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| TEXT BOOK of MEDICINE |
Section XVIII Endocrine Diseases
| 244 THYROID Paul Ladenson • Matthew Kim • |
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EMBRYOLOGY
The embryonic thyroid gland develops from endoderm at the foramen cecum that migrates downward and elongates to form two clusters of spherical follicles. The follicles proliferate to form the lobes of the thyroid gland.
Ectopic thyroid tissue can remain at the base of the tongue to form a lingual thyroid or may remain along the thyroglossal duct. It can migrate as far inferiorly as the diaphragm. A thyroglossal duct cyst can present as a fluctuant midline cervical mass that elevates with extension of the tongue.
ANATOMY
The adult thyroid gland contains two lobes that wrap along the right and left anterolateral aspects of the trachea midway between the thyroid cartilage and the suprasternal notch. Each lobe is demarcated into upper, middle, and lower poles. The right and left lobes are connected by an isthmus on the anterior aspect of the trachea just below the cricoid cartilage. The normal terminus of the thyroglossal duct can persist as a pyramidal lobe. A pyramidal lobe is often palpably enlarged in diffuse thyroid disorders, such as autoimmune thyroiditis and Graves' disease. The adult thyroid gland weighs 15 to 20 g. Each lobe measures approximately 4 cm in length, 2 cm in width, and 1.5 cm in depth.
After thyroid enlargement, the attachment of the sternothyroid muscle to the trachea limits upward expansion of the superior aspect of each lobe. Lateral and posterior growth may cause inferior expansion that may extend into the superior mediastinum, compressing the trachea and veins at the thoracic outlet. The parathyroid glands usually lie beneath the posterior aspects of each thyroid lobe. The recurrent laryngeal nerves course upward along the tracheoesophageal groove, from which branches pass behind each thyroid lobe to innervate the larynx.
HISTOLOGY
Thyroid tissue is composed of clustered spherical follicles, each containing a single layer of follicular epithelial cells known as thyrocytes that surround a lumen containing colloid. The principal component of colloid is thyroglobulin, a thyrocyte-specific protein. Microvilli on the luminal surface of thyrocytes play active roles in thyroid hormone synthesis and secretion. Aggregated clusters of follicles are surrounded by dense networks of capillaries innervated by sympathetic and parasympathetic nerve fibers. Parafollicular C cells, which are derived from neural crest tissue and produce calcitonin, are widely dispersed between follicles.
PHYSIOLOGY
Thyroid Hormone Synthesis and Secretion
Dietary iodine in the form of iodide (I−) or iodate (IO3−) is absorbed from the gastrointestinal tract and distributed in the extracellular fluid. The median urinary iodide level in an iodine-sufficient population is 10 μg/dL. The current average daily intake of iodine in the United States equals the recommended daily intake of 150 μg because of widespread use of iodized salt, iodate as a preservative in baked goods, and dairy products that contain iodine. Circulating iodide is actively transported into the thyrocyte by the sodium-iodide symporter. Within the thyrocyte, iodide is rapidly oxidized by H2O2 in a reaction catalyzed by thyroid peroxidase. The reactive intermediate formed is covalently bound to tyrosyl residues present in thyroglobulin to generate monoiodotyrosine and diiodotyrosine residues through a process known as organification. Thyroid peroxidase also catalyzes the coupling of the monoiodotyrosine and diiodotyrosine residues to generate thyroxine (T4) and triiodothyronine (T3). Exposure to excessive amounts of circulating iodide may transiently inhibit thyroid hormone synthesis by disrupting organification. T4 and T3 are secreted after proteolysis of thyroglobulin. This hydrolytic process may be inhibited by exposure to excessive amounts of iodide or lithium. In the normal state, 100 μg of T4 and 5 μg of T3 are directly released into the circulation each day.
Thyroid Hormone Transport and Metabolism
Circulating thyroid hormones are more than 99% bound to one of three classes of plasma proteins. Thyroxine-binding globulin (TBG) synthesized by the liver functions as the principal transport protein. Pregnancy and exposure to pharmacologic doses of estrogens can increase TBG levels, as can hepatitis, familial TBG excess, and certain medications including 5-fluorouracil, tamoxifen, and methadone. Conversely, decreased TBG levels may occur with systemic illness, severe hepatic disease, nephrotic syndrome, and treatment with androgens, glucocorticoids, and slow-release nicotinic acid. Whereas total T4 and T3 levels rise and fall with changes in the TBG level, free T4 and T3 levels remain relatively constant. Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant disorder characterized by the production of albumin that binds T4 with a high affinity. Affected individuals may present with high total T4 levels and normal free T4 levels. Thyroxine-binding prealbumin and albumin make lesser contributions to T4 and T3 transport in blood.
The receptor binding and biologic activity of T3 is eightfold greater than that of T4. More than 80% of the T3 present in target tissues is derived from T4 through the action of deiodinase enzymes. Type 1 deiodinase, present in the liver and kidneys, converts T4 to T3, which contributes to the pool of T3 in the circulation. The activity of type 1 deiodinase may be inhibited by systemic illness, iodide-containing compounds including amiodarone and radiocontrast agents, glucocorticoid therapy, and selenium deficiency. Type 2 deiodinase is present in the pituitary gland and brain. Type 3 deiodinase is present in the glial cells of the central nervous system. It deactivates thyroid hormone by inner ring monodeiodination, a process that converts T4 to inactive reverse triiodothyronine (rT3) and T3 to inactive diiodothyronine (T2).
Control of Thyroid Function
The growth of thyroid tissue and the synthesis and secretion of thyroid hormones are controlled by the hypothalamus and the pituitary gland. Thyrotropin-releasing hormone (TRH) synthesized in the supraoptic and paraventricular nuclei of the hypothalamus is transported to the anterior pituitary gland through the hypophysial portal system. TRH binds to receptors on thyrotrophic cells in the anterior pituitary, stimulating the synthesis and secretion of thyroid-stimulating hormone (TSH). TSH is a heterodimeric glycoprotein composed of a unique β subunit coupled to an α subunit identical to that present in follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. It is transported in the circulation to the thyroid gland, where it binds to the extracellular domain of TSH receptors on thyrocytes. The binding of TSH to the TSH receptor stimulates growth of individual thyrocytes, iodide transport and organification, hydrolysis of thyroglobulin, and secretion of thyroid hormone. Circulating T4 and T3 exert negative feedback at the levels of both the hypothalamus and the pituitary gland, inhibiting the synthesis and secretion of TRH and TSH, respectively.
Thyroid Hormone Action
Thyroid hormone binds receptors that are members of the nuclear receptor superfamily, regulating expression of thyroid hormone–responsive genes. Isoforms of the thyroid hormone receptors (α1, β1, and β2) bind to a specific hexameric oligonucleotide sequence in the transcriptional regulatory region of thyroid hormone–responsive genes. Thyroid hormone increases oxygen consumption, thermogenesis, and expression of the low-density lipoprotein (LDL) receptor, resulting in accelerated LDL cholesterol degradation. In myocardium, T3 increases myocyte contractility and relaxation by altering myosin heavy chain and sarcoplasmic reticulum adenosine triphosphatase (ATPase). In the cardiac conducting system, T3 increases the heart rate by altering sinoatrial node depolarization and repolarization. Other physiologic effects of thyroid hormone include increased mental alertness, ventilatory drive, gastrointestinal motility, and bone turnover. During fetal development, thyroid hormone plays a critical role in brain development and skeletal maturation.
Diagnosis
Physical Examination
Examination of the thyroid begins with inspection of the lower anterior portion of the neck to check for diffuse or asymmetrical gland enlargement, tracheal deviation, lymphadenopathy, and jugular venous distention. Palpation can be performed by an anterior or posterior approach. Anterior palpation can be performed by using the thumb of one hand to locate the isthmus of the gland beneath the cricoid cartilage. The right lobe of the thyroid gland can be palpated by placing the left thumb along the left side of the trachea to brace the contralateral lobe, using the tips of the fingers of the right hand to laterally retract the right sternocleidomastoid muscle at the level of the isthmus, and using the pads of the fingers of the right hand to explore and define the tissue composing the lobe. The mass of tissue that moves beneath the fingertips when the patient swallows represents the lobe. This maneuver can be reversed to examine the left lobe.
Laboratory Findings
TSH and Thyroid Hormone Levels
The log-linear negative relationship between levels of T4 + T3 and TSH makes it a sensitive indicator of primary thyroid gland dysfunction. Current TSH immunoassays with a functional sensitivity of less than 0.02 mIU/L permit accurate detection of all common causes of thyroid hormone deficiency and excess. Indeed, TSH levels become abnormal when patients' thyroid hormone levels remain within broad reference ranges, conditions termed subclinical hypothyroidism and subclinical thyrotoxicosis. In most patients with primary thyroid gland dysfunction, measurement of a single TSH level permits accurate classification of thyroid status. Limitations of TSH testing occur when there is TSH-mediated secondary thyroid dysfunction, reduced biologic activity of T3 or TSH itself, temporary disequilibrium of the hypothalamic-pituitary-thyroid axis, or analytical derangements affecting the TSH immunoassay.
Measurements of T4 and T3 levels confirm the significance of an abnormal TSH level, define the severity of thyroid dysfunction, and provide a clue to the underlying etiology. Thyroid hormone measurements are also essential to define patients' thyroid status when TSH levels cannot be trusted. Immunoassays are available to measure total and free levels of T4 and T3. Whereas assays that measure total T4 and T3 levels are accurate, their results do not distinguish between large plasma protein–bound and free fractions of each hormone. Consequently, congenital and acquired derangements of TBG (and less commonly transthyretin and albumin) can alter total but not free T4 and T3 levels. These conditions can be misdiagnosed as abnormal thyroid function unless a discordance in TSH is noted or one of these underlying conditions is suspected (Tables 244-1 and 244-2).
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There are several methods of estimating unbound T4 and T3 levels. Free T4 and free T3 immunoassays are widely employed for this purpose and yield reliable results in common conditions that alter plasma protein levels, such as estrogen-induced TBG excess. Free T4 measurement after equilibrium dialysis of serum is the most accurate approach but is technically demanding and not readily available in most settings.
Other Laboratory Tests
Measurement of thyroid autoantibody titers can be useful in the evaluation of thyroid dysfunction. Antithyroid peroxidase and antithyroglobulin antibody titers can confirm a diagnosis of autoimmune thyroiditis. Thyroid-stimulating immunoglobulin activity levels can be measured to evaluate Graves' disease. The erythrocyte sedimentation rate can be helpful in the diagnosis of subacute thyroiditis. Serum thyroglobulin and calcitonin levels are used as tumor markers in observing patients with treated differentiated and medullary thyroid cancers, respectively.
