Thyroid Gland Disorders

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[edit] Thyroid Gland Disorders

Alan P. Farwell

Susana A. Ebner

Clinical disorders of the thyroid gland are the most common endocrinopathies. As such, it is essential for the primary care physician to recognize the clinical features of the various forms of thyroid dysfunction. In addition, subclinical thyroid disease, a disorder in which mild abnormalities in circulating thyroid hormones are present in the absence of overt symptomatology, is present in up to 17% of patients based on population screening studies. The diagnosis of subclinical thyroid disease allows the identification of clinically euthyroid patients at risk to develop overt thyroid dysfunction. To appropriately identify and manage patients with clinical and subclinical thyroid dysfunction, the physician must first possess an understanding of the fundamentals of thyroid hormone economy, the laboratory evaluation of thyroid function, and the availability of thyroid imaging techniques.

[edit] NORMAL THYROID HORMONE ECONOMY

[edit] Regulation of the Thyroid-Pituitary Axis

Synthesis and secretion of thyroid hormone is under the control of the anterior pituitary hormone, thyrotropin (thyroid-stimulating hormone [TSH]). TSH secretion increases when serum thyroid hormone concentrations fall, and decreases when they rise, in a classic negative feedback system. TSH is also under the regulation of the hypothalamic hormone, thyrotropin-releasing hormone (TRH). The negative feedback of thyroid hormone is targeted mainly at the pituitary level but probably affects TRH release from the hypothalamus as well. In addition, input from higher cortical centers affects TRH secretion.

Under the influence of TSH, the thyroid gland synthesizes and releases thyroid hormone. Thyroxine (T₄) is the principal secretory product of the thyroid gland, constituting about 90% of the secreted hormone under normal conditions. T₄ is also the most abundant thyroid hormone in serum. Although some effects of thyroid hormone are attributed specifically to T₄, for the most part T₄ functions as a hormone precursor that is metabolized in peripheral tissues to a more active form.

[edit] Metabolic Pathways

The major pathway of metabolism of T₄ is by sequential monodeiodination. Removal of the 5′-, or outer ring, iodine is the activating metabolic pathway, leading to the formation of the metabolically active form of thyroid hormone,l-3,5,3′- triiodothyronine (T₃). Removal of the inner ring, or 5-, iodine is an inactivating pathway, producing the metabolically inactive hormone,l-3,3′,5′-triiodothyronine (reverse T₃ [rT₃]). Under normal conditions about 41% of T₄ is converted to T₃, about 38% is converted to rT₃, and about 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile.

T₃ is the metabolically active thyroid hormone and exerts its actions via binding to chromatin-bound nuclear receptors and regulating gene transcription in responsive tissues. Only about 10% of circulating T₃ is secreted directly by the thyroid gland, whereas more than 80% is derived from conversion of T₄ in peripheral tissues, primarily in the liver. Thus factors that affect peripheral T₄ to T₃ conversion have significant effects on circulating T₃ levels. Peripheral T₄ to T₃ conversion is catalyzed by type I 5′-deiodinase, which is found primarily in the liver. Serum levels of T₃ are about 100-fold less than those of T₄ and, like T₄, T₃ is metabolized by deiodination, forming diiodothyronine, and by conjugation in the liver.

[edit] Serum-binding Proteins

Both T₄ and T₃ circulate in the serum bound to several proteins that are synthesized in the liver. Thyronine-binding globulin (TBG) is the major serum-binding protein and binds about 80% of the serum thyroid hormones. The affinity of T₄ for TBG is about tenfold greater than that of T₃ and is part of the reason that circulating T₄ levels are higher than T₃ levels. Other serum-binding proteins include transthyretin, which binds about 15% of T₄ but little if any T₃, and albumin, which has a low affinity but a very large capacity for binding T₄ and T₃. Overall, 99.97% of circulating T₄ and 99.7% of circulating T₃ are bound to plasma proteins.

[edit] Thyroid Function Tests

The development of immunoassays has allowed the easy and reliable measurement of circulating T₄ and T₃ concentrations (Table 97-1). The most widely available assays measure total hormone levels, consisting of both bound and free hormone. Essential to the understanding of the regulation of thyroid function is the free hormone concept (i.e., only the unbound hormone has any metabolic activity). Because of the high degree of binding of T₄ and T₃ to the serum-binding proteins, changes in either the concentrations of these proteins or the binding affinity of thyroid hormone to the serum-binding proteins would have major effects on the total serum hormone levels. However, since the pituitary responds to and regulates the circulating free hormone levels, minimal changes in the free hormone concentrations and thus overall thyroid function are seen.

Table 97-1 Tests of Thyroid Function

The gold standard for the direct measurement of free T₄ concentrations is equilibrium dialysis. However, this technique requires expertise and is time-consuming. The free T₄ index (FTI) is the most widely available test of free T₄ concentrations and is determined by multiplying the total T₄ concentration by a factor that corrects for changes in serum-binding proteins. This factor is often the T₃ resin uptake, which is an inverse estimate of serum TBG concentrations and is expressed as a percent. The T₃ resin uptake is reduced if the capacity of serum-binding proteins is high and is increased when serum-binding proteins have diminished ability to bind hormone. An attempt to improve on the accuracy of the FTI multiplies the total T₄ by the thyroid hormone binding ratio (THBR), which is determined by dividing the T₃ resin uptake by a standardized “normal” T₃ resin uptake. Other methods to directly measure free thyroid hormone levels besides equilibrium dialysis are also available but are more expensive than the FTI and may be no more accurate. Direct measurements of free T₃ concentrations are also available, but are of limited utility. Serum T₃ concentrations are only useful in the evaluation of thyrotoxicosisand, for the most part, measurements of total T₃ are sufficient. Assays that measure serum levels of rT₃ are also available but are of little use clinically.

[edit] Sensitive TSH Assays.

Serum determination of TSH by a sensitive TSH assay is currently the best first test of thyroid status in ambulatory patients. Although TSH assays have been available since 1965, the first-generation assays were useful only for diagnosing primary hypothyroidism, since a lower limit to the normal range could not be reliably measured. The first sensitive TSH assay was developed in 1985, resulting in the expansion of the assay detection limit below the normal range. The main utility of the sensitive TSH assay is to differentiate between normal and thyrotoxic patients, who should exhibit suppressed TSH values. Currently, commercially available TSH assays have a limit of detection of 0.05 mU/L or lower.

With the advent of the sensitive TSH assay came the realization that abnormal TSH values, especially subnormal values, were very common. Abnormal TSH values have been reported in over 15% of hospitalized patients, with more than two thirds of these patients having no intrinsic thyroid dysfunction on follow-up testing after recovery from illness. In addition, 20% to 30% of patients over the age of 60 have abnormal TSH values. The vast majority of these abnormal TSH values are associated with normal FTI determinations, giving rise to the syndromes of subclinical thyroid disease (discussed below). Despite these pitfalls, the following conclusions can be made regarding sensitive TSH assays: (1) normal TSH values are both sensitive and specific to identify normal patients; (2) subnormal and suppressed TSH values are sensitive but not specific to identify thyrotoxic patients; (3) abnormal TSH values require additional biochemical and clinical evaluation before a diagnosis of thyroid dysfunction can be made.

[edit] Thyroid Antibodies.

Antibodies directed against the thyroid proteins thyroglobulin (Tg) and thyroid peroxidase (TPO, formerly microsomal protein) are markers of autoimmune thyroid disease and are often helpful in determining the etiology of thyroid dysfunction. Of the two, anti-TPO antibodies are most closely associated with autoimmune thyroid disease. Measurement of these antibodies is always a secondary test and may be useful to predict the development of overt thyroid dysfunction. Thyroid-stimulating immunoglobulins (TSI) are the cause of Graves' disease, the most common form of thyrotoxicosis. However, the routine measurement of TSI is not indicated in most patients with Graves' disease. Determination of TSI titers is best reserved for special circumstances, such as in the pregnant patient with Graves' disease (see below).

[edit] Thyroid Imaging Studies.

