dermal fibroblasts and adipocytes.29
Finally, thyroid acropachy is the characteristic changes in the digits seen in some patients with Graves' disease. This is also a rare finding, occurring in less than 1% of these patients, with usually only those with ophthalmopathy or long-standing hyperthyroidism developing this clinical finding. Thyroid acropachy presents as soft tissue swelling of the digits and clubbing of the distal phalanges, usually of the upper extremities, and is thought to be caused by subperiosteal bone formation.30
The treatment of patients with Graves' disease involves three primary modalities, including pharmacologic therapy, RAI ablation therapy, and surgical excision. All three modalities have roles according to the clinical situation and patient preference, differing in the risks of the therapy themselves as well as the risks of recurrence of clinical hyperthyroidism.
Antithyroid drugs are frequently used as initial therapy in patients diagnosed with Graves' disease. The most common antithyroid drugs are thionamides, which include methimizole and propylthiouracil. They work primarily by inhibiting the oxidation and organic binding of thyroid iodide. Additionally, propylthiouracil inhibits the peripheral conversion of T4 to T3 by inhibiting type 1 deiodinase.31 Methimizole has a longer half-life than propylthiouracil (6 hours vs. 1.5 hours) and can be given once daily compared with three times a day. The most serious side effect is agranulocytosis, which occurs in only 1% to 3% of patients. Signs of agranulocytosis include the development of fever, sore throat, and oral ulcers. Patients should be advised to discontinue these medications if any of these side effects occur.
A significant reduction in symptoms of thyrotoxicosis is usually seen within 3 to 4 weeks of therapy, and β-adrenergic blocking drugs may be used in the interim for more immediate control of symptoms such as tachycardia, palpitations, tremor, and sweating. Dosages of antithyroid medications should be tailored to achieve normalization of serum T3 and T4 levels and eventually TSH levels in the normal range. Among patients with Graves' disease treated with antithyroid medications, remission is achieved 30% to 50% of the time, meaning TSH in the normal range while the patient is not receiving therapy. However, more than 50% of these patients experience a relapse.32
RAI therapy with iodine 131 (131I) may be used as an initial treatment modality or after treatment with antithyroid medications, which should be discontinued 3 days to 1 week before treatment to avoid diminishing its effect. Before treatment, a 24-hour radioiodine uptake study is frequently performed, and if the diagnosis is in question, the finding of diffuse increased uptake throughout the entire gland confirms the diagnosis. This test may also be used to calculate the dose of radioiodine.33
The goal of RAI therapy is to induce hypothyroidism and hopefully prevent recurrence of Graves' hyperthyroidism, which is successful in approximately 80% of cases.34 Various dosing regimens have been tried, but there seems to be no significant difference in efficacy with standard doses compared with those calculated by dosimetry.35 These doses vary between 55 and 200 μCi per estimated gram of thyroid tissue, which delivers a dose of radiation to the thyroid between 50 and 100 Gy.36 Patients with persistent hyperthyroidism after initial therapy should undergo a second ablation in approximately 6 months. Recurrent hyperthyroidism occurs at a rate of 3% per year, so patients must continue to be monitored.
RAI therapy is contraindicated in pregnant women, and all women of childbearing age must have a pregnancy test before undergoing treatment. RAI is excreted in the urine, so the pelvic contents are exposed to radiation. Additionally, radioiodine crosses the placenta and can be taken up by the fetal thyroid gland after the late stages of the first trimester. Despite only having a half-life of 1 week, women are encouraged not to attempt conception for 6 to 12 months after undergoing RAI.35
Other side effects and adverse reactions to RAI include radiation thyroiditis, which may cause neck tenderness and the release of preformed hormone 10 to 14 days after treatment.37 Several studies have shown that RAI may worsen ophthalmopathy in approximately 10% of patients,38 although other studies suggest this is not the case in patients with mild orbitopathy.39 Treatment with corticosteroids may decrease this effect,40but some clinicians believe the presence of ophthalmopathy is a relative contraindication to RAI therapy and that surgical resection should be recommended in these patients.41Some published studies show that surgical resection improves the symptoms of ophthalmopathy in up to 64% of patients, although the extent of resection (total vs. subtotal thyroidectomy) did not seem to influence symptomatic improvement; therefore, the authors advocate surgical resection as the therapy of choice in Graves' disease patients with significant eye disease.42,43 Previously held beliefs that RAI therapy increased the incidence of other malignancies such as thyroid cancer or lymphoproliferative disorders have not appeared to be justified.44
Thyroidectomy has been the least used modality in the treatment of patients with Graves' disease. Surgery has been reserved for selected patients, including those with complications or side effects from antithyroid medications, pregnant or nursing women, patients with large goiters or suspicious nodules, patients who do not wish to have exposure to even a low dose of radioactivity, and patients who want definitive treatment in a short time frame. Patients with suspicious nodules should undergo FNA to rule out malignancy before undergoing RAI therapy. A growing school of thought believes that patients with Graves' disease and discrete nodules should be treated with surgical resection because of the high risk of malignancy in this setting (as high 40% in some studies).45 Also, as previously mentioned, more clinicians now favor surgical resection in patients with significant ophthalmopathy.