Imaging
Anatomic Imaging
Ultrasonography provides detailed views that help measure the size of the thyroid gland, characterize its texture, and identify structural abnormalities including solid nodules and simple or partially cystic nodules. Diffuse heterogeneity may suggest autoimmune thyroiditis. Certain characteristics of nodules—including the appearance of capsules, vascularity, and patterns of calcification—can alter the probability of malignancy but do not confirm or exclude thyroid cancer with certainty. Imaging of surrounding structures may identify cervical lymphadenopathy not detectable on physical examination.
Computed tomographic (CT) and magnetic resonance imaging (MRI) scans can also define the size and anatomic relationships of thyroid tissue but are less sensitive than ultrasonography in characterizing thyroid lesions. The value of these modalities is their ability to delineate tracheal deviation, narrowing, and substernal extension of the thyroid into the mediastinum. Cervical CT scanning can also help define and localize regional lymphadenopathy. Positron emission tomography (PET) plays a role in the localization of residual thyroid cancer.
Functional Imaging
Radionuclide scanning takes advantage of the fact that gamma ray–emitting tracers transported into thyrocytes by the sodium-iodide symporter can generate images that reflect the regional activity of thyroid tissue. Technetium Tc 99m and iodine 123 are commonly used. 99mTc-pertechnetate is rapidly trapped by thyrocytes, and 99mTc scans can be acquired 20 to 30 minutes after injection. 123I and 131I thyroid scans generate images providing a more accurate representation of regional thyroid tissue function that can indicate whether a nodule is hypofunctioning (cold), hyperfunctioning (hot), or equivalent in function to extranodular tissue (warm). Radionuclide imaging no longer plays a central role in the differential diagnosis of most thyroid nodules. When it is necessary, 123I is the preferred tracer for use because of its lower thyroidal and whole body radiation dose.
Thyroid Uptake
The fraction of an administered radioactive iodine or technetium dose taken up and retained by the thyroid gland during a defined period represents an index of the gland's activity. Typically, technetium pertechnetate uptakes are determined at 20 minutes and range from 0.5 to 3%; radioiodine uptakes are usually determined at 6 or 24 hours and range from 8 to 28%. These fractional thyroid uptakes can be useful in the differential diagnosis of thyrotoxicosis. Radioiodine uptake values are also used to calculate effective 131I doses for treatment of hyperthyroidism and thyroid cancer.
▪ HYPOTHYROIDISM
Definition
Primary hypothyroidism (termed myxedema when it is severe) refers to hormone deficiency caused by intrinsic dysfunction of the thyroid gland that disrupts the synthesis and secretion of T4 and T3 (Table 244-3). Overt hypothyroidism is characterized by an elevated TSH level, usually greater than 10 mIU/L, in conjunction with a free T4 level below the lower limit of the reference range. In mild or subclinical hypothyroidism, the TSH level is only modestly elevated; the free T4 level remains in the low-normal to normal range.
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Secondary or central hypothyroidism refers to deficient thyroid gland function that is the result of inadequate stimulation by TSH. This is due, in turn, to production of either insufficient or ineffective TSH from a number of congenital or acquired pituitary and hypothalamic disorders.
Epidemiology
Primary hypothyroidism is common. Population-based surveys reveal that it is present in almost 5% of individuals. It is more commonly diagnosed in women and with advancing age, although it occurs in men and younger individuals. It is more prevalent among whites and Latinos. Secondary hypothyroidism is rare, representing less than 1% of all cases.
Pathobiology
Dietary iodine deficiency is the chief cause of primary hypothyroidism in certain underdeveloped regions of the world. The most common cause of primary hypothyroidism in the United States and most other countries is autoimmune (or Hashimoto's) thyroiditis, a condition in which altered T cell–mediated immunity causes destruction of thyroid tissue and impaired gland function. On histologic examination, the condition is characterized by a lymphocytic infiltrate and fibrosis. Circulating antithyroid antibodies directed against thyroid peroxidase and thyroglobulin are clinically useful markers of the disease, but glandular inflammation is principally the result of altered T cell–mediated function. There is a genetic predisposition to the condition. Linkage studies suggest a polygenic basis. Patients with autoimmune thyroiditis may have other endocrine and nonendocrine autoimmune disorders. It may be a component of the type 2 polyglandular autoimmune syndrome associated with autoimmune adrenal insufficiency and type 1 diabetes mellitus. It is less commonly a component of the type 1 syndrome that includes adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis. Other nonendocrine autoimmune conditions associated with autoimmune thyroiditis include atrophic gastritis, pernicious anemia, systemic sclerosis, Sjügren's syndrome, and vitiligo. Individuals treated with interferon alfa may develop autoimmune thyroiditis with transient or permanent hypothyroidism.
Surgical resection of thyroid tissue to treat thyroid disorders or other head and neck cancers predictably leads to hypothyroidism. Radioactive iodine therapy for treatment of hyperthyroidism commonly destroys sufficient thyroid tissue to cause postablative hypothyroidism. External beam radiation therapy for head and neck cancer also commonly causes thyroid gland failure. Exposure to certain pharmacologic and radiocontrast agents that contain large amounts of iodine, such as the antiarrhythmic agent amiodarone, radiocontrast dyes, and some expectorants and topical disinfectants, can disrupt key steps in thyroid hormone production. Lithium used to treat affective disorders inhibits secretion of T4 and T3, leading to hypothyroidism in 10% of treated patients. Other pharmacologic agents reported to cause hypothyroidism include stavudine, thalidomide, and aminoglutethimide.
There are a number of other rare causes of primary hypothyroidism. Agenesis or dysgenesis of the thyroid gland and defects in thyroid hormone synthesis cause congenital hypothyroidism. Infiltrative disorders can disrupt thyroid function, including hemochromatosis, amyloidosis, systemic sclerosis, and invasive fibrous thyroiditis (also known as Riedel's thyroiditis). The thyroid gland inflammation that occurs with subacute thyroiditis and painless (postpartum) thyroiditis causes transient hypothyroidism, from which most patients recover.
Secondary or central hypothyroidism may be caused by a number of disorders that impair normal hypothalamic or pituitary control of the thyroid gland. Infiltrative disorders affecting the hypothalamus that can interfere with TRH secretion include sarcoidosis, hemochromatosis, and histiocytosis. Masses that impinge on the pituitary stalk can impede TRH delivery through the hypophysial portal system. Compression of thyrotrophic cells by pituitary adenomas and other masses in the sella turcica can inhibit synthesis and secretion of TSH. Surgery and radiotherapy to treat pituitary adenomas can destroy thyrotrophic cells, leading to secondary hypothyroidism that develops as a component of panhypopituitarism. Other disorders that may be associated with secondary hypothyroidism include lymphocytic hypophysitis, pituitary metastases from primary malignant neoplasms, apoplexy, infarction caused by hemorrhage at the time of delivery in women (also known as Sheehan's syndrome), and head trauma.
Clinical Manifestations
Symptoms and Signs
Symptoms of hypothyroidism include fatigue, lethargy, weight gain despite poor appetite, cold intolerance, hoarseness, constipation, weakness, myalgias, arthralgias, paresthesias, dry skin, and hair loss. Females may develop precocious puberty, menorrhagia, amenorrhea, and galactorrhea. Affected individuals may experience depressed mood with limited initiative and sociability. Cognitive deficits can range from mild lapses in memory to delirium, dementia, seizures, and coma. The nonspecific nature of most of these symptoms makes it difficult to determine which patients presenting with them have hypothyroidism compared with other causes. In most cases, hypothyroidism is insidious in onset, making its recognition difficult. Symptoms that are new, progressive, or present in combination are more likely to be due to hypothyroidism.
The physical findings associated with hypothyroidism vary according to the age at onset and disease severity. Children may present with delayed linear growth despite weight gain, precocious or delayed puberty, and pseudohypertrophy of muscle. Adults can present with bradycardia, diastolic hypertension, and mild hypothermia. The skin may be coarse, dry, yellow, and cool to the touch as a result of peripheral vasoconstriction. Diffuse thinning of scalp hair accompanied by thinning of the lateral eyebrows may occur. The nails may be brittle. Examination of the chest may reveal distant heart sounds. Examination of the extremities may reveal diffuse nonpitting edema caused by the deposition of glycosaminoglycans. Neurologic examination may reveal slow dysarthric speech and diffuse slowing of deep tendon reflexes with a marked delay in the terminal relaxation phase.
Examination of the neck may reveal a range of findings. Healed transverse or lateral incisional scars in this region indicate a history of surgical resection of thyroid tissue. The thyroid gland may be normal in size, diffusely enlarged, or atrophic to the point at which it may be difficult to palpate with any degree of certainty. It may be soft and smooth with a lobular texture or firm and irregular with a variegated nodular texture.
Other Routine Test Abnormalities
Blood tests may reveal anemia, hyponatremia, hypoglycemia, and elevated creatine phosphokinase, prolactin, homocysteine, triglyceride, and total and LDL cholesterol levels. Electrocardiography may show sinus bradycardia with low voltage in the limb leads. Chest radiography and echocardiography may demonstrate a pericardial effusion.
Diagnosis
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| FIGURE 244-1 Laboratory assessment of suspected hypothyroidism. |
Suspected primary hypothyroidism is confirmed by an elevated TSH level (Fig. 244-1). Established reference ranges for TSH levels typically extend from 0.5 to 4.5 mIU/L. However, the distribution of values within this range is skewed toward the lower half, such that the mean TSH level is estimated to be 1.5 mIU/L. Measurement of the free T4 level confirms the diagnosis of primary hypothyroidism and characterizes its severity. A low free T4 level in conjunction with a persistently elevated TSH level establishes the diagnosis of overt primary hypothyroidism, whereas a low-normal free T4 level with an elevated TSH level is termed mild primary hypothyroidism. Other uncommon causes of isolated TSH elevation should be considered in appropriate settings, including recovery from severe systemic illness, renal failure, and adrenal insufficiency.
Testing to determine the underlying cause of primary hypothyroidism is usually unnecessary. The condition can almost always be ascertained from the patient's history, and if not, autoimmune thyroiditis is usually the etiology. When confirmation is required (e.g., to convince a patient that the condition is permanent), serum antithyroid antibodies may be assessed. Measurement of antithyroid peroxidase antibody is a more sensitive test than antithyroglobulin antibody for this purpose. Ten percent of patients with histologic autoimmune thyroiditis will not have any circulating antithyroid antibodies.