Thyroid imaging studies can be divided into those that provide an assessment of gland function vs. those that provide imaging alone. Radioisotope imaging with radioiodine (¹²³I) is commonly utilized to determine the overall activity of the gland in patients with thyrotoxicosis (24-hour radioactive iodine uptake [RAIU]) as well as to provide information regarding the function of parts of the gland, such as nodules. Nodules that take up radioiodine are considered to be functioning, or warm. If all of the radioiodine is concentrated within a solitary nodule and serum TSH values are suppressed, the nodule is considered to be toxic, or hot. Nodules that fail to concentrate radioiodine are considered to be hypofunctioning (cool or cold), increasing the chances that those nodules harbor a malignancy. Radioisotope imaging with technetium (^99mTc pertechnetate) provides information on the regional function within the gland but is less informative regarding the overall function of the gland. In addition, an occasional nodule that is functioning with technetium will be cold on imaging with radioiodine. Thus most physicians prefer radioiodine imaging.

Ultrasound provides only structural information and is helpful in identifying cysts and in following the size of nodules, and occasionally is necessary to guide the fineneedleaspiration biopsy of a nodule. Other anatomic imaging modalities include magnetic resonance imaging (MRI) and computed tomography (CT). These latter two studies should never be first-line tests and should be reserved for specialized indications.

[edit] HYPOTHYROIDISM

Hypothyroidism is the most common disorder of thyroid function. Worldwide, hypothyroidism is most often the result of iodine deficiency. In the United States, where iodine is sufficient, autoimmune processes account for the majority of cases. The prevalence of newly diagnosed overt hypothyroidism in the United States ranges from two to six cases per 1000 women, and the prevalence of established cases is in the range of 20 to 40 per 1000 women. The prevalence of overt hypothyroidism worldwide is ∼5%.

Failure of the thyroid to produce sufficient thyroid hormone is the most common cause of hypothyroidism and is referred to as primary hypothyroidism (Box 97-1). Central hypothyroidism occurs much less often and results from diminished thyroidal stimulation by TSH due to pituitary failure (secondary hypothyroidism) or hypothalamic failure (tertiary hypothyroidism). Chronic autoimmune thyroiditis accounts for about 60% of the cases of hypothyroidism in the United States and is further subdivided into goitrous (Hashimoto's thyroiditis) and atrophic forms. As with other autoimmune diseases, females are affected much more frequently than males (∼8:1). Chronic autoimmune thyroiditis is characterized by the presence of thyroid antibodies, which are present in about 7% of the population.

Hypothyroidism resulting from the treatment for hyperthyroidism is the second most common cause and accounts for about 30% of cases. Secondary and tertiary hypothyroidism constitute less than 5% of cases. Congenital hypothyroidism occurs in about 1 in 4000 live births and is the major preventable cause of mental retardation in the world today. Untreated congenital hypothyroidism results in multiple developmental abnormalities known as cretinism. Diagnosis is made primarily through newborn thyroid function screening. Early institution of thyroid hormone replacement therapy results in normal IQ values in treated infants. A rare but increasingly recognized cause of hypothyroidism is generalized thyroid hormone resistance. Serum thyroid hormone concentrations are elevated but unable to exert any action due to genetic defects in the nuclear receptors for thyroid hormone.

Transient hypothyroidism is, by definition, the only reversible form of hypothyroidism. Postpartum thyroiditis, occurring 1 to 6 months after delivery, approaches an incidence of 20% in some series. A hypothyroid phase occurs in more than 60% of individuals and may last up to 1 year. Permanent hypothyroidism occurs in 20% to 30% of those affected. Subacute thyroiditis is also associated with a hypothyroid phase in over two thirds of patients; however, the incidence of permanent hypothyroidism is ∼5%.

[edit] Patient Evaluation

Regardless of the etiology, the clinical features of hypothyroidism are similar (Box 97-2). The onset of symptoms is usually insidious; thus hypothyroidism may be present for years before it is diagnosed. Despite the fact that every organ system can be involved, most of the symptoms and signs of hypothyroidism are nonspecific. Indeed, in one series a diagnosis of hypothyroidism was established in less than 4% of ambulatory patients with symptoms potentially attributable to the disease. In addition, symptoms do not always correlate with the severity of the hypothyroidism and may be lacking altogether in individuals with overt biochemical evidence of the disease. Weakness, lethargy, constipation, dry skin, and hair loss are common nonspecific symptoms. Characteristic clinical features of hypothyroidism include cold intolerance, facial puffiness, deepening of the voice, and carpal tunnel syndrome (Fig. 97-1).

Figure 97-1 Thirty-year-old patient with Hashimoto's thyroiditis and hypothyroidism. Presenting complaint was thyroid enlargement. T₄=4.5 μg/dl, TSH=84 μU/ml. Note puffiness of face and visible goiter.

Some presentations are age specific, such as delayed growth in the child, menorrhagia in premenopausal women, and dementia in the elderly. The clinical picture of florid myxedema includes dull, expressionless facies; slow movements; periorbital puffiness; sparse, coarse hair; macroglossia; and cool, pale, coarse skin (Table 97-2) (Figs. 97-2 and 97-3). The most characteristic clinical finding in hypothyroidism is the delayed relaxation phase of deep tendon reflexes. This is most commonly seen with the Achilles reflex. Small pericardial and pleural effusions are common and occasionally may be massive. Hypothyroid-related pericardial effusions typically do not cause tamponade and nearly always resolve with T₄ therapy.

Figure 97-2 Advanced hypothyroidism. Note dulled expression, facial puffiness, and periorbital edema.

Figure 97-3 Macroglossia of hypothyroidism.

Table 97-2 Signs of Hypothyroidism

Sinus bradycardia and flattened T waves are characteristic electrocardiographic (ECG) findings in hypothyroidism.Hypercholesterolemia occurs in 95% of patients due to impaired clearance of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. Dilutional hyponatremia is common due to impaired water excretion. Increased free water retention also produces increased diastolic blood pressure. Elevated creatine phosphokinase (CPK) concentrations (MM variant), occasionally over 1000 U/L, are often seen due to impaired clearance and may raise the possibility of a myocardial infarction until fractionation is performed. A normochromic, normocytic anemia is frequently found.

[edit] Diagnosis

The best initial test in the evaluation of hypothyroidism is a sensitive TSH, since 95% of hypothyroid patients have primary thyroid failure. Indeed, increased serum TSH concentrations are the most sensitive indicator of the failing thyroid. However, modest elevations of TSH (usually under 15 mU/L) are often associated with normal T₄ values, identifying those individuals with subclinical hypothyroidism. At present there is no consensus on the indications for treatment in healthy individuals with subclinical hypothyroidism (see further).

Since the hallmark of hypothyroidism is the presence of decreased serum concentrations of thyroid hormones, the measurement of T₄ should be considered in most individuals (see Table 97-1). Since alterations in serum hormone binding capacity can alter total T₄ concentrations and obscure the diagnosis of hypothyroidism (Box 97-3), an estimation of free T₄ concentrations by the FTI method is often valuable. The measurement of serum T₃ concentrations has a low sensitivity in the laboratory evaluation of hypothyroidism and is almost never indicated. T₃ values can be normal in up to one third of patients with overt hypothyroidism and are commonly depressed in euthyroid patients with nonthyroidal illness (see further).

The vast majority of cases of hypothyroidism can be diagnosed based on clinical findings and the serum FTI and TSH concentrations. Thyroid antibodies (see Table 97-1) arehelpful in providing an etiology for the hypothyroidism and to identify a population with subclinical hypothyroidism that has a high risk of progression to overt disease. Radioisotope scanning is almost never indicated unless used either to document congenital thyroid abnormalities or to evaluate a nodular goiter (see further).

[edit] Differential Diagnosis

Changes in serum TBG concentrations can have marked effects on serum T₄ values and may obscure the diagnosis of hypothyroidism (see Box 97-3). Factors that either decrease TBG concentrations or interfere with binding to TBG can result in low T₄ values in the hypothyroid range. Drugs such as dilantin and salicylates are the most common cause of low serum T₄ levels in euthyroid ambulatory individuals. FTI values are often low as well, but a normal serum TSH value in the absence of signs or symptoms of pituitary or hypothalamic failure confirms the diagnosis of drug effect in most cases. Conversely, factors that increase TBG concentrations can result in T₄ values in the normal range in the hypothyroid patient.

Abnormal thyroid function tests are often seen in patients with nonthyroidal illness (see further). In one large series fewer than 10% of hospitalized patients with elevated serum TSH values less than 20 mU/L and only 50% of those with serum TSH values over 20 mU/L were subsequently diagnosed with hypothyroidism. Retesting thyroid functions 2 to 3 months after complete recovery from an acute illness usually distinguishes nonthyroid illness from hypothyroidism.