The type of surgery used to treat patients with Graves' disease traditionally involved subtotal thyroidectomy with an attempt to leave approximately 2 g of tissue overlying the recurrent laryngeal nerves (RLNs). This method was believed to offer the best chance at cure of hyperthyroidism while minimizing the risk of injury to the parathyroids and RLNs, as well as minimizing the incidence of hypothyroidism. More recently, total thyroidectomy has become the accepted surgical therapy for patients with Graves' disease because of the avoidance of the 2% to 20% reported recurrence rate of hyperthyroidism with subtotal resection,41 with studies showing no increase in complication rates.46
Patients undergoing surgical resection for Graves' disease should be rendered euthyroid with antithyroid drugs preoperatively. This should be established by following the patient's serum free T3 and free T4 because the serum TSH levels take longer to normalize. Additionally, these patients should receive a saturated solution of potassium iodide (SSKI) for 7 to 10 days before surgery. This has been shown to decrease the size and vascularity of the gland, making the surgery less technically challenging (Table 3-3).
TMNG occurs in the setting of preexisting nontoxic multinodular goiter where structural and functional heterogeneity and subsequent autonomy develop slowly over time and ultimately lead to hyperthyroidism and clinical thyrotoxicosis. TMNG is responsible for approximately 5% of cases of hyperthyroidism in the United States, but it may be much more common in areas of endemic goiter caused by iodine deficiency.47 TMNG usually presents in patients older than 50 years of age who have had a long-standing multinodular goiter. Nodules are frequently monoclonal, and TSH receptor mutations leading to constitutive activation have been identified in 60% of nodules in patients with TMNG.48
Although the development of thyrotoxicosis is typically gradual, it may be more rapid in the setting of iodine administration in the form of iodinated contrast during radiology studies and with medications such as amiodarone, the so-called Jod-Basedow effect. These patients present with the typical symptoms and signs of hyperthyroidism and are found to have a multinodular goiter on examination or ultrasonography. RAI uptake scans show overall normal uptake of radioiodine, with several areas of increased uptake and suppression of the remaining gland.
In the United States, treatment of patients with TMNG has typically been with RAI therapy. This often requires higher doses of radioiodine with consequent higher levels of radiation exposure than in RAI therapy for Graves' disease because of the overall normal uptake of iodine by the thyroid gland. The risk of recurrence of hyperthyroidism after RAI therapy is similar to that in patients with Graves' disease.49
Surgery, again, is usually reserved for patients with compressive symptoms, those who wish to avoid exposure to radioactivity, and those who have failed medical therapy or RAI therapy. Suspicious cold nodules should be evaluated with FNA before RAI therapy to rule out malignancy. If biopsy results are suspicious or positive for malignancy, surgical resection should ensue. Although patients should be rendered euthyroid with antithyroid medications before surgery, these do not tend to be significantly hypervascular, so treatment with SSKI is not necessary.
Toxic adenomas are true follicular adenomas and are the least common cause of hyperthyroidism after Graves' disease and TMNG (<5 activating="" again="" amp="" as="" autonomy="" been="" class="supclass" cyclic="" downstream="" functional="" g-protein="" have="" identified="" in="" linked="" mutations="" nbsp="" nodules="" of="" pathogenesis="" pathway="" production.="" receptor="" signaling="" span="" stimulatory="" style="display: inline; font-size: 11px; vertical-align: super;" the="" these="" to="" well="" xmlns:xlink="http://www.w3.org/1999/xlink">50
Clinical presentation is usually in the setting of a solitary nodule with a suppressed TSH level and normal or mildly elevated free T3 and T4 levels. RAI uptake scans show a single focus of increased uptake with suppression of the remaining gland. Thyrotoxicosis is rare in nodules less than 3 cm in size. As with Graves' disease and TMNG, treatment consists of RAI therapy and surgery; medical therapy alone is rarely used for patients with this condition. RAI therapy is used frequently in the United States, with surgery performed more often in other parts of the world.
When performed, surgery involves total thyroid lobectomy and isthmusectomy. FNA is generally not indicated in the setting of toxic solitary nodule because the risk for malignancy in a hyperfunctioning nodule is extremely low. Patients should be rendered euthyroid before surgery with antithyroid medications as necessary until free T3 and free T4 are in the normal range. As is the case with TMNG, SSKI is not necessary in these patients before surgery.
- Recurrence rates after treatment of Graves' disease are as follows:
- Medical therapy: Remission is seen in 30% to 50% of patients treated with antithyroid medications; however, 50% of these patients develop recurrent hyperthyroidism.
- RAI: Recurrence after treatment occurs in approximately 20% of patients, with recurrence of thyrotoxicosis occurring at about a rate of 3% per year.
- Surgery: Recurrence after total thyroidectomy is essentially 0%. Rates of recurrent symptoms after subtotal thyroidectomy have been reported to be as high as 20%.
- Surgery and Graves' ophthalmopathy: A growing number of clinicians believe that the presence of ophthalmopathy is a relative contraindication to RAI treatment because it has been shown to worsen the retrobulbar inflammatory process; these clinicians recommend surgical resection instead. This area remains controversial, with several published reports showing improvement in orbitopathy in most patients after surgical resection and others showing no increase in incidence of worsening eye pathology after RAI therapy, especially if the patient is treated with corticosteroids.
- Initial evaluation of a patient with thyrotoxicosis: The first test to obtain after history and physical examination is the TSH level. If this is found to be suppressed, then one can proceed along the diagnostic algorithm (Figure 3-1).
- Use of RAI uptake scans: These should be obtained only when the cause of the thyrotoxicosis remains uncertain after history, physical examination, and initial laboratory tests. For example, in patients with thyrotoxicosis and several thyroid nodules, an uptake scan may be used to differentiate between TMNG, Graves' disease with the presence of discrete nodules, and toxic adenoma in the presence of other cold nodules.
FIGURE 3-1.
Diagnostic algorithm for thyrotoxicosis. MNG = multinodular goiter; RAI = radioactive iodine; TSH = thyroid-stimulating hormone.
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