When clinical findings suggest the possibility of secondary hypothyroidism, the TSH level cannot be relied on to provide an accurate index of thyroid function. These circumstances include presence of a sellar mass, previous pituitary surgery or irradiation, other pituitary axis hormone deficiencies, and conditions known to cause hypothalamic or pituitary dysfunction. In these settings, the serum free T4 level must be assessed, and a low or even low-normal free T4 level can confirm the diagnosis. The TSH level in patients with secondary hypothyroidism can be low, normal, or even modestly elevated.
Treatment
The goals of thyroid hormone replacement therapy are straightforward: to replace endogenous thyroid hormone production, to avoid iatrogenic thyrotoxicosis, and rarely to treat systemic complications of severe hypothyroidism. Levothyroxine sodium (hereafter thyroxine) is the hormonal preparation of choice for both primary and secondary hypothyroidism. Thyroxine has a number of favorable pharmacokinetic characteristics. It is well absorbed, and its plasma protein binding gives it a 7-day half-life, permitting daily dosing. Thyroxine is physiologically deiodinated to the more biologically active T3 in peripheral tissues. However, thyroxine is a narrow therapeutic index drug, and doses differing by as little as 12% can have clinical consequences. Tablets of multiple dose strengths ranging from 25 to 300 μg are available in the United States. Whereas regulatory standards ensure pharmaceutical equivalence in terms of mass of thyroxine, bioavailability may differ by as much as 12% among different preparations. Consequently, adherence to a single thyroxine formulation is advisable.
The optimal dose of thyroxine for replacement therapy is related to lean body weight, with most adults requiring a daily dose of 1.8 μg/kg. The dose requirement for elderly adults is typically lower (e.g., 1.0 μg/kg/day) because of reduced metabolic clearance. Patients with postsurgical or postablative hypothyroidism usually require a higher daily dose than patients with autoimmune thyroiditis who may have some residual gland function. Patients with coexisting malabsorptive disorders may require higher and variable doses. Certain medications, mineral supplements, and foods can interfere with thyroxine absorption, including ferrous sulfate, calcium carbonate, aluminum hydroxide, sucralfate, cholestyramine, and soy-containing foods (Table 244-4). Thyroxine doses should be separated from these substances by 4 or more hours.
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Thyroxine dose requirements may increase as a result of accelerated metabolic clearance in several circumstances. Patients with nephrotic syndrome and other systemic illnesses that lead to rapid clearance of thyroid hormone require higher daily doses. Dose requirements increase by an average of 75% in most pregnant women, probably as a result of placental metabolism of thyroxine. Simultaneous treatment with phenytoin, phenobarbital, carbamazepine, or rifampin also typically accelerates thyroxine metabolism. One third of postmenopausal women beginning estrogen replacement therapy have increased dose requirements.
Most adults without known or suspected coronary artery disease can be started on a full replacement dose of thyroxine. The initial dose can be calculated on the basis of the patient's weight and age, rounding down to the nearest available dose strength. For patients with primary hypothyroidism, adequacy of thyroxine therapy can be assessed by TSH measurement 4 to 6 weeks after the dose is started or adjusted. The target TSH level for most individuals should be the lower half of the reference range (i.e., 1.0 to 2.0 mIU/L). Once an adequate dose has been established, a TSH level should be checked annually. In patients with secondary hypothyroidism, the serum free T4 level should be monitored 2 to 4 weeks after the thyroxine dose is started or adjusted, with a target free T4 level in the upper half of the reference range.
Management of Complications
Complications of thyroxine therapy are limited to iatrogenic thyrotoxicosis and rarely adverse effects of restoring euthyroidism. Typical symptoms and signs of thyrotoxicosis accompany overtreatment. Even a modestly excessive thyroxine dose can induce bone mineral loss, especially in postmenopausal women, and can increase the risk of atrial fibrillation in older individuals. In patients with underlying coronary artery disease, the positive chronotropic and inotropic effects of thyroxine may exacerbate myocardial ischemia. Adults with known or suspected ischemic heart disease should be started on a low dose that is titrated upward in small increments once tolerance is ensured (e.g., starting with 25 μg daily, then increasing the dose by 12.5 to 25 μg every 4 to 6 weeks). In some cases, β-blocker therapy may need to be intensified to counter the induction of myocardial ischemia. Deliberate suboptimal dosing of thyroxine should be avoided. If necessary, coronary revascularization may be required before euthyroidism can be fully restored. Coexisting adrenal insufficiency associated with hypopituitarism or the type 2 polyglandular autoimmune syndrome may be unmasked when cortisol clearance is accelerated by a return to a euthyroid state. Other adverse effects that infrequently occur with thyroxine therapy include transient hair loss, acute sympathomimetic symptoms that resolve with dose reduction and slow advancement, and pseudotumor cerebri in children.
A minority of patients with thyroxine-treated hypothyroidism report bothersome symptoms ascribed to hypothyroidism, despite biochemical evidence of adequate thyroid hormone replacement. Some of these patients improve with prescription of a higher thyroxine dose that restores the serum free T4 level to the upper limit of normal. It was anecdotally suggested that combination thyroxine and T3 therapy could aid such patients. Several studies have shown that provision of a physiologic T3 supplement is not superior to placebo when iatrogenic thyrotoxicosis is avoided and depressed patients are excluded. Consequently, combination T4 and T3 therapy, including the use of desiccated thyroid, appears to offer no advantage.
Mild Hypothyroidism
Whether individuals diagnosed with mild hypothyroidism (i.e., an elevated or high-normal TSH level with a free T4 level within the reference range) benefit from thyroxine therapy is controversial. Proponents argue that treatment with thyroxine relieves symptoms, lowers cholesterol, avoids the emergence of overt hypothyroidism, and is relatively safe. Detractors counter that these purported benefits have not been confirmed in adequately powered, randomized controlled trials. In practice, many providers opt for a trial of therapy in mildly hypothyroid patients who are symptomatic, have underlying hypercholesterolemia, or demonstrate a high likelihood of progressing to overt hypothyroidism. Predictors of progressive thyroid failure include age older than 65 years, TSH level higher than 10 mIU/L, and the presence of circulating antithyroid antibodies indicating underlying autoimmune thyroiditis.
Myxedema Coma
Severe hypothyroidism can culminate in myxedema coma, a life-threatening condition characterized by hypothermia, bradycardia, hypotension, altered mental status, and multisystem organ failure. Risk factors include advanced age, poor access to health care, and other underlying major organ system diseases. Most patients have long-standing thyroid hormone deficiency. Treatment should include thyroxine (1.8 μg/kg daily with or without a 500-μg loading dose). Some experts advocate coadministration of triiodothyronine in divided doses to compensate for impaired conversion of T4 to T3. No controlled trials have been performed to evaluate the relative benefits and risks of these different approaches. Glucocorticoids should be administered in stress doses after a cosyntropin stimulation test has been performed to check for evidence of concomitant adrenal insufficiency. Care should be taken to avoid exposure to potent sedative or analgesic agents that may exacerbate altered mental status. Hypothermia should be treated with external warming to reduce the risk of circulatory collapse.
Nonthyroidal Illness
In patients with severe nonthyroidal illness, a characteristic constellation of thyroid function test changes occur that often appear to be consistent with hypothyroidism (Fig. 244-2). The T3 level usually declines as a result of decreased extrathyroidal T4 to T3 conversion. With increasingly severe disease, total T4 and free T4 levels also decline. TSH levels are usually low to low-normal. During the course of recovery, the TSH level can rise above the upper limit of the normal range, producing a profile that can be mistaken for primary hypothyroidism. Clinical correlation is essential to assess thyroid function in severely ill patients (e.g., a history of preexisting thyroid or pituitary disease, the presence of a goiter, or features suggesting other elements of hypopituitarism). Because no benefit of thyroid hormone treatment has been shown for these patients, observation with retesting 6 to 8 weeks after recovery is the preferred approach.
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| FIGURE 244-2 Changes in thyroid hormone levels during nonthyroidal illness. |
▪ THYROTOXICOSIS
Definition
Thyrotoxicosis is defined as a systemic syndrome caused by exposure to excessive amounts of thyroid hormone (Table 244-5).
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Epidemiology
It presents in 1 of every 2000 adults, affecting 1% of all individuals during the course of a lifetime.
Pathobiology
Hyperthyroidism develops when there is excessive synthesis and secretion of thyroid hormone caused by thyrotropic stimulus or autonomous function of thyroid tissue. Strictly speaking, hyperthyroidism refers to those forms of thyrotoxicosis that are caused by excessive production of thyroid hormone by the thyroid gland. The two terms are often used interchangeably. In Graves' disease, the most common cause of hyperthyroidism, the thyroid gland is stimulated by autoantibodies that bind to and activate the TSH receptor. Excessive secretion of TSH causes hyperthyroidism in patients with rare TSH-secreting pituitary adenomas. Human chorionic gonadotropin (hCG), a glycoprotein with high TSH homology, can cause transient gestational hyperthyroidism during pregnancy. This type of hyperthyroidism can also occur when choriocarcinoma, molar pregnancy, or a germ cell tumor produces variant forms of hCG that are more active, or when mutant TSH receptors bind hCG more avidly, as occurs in familial gestational thyrotoxicosis.
Autonomous production of thyroid hormone occurs when thyrocytes function independently of TSH receptor activation. This can occur as a result of growth of a benign functioning thyroid adenoma, as a result of growth of multiple autonomously functioning nodules forming a toxic multinodular goiter, or in rare cases when patients with well-differentiated thyroid cancer present with functioning metastases. In some toxic adenomas, somatic mutations in the TSH receptor gene lead to constitutive activation. In patients whose thyroid glands have the potential for autonomous function, exposure to excessive amounts of iodine in the form of amiodarone or iodinated contrast agents can sometimes provoke hyperthyroidism.
Transient thyrotoxicosis also can be caused by inflammatory conditions that release excessive amounts of thyroid hormone stored in the gland. These include subacute thyroiditis that is believed to be caused by a viral infection, acute or suppurative thyroiditis caused by bacterial infection, radiation-induced thyroiditis, and pharmacologic thyroiditis precipitated by exposure to amiodarone. Autoimmunity can also provoke an inflammatory thyroiditis that causes transient thyrotoxicosis. This commonly occurs in the setting of lymphocytic thyroiditis (also known as silent, painless, or postpartum thyroiditis). It rarely occurs in the setting of autoimmune thyroiditis (also known as Hashimoto's thyroiditis).