[edit] Management

The synthetic preparation of levothyroxine sodium (l-T₄) is the drug of choice for thyroid hormone replacement therapy. T₄ is converted to T₃ in peripheral tissues such as the liver, which produces >80% of the circulating T₃ in both euthyroid and T₄-treated hypothyroid individuals. The hormonal content of the various brands of syntheticl-T₄ is reliably standardized; however, clinical experience suggests that it is best to stay with a single brand for an individual patient due to potential small deviations of a specific dose between manufacturers.

The use of liothyronine (l-T₃) alone should be discouraged, due to the need for multiple daily doses and peak-and-valley serum concentrations, as well as the need for target tissues such as the brain to locally convert T₄ to T₃. Similarly, synthetic fixed combinations ofl-T₄ andl-T₃ are expensive relative tol-T₄ alone and are unnecessary except in a few highly unusual circumstances. Desiccated thyroid preparations, derived from bovine thyroid, contain T₄ and T₃ and have drawn some interest as a “natural” thyroid hormone replacement. However, desiccated thyroid also contains thyroidal proteins and hormone precursors and metabolites that do not usually find their way into the circulation. In addition, these preparations have a highly variable biologic activity. Since the synthetic T₄ is identical to the T₄ produced by the thyroid, there is no indication for the use of desiccated thyroid in the management of hypothyroidism.

The average replacement dosage ofl-T₄ in the United States is 0.112 mg (112 μg) per day. Institution of therapy in healthy individuals under the age of 60 can begin at dosages of 0.05 to 0.1 mg (50 to 100 μg) per day (Table 97-3). Adequacy of the replacement dose can best be determined by serum TSH measurements. Because of the prolonged half-life of T₄ (7 days), new steady-state concentrations of T₄ are not achieved until 4 to 6 weeks after a change in dosage. Thus measurement of serum TSH values should not be performed any earlier than this time frame. The goal ofl-T₄ replacement therapy is to achieve a TSH value in the normal range, since overreplacement ofl-T₄ suppressing TSH values to the subnormal range has been shown to have a deleterious effect on bone density (see further). Once a normal serum TSH value is achieved, monitoring replacement therapy by determining serum TSH concentrations at 6-to 12-month intervals is appropriate.

Table 97-3 T₄ Replacement Therapy in Hypothyroidism

Certain drugs can interfere with the absorption ofl-T₄ in the gut. Iron and calcium supplements are the most common interfering agents; others include sucralfate, cholestyramine, and certain antacids.l-T₄ administration should be spaced as far apart as possible from these medications. Higherl-T₄ doses may be necessary in patients who are taking drugs that accelerate the metabolism of T₄, such as anticonvulsants and rifampin.

In individuals over the age of 60, institution of therapy at a lower daily dosage (0.025 mg) ofl-T₄ is indicated to avoid exacerbation of cardiac disease. The dosage can be increased at a rate of 0.025 mg per day every 4 to 6 weeks, with reevaluation after a total daily dose of 0.075 mg is achieved. For individuals with preexisting cardiac disease an initial dosage of 0.0125 mg with increases of 0.0125 to 0.025 mg per day every 6 to 8 weeks is indicated.

Daily doses ofl-T₄ may be interrupted periodically because of intercurrent medical or surgical illnesses that prohibit taking anything by mouth. A lapse of several days of hormone replacement usually has no metabolic consequences. However, if more prolonged interruption is necessary,l-T₄ may be given parenterally at a dosage 25% to 50% less than the daily oral requirements.

[edit] Special Considerations

[edit] Myxedema Coma.

Myxedema coma is a rare syndrome that represents the extreme expression of severe, longstanding hypothyroidism. It is a medical emergency, and even with early diagnosis and treatment the mortality can be as high as 60%. Myxedema coma occurs most often in the elderly during the winter months. Common precipitating factors include pulmonary infections, cerebrovascular accidents, and congestive heart failure. The clinical course of lethargy proceeding to stupor and then coma is often hastened by drugs, especially sedatives, narcotics, antidepressants, and tranquilizers. Indeed, many cases of myxedema coma have occurred in the undiagnosed hypothyroid patient who has been hospitalized for other medical problems.

Cardinal features of myxedema coma are (1) hypothermia, which can be profound, (2) respiratory depression, and (3) unconsciousness. Other clinical features include bradycardia, macroglossia, delayed reflexes, and dry, rough skin. Dilutional hyponatremia is common and may be severe. Elevated CPK and lactate dehydrogenase (LDH) concentrations, acidosis, and anemia are common findings. Lumbar puncture reveals increased opening pressure and high protein content. Hypothyroidism is confirmed by measuring serum FTI and TSH values. Ultimately, however, myxedema coma is a clinical diagnosis.

The mainstay of therapy is supportive care, with ventilatory support, rewarming, correction of hyponatremia, and treatment of the precipitating incident. Because of a 5% to 10% incidence of coexisting adrenal insufficiency in patients with myxedema coma, intravenous steroids are indicated before initiating T₄ therapy. Parenteral administration of thyroid hormone is necessary due to uncertain absorption through the gut. A reasonable approach is an initial intravenous loading dose of 200 to 300 μgl-T₄, with a second dose of 100 μg given 24 hours later. Simultaneously, with the initial dose ofl-T₄, some physicians recommend addingl-T₃ at a dosage of 10 μg intravenously every 8 hours until the patient is stable and conscious. The dose of thyroid hormone should be adjusted on the basis of hemodynamic stability, the presence of coexisting cardiac disease, and the degree of electrolyte imbalance.

[edit] Subclinical Hypothyroidism.

Subclinical hypothyroidism is defined as mild elevations of serum TSH in conjunction with normal serum thyroid hormone concentrations and lack of any overt clinical manifestations of hypothyroidism. The prevalence of subclinical hypothyroidism ranges from 10% to 20%, depending on the population, and is frequently observed in the elderly. The presence of thyroid antibodies in these patients clearly identifies a subset of patients who are at high risk of progressing to overt hypothyroidism. Potential benefits of institutingl-T₄ therapy in patients with subclinical hypothyroidism include prevention of overt hypothyroidism, improvement in mild metabolic and physiologic abnormalities, and improvement in symptomsnot originally attributed to thyroid dysfunction. Several small studies have demonstrated that treatment of subclinical hypothyroidism withl-T₄ improved serum lipid profiles in patients with hypercholesterolemia, improved cognitive function in the elderly, and relieved hypothyroid-related symptoms in patients who initially characterized themselves as asymptomatic.

Although there is currently no consensus for the management of patients with subclinical hypothyroidism, an approach to the management, based on the published literature, is shown in Table 97-4. In addition, a therapeutic trial ofl-T₄ is reasonable in individuals with symptoms that are out of proportion to the TSH elevations and that do not fit any of the criteria listed. In these individuals, and in those with hypercholesterolemia or cognitive dysfunction, reassessment after 6 months ofl-T₄ therapy that normalizes the serum TSH is reasonable to determine if therapy should be continued. All individuals with subclinical hypothyroidism who are not treated should be followed with periodic determination of serum TSH concentrations (i.e., semiannually or annually).

Table 97-4 Management of Subclinical Hypothyroidism

[edit] Thyroid Hormone Replacement and Osteoporosis.

Thyroid hormone has a direct effect on bone resorption and has been shown in several studies to decrease bone density in women taking thyroid hormone in suppressive doses for many years. When analyzed carefully, a significant decrease in bone density has been demonstrated in women taking doses ofl-T₄ that result in undetectable TSH values, with the hip affected to a greater degree than the spine. This is mainly seen in those individuals requiring suppressive therapy after surgery for thyroid cancer, in whom TSH suppression is the goal of therapy. However, increased fracture rates have not been demonstrated in patients takingl-T₄. Women on replacement therapy with normal serum TSH concentrations show no changes in bone mineral density compared with age-matched women not onl-T₄ therapy. Thus, as stated above, the goal of replacement therapy in patients with hypothyroidism should be to achieve a serum TSH in the normal range.

[edit] Thyroid Hormone Replacement in Pregnancy.