In rare cases, excess thyroid hormone can be secreted by ectopic thyroid tissue located anywhere from the base of the tongue to the mediastinum, or by heterotopic thyroid tissue that develops as part of an ovarian teratoma (a condition known as struma ovarii).
Thyrotoxicosis can also be caused by ingestion of excessive amounts of thyroid hormone. This is most often the result of prescription of excessive doses of pharmacologic preparations of thyroid hormone, but it can rarely be due to surreptitious or accidental ingestion.
Clinical Manifestations
Symptoms and Signs
When classic symptoms of thyrotoxicosis are present, including weight loss despite a hearty appetite, heat intolerance, palpitations, tremor, and hyperdefecation (increased frequency of formed bowel movements), clinical diagnosis should be straightforward. Thyrotoxicosis can escape early detection because of presentation with common nonspecific symptoms such as fatigue, insomnia, anxiety, irritability, weakness, atypical chest pain, or dyspnea on exertion. Delayed recognition may also occur when atypical symptoms such as headache, weight loss, periodic paralysis, or nausea and vomiting dominate the clinical picture. Elderly patients may present with apathetic thyrotoxicosis typified by weight loss and the absence of sympathomimetic symptoms and signs.
Signs of thyrotoxicosis include resting tachycardia, systolic hypertension with a widened pulse pressure, warm moist skin with a velvety texture, onycholysis, and staring gaze with lid lag (noted to be present when a rim of sclera is visible between the upper eyelid and superior margin of the iris on downward gaze). Cardiac examination may reveal a prominent apical impulse and a systolic flow murmur. Neurologic findings may include a restless impatient demeanor, pressured speech, proximal muscle weakness, distal hand tremor, and brisk deep tendon reflexes.
Clinical findings often provide a strong indication of the underlying cause of thyrotoxicosis. In Graves' disease, the gland is diffusely enlarged with a smooth or slightly lobulated contour and may manifest an audible bruit. Ophthalmopathy and dermopathy are also unique to Graves' disease. In patients with toxic nodular goiter, one or more discrete nodules may be appreciated. In subacute thyroiditis, the gland is modestly enlarged, extremely tender, and firm. A history of recent pregnancy suggests possible painless thyroiditis. Recent exposure to amiodarone, other iodine-containing compounds, interferon alfa, or pharmacologic preparations of thyroid hormone may suggest the characteristic forms of thyrotoxicosis associated with these agents.
▪ Graves' Disease
Definition
Graves' disease is an autoimmune disorder characterized by a variable combination of hyperthyroidism, ophthalmopathy (also known as thyroid eye disease), and dermopathy.
Epidemiology
Graves' disease is more common among women but also affects men. It can develop at any time, but onset most often occurs between 30 and 60 years of age.
Pathobiology
The proximate cause of hyperthyroidism is production of thyroid-stimulating immunoglobulins that bind to and activate the TSH receptor, promoting thyroid hormone secretion and growth of the thyroid gland. Other thyroid autoantibodies also commonly identified in the setting of Graves' disease include antithyroid peroxidase antibodies, antithyroglobulin antibodies, and anti–TSH receptor antibodies that block TSH binding. The fundamental pathogenesis of Graves' disease remains unknown. A genetic predisposition is implicated by a higher incidence in monozygotic twins and first-degree relatives of affected individuals. Environmental factors implicated in triggering the onset of Graves' disease include exposure to cigarette smoke, high dietary iodine intake, stressful life events, and certain antecedent infections.
Clinical Manifestations
Affected individuals usually present with thyrotoxicosis and a thyroid gland that is diffusely enlarged with a rubbery consistency, smooth contour, definable pyramidal lobe, and audible bruit or palpable thrill due to increased blood flow. When it is clinically evident, thyroid eye disease usually presents within a few months of the onset of hyperthyroidism. In rare cases, it may develop long before, long after, or without any biochemical confirmation of hyperthyroidism.
Prognosis
The hyperthyroidism associated with this condition often follows a persistent and progressive course, but approximately one fourth of patients with Graves' disease demonstrate spontaneous disease remission.
▪ Ophthalmopathy
Definition
Thyroid eye disease is a distinctive disorder characterized by inflammation and swelling of the extraocular muscles and orbital fat, eyelid retraction, periorbital edema, episcleral vascular injection, conjunctival swelling (chemosis), and proptosis (also called exophthalmos). Swelling of soft tissues within the confines of the orbits precipitated by fibroblast growth and inflammatory cell infiltrate can cause proptosis, entrapment of extraocular muscles, and compression of the optic nerve.
Clinical Manifestations
Affected individuals typically complain of a change in eye appearance, ocular irritation, foreign body sensation, dryness, and, ironically, excessive tearing. More severe involvement may cause exposure keratitis with corneal ulceration, diplopia, and blurred vision. On examination, patients may have staring gaze; a rim of sclera visible between the upper eyelid and superior margin of the iris during downward gaze (lid lag); signs of conjunctival inflammation; periorbital edema; and abnormalities of conjugate gaze, color vision, and visual acuity. The precise degree of proptosis can be measured by an exophthalmometer. Orbital imaging with CT scanning or ultrasonography can confirm the diagnosis, which must sometimes be distinguished from other causes of bilateral and unilateral proptosis.
Treatment
Treatment of mild thyroid-related eye disease focuses on protecting the corneas from exposure and desiccation with moisturizing drops and ointment, glasses, and sometimes taping the eyelids closed at bedtime to prevent exposure during sleep. High-dose systemic glucocorticoid therapy can attenuate orbital inflammation but does not represent an attractive long-term solution. Orbital irradiation may be helpful in controlling inflammatory symptoms in some patients. Persistent corneal exposure, diplopia, altered vision due to optic nerve compression, and cosmetic issues may require surgery to decompress the orbits and readjust the extraocular muscles. Immunosuppressive agents and plasmapheresis have been used in severely affected patients with anecdotal success.
▪ Dermopathy
Infiltrative dermopathy, the least commonly seen complication of Graves' disease, is precipitated by the deposition of glycosaminoglycans in the dermis of the skin. Affected individuals usually present with mildly pruritic, orange peel–like thickening of the skin along the anterior aspects of the shins, commonly known as pretibial myxedema. The dorsal aspects of the feet and fingers, the extensor surface of the elbows, and the face are more rarely affected.
When the diagnosis is not clinically obvious, it can be confirmed by skin biopsy. Treatment of early infiltrative dermopathy with topical glucocorticoids under an occlusive wrap may limit its progression. Treatments involving the use of intradermal or systemic glucocorticoids, long-acting somatostatin analogues, and even surgical resection of soft tissue have shown limited success.
▪ Toxic Adenoma
A toxic adenoma is a solitary, autonomously functioning thyroid neoplasm that synthesizes and secretes excessive amounts of thyroid hormone independent of TSH stimulation. These neoplasms are almost always benign, although rare cases of malignant conversion have been reported. Most grow large enough to be palpated by the time they present with thyrotoxicosis. Somatic gene mutations causing constitutive activation of the TSH receptor and the stimulatory subunit of the guanine nucleotide (Gsα) have been identified in a subset of toxic adenomas. The hyperthyroidism caused by a toxic adenoma does not remit, except in unusual cases complicated by hemorrhagic infarction of the neoplasm.
▪ Toxic Multinodular Goiter
A toxic multinodular goiter is composed of multiple autonomously functioning thyroid nodules that collectively synthesize and secrete excessive amounts of thyroid hormone. In some patients with nontoxic multinodular goiters, hyperthyroidism can be precipitated by exposure to excessive amounts of iodine. Most affected individuals have a goiter with multiple palpable thyroid nodules. Progressive enlargement may go undetected when there is substernal extension of nodular tissue. Toxic multinodular goiters are more common among older individuals.
▪ TSH-Secreting Pituitary Adenomas
TSH-secreting pituitary adenomas (also known as thyrotropinomas) represent less than 1% of all functioning pituitary tumors. By the time of diagnosis, most patients have developed macroadenomas that are larger than 1 cm in diameter. Smaller microadenomas may also be identified. Patients may present with typical clinical manifestations of thyrotoxicosis, a diffuse goiter, symptoms and signs precipitated by an expanding sellar mass, syndromes associated with co-secretion of other anterior pituitary hormones (growth hormone, prolactin, or adrenocorticotropic hormone), or symptoms and signs of hypopituitarism. The key to suspecting the condition is usually recognition of an inappropriately nonsuppressed TSH level in a patient with thyrotoxicosis. The diagnosis is confirmed in most cases when laboratory testing reveals an elevated circulating level of the pituitary glycoprotein α subunit in conjunction with a radiographically definable sellar mass.
Diagnosis
Laboratory Findings
Abnormalities detected in routinely ordered laboratory tests are often the first clues that suggest thyrotoxicosis. Thyrotoxic patients may have hypercalcemia or hypercalciuria, increased alkaline phosphatase levels, modestly elevated transaminase levels, and low or declining total and LDL cholesterol levels. When they are measured, ferritin and angiotensin-converting enzyme levels are often increased. Electrocardiography typically reveals resting sinus tachycardia or other atrial tachyarrhythmias, particularly atrial fibrillation with a rapid ventricular response. In severe cases, chest radiography may reveal cardiomegaly.
In most patients with suspected thyrotoxicosis, the diagnosis can be determined by measurement of TSH (Fig. 244-3). Sensitive TSH immunoassays with a detection limit less than 0.02 mIU/L can accurately discriminate between clearly suppressed TSH levels characteristic of all common forms of thyrotoxicosis and mildly suppressed levels that fall just beneath the reference range, as may occur in otherwise sick and elderly euthyroid individuals. Only the rare conditions associated with TSH-mediated hyperthyroidism (TSH-secreting pituitary tumors and isolated pituitary resistance to thyroid hormone) will yield false-negative TSH results in screening for thyrotoxicosis. Conversely, there are other conditions that present with suppressed TSH levels. In these conditions, serum free T4 and T3 levels will not be elevated on subsequent testing.
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| FIGURE 244-3 Laboratory assessment of suspected thyrotoxicosis. |
Measurement of serum free T4 and total or free T3 levels will confirm a diagnosis of thyrotoxicosis, define its severity, and occasionally provide a clue to its underlying etiology. Overt thyrotoxicosis is characterized by free T4 or T3 levels above the upper limit of the reference range, whereas mild or subclinical thyrotoxicosis is characterized by a suppressed TSH level with free T4 and T3 levels within the normal reference range. When only the free T4 or T3 concentrations are elevated, the terms T4 toxicosis and T3 toxicosis are applied, respectively.
Differential Diagnosis
Once a diagnosis of thyrotoxicosis has been confirmed, it is important to define its underlying cause to determine the most appropriate treatment. The relative degrees of T4 and T3 elevation sometimes can be helpful. Predominantly T3 toxicosis is typical of Graves' disease and can also occur with toxic nodular goiter. In contrast, predominantly T4 toxicosis is more typical of subacute or painless thyroiditis. T4 toxicosis also is more common in patients with iodine-induced hyperthyroidism.
Other laboratory tests sometimes can be helpful in differential diagnosis. Thyroid-stimulating immunoglobulins are pathognomonic of Graves' disease. An elevated erythrocyte sedimentation rate typically is seen in subacute thyroiditis.
Imaging studies can also help establish a differential diagnosis. The fractional thyroidal uptake of radiotracer within the thyroid gland on scintigraphic scanning often helps establish a definitive diagnosis (Table 244-6). Thyroid ultrasonography can confirm the presence of solitary or multiple thyroid nodules. Chest radiography and CT scanning may help delineate a substernal goiter.
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Treatment
Selection of the most effective treatment for a specific condition causing thyrotoxicosis requires an understanding of the underlying pathophysiologic process and natural history. For example, a toxic multinodular goiter will not remit and requires radioiodine treatment or surgery; subacute thyroiditis will subside spontaneously and requires only temporizing symptomatic therapy.
β-Blockers
β-Blockers help alleviate the sympathomimetic manifestations of thyrotoxicosis, regardless of the underlying cause. Palpitations, tremor, and anxiety can often be promptly controlled. However, certain other clinical features of thyrotoxicosis, including weight loss, heat intolerance, and fatigue, are not ameliorated by these agents. In thyrotoxic patients with marked sinus tachycardia or atrial fibrillation with a rapid ventricular response rate, β-blockers can be used as rate-controlling agents. Propranolol also partially inhibits extrathyroidal conversion of T4 to T3, which may be of added benefit in patients with severe thyrotoxicosis.
Propranolol can be started at a dose of 20 to 40 mg every 8 hours and titrated upward to a maximal daily dose of 240 mg on the basis of symptom control. Sustained-release propranolol or longer-acting β-blockers, such as metoprolol and atenolol, can also be used. Esmolol can be used when a short-acting parenteral agent is required. β-Blockers should be used with caution in thyrotoxic patients with a history of heart failure, obstructive pulmonary disease, or Raynaud's phenomenon.
For patients with transient forms of thyrotoxicosis (subacute thyroiditis, autoimmune thyroiditis, or exogenous thyroid hormone intoxication), a β-blocker may be the only treatment required. In patients with more sustained conditions, such as Graves' disease or toxic nodular goiter, β-blockers provide prompt initial relief of symptoms while definitive treatment with antithyroid drugs, radioiodine, or surgery is planned and implemented.
Antithyroid Drugs
The thionamides inhibit thyroid hormone biosynthesis by competitively inhibiting iodine organification and iodotyrosine coupling in thyrocytes. These agents are used for the treatment of thyrotoxicosis caused by glandular overproduction of thyroid hormones. Because the thionamides block only new thyroid hormone synthesis, glandular stores of preexisting thyroid hormone must be exhausted before they are fully effective. Secretion of preexisting thyroid hormone may continue for up to 3 to 8 weeks in patients with Graves' disease or toxic multinodular goiters. Although antithyroid drugs can provide long-term control of hyperthyroidism, they are most appropriately used when there is a possibility that the underlying condition will remit, as in Graves' disease, or when thyrotoxicosis must be attenuated before radioiodine treatment or surgery.
Two thionamide agents are currently available, methimazole and propylthiouracil. Methimazole may be taken as a single daily dose because of its longer half-life and higher effective intrathyroidal concentration. This can bolster adherence of patients and drug effectiveness. Propylthiouracil acts to partially inhibit extrathyroidal conversion of T4 to T3, an effect that may be beneficial in patients with severe complicated thyrotoxicosis. Propylthiouracil is also preferred for treatment of pregnant women with thyrotoxicosis because it crosses the placental barrier less readily than methimazole does. However, the shorter half-life of propylthiouracil necessitates administration of three or four daily doses.
For patients with mild to moderate hyperthyroidism, methimazole is usually started at a dose of 10 to 30 mg once daily that can be increased to as much as 90 mg once daily. For patients with more severe hyperthyroidism, thyrotoxicosis complicated by cardiac disease, or concomitant pregnancy, propylthiouracil should be started at doses of 50 to 200 mg every 6 to 8 hours. Methimazole may be given rectally if necessary. The anticipated duration of treatment depends on the underlying cause. In patients with toxic multinodular goiters, antithyroid drugs are generally used only to restore euthyroidism in anticipation of definitive therapy. An effective dose can be continued for a period of 6 to 24 months in a patient with Graves' disease before it is tapered off to determine whether there has been a remission of the patient's autoimmune thyroid disease. Patients most likely to respond are those presenting with mild clinical and biochemical hyperthyroidism, a small thyroid gland, and no active ophthalmopathy.
Patients treated with antithyroid drugs should have thyroid function tests checked every 3 to 12 weeks during dose titration to monitor for iatrogenic hypothyroidism. Common side effects include rash, pruritus, fever, and arthralgias, which affect 5% of thionamide-treated patients. Agranulocytosis and hepatitis are rare but potentially fatal adverse reactions to thionamide medications. Their presentations are relatively sudden in onset and unpredictable. Monitoring of leukocyte counts and liver function test results is not useful as a preventive measure. Patients who are prescribed antithyroid drugs should be cautioned about manifestations of these adverse reactions and should be instructed to discontinue treatment and to seek medical attention if they develop a high fever, pharyngitis, jaundice, or abdominal pain.
Radioactive Iodine
The selective uptake and concentration of iodide in thyrocytes permits the use of radioactive iodine to treat hyperthyroidism. Once it is concentrated in the gland after oral administration, 131I emits β particles that cause localized destruction of thyroid tissue, effectively controlling hyperthyroidism. A dose of 131I can be calculated on the basis of the fractional uptake of radioiodine, but the outcome of dosimetry has not been shown to be superior to administration of 10 mCi. Patients can be treated on an outpatient basis with precautions to prevent exposure of others. Approximately three quarters of patients will be cured with a single dose of radioiodine.
The principal side effect of radioactive iodine therapy is postablative hypothyroidism, which develops in most individuals receiving treatment for Graves' disease and a lesser proportion of patients treated for toxic nodular goiter. Lifelong monitoring of thyroid function is important, as patients who initially remain euthyroid after treatment continue to develop postablative hypothyroidism at a rate of 3% per year. Another less common complication is a transient exacerbation of thyrotoxicosis that occurs in one quarter of patients during the first month after treatment as a result of radiation thyroiditis. Long-term follow-up studies have shown that radioiodine-treated patients with Graves' disease do not have any greater risk of thyroid cancer or other malignant neoplasms. However, hyperthyroid children and adolescents treated with radioactive iodine are more likely to develop benign nodules. Among hyperthyroid women treated with radioiodine, incidences of infertility, spontaneous abortion, and children with birth defects are not increased. Diagnostic or therapeutic radioactive iodine is contraindicated in women during pregnancy, and treated women should avoid pregnancy until euthyroidism has been confirmed 3 to 6 months after administration of a dose.
Other Drugs
A saturated solution of potassium iodide (SSKI) or Lugol's solution transiently inhibits the synthesis and release of thyroid hormone from the gland. It may be used to accelerate recovery after radioactive iodine treatment, to prepare patients for thyroidectomy, and to augment other treatments used to control severe thyrotoxicosis (see later). Iodinated radiocontrast agents inhibit release of thyroid hormone while blocking peripheral conversion of T4 to T3. Lithium carbonate also inhibits glandular release of thyroid hormone. These agents are rarely used in combination with thionamides to treat patients with severe thyrotoxicosis. They may also help provide temporary control of hyperthyroidism when severe allergies preclude continued use of thionamides. Cholestyramine can be used to bind thyroid hormone in the gut to interrupt enterohepatic circulation in cases of suspected exogenous thyroid hormone intoxication.
Surgical Therapy
Surgery has a limited role in treatment of hyperthyroid patients because of its potential for injury to the adjacent recurrent laryngeal nerves and parathyroid glands. Resection of a toxic adenoma by lobectomy is curative and often preserves sufficient normal thyroid tissue for euthyroidism to be maintained. Consequently, it is often recommended for treatment of younger individuals. Toxic multinodular goiters causing compressive symptoms or cosmetic disfigurement may be appropriately managed with surgical resection. Although surgery is seldom recommended for the treatment of hyperthyroid Graves' disease, it may be appropriate when other modalities are contraindicated, or when a thyroid nodule thought to be malignant or hyperparathyroidism also requires surgical intervention.
Specific Treatment Scenarios
Pregnancy
Pregnant patients with hyperthyroidism present special challenges. Diagnosis requires careful assessment of symptoms, especially heat intolerance, palpitation, and vomiting, which also occur during normal pregnancy. The serum total T4 level is elevated because of increased TBG, and the TSH level can be suppressed in the first trimester as a result of hCG-mediated thyroid stimulation. Diagnostic radioiodine studies are contraindicated. After diagnostic confirmation, hyperthyroidism must be treated because it is associated with an increased risk of spontaneous abortion, premature labor, low birthweight, and toxemia. β-Blockers should be used only transiently to treat severe symptoms. Propylthiouracil is the preferred thionamide for treatment of Graves' disease during pregnancy because it is less likely to cross the placenta. Treatment with methimazole during pregnancy may be associated with aplasia cutis. Because Graves' disease often remits later in pregnancy, antithyroid drug dose requirements decline as gestation progresses. Measurement of maternal thyroid-stimulating immunoglobulin levels can help predict the risk of an infant's developing neonatal Graves' disease.
Mild Hyperthroidism
Patients with mild hyperthyroidism may have symptoms that justify treatment. In patients with TSH levels suppressed to less than 0.1 mIU/L, there may be skeletal and cardiac consequences of even mild thyroid hormone excess. Atrial fibrillation occurs more commonly in mildly hyperthyroid patients aged 60 years and older. Osteoporosis can be associated with chronic mild hyperthyroidism, particularly in postmenopausal women. It is less clear, however, that asymptomatic patients with modestly suppressed TSH levels (e.g., 0.1 to 0.5 mIU/L) require anything more than periodic monitoring.