In general,l-T₄ replacement requirements increase during pregnancy. This is primarily due to an estrogen-dependent increase in serum TBG concentrations that occurs during the first trimester. In addition, gastrointestinal absorption ofl-T₄ may be decreased during pregnancy. Approximately 80% of hypothyroid patients need an increase in their replacement dosage during pregnancy, with an average increase equivalent to about 45% of the basal dosage. In addition, pregnancy may unmask hypothyroidism in patients with decreased thyroid reserve, such as those residing in areas of iodine deficiency or those with euthyroid chronic autoimmune thyroiditis. Thus all patients receiving thyroid hormone replacement who become pregnant should have a serum TSH determination at or near the end of their first trimester. Similarly, evaluation of thyroid function during pregnancy in normal patients is indicated in those patients at high risk for hypothyroidism, such as those residing in areas of iodine deficiency or with a family history of thyroid or other autoimmune disease.

[edit] THYROTOXICOSIS

Thyrotoxicosis is a condition caused by elevated concentrations of the circulating free thyroid hormones T₄ and T₃. Various disorders of different etiologies can result in this syndrome. The term hyperthyroidism should be restricted to those conditions in which thyroid hormones are overproduced due to hyperfunction, rather than thyroid inflammation or destruction or thyroid hormone administration.

[edit] Etiology

For practical purposes hyperthyroidism can be classified according to the 24-hour radioactive iodine uptake (RAIU) (Box 97-4). An elevated RAIU indicates that the etiology of the elevated serum thyroid hormones is a hyperfunctioning thyroid gland. Graves' disease is the most common cause of high RAIU thyrotoxicosis. It accounts for 60% to 90% of the cases, depending on age and geographic region. Toxic nodular and multinodular goiter follows in frequency, accounting for 10% to 40% of the cases, and is more common in older patients. A low RAIU is seen in destructive thyroiditides and in thyrotoxicosis resulting from exogenous thyroid hormone. Low RAIU thyrotoxicosis caused by subacute and painless thyroiditis represents about 5% to 20% of all cases. Other causes of thyrotoxicosis are much less common.

[edit] Patient Evaluation

Thyroid hormone excess affects multiple organ systems. Although the resulting signs or symptoms in thyrotoxicosis can be nonspecific, their combination usually creates a characteristic clinical picture. Age, presence of other underlying disturbances, and rapidity of onset of the disease can modify both the type and severity of the clinical presentation. Symptoms of thyrotoxicosis may start slowly or precipitously and may range from subtle to florid.

Typical patient complaints include nervousness, irritability, hyperactivity, insomnia, hand tremor, excessive sweating, and palpitations (Box 97-5). Most of these symptoms are due to increased sympathetic tone. Weight loss, despite an increased appetite, and heat intolerance are common due to increased energy production and utilization. Pruritus, when present, results from increased blood flow to the skin. Proximal muscle weakness is often manifested as difficulty climbing stairs or standing up. Increased gut motility may result in hyperdefecation and occasionally in malabsorption or diarrhea. Hyperthyroidism may exacerbate angina pectoris. Oligomenorrhea in women and decreased libido and impotence in men are described.

Less often patients develop nausea, vomiting, and dysphagia. Dyspnea on exertion, due to increased oxygen consumption and respiratory muscle weakness, can be seen. Rarely tracheal compression from a large goiter can cause dyspnea. Periodic paralysis is rare and is seen usually in Asian males usually in association with low serum potassium levels.

The thyroid gland is diffusely enlarged in most patients with Graves' disease. Typically both thyroid lobes are symmetrically enlarged, firm, and nontender. The gland may be particularly firm in those thyroids with coexistent Hashimoto's thyroiditis. In patients with a multinodular goiter the thyroid gland is often asymmetric, irregular, and bumpy. A unilateral nodule, usually larger than 3 cm, is found in a solitary toxic adenoma. A tender thyroid raises the possibility of subacute thyroiditis. A normal or nonpalpable thyroid gland points toward a diagnosis of thyrotoxicosis factitia (see further) or painless thyroiditis, although goiter may rarely be absent in Graves' disease. Hyperthyroidism without goiter is more common in the elderly. Because of increased blood supply to the thyroid, a systolic bruit and a thrill may be present in Graves' disease.

Cardiac findings are the result of both direct thyroid hormone effects on the cardiovascular system and indirect effects through the increased metabolism and oxygen consumption. Sinus tachycardia, elevated systolic blood pressure, and widened pulse pressure are common. A systolic ejection flow murmur may be present. Although sinus tachycardia is the most common rhythm in thyrotoxicosis, other arrhythmias, especially atrial fibrillation, occur in 10% to 25% of patients. Atrial fibrillation is more common in older patients and may be the presenting feature of thyrotoxicosis. In these patients the presence of left atrial enlargement is the rule. Arterial embolism occurs in about 10% of patients with atrial fibrillation.

The skin is often warm, moist, and smooth. Onycholysis, or separation of the nail from the nailbed, is often seen in thyrotoxicosis (Fig. 97-4). Acropachy and clubbing are associated with Graves' disease. Hair texture is fine and alopecia may occur. Hyperpigmentation of the skin may be observed. Vitiligo is associated with Graves' disease. Distal fine tremor, brisk deep tendon reflexes, and proximal muscle weakness are common neurologic findings. Ophthalmopathy associated with thyrotoxicosis is classified as noninfiltrativeor infiltrative. Noninfiltrative ophthalmopathy is associated with thyrotoxicosis of any origin. It is characterized by upper lid retraction, which results in lid lag and stare (Fig. 97-5). Infiltrative ophthalmopathy is specifically associated with Graves' disease and is discussed later.

Figure 97-4 Onycholysis involving the ring finger in a patient with Graves' disease.

Figure 97-5 Classic appearance of Graves' disease with advanced hyperthyroidism. (From Bramwell B:Atlas of clinical medicine, Edinburgh, 1892, University Press.)

[edit] Diagnosis

Elevated serum concentrations of thyroid hormones and suppressed serum TSH concentrations are the hallmarks of thyrotoxicosis. Both total and free thyroid hormone concentrations are elevated, although isolated increases of either T₄ or T₃ may also occur. An increase in serum T₄ binding protein concentrations or capacity, as seen during pregnancy and estrogen replacement therapy, can result in an increase of total T₄ concentrations into the thyrotoxic range. Therefore estimation of free T₄ concentrations by the FTI is helpful to clarify the diagnosis in these situations. Disorders that are associated with elevated total T₄ concentrations, but normal free T₄ concentrations (see Box 97-3), may mimic the diagnosis of thyrotoxicosis and are collectively known as the euthyroid hyperthyroxinemia syndrome. In these patients serum T₃ and TSH concentrations are normal.

T₄-toxicosis is described in thyrotoxic patients with concomitant diseases, such as hospitalized patients, in whom T₄ to T₃ conversion in peripheral tissues is inhibited because of nonthyroidal illness or drugs. On the patient's recovery from the acute illness, serum T₃ levels may rise up to the hyperthyroid range. Similarly, hyperthyroid patients who received iodinated preparations, for example, those used for radiologic studies, may also develop T₄-toxicosis. Occasionally patients may have increased serum T₃ levels and normal T₄ levels. Hyperthyroidism due to T₃ alone is referred to as T₃-toxicosis. This disorder is more frequent in areas of iodine deficiency, in patients with solitary nodules, and in early or relapsing Graves' disease.

Serum TSH determination by a sensitive TSH radioimmunoassay (limit of detection <0.05 mU/L) is a very accurate indicator of thyrotoxicosis. Serum TSH levels should be low or undetectable. Indeed, with the rare exception of a TSH-secreting pituitary tumor, a serum TSH concentration in the normal range rules out the diagnosis of hyperthyroidism. The new sensitive TSH assays have replaced the thyrotropin-releasing hormone stimulation test as a tool in the diagnosis of hyperthyroidism.

Thyroid autoantibody titers (antithyroglobulin and anti-TPO) are elevated in up to 70% of patients with Graves' disease. Their measurement is not routinely necessary but many times is helpful in establishing the diagnosis, especially in the absence of ophthalmopathy. TSH receptor antibodies can be commercially measured as thyroid-stimulating (TSI) or thyroid-binding inhibitor (TBII) immunoglobulins. TSI is more sensitive than TBII, but both are very specific. Nevertheless, their measurement is costly and is not routinely recommended. Measurement of TSH receptor antibodies in pregnant women is helpful in predicting the risk of developing neonatal Graves' disease (see below). TSI measurements can occasionally be useful in the diagnosis of euthyroid Graves' disease and in the differential diagnosis of Graves' disease from other hyperthyroid disorders.