Thyrotoxic Crisis
Thyrotoxic crisis, also known as thyroid storm, is a potentially life-threatening syndrome that is usually the end result of severe and sustained thyrotoxicosis. It can affect patients with other medical conditions that render them vulnerable to the cardiovascular, neuropsychiatric, and gastrointestinal effects of exposure to excessive amounts of thyroid hormone. Thyrotoxic crisis typically develops in the setting of inadequately treated Graves' disease and may be precipitated by intercurrent illness, surgery, or treatment with radioactive iodine. Affected individuals present with fever, atrial tachyarrhythmias, congestive heart failure, nausea and vomiting, diarrhea, and seizures. Mental status changes can include agitation, delirium, psychosis, and coma. Prompt recognition and treatment in a monitored setting is crucial. A multifaceted treatment regimen should incorporate antipyretics, β-blockers, thionamides, iodinated contrast agents, and glucocorticoids as well as aggressive evaluation and management of underlying medical problems.
▪ THYROIDITIS
▪ Subacute (de Quervain's) Thyroiditis
Pathobiology
Transient thyrotoxicosis results from uncontrolled leakage of thyroid hormone from the inflamed gland. After 2 to 8 weeks, when the supply of stored hormone is exhausted, thyrotoxicosis resolves spontaneously. Hypothyroidism ensues as the gland's biosynthetic capabilities remain impaired. This is also transient, lasting approximately 1 month, with subsequent restoration of normal thyroid function in most patients.
Clinical Manifestations
Subacute thyroiditis is characterized by painful enlargement of the thyroid, systemic inflammatory symptoms, and transient thyrotoxicosis that is often followed by transient hypothyroidism. The histologic pattern shows inflammatory cell infiltrates that are believed to be the result of a viral infection. Many patients with subacute thyroiditis report antecedent upper respiratory infections.
Patients usually present with pain localized to the thyroid or radiating to the throat, ears, or jaw. Constitutional symptoms, including fever, chills, sweats, and malaise, are generally present. On occasion, these features may dominate the presentation. Examination of the thyroid typically reveals an exquisitely tender, modestly enlarged, and woody hard gland.
Diagnosis
Differential Diagnosis
The differential diagnosis of thyroid pain must be considered in the evaluation of patients presenting with pain and tenderness localized to the lower anterior neck. In addition to subacute thyroiditis, potential causes of thyroid pain include acute (suppurative) thyroiditis; hemorrhage into an existing thyroid nodule; and rapid growth of anaplastic thyroid cancer, diffusely infiltrating thyroid cancer, or thyroid lymphoma.
Laboratory Findings
Laboratory testing in patients with subacute thyroiditis reveals a profile of overt thyrotoxicosis. Elevated T4 levels are usually proportionately higher than T3 levels. Patients typically have an elevated erythrocyte sedimentation rate during the acute phase. The fractional uptake of radioiodine is typically less than 2% at 24 hours.
Treatment
High-dose aspirin or naproxen sodium can be used to treat thyroid pain and systemic inflammatory symptoms. Patients who fail to respond may require glucocorticoid therapy, but it must be tapered over several weeks or patients will relapse, prolonging the overall course of their illness. Symptoms ascribed to transient thyrotoxicosis may respond to treatment with a β-blocker continued for a limited course of 1 to 3 weeks. Patients who progress to symptomatic hypothyroidism may then need short-term thyroxine replacement therapy, but most will not require long-term thyroid hormone replacement.
▪ Lymphocytic (Postpartum, Painless, Silent) Thyroiditis
Epidemiology
Lymphocytic thyroiditis occurs most commonly in postpartum women, affecting as many as 6% of women 2 to 12 months after delivery or termination. Rarely, this condition occurs in non-postpartum women or in men. Predisposing factors include a history of previous episodes of postpartum thyroiditis, type 1 diabetes mellitus, and circulating antithyroid autoantibodies.
Pathobiology
This painless inflammation of the thyroid gland can cause transient thyrotoxicosis followed by transient or persistent hypothyroidism. These phases of thyroid dysfunction typically last 2 to 8 weeks. This condition is believed to reflect transient autoimmunity.
Diagnosis
The diagnosis of lymphocytic thyroiditis is often overlooked when nonspecific symptoms of thyrotoxicosis (e.g., weight loss, insomnia, and anxiety) or hypothyroidism (e.g., fatigue and depression) are misinterpreted as common postpartum complaints. The thyroid gland is nontender and either normal in size or modestly enlarged. Once it is considered, a diagnosis of lymphocytic thyroiditis can be readily confirmed or excluded by laboratory testing, which will reveal a suppressed TSH level during phases of thyrotoxicosis and an elevated TSH level during phases of hypothyroidism. This condition must be distinguished from Graves' disease, which can also present in the same timeframe after delivery. Relative degrees of T4 and T3 elevation can sometimes provide a clue as to which condition is present; lymphocytic thyroiditis is typically characterized by predominant increases in T4 levels. Fractional uptake of radioiodine is either absent or very low in the setting of lymphocytic thyroiditis but increased in active Graves' disease, thus providing a useful diagnostic test.
Treatment
Lymphocytic thyroiditis can sometimes be managed with reassurance and observation alone. Symptomatic thyrotoxicosis can be treated with a limited course of β-blocker therapy. Overt hypothyroidism may require transient thyroxine replacement.
Prognosis
Whereas most affected patients eventually return to a euthyroid state, 25% develop persistent hypothyroidism due to classic autoimmune thyroiditis.
▪ Acute (Suppurative) Thyroiditis
Infection of the thyroid gland is a rare condition that typically presents with severe thyroid pain, fever, and other systemic manifestations of infection. Bacterial infection of thyroid tissue can be the result of direct spread of gram-positive or gram-negative pathogens through fistulas communicating with the piriform sinus or the skin. Hematogenous spread of bacterial, mycobacterial, fungal, or parasitic organisms, especially Pneumocystis carinii, can occur in immunocompromised individuals. On examination, affected patients are typically febrile with asymmetrical swelling of a thyroid that is tender, warm, and fluctuant to firm in consistency beneath erythematous skin. Ultrasonography may reveal an abscess that can be aspirated to identify a pathogen. Patients with suppurative thyroiditis require prompt treatment with appropriate antibiotics. Surgical drainage of abscesses may be required.
▪ Other Forms of Thyroiditis
Certain drugs can cause thyroid gland inflammation. Amiodarone can produce a painless thyroiditis associated with thyrotoxicosis. Whenever possible, this should be distinguished from the iodine-induced form of thyrotoxicosis that can also be associated with amiodarone therapy. The former is optimally treated with glucocorticoid therapy, whereas the latter is managed with antithyroid drugs. Interferon alfa can provoke a painless thyroiditis associated with transient thyrotoxicosis similar to lymphocytic thyroiditis. This must be differentiated from interferon alfa–induced Graves' disease, as the former is managed with β-blockers and the latter with antithyroid drugs.
Riedel's thyroiditis or struma is characterized by fibrotic replacement of the thyroid with adherence and infiltration of adjacent structures that causes local compressive symptoms. In this idiopathic condition, the thyroid is substantially enlarged, hardened, and fixed. Affected patients may also develop mediastinal and retroperitoneal fibrosis, sclerosing cholangitis, or orbital pseudotumor. Diagnosis requires open biopsy. Surgical excision is difficult or impossible. Glucocorticoid therapy and tamoxifen therapy have been anecdotally reported to be effective.
▪ GOITER
Definition
Goiters can be classified as diffuse or nodular, nontoxic or toxic (i.e., associated with thyroid hormone overproduction), and benign or malignant. Thyroid enlargement can be the result of thyrocyte proliferation stimulated by circulating factors (e.g., TSH and thyroid-stimulating immunoglobulins), infiltration of the gland by inflammatory or malignant cells, or benign or malignant neoplastic changes arising within the gland itself. In a patient with a goiter, three potential clinical issues must be considered: local compressive or cosmetic problems, gland hyperfunction or hypofunction, and potential malignancy.
Epidemiology
Dietary iodine deficiency represents the most common cause of endemic goiter worldwide. It is encountered in the United States only among immigrants from iodine-deficient regions. Younger patients present with diffuse or simple goiters that shrink in response to adequate iodine supplementation. In older individuals, iodine-deficient goiters typically become multinodular and do not decrease in size with iodine repletion. Excessive iodine exposure can provoke thyrotoxicosis in these patients.
Pathobiology
Benign multinodular goiter and its histologic correlate, benign adenomatous hyperplasia, can be the result of genetic defects that lead to dyshormonogenesis including mutations in the thyroglobulin, thyroid peroxidase, and pendrin genes. Similarly, exposure to goitrogenic substances in foodstuffs, water, or drugs (e.g., lithium carbonate) that inhibit normal steps in thyroid hormone synthesis can lead to goiter. In most patients with benign nodular goiter, the underlying cause is unknown.
Autoimmune thyroiditis typically produces a modest goiter as a result of glandular infiltration with lymphocytes, inflammatory changes in thyrocytes, and fibrosis. The hypothyroid state caused by autoimmune thyroiditis results in increased TSH that further stimulates thyroid enlargement. Graves' disease is also characterized by diffuse thyroid enlargement due to the action of thyroid-stimulating immunoglobulins. Other forms of thyroiditis can also present with goitrous enlargement of the thyroid gland, including subacute, lymphocytic, and acute (suppurative) thyroiditis.
Malignant neoplasms that involve the gland diffusely, including thyroid lymphoma and infiltrative papillary, medullary, and anaplastic thyroid cancer, may present as rapidly enlarging goiters. Affected patients often experience local pain and symptoms related to tumor expansion and invasion.
Diagnosis
Clinical Examination
The first step in evaluating a suspected goiter is to confirm whether the observed swelling represents enlargement of the thyroid. Redundant skin and subcutaneous fat in the lower anterior neck can be mistaken for an enlarged thyroid. These findings can usually be distinguished from true thyroid enlargement by palpating a normal thyroid beneath the misleading soft tissue and by observing that the fullness does not rise and fall with deglutition. Ultrasonography may help resolve uncertainty.
A patient's history can provide important clues to the underlying cause. A childhood medical and social history may confirm previous iodine deficiency. Symptoms of hypothyroidism may suggest autoimmune thyroiditis, whereas clinical evidence of thyrotoxicosis may suggest Graves' disease or toxic multinodular goiter. Clinical findings may lead to recognition of one of the various forms of thyroiditis (e.g., pain in subacute thyroiditis or postpartum status in lymphocytic thyroiditis). Symptoms suggesting invasion of adjacent structures may raise concern for malignant disease or Riedel's thyroiditis.