Normochromic normocytic anemia and mild neutropenia with lymphocytosis are sometimes found in Graves disease. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) may be minimally increased. Mild elevations of serum calcium levels are seen in up to 20% of thyrotoxic patients. This is due to increased bone resorption by thyroid hormones, and resolves with the treatment of hyperthyroidism. Bone and liver alkaline phosphatase fractions may also be elevated. Serum cholesterol levels may be decreased.

As mentioned previously, the 24-hour RAIU separates thyrotoxicosis into two categories. When the diagnosis of Graves' disease is clinically obvious, especially in the presence of coexisting Graves' ophthalmopathy, RAIU determination is unnecessary. However, RAIU is a useful tool in the differential diagnosis of thyrotoxicosis in unclear cases. Whereas RAIU distinguishes etiology based on iodine uptake, thyroid radionuclide imaging can distinguish different forms of goiter. A thyroid scan should be requested when the thyroid gland appears to be nodular on physical examination to establish the diagnosis of toxic nodular or multinodular goiter. In addition, a thyroid scan may be ordered in a patient with Graves' disease when a thyroid nodule is palpated so as to rule out a coexistent cold nodule.

[edit] Differential Diagnosis

When the clinical picture is classic with a diffuse goiter and ophthalmopathy, the diagnosis of Graves' disease is straightforward. The absence of ophthalmopathy or the presence of subtle hyperthyroid symptoms may obscure the diagnosis. This is particularly true in the elderly (Fig. 97-6). Certainpsychiatric diseases, such as anxiety and bipolar disorder, can mimic thyrotoxicosis. Conversely, thyrotoxicosis can be manifest as a psychiatric disorder or can expose a previously unrecognized one.

Figure 97-6 Apathetic hyperthyroidism in an older patient. (From Thomas FB, et al:Ann Intern Med 72;679, 1970.)

History, physical examination, and determination of serum FTI, T₃, and TSH concentrations usually provide enough information to make the diagnosis. RAIU is helpful in borderline patients or in those with atypical or few clinical manifestations. High T₃/T₄ ratios (greater than 20) are suggestive of Graves' disease. In contrast, inflammatory thyroiditis or exogenousl-T₄ administration is characterized by a low T₃/T₄ ratio, usually less than 15. TSH receptor antibody determinations and radionuclide imaging studies can be helpful but should be reserved for unusual cases (see above). An elevated sedimentation rate is essential for a diagnosis of subacute thyroiditis (see below). Serum thyroglobulin concentration, which is elevated in most forms of thyrotoxicosis, is low or suppressed in thyrotoxicosis factitia.

[edit] Graves' Disease.

Graves' disease, or toxic diffuse goiter, is an autoimmune disorder characterized by thyrotoxicosis, diffuse goiter, and antibodies directed against the TSH receptor. This is a relatively common disorder, with an incidence of 0.02% to 0.4% in the United States. Endemic areas of iodine deficiency have a lower incidence of autoimmune thyroid disease. As with most types of thyroid dysfunction, women are affected more than men, with a ratio of 5 to 7:1. Graves' disease is more common between the ages of 20 and 50 but can occur at any age. HLA B8 and DR3 haplotypes are associated with Graves' disease in the white population. The disease is commonly associated with other autoimmune disorders (Box 97-6).

[edit] Pathogenesis.

Hyperthyroidism results from the stimulation of TSH receptors on thyroid cells by TSH receptor antibodies. The TSH receptor antibody is believed to stimulate the generation of cyclic adenosine monophosphate in the thyroid, resulting in the increased synthesis and release of the thyroid hormones. Proposed hypotheses regarding the abnormal generation of thyroid-stimulating antibody include (1) a primary defect on antigen-specific suppressor T cells that results in unregulated helper T cell function and therefore abnormal antibody synthesis, (2) direct helper T cell activation by thyroid follicular cells expressing HLA class II antigens, and (3) cross-reactivity between bacterial or parasitic antigens and the TSH receptor, provoking the generation of autoantibodies.

The abnormal function of the immune system found in patients with this disease is strongly linked to a genetic predisposition. However, the specific genes involved have not been identified. Concurrence rates for Graves' disease are approximately 50% for monozygotic twins and 5% for dizygotic twins. This lack of complete concordance suggests that environmental factors, including infectious agents such as Yersinia enterocolitica or retrovirus, and stressful events, either physical or psychologic, may be involved.

[edit] Specific Clinical Manifestations.

The general manifestations of thyrotoxicosis have already been described. Specific findings in Graves' disease include infiltrative ophthalmopathy, pretibial myxedema, and acropachy.

[edit] Graves' ophthalmopathy.

The infiltrative ophthalmopathy associated with Graves' disease is considered an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscle. This disorder is clinically evident with various degrees of severity in about 50% of patients with Graves' disease but is present on radiologic studies, such as ultrasound and CT scan, in almost all patients. The majority of patients have mild or moderate disease. Euthyroid Graves' disease refers to patients with ophthalmopathy who have not developed hyperthyroidism; only 5% of these patients remain euthyroid indefinitely. Overall, ophthalmopathy precedes the diagnosis of hyperthyroidism in 15% of patients, coincides with the diagnosis of hyperthyroidism in about 40% of patients, and develops afterthe diagnosis and treatment of hyperthyroidism in the remaining patients.

Although there is good evidence that this disorder is autoimmune in origin, the target antigen in the orbital tissue has not yet been identified. Thyroid and orbital tissue, such as the eye muscle, may share antigens toward which autoantibodies react. Smoking appears to be a risk factor for the development or worsening of Graves' ophthalmopathy. Graves' ophthalmopathy may also be exacerbated after radioactive iodine therapy, and this exacerbation can be prevented by the use of high-dose corticosteroids.

Patients with Graves' ophthalmopathy may complain of retroocular pressure, photophobia, lacrimation, and blurred vision. Muscle inflammation and fibrosis can result in ophthalmoplegia and diploplia. Optic nerve damage due to increased intraocular pressure can lead to decreased vision and blindness, although this is quite rare. On physical examination the most obvious sign is proptosis. Although usually bilateral, only one eye may be involved. Conjunctival injection, chemosis, and periorbital and eyelid edema may also be present. The combination of proptosis and lid retraction may lead to corneal exposure and ulceration.

The diagnosis of ophthalmopathy is based on the findings just described. Proptosis is measured with a Hertel exophthalmometer, with a reading of 20 to 22 mm suggestive and more than 24 mm diagnostic of exophthalmos. Similarly, an asymmetric reading of more than 2 mm is abnormal. Orbital ultrasound, CT, or MRI will show the thickened eye muscle and increased orbital content. These radiologic studies are not routinely ordered to assess the ophthalmopathy, but they may be occasionally useful in the differential diagnosis of exophthalmos, especially if the patient is euthyroid. Unilateral exophthalmos should be evaluated by imaging studies even in patients with documented Graves' disease so as to exclude other causes of orbital pathology (Fig. 97-7).

Figure 97-7 Unilateral (left) lid retraction in a patient with hyperthyroidism.

Treatment of Graves' ophthalmopathy should be performed in conjunction with an ophthalmologist. Conversion to euthyroidism, preferably with antithyroid drugs, is first required. Radioactive iodine treatment should be avoided in patients with clinically significant ophthalmopathy due to potential worsening of the eye disease after treatment, although the frequency with which this occurs is controversial. If the eye disease is mild, local, nonspecific measures should be prescribed for symptom relief and to protect the eye from corneal exposure, including lubricants, dark-colored glasses, and adhesive taping of eyelids during sleep.

Systemic treatments with immunosuppressive drugs (high-dose steroids or cytotoxic agents) are reserved for severe cases with active and progressive inflammation. Orbital radiation is also used in severe disease. Similar results are obtained with both treatments. When systemic treatment is ineffective or contraindicated, surgical orbital decompression may be beneficial. In patients with severe diplopia, surgical release of the fibrosed extraocular muscle is indicated. Lid retraction that persists after the patient is rendered euthyroid can be corrected with Müller myotomy.

[edit] Pretibial myxedema.