Careful examination of the thyroid is informative. Diffuse enlargement favors one of the forms of thyroiditis, Graves' disease, or a diffusely infiltrating malignant neoplasm. Nodular enlargement is more likely to reflect a benign multinodular goiter or malignant neoplasm. The precise size of the gland should be documented. Dysphonia, tracheal deviation, cervical lymphadenopathy, and venous engorgement in the neck should be noted. Dynamic obstruction of the thoracic outlet may be revealed by having the patient touch the hands together above the head (Pemberton's maneuver) while checking for signs of facial plethora and cervical venous distention.
Laboratory Findings
A TSH level will determine whether there is primary hypothyroidism or thyrotoxicosis. Elevated antithyroid peroxidase antibody titers can confirm suspected autoimmune thyroiditis. In asymptomatic patients with a modest diffuse goiter, no further evaluation may be indicated. Other blood tests (e.g., erythrocyte sedimentation rate for subacute thyroiditis or calcitonin for medullary thyroid cancer) can be useful when clinical clues suggest specific diagnoses.
Imaging
Cervical ultrasonography is usually the best imaging technique to define the character and extent of a goiter limited to the neck. It can help determine if a goiter is diffuse or nodular, if the thyroid is impinging on other cervical structures, and if lymphadenopathy is present. When a goiter extends posteriorly or beneath the sternal notch into the thorax, CT or MRI scanning may be required. Administration of iodine-containing radiocontrast dye should be avoided in the evaluation of patients with goiters because the stable iodide load may interfere with subsequent radioiodine imaging or therapy. Thyroid uptake studies may help define whether quantitative tracer uptake is subnormal or supranormal. Radioiodine scanning can help determine if a superior mediastinal mass is thyroid tissue. Barium swallow radiographs with fixed-diameter markers and pulmonary function testing with flow-volume loops can help determine if symptoms are directly related to compression of the esophagus or trachea. Laryngoscopy is useful to evaluate vocal cord function in patients with potential recurrent laryngeal nerve involvement.
Treatment
Once thyroid dysfunction and malignant disease have been excluded, asymptomatic patients with goiters can be observed conservatively with periodic clinical assessment. Ultrasonography can be relied on as a reproducible technique for monitoring the size of an enlarged thyroid gland. Thyroxine therapy to suppress TSH levels is effective in shrinking goiters only in a minority of patients. Furthermore, chronic thyroid hormone treatment carries with it risks of symptomatic thyrotoxicosis, atrial fibrillation, and bone mineral loss.
Patients with benign multinodular goiters causing local compressive symptoms or cosmetic concerns may be treated with surgery or radioactive iodine therapy. Surgery is often preferred when a patient has substantial gland enlargement causing compressive complications, especially when there is substernal extension of the goiter or acute obstructive symptoms. When surgery may be contraindicated by a patient's health status, radioactive iodine therapy has been shown to reduce goiter size by an average of 50% over a period of 12 to 24 months.
▪ THYROID NODULES
Epidemiology
Thyroid nodules are common, being detected by palpation in 6% of women and 2% of men. Furthermore, contemporary high-resolution ultrasonography identifies thyroid nodules in as many as 50% of all adults. Although the majority of these represent small benign adenomatoid nodules or cysts, 5 to 10% of thyroid nodules are malignant. Less commonly, thyroid nodules are clinical problems by virtue of being hyperfunctioning or by causing local compressive symptoms or cosmetic dissatisfaction.
Diagnosis
Thyroid nodules are usually noted by the patient or physician in the absence of any other complaints. It is also common for thyroid nodules to be incidentally detected on imaging procedures, such as carotid ultrasonography and cervical spine CT or MRI scans. Symptoms suggesting compression or invasion of adjacent tissues suggest that a nodule may be malignant. These include pain in the lower anterior neck, cough or dyspnea due to tracheal compression, hemoptysis due to tracheal invasion, dysphonia due to recurrent laryngeal nerve encasement, and dysphagia or odynophagia due to esophageal compression. Certain other symptoms and signs lead to consideration of specific underlying conditions. A toxic adenoma should be suspected in a patient with a thyroid nodule who has classic clinical manifestations of thyrotoxicosis. Hypothyroid symptoms and signs suggest the possibility of autoimmune thyroiditis with asymmetrical thyroid enlargement. Hypercalcitonemia associated with the metastatic spread of medullary thyroid cancer can cause pruritus, flushing, and diarrhea. Clinical assessment should also check for symptoms and signs related to common sites of thyroid cancer metastasis, such as chest pain, dyspnea, bone pain, and neurologic findings. Thyroid nodules rarely can be due to metastasis from other primary malignant neoplasms, including kidney, colon, and breast cancer.
History
Special predisposition to thyroid cancer is suggested by a personal history of therapeutic neck irradiation in childhood. Family history can be informative if relatives have had medullary or papillary thyroid cancers, which are familial in 50% and 10% of cases, respectively. The possibility of medullary thyroid cancer should also be considered when there is a personal or family history of clinical problems associated with the multiple endocrine neoplasia type 2 (MEN 2) syndrome, including hyperparathyroidism and pheochromocytoma.
Physical Examination
Physical examination of the thyroid nodule should seek to define its size, consistency, surface texture, mobility, and tenderness. The presence of malignant disease is suggested by fixation and ipsilateral regional adenopathy or vocal cord paresis. Multinodularity of the gland may reflect benign nodular goiter, but it is not sufficiently reassuring to avoid further diagnostic testing. This is particularly true for a so-called dominant nodule, which is larger, enlarging faster, or more symptomatic than others present in the thyroid.
Laboratory Findings
Routine laboratory testing includes measurement of TSH levels to identify patients with hyperthyroidism or hypothyroidism. When the TSH level is low or undetectable, the possibility of a benign autonomously functioning toxic adenoma can be pursued with radionuclide thyroid scanning. If an elevated TSH level indicates primary hypothyroidism, antithyroid peroxidase antibody titers should be measured to confirm whether the patient has autoimmune thyroiditis. Ultrasonography can often distinguish asymmetrical enlargement caused by autoimmune thyroiditis from a discrete encapsulated nodule. Calcitonin levels should be measured in patients with a known or suspected family history of MEN 2 or familial medullary thyroid cancer. Serum thyroglobulin measurement is not helpful in distinguishing benign from malignant thyroid abnormalities as it can be elevated in both settings.
Imaging
Cervical ultrasonography is not required before biopsy, but it can help confirm that a mass is within the thyroid, accurately define its size, classify it as cystic or solid, and determine whether additional nodules are present. Ultrasonography occasionally reveals other suspicious findings, such as fine calcifications, irregular nodule borders, and cervical adenopathy.
Radionuclide scanning with radioiodine or technetium pertechnetate is helpful only in certain cases. In patients with a thyroid nodule and a suppressed TSH level, scanning can confirm that the nodule is hyperfunctioning or “hot,” in which case biopsy is usually not required. CT, MRI, and PET imaging are generally unnecessary in the evaluation of patients with thyroid nodules. Furthermore, administration of iodinated radiocontrast dye can interfere with the subsequent management of patients who prove to have thyroid cancer.
Invasive Evaluation
Fine-Needle Aspiration Biopsy
Fine-needle aspiration biopsy is the most accurate test to exclude or confirm malignant disease in patients who have a nodule and a normal TSH level (Fig. 244-4). Most solid nodules and complex cysts larger than 1.0 to 1.5 cm in diameter should be sampled. Although aspiration can be directed by palpation alone when a nodule is readily definable, ultrasonography provides more certain guidance for sampling of poorly localized lesions, often revealing additional nodules that should be assessed.
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| FIGURE 244-4 Evaluation of a thyroid nodule. |
The cytologic assessment of aspirated material must first confirm that there is adequate material for assessment (e.g., six clumps of 10 cells on two slides). Biopsies with inadequate specimens, which are more common in cystic lesions, must be repeated. Ultrasonographic guidance and on-site preliminary cytologic assessment can improve the yield of biopsy. When adequate cytologic material is obtained, a sampled nodule can be categorized as benign, malignant, or indeterminate (suspicious).
Benign adenomatoid nodules typically yield samples containing clusters of normal-appearing follicular epithelial cells with colloid. Pure colloid cysts may have scant epithelium. These benign cytologic categories are highly accurate, with a false-negative rate of less than 3%, and surgical resection is not required. In most cases, conservative observation based on yearly clinical or sonographic reassessment can be recommended. Further enlargement during observation should prompt repeated biopsy. If a nodule is determined to be benign, a trial of thyroxine therapy to suppress the TSH level to the low but detectable range (e.g., 0.1 to 0.5 mIU/L) can be considered, although this approach is likely to shrink nodules in less than 50% of cases. Surgical resection should be considered if a cytologically benign nodule continues to grow, causing compressive symptoms or cosmetic disfigurement.
Cytologic material categorized as malignant typically contains abundant epithelial cells with atypical nuclear features and scant or absent colloid. This is also a highly reliable finding, with 95% of such lesions found to be thyroid cancers on subsequent resection. Consequently, bilateral thyroidectomy is indicated in patients without contraindication to operation.
One in five biopsies yields adequate but diagnostically indeterminate cytologic material. Such uncertain findings include abundant follicular or Hürthle cells in microfollicles with little or no colloid and minor degrees of nuclear atypia potentially indicative of papillary cancer. Although the majority of such indeterminate nodules are benign follicular adenomas, up to 20% represent thyroid carcinomas. Consequently, surgery is advisable in most otherwise healthy patients with nodules that fall within this diagnostic category. Unilateral thyroid lobectomy has the advantage of a lower incidence of surgical complications and postoperative hypothyroidism when the lesion is benign but necessitates a subsequent completion thyroidectomy for most patients who prove to have cancer. For patients with no clinical features of malignancy, particularly women in or beyond middle life with multinodular glands in whom the prevalence of malignancy is 5% or less, vigilant observation with serial sonography is an alternative.
▪ THYROID CANCER
Cancers of the thyroid gland have a spectrum of behavior that ranges from incidentally detected and clinically inconsequential microcarcinomas to aggressive and virtually untreatable anaplastic malignant neoplasms. Approximately 25,000 new cases are diagnosed annually in the United States. Thyroid cancer is three times more common in women. When it is diagnosed early, treatment of most thyroid cancer types is effective. There are an estimated 350,000 U.S. thyroid cancer survivors, who require lifelong follow-up for recurrence. Most thyroid cancers present as thyroid nodules that are either asymptomatic or associated with local cervical symptoms or adenopathy. Less often, thyroid cancers first present with manifestations of metastatic disease, such as a pulmonary mass or bone pain.