Pretibial myxedema is an uncommon autoimmune disorder associated with Graves' disease that is present in fewer than 5% of patients. It is characterized by localized dermal accumulation of mucopolysaccharides, most commonly over the tibial surface. It may present as a diffuse nonpitting lesion of the anterior lower leg or as a sharply circumscribed lesion (Fig. 97-8). An elephantiasis form is rare. The lesions are usually asymptomatic. Rarely, they may cause pain or ulcerate. Topical occlusive treatment with potent fluorinated steroids has been reported to be successful.

Figure 97-8 Pretibial myxedema (arrows) in a patient with Graves' disease.

[edit] Thyroid acropachy.

Thyroid acropachy is the rarest manifestation of Graves' disease. It is characterized by subperiosteal new bone formation, predominately of the digits, associated with clubbing of the fingers and localized soft tissue swelling. There is no effective treatment for acropachy.

[edit] Management.

The course of hyperthyroidism in Graves' disease is characterized by cycles of relapse and remission of variable duration, although an unremitting course or a single episode of the disease is also possible. There is no available treatment aimed at the cause of Graves' disease, namely antibodies to the TSH receptor, thus there is no true cure for this disorder. Instead, treatment is aimed at decreasingcirculating thyroid hormone levels either by inhibiting thyroid hormone production or by destroying thyroid tissue. There are three major ways of achieving these goals: (1) antithyroid drugs, (2) radioactive iodine, and (3) surgery. The goal of treatment with antithyroid drugs is to alter the natural history of the disease and to induce a remission of the hyperthyroidism. Radioactive iodine and surgery seek to alter the natural history of the disease by decreasing the amount of thyroid tissue available to respond to stimulation by TSH receptor antibodies. The choice of therapy should be individualized based on the patient's interest and the availability of experienced thyroid surgeons.

[edit] Antithyroid drugs.

Antithyroid drugs (ATDs) belong to a group of compounds known as thionamides. They act by inhibiting thyroid peroxidase and therefore block iodine organification and thyroid hormone synthesis. In addition, they exhibit extrathyroidal actions that may be beneficial (Table 97-5). The two available antithyroid drugs in the United States are propylthiouracil (PTU) and methimazole (Tapazole). Both are effective in controlling hyperthyroidism. In most cases the choice between the two drugs is up to the physician's individual experience and preference. PTU is recommended for use during pregnancy because its transplacental passage is much less than that of methimazole (see further). PTU is also transmitted into breast milk to a lesser degree than is methimazole and has the additional benefit of inhibiting T₄ to T₃ conversion, allowing for a more rapid fall in serum T₃ concentrations and thus a more rapid improvement in symptoms than methimazole. However, in practice this effect of PTU is important only in the most severely toxic individuals.

Table 97-5 Characteristics of Antithyroid Drugs

The usual starting dosage of methimazole is 20 to 40 mg daily as a single dose; for PTU it is 100 to 150 mg two to three times daily. Higher dosages may be required for the severely toxic patient, as well as those with very large goiters. After treatment is initiated, patients should be examined and thyroid function tests (FTI and serum T₃ levels) monitored every 4 to 6 weeks. Once euthyroidism is achieved, usually within 12 weeks, the dosage of the antithyroid drug can be decreased. Maintenance dosages are usually 5 to 10 mg daily for methimazole and 50 to 200 mg daily for PTU. Thereafter, follow-up visits every 3 months are reasonable.

Remission rates after a treatment course with ATDs vary from 10% to 90% 1 year after stopping the drug, with a mean remission rate of about 50%. Longer durations of therapy have been associated with higher remission rates. We recommend that therapy be administered for 1 to 2 years. Remission rates have been lower in recent years compared with those initially described in the 1950s and 1960s. Increased dietary iodine has been implicated in the latter, less favorable, rates. Although it is difficult, if not impossible, to predict which individual patient will go into remission with ATDs, factors associated with higher chances of remission after discontinuation of ATD treatment include negative TPO antibody titers, HLA DR3 negative haplotype, milder thyrotoxicosis at presentation, and reduction in goiter size with ATD therapy. Conversely, patients with large goiters and a long duration of symptoms are less likely to go into remission with ATDs. Among those patients who experience remission, about 25% ultimately become hypothyroid, probably due to concurrent Hashimoto's thyroiditis.

Concomitant use ofl-T₄ therapy along with ATDs, primarily methimazole, has been reported to increase rates of remission in Japan. However, similar studies carried out in Europe and in the United States, as well as a subsequent study in Japan, have shown no advantage to concomitant use ofl-T₄ and ATDs. Thus the use of combinationl-T₄ and ATD therapy is not recommended.

Relapse of Graves' disease after discontinuation of ATDs usually occurs within the first few months. In that case a repeat course of ATDs may be indicated; however, ablation therapy should be considered. In any event, long-term (years) use of ATDs appears to be safe in the patient who is unable to achieve a drug-free remission and is not interested in radioactive iodine or surgery. Patients who remain in remission should be reevaluated for a relapse every 3 to 6 months or with the recurrence of symptoms.

The most serious side effect of ATDs is agranulocytosis, which usually, but not always, occurs within the first 3 months of treatment. The incidence of agranulocytosis is the same for both PTU and methimazole (0.1% to 0.5%). There is some evidence that methimazole-induced agranulocytosis is dose-related and is rarely seen at dosages under 30 mg daily, whereas there is no relationship between dose and agranulocytosis with PTU. Patients should be instructed to discontinue the medication and to contact the physician in case of fever or sore throat. Any patient taking ATDs who develops a fever or a sore throat should have an urgent white blood cell (WBC) count and differential performed, and the ATD should not be resumed until the results of the WBC count are obtained. Since ATD-related agranulocytosis occurs rapidly, routine monitoring of complete blood counts (CBCs)is not recommended. It is useful to check a pretreatment CBC, since WBCs are often depressed by Graves' disease itself. If agranulocytosis occurs, preparations for definitive therapy with radioactive iodine or surgery should be made because it is not recommended to rechallenge the patient with the other ATD due to cross-reactivity between drugs. Minor side effects, such as rash and urticaria, are relatively more common (1% to 5%). If acceptable to the patient, the medication can be safely continued and an antihistaminic may be added. Otherwise, one can replace one ATD for the other, realizing that cross-reactivity for minor side effects has also been reported.

[edit] Radioactive iodine treatment.

Radioactive iodine (RAI) in the form of¹³¹I is taken up by the thyroid gland and produces destruction of thyroid follicular cells. Use of RAI is recommended by many physicians, especially in the elderly. RAI is generally avoided in children and is contraindicated during pregnancy and breastfeeding. The dosage of¹³¹I to be administered is usually in the range of 5 to 10 mCi, with the dosage calculation based on thyroid size (80 to 120 μCi/gm tissue) and 24-hour RAIU. Administration of ATDs before radioiodine treatment is recommended to decrease thyroid hormone storage and prevent transient worsening of symptoms of hyperthyroidism or development of thyrotoxic storm. The ATDs should be stopped at least 3 to 5 days prior to the RAI treatment. About 75% of patients are rendered euthyroid after one dose of radioiodine. The rest of the patients require a second and rarely a third dose. RAI treatment often produces mild thyroidal pain, which may be managed by nonsteroidal antiinflammatory medications. In addition, the radiation thyroiditis that is produced after RAI therapy may result in transient worsening of the thyrotoxic state 7 to 14 days after treatment, especially if the patient has not been pretreated with ATDs. Supportive treatment with β-blockers is occasionally necessary for a short (2 to 3 weeks) period of time.

Normalization of thyroid function, including normalization of serum TSH, usually takes 1 to 2 months but may be delayed for up to a year. Retreatment should not be considered for at least 3 to 6 months after the initial treatment in order to document a treatment failure, except in extenuating circumstances. Permanent hypothyroidism is the major complication of radioactive iodine treatment. Hypothyroidism eventually develops in about 80% of the patients; therefore lifelong follow-up is warranted. Extensive studies involving over 5000 patients for up to 40 years have revealed no increase in the incidence of any malignancy after the RAI treatment for hypothyroidism. Radioiodine may cause exacerbation in Graves' ophthalmopathy, the risk of which may be reduced with the concomitant use of corticosteroids.

[edit] Surgery.