▪ Epithelial (Papillary and Follicular) Thyroid Carcinomas
Papillary and follicular thyroid cancers arise from follicular epithelium and often retain responsiveness to TSH, produce thyroglobulin, and concentrate iodide. They are distinguished by their histopathologic appearances and characteristic patterns of progression. Hürthle cell carcinoma of the thyroid is composed of thyrocytes with abundant cytoplasm and behaves like a follicular thyroid cancer, although it typically does not retain iodine-concentrating ability.
Epidemiology
Papillary thyroid carcinoma is the most common form of thyroid cancer, representing more than 80% of cases. Whereas the mean age at diagnosis is 45 years, papillary thyroid carcinoma does occur in children and increases in incidence with age.
Pathobiology
Irradiation of the thyroid gland in childhood is a risk factor, as evidenced by the epidemics of thyroid cancer that followed both external beam radiotherapy for benign childhood conditions and radioiodine exposure after nuclear incidents. A substantial body of evidence now implicates RET/PTC and B-Raf kinase gene mutations that activate the MAP kinase signaling pathway in the pathogenesis of papillary thyroid cancer. Most papillary thyroid carcinomas are slow growing and either remain confined to the gland or metastasize to a few cervical lymph nodes. Papillary microcarcinomas are a common incidental pathologic finding in 5% of thyroid glands excised for other reasons. Some papillary thyroid carcinomas are more aggressive, with extension into adjacent tissues, extensive nodal involvement, and distant metastatic spread, most commonly to the lungs. This is more common in older patients.
Follicular and Hürthle cell thyroid carcinomas account for 10% of all thyroid cancers. When these tumors show histologic evidence of only invading the tumor capsule, they are termed minimally invasive and behave like papillary thyroid carcinomas. However, follicular and Hürthle cell carcinomas with vascular invasion are more likely to be associated with distant metastatic disease, which most commonly involves the lungs and skeleton.
Treatment
Treatment of epithelial thyroid cancer entails surgery, often followed by radioiodine ablation of remnant thyroid tissue. Total or nearly total thyroidectomy with selective central compartment lymph node resection is usually the appropriate initial surgical procedure. Thyroid surgery can be complicated by hypoparathyroidism or recurrent laryngeal nerve injury, which causes hoarseness if it is unilateral and airway obstruction if it is bilateral. The rationale for bilateral surgery is the frequent presence of bilateral disease in papillary thyroid cancer and lower risk of recurrence. In addition, there is greater accuracy in detection of residual disease after eradication of all remaining normal thyroid tissue.
Follow-up
Postoperatively, 131I administration can ablate the small amount of normal thyroid tissue usually still present after thyroid surgery. This tissue, if it is left in place, leaves patients with circulating thyroglobulin and iodine-concentrating tissue, thus decreasing the accuracy of long-term monitoring for residual disease. In nonrandomized trials, radioiodine has been associated with a lower rate of tumor recurrence in patients with advanced disease at presentation (see later) but no clear clinical benefit for patients with lower stages of disease. TSH stimulation of residual thyroid tissue is essential for effective radioiodine therapy. This can be accomplished either by administration of recombinant thyrotropin or by temporary withdrawal of thyroid hormone therapy to promote endogenous TSH production during resulting hypothyroidism.
Thyroxine therapy is appropriate for all patients with treated thyroid cancer, regardless of the preceding extent of surgery and whether they received radioiodine ablative therapy. Thyroid hormone therapy is intended to suppress the patient's circulating TSH level to reduce the likelihood of thyroid tumor recurrence. In determining the extent to which the TSH level should be suppressed, the patient's risk of cancer recurrence must be balanced against potential complications such as bone mineral loss in postmenopausal women and atrial fibrillation in older patients.
Long-term monitoring of patients entails periodic clinical assessment, measurement of thyroglobulin levels, radioiodine imaging in the early postoperative phase, and occasional use of ultrasonography. Clinically, patients should be assessed for local neck symptoms or recurrent cervical masses as well as for optimization of thyroid hormone therapy. For patients with treated epithelial thyroid cancers, thyroglobulin is a tumor marker that is more specific if all remaining normal thyroid tissue has been ablated. For patients with undetectable thyroglobulin levels on TSH-suppressive thyroid hormone therapy, thyroglobulin measurement after recombinant TSH stimulation can sometimes reveal residual disease. Radioiodine scanning after TSH stimulation can be helpful in patients who have previously undergone radioiodine ablation, but once iodine imaging is normal, it offers little or no advantage over measurement of stimulated thyroglobulin levels. This is particularly true in recurrent papillary thyroid cancers, which often lose the ability to concentrate iodine. Unfortunately, thyroglobulin testing is impossible in the 20% of patients who have circulating thyroglobulin autoantibodies that interfere with thyroglobulin immunoassays. Because most epithelial thyroid cancer recurrences are in cervical nodes or soft tissues, ultrasonography is useful in postoperative monitoring, particularly for patients who presented with extensive cervical disease or who have persistent detectable serum thyroglobulin. CT scanning of the chest should be employed to detect intrathoracic disease in patients whose findings suggest recurrence outside the neck. In patients with substantial detectable thyroglobulin levels (e.g., >10 ng/dL) and normal findings on standard imaging studies, PET scanning can identify sites of residual disease in more than 50% of patients.
Localization of recurrent cervical disease is usually an indication for modified lateral neck dissection. Distant and nonresectable metastases that are iodine avid, as occur more commonly in patients with invasive follicular thyroid cancer, can be treated with repeated doses of 131I. Symptomatic hilar node and bone metastases can be treated palliatively with external beam radiation therapy. Surgery can sometimes be employed for isolated metastatic disease sites. Conventional chemotherapy has limited efficacy in the treatment of differentiated thyroid cancer, but newer agents targeting the molecular pathogenesis of these tumors hold promise.
Prognosis
The TNM (tumor, node, metastasis) staging system is commonly used for staging epithelial thyroid cancers. In addition to tumor size, extent of node involvement, and presence of distant metastatic disease, the age of the patient at presentation is an important predictor of outcome. Patients younger than 45 years have a better prognosis than older individuals. The overall age-adjusted 10-year survival rates for patients with papillary and follicular thyroid cancer are 98% and 92%, respectively. However, disease recurrence is relatively common, occurring in approximately one third of patients with papillary thyroid cancer. Consequently, patients with treated thyroid cancer must be monitored for recurrent disease.
▪ Medullary Thyroid Carcinoma
Pathobiology
Medullary thyroid carcinoma arises from the thyroid's parafollicular C cells. It accounts for less than 5% of all thyroid cancers. It may occur as sporadic medullary cancer or as a component of the MEN 2a syndrome, MEN 2b syndrome, or familial medullary thyroid cancer syndrome. These inherited syndromes are autosomal dominant disorders caused by mutations of the ret proto-oncogene. In patients with no known family history, genetic testing at the time of diagnosis identifies approximately 6% with new or previously unrecognized heritable disease.
Patients with medullary thyroid cancer typically present with a thyroid nodule, cervical adenopathy, distant disease, or clinical manifestations of markedly elevated circulating calcitonin levels that may include flushing, diarrhea, and pruritus. Features of the other elements of MEN 2a (e.g., hypertension) or MEN 2b (e.g., marfanoid habitus, submucosal neuromas) should be sought.
Treatment
Initial treatment is surgical resection of the thyroid and regional lymph nodes, which are involved in 50% of affected patients at the time of diagnosis. The high risk of extrathyroidal disease and limited availability of secondary treatment options mandate aggressive initial surgery, including central neck compartment dissection, unilateral or bilateral modified neck dissection, and even superior mediastinal exploration to extirpate suspicious lymphadenopathy. The risk for development of medullary thyroid carcinoma has been determined to be so high in children with inherited ret proto-oncogene mutations that prophylactic thyroidectomy is advisable during childhood. Distant metastases involving the liver are present in a small minority of patients and can often be established by laparoscopically guided liver biopsy.
Follow-up
Because medullary thyroid carcinoma cells produce calcitonin and carcinoembryonic antigen, these tumor markers can be measured serially to monitor patients for recurrence and progression of disease. Surgery can be repeated to treat significant cervical and mediastinal node disease. External beam radiation therapy has been used for nonresectable cervical disease, but its value has not been established in controlled trials. Radioiodine therapy is ineffective, and thyroid hormone therapy is intended only to maintain euthyroidism as TSH suppression is not required. Somatostatin analogues can be used to control the diarrhea and flushing associated with hypercalcitonemia.
▪Anaplastic Thyroid Carcinoma
Anaplastic thyroid carcinoma is a rare histologically undifferentiated and clinically aggressive malignant neoplasm that typically arises in older patients, one fourth of whom present with evidence of a preceding or concurrent differentiated type of thyroid cancer. Affected patients present with a rapidly enlarging mass in the anterior or lateral neck associated with pain, tenderness, and compressive symptoms including dysphagia, dysphonia, and stridorous dyspnea. Fine-needle aspiration biopsy of the mass usually yields large pleomorphic undifferentiated cells, but open surgical biopsy is sometimes required to confirm the diagnosis.
Most cases are unresectable at presentation because of invasion of cervical structures. Surgery is not curative and should aim to secure the patient's airway. A percutaneous gastrostomy tube is often placed to ensure adequate nutrition in the face of esophageal impingement. Conventional therapy consisting of combined external beam radiation therapy and chemotherapy with doxorubicin with or without cisplatin produces an initial response in 25% of patients. Those with disease limited to the neck may have extended survival, but almost all patients relapse within a few months and succumb to their disease, with median survival rates ranging from 3 to 7 months. Current research initiatives are focused on the use of targeted antiangiogenic agents to treat unresponsive disease.
▪ Thyroid Lymphoma
Lymphoma rarely arises in the thyroid gland, typically presenting in older persons as a rapidly enlarging and painful diffuse goiter. Patients often have a preceding history of autoimmune thyroiditis. The diagnosis is further suspected when fine-needle aspiration biopsy yields abundant lymphocytes without other cellular features of autoimmune thyroiditis. Immunohistochemical staining and flow cytometry of sampled material can serve to characterize a monoclonal lymphocyte population. Surgical biopsy is sometimes required to establish the diagnosis. In 50% of cases, lymphoma is primary to the thyroid gland, usually an intermediate-grade non-Hodgkin's type lymphoma.
Surgical resection of the thyroid is not indicated, but elective tracheostomy should be considered as a prophylactic measure when tracheal compression is imminent. Most patients respond to treatment with combined external beam radiation therapy and chemotherapy. Disease-free survival rates vary with the disease stage at diagnosis and the initial response to combination therapy.
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