Subtotal thyroidectomy is reserved for the following conditions: (1) patients with large goiters, (2) children who are allergic to ATDs, (3) pregnant women (usually in the second trimester) who are allergic to ATDs, and (4) patients who prefer surgery over ATDs or RAI. Preparation of the patient before undergoing surgery involves depletion of the gland of thyroid hormone with ATDs and decreasing the vascularity of the gland with iodide administration (1 to 3 drops of super-saturated potassium iodide (SSKI) or Lugol's solution daily for 10 days). β-Adrenergic blockers alone have been used in some cases to prepare toxic patients for thyroidectomy.

The two most common complications from subtotal thyroidectomy are hoarseness due to recurrent laryngeal nerve damage and hypoparathyroidism. Complication rates in the hands of an experienced thyroid surgeon are low (less than 1%). Hyperthyroidism recurs in about 5% of patients and hypothyroidism develops in up to 60% of patients. RAI should be considered for surgically treated patients who relapse.

[edit] Adjuvant therapy.

Iodide inhibits synthesis and release of thyroid hormones, but its effect is transient and may result in eventual exacerbation of the hyperthyroid state if not administered concomitantly with ATDs. Iodide, in the form of Lugol's solution or SSKI (8 drops every 6 hours), is used in the treatment of thyroid storm and for preparation of patients for surgery. Iodinated contrast agents (e.g., iopanoic acid [Telepaque], 1 gm/day) have the additional advantage of inhibiting peripheral T₄ to T₃ conversion and may be used in the management of thyrotoxic crisis.

β-Adrenergic blockers and calcium channel blockers are useful drugs in the symptomatic treatment of hyperthyroidism and are quite effective in decreasing heart rate. Propranolol, 20 to 40 mg four times daily, or atenolol, 100 to 200 mg daily, is the usual starting dosage. Propranolol and esmolol can be given intravenously if needed. Diltiazem can be used for heart rate control if β-blockers are contraindicated. These drugs should be discontinued once the patient is euthyroid.

[edit] Toxic Multinodular Goiter.

Typically, toxic multinodular goiter presents in older patients who have longstanding asymptomatic nodular goiters. Administration of iodine-containing preparations, such as radiographic contrast media, amiodarone, or cough medicines, can precipitate hyperthyroidism in these patients. The onset of hyperthyroidism is more gradual and symptoms are usually milder than those of Graves' disease. Weight loss, atrial fibrillation, and depression are common presentations.

Physical examination usually reveals a large and firm goiter. Discrete nodules may be palpable. Lid lag can be observed, but infiltrative ophthalmopathy is absent. Borderline serum T₄ and T₃ levels and suppressed serum TSH concentrations are frequent. Radionuclide thyroid imaging is characterized by multiple functioning areas with suppression of other portions of the gland. Substernal thyroid extension may be detected. RAIU is usually elevated but may be normal.

Once hyperthyroidism occurs, it follows an unremitting course; therefore definitive treatment by ablation therapy is recommended. RAI is the treatment of choice in the elderly and large doses of¹³¹I are usually required. Surgical removal of the thyroid is advised in patients with large, compressive goiters. Subtotal thyroidectomy is commonly performed in these cases. ATDs are given to render the patient euthyroid before radioiodine treatment or surgery to avoid the precipitation of cardiac arrhythmias or thyrotoxic crisis in an unprepared patient. In contrast to Graves' disease, ATD treatment of the toxic multinodular goiter does not result in remission of the hyperthyroidism, and discontinuation of ATDs without ablative therapy will result in the return of the thyrotoxic state.

[edit] Autonomously Functioning Thyroid Nodules (AFTNs).

In this condition, hyperthyroidism is associated with a single thyroid nodule that functions independently of the normal thyroid regulatory axis. About 75% of patientswith functioning nodules are euthyroid at diagnosis, 20% are overtly hyperthyroid, and 5% are borderline thyrotoxic. AFTNs are more frequent in areas of iodine deficiency, such as Europe, than in the United States and account for 5% of all solitary nodules. In patients with euthyroid AFTNs, factors that increase the likelihood of developing thyrotoxicosis include (1) nodule size 3 cm or larger, (2) older age, and (3) serum T₃ levels in the upper normal range. Overall, about 20% to 25% of functioning nodules eventually become thyrotoxic.

A laboratory picture of T₃ toxicosis can be observed, since nodules secrete relatively more T₃ than T₄. Radionuclide thyroid imaging with either¹²³I or^99mTc shows a concentration of radioisotope in a single area corresponding to the nodule. There is partial or complete suppression of the rest of the thyroid gland.

In thyrotoxic patients treatment options and considerations are similar to those discussed for a toxic multinodular goiter. For those patients who are asymptomatic, observation and periodic thyroid function monitoring are reasonable, especially if the patient is young and healthy. In older patients and in those with preexisting medical conditions, such as cardiovascular disease, ablation treatment may be indicated.

[edit] Thyroiditis

[edit] Subacute Thyroiditis.

Subacute thyroiditis, the most common cause of the painful thyroid, is a self-limited inflammation of the thyroid, probably due to a viral infection of the gland. Transient thyrotoxicosis results from leakage of large quantities of stored thyroid hormones from the inflamed gland. The thyrotoxic phase lasts weeks to months and is followed by a euthyroid then a hypothyroid phase as the gland is depleted of hormone. Normal thyroid function recovers in 95% of patients within 6 to 12 months.

A prodromal upper respiratory tract illness is common. Typical symptoms include pain in the thyroid area with radiation to the ears or jaw, malaise, and low-grade fever. Thyrotoxicosis is present in ∼50% of patients. On physical examination a tender, mildly enlarged thyroid is characteristic. Acute hemorrhage into a thyroid nodule and suppurative thyroiditis can also cause a painful thyroid, but are less common. In addition to elevated serum thyroid hormone concentrations and suppressed serum TSH values in the toxic phase, an elevated erythrocyte sedimentation rate and a low RAIU are essential to confirm the diagnosis. Thyroid antibodies (antithyroglobulin and anti-TPO) are usually absent or only weakly positive. Although most patients are only mildly to moderately ill, subacute thyroiditis may have a dramatic presentation, with marked fever and severe thyrotoxicosis.

Treatment is aimed at the relief of symptoms. Aspirin or other nonsteroidal antiinflammatory agents are very effective for mild to moderate thyroid pain. Steroid administration (prednisone 20 to 40 mg/d) may be necessary for treatment of severe thyroid pain. Up to 20% of patients will have recurrence of pain on discontinuation of the steroids, which responds to the reinstitution of the drug. In general, steroids should be tapered over a 2 to 4 week period. Subacute thyroiditis rarely recurs. Control of the thyrotoxic symptoms can be achieved with β-adrenergic blockers, whilel-T₄ replacement may be indicated for relief of symptoms in the hypothyroid phase.

[edit] Postpartum and Painless Thyroiditis.

Postpartum and painless thyroiditis are also inflammatory thyroid disorders; in contrast to subacute thyroiditis, the thyroidal injury is immune-mediated. Postpartum thyroiditis is very common, affecting up to 20% of women in the postpartum period, usually within the first 4 months. Painless thyroiditis is much less common and can occur in both men and women.

Similar to subacute thyroiditis, inflammation and destruction of thyroid tissue results in the release of thyroid hormone, resulting in a thyrotoxic phase. As the gland becomes depleted, the thyrotoxicosis abates and a hypothyroid phase ensues, followed by restoration of normal thyroid function within 1 year. In general, one third of patients will demonstrate the classic biphasic pattern, one third will have only the thyrotoxic phase, and one third will present with only the hypothyroid phase. In contrast to subacute thyroiditis, the hypothyroid phase is permanent in up to 20% of patients and relapse of postpartum thyroiditis after subsequent pregnancies is common.

As in subacute thyroiditis, elevated serum thyroid hormone concentrations, suppressed serum TSH values, and a low RAIU are observed in the toxic phase. In contrast to subacute thyroiditis, thyroid antibodies (antithyroglobulin and anti-TPO) are usually present in high titer. Measurement of the serum thyroglobulin concentration is helpful to differentiate thyroiditis (high serum thyroglobulin concentrations) from surreptitious thyroid hormone administration (low serum thyroglobulin concentrations). Control of the thyrotoxic symptoms can be achieved with β-adrenergic blockers, whilel-T₄ replacement may be indicated for relief of symptoms in the hypothyroid phase in these self-limited disorders.l-T₄ replacement, if begun, should be discontinued after 6 to 9 months to determine if there has been recovery of thyroid function.

[edit] Rare Causes of Thyrotoxicosis (Box 97-7).

TSH- induced hyperthyroidism results from both tumoral and nontumoral TSH hypersecretion from the pituitary. In a hyperthyroid patient the finding of normal or high serum TSH concentrations in conjunction with elevated serum T₄ levels is the most distinctive feature of this disorder. Pituitary TSH-secreting tumors are usually macroadenomas and identifiable on MRI scan of the sellar region and require surgical excision. Although medical therapy is limited, octreotide, a long-acting somatostatin analog, has been successfully used as adjunctive therapy in these patients. Nontumoral pituitary TSH hypersecretion may be due to therare syndrome of thyroid hormone resistance. Thyrotoxicosis is seen in a subset of these patients with selective pituitary thyroid hormone resistance.

Trophoblastic tumors, either hydatidiform moles or choriocarcinomas, secrete human chorionic gonadotropin (hCG), which has weak TSH-like biologic activity. Very high concentrations of serum hCG, such as those detected in patients with these tumors, can result in hyperthyroidism. Therapy is aimed at either surgical removal of the tumor or appropriate chemotherapy. Differentiated follicular thyroid carcinoma, particularly if metastatic, is a rare cause of thyrotoxicosis. A whole-body¹³¹I scan shows increased uptake in thyroidal and extrathyroidal areas. High-dose radioiodine ablation treatment is warranted in these situations. Struma ovarii is a benign ovarian tumor that contains ectopic thyroid tissue. Very rarely this tumor produces enough thyroid hormone to cause thyrotoxicosis. Surgical removal of the tumor treats the thyrotoxicosis. Autosomal dominant nonautoimmune hyperthyroidism has been described in children, including newborns. It is caused by constitutively activating germline mutations in the TSH-receptor gene.

Thyrotoxicosis factitia results from the ingestion of large doses of thyroid hormone. The self-administration of thyroid hormones is often surreptitious. Occasionally accidental ingestions can occur, especially in children. Thyrotoxicosis may be clinically evident, but the thyroid gland is not enlarged. A low RAIU and a low serum thyroglobulin concentration are characteristic findings. Depending on the thyroid preparation ingested, either or both serum T₄ and T₃ concentrations are elevated.

[edit] Special Considerations

[edit] Hyperthyroidism in Pregnancy.

Thyrotoxicosis occurs in about 0.2% of pregnancies and is most frequently caused by Graves' disease. Physiologic changes that occur in pregnancy result in clinical features that resemble those of hyperthyroidism (i.e., increased heart rate, palpitations, heat intolerance, diaphoresis). Signs that are more specific to thyrotoxicosis include lid lag, tremor, and diffuse goiter. Weight gain during pregnancy may be inappropriately low.

High serum total T₄ and T₃ concentrations and low serum THBR values are characteristic findings in normal pregnancy and may obscure the diagnosis of thyrotoxicosis (see Box 97-3). As in the nonpregnant patient, thyrotoxicosis is confirmed biochemically with an elevated FTI, an elevated total T₃, and a suppressed TSH. Mild hyperthyroidism may be seen in association with hyperemesis gravidarum during or at the end of the first trimester. This is due to thyroidal stimulation from elevated serum hCG concentrations and rarely requires the institution of antithyroid therapy. The hyperthyroidism resolves as serum hCG concentrations fall.

RAIU and radioisotope imaging studies are contraindicated in the pregnant patient. ATDs are the treatment of choice. PTU is preferred over methimazole because of lower transplacental passage and extensive clinical experience with PTU in pregnancy. PTU dosage should be minimized to keep serum FTI in the upper half of the normal range. As pregnancy progresses, Graves' disease often improves. Indeed, it is not uncommon for patients to require daily PTU dosages of less than 100 mg or to be off all ATDs by the end of pregnancy. Therefore PTU dosage should be reduced and maternal thyroid function should be frequently monitored to decrease chances of fetal hypothyroidism. Relapse or worsening of Graves' disease is common after delivery, and patients should be monitored closely in the postpartum period.

If the pregnant woman is allergic to thionamides, subtotal thyroidectomy in the second trimester is recommended. As indicated above, RAI therapy is contraindicated because it can cause fetal hypothyroidism. Similarly, iodide administration is associated with fetal goiter and hypothyroidism and should be avoided. Since ATDs are transferred in small amounts to breast milk, the infant's thyroid function should be frequently monitored if nursing is desired.

Transplacental passage of maternal thyroid-stimulating immunoglobulins may result in fetal or neonatal hyperthyroidism. In the fetus, the diagnosis is based on increased fetal heart rate and hyperactivity. In this situation increased doses of ATDs may be advised and methimazole, with its higher degree of transplacental passage, may be preferable. Therapy is titrated based on the fetal heart rate. Neonatal Graves' disease occurs in 2% of the infants born to mothers with Graves' disease. Very high values of TSI (over 500% of controls) measured in the mother during the third trimester of pregnancy should alert the physician to the possibility of fetal and neonatal hyperthyroidism. ATDs and iopanoic acid (Telepaque) have been used to manage this disorder. Therapy is rarely required longer than 6 to 8 weeks.

[edit] Thyroid Storm.

Thyroid storm is an uncommon but life-threatening complication of thyrotoxicosis in which a severe form of the disease is usually precipitated by an intercurrent medical problem. It occurs in untreated or partially treated thyrotoxic patients. Precipitating factors associated with thyroid storm include infections, stress, trauma, thyroidal or nonthyroidal surgery, diabetic ketoacidosis, labor, heart disease, and RAI treatment (especially if there was no pretreatment with ATDs).

Clinical features are similar to those of thyrotoxicosis, but more exaggerated. Cardinal features include fever (temperature usually over 38.5°C) and tachycardia out of proportion to the fever. Nausea, vomiting, diarrhea, agitation, and confusion are frequent presentations. Coma and death may ensue in up to 20% of patients. Thyroid function abnormalities are similar to those found in uncomplicated hyperthyroidism. Therefore thyroid storm is primarily a clinical diagnosis.

Treatment includes supportive measures such as intravenous fluids, antipyretics, cooling blankets, and sedation. ATDs are given in large doses. PTU is preferred over methimazole due to its additional advantage of impairing peripheral conversion of T₄ to T₃. Recommended initial dose for PTU is 200 to 300 mg every 6 hours. PTU and methimazole can be administered by nasogastric tube or rectally if necessary. Neither of these preparations is available for parenteral administration.

Iodides, orally or intravenously, may be used only after ATDs have been administered. The radiographic contrast dye iopanoic acid (Telepaque), 1 gm daily, is used to block thyroid hormone release and to inhibit T₄ to T₃ conversion. β-Adrenergic blockers, such as propranolol (oral or IV) and esmolol (IV), are given for heart rate control. Calcium channel blockers may also be used to control tachyarrhythmias.High-dose dexamethasone (0.5 to 1 mg every 6 hours IV) is recommended both as supportive therapy and as an inhibitor of T₄ and T₃ conversion. Plasmapheresis has also been used in severe cases. Finally, treatment of the underlying precipitating illness is essential to survival in thyroid storm.

[edit] Subclinical Hyperthyroidism.

Subclinical hyperthyroidism is defined as TSH values in the subnormal or suppressed range, normal circulating thyroid hormone levels, and no specific signs of thyrotoxicosis. The prevalence of subnormal TSH concentrations varies depending on the patient population sample, ranging from 4% in an ambulatory setting to 30% in a hospitalized setting. The majority of the patients with subclinical hyperthyroidism are receiving exogenous thyroid hormone therapy. Endogenous subclinical hyperthyroidism is commonly associated with an autonomous nodular or multinodular goiter and, to a lesser degree, with early Graves' disease, thyroiditis, or an iodine load. Other causes of subnormal and suppressed TSH values that must be differentiated from subclinical hyperthyroidism include hypopituitarism and nonthyroidal illness (see below).

The slight increases in thyroid hormone production or intake that translate in the low serum TSH values seen in subclinical hyperthyroidism have been reported to have adverse effects on both the skeletal and the cardiovascular systems. As noted above, a significant reduction in bone mineral density, especially among postmenopausal women, has been reported in several studies in patients taking suppressive doses ofl-T₄. Adverse cardiac effects include arrhythmias, such as atrial fibrillation, and worsening of angina. Up to 10% of patients presenting with atrial fibrillation have suppressed serum TSH values, with up to 40% of these patients fitting the definition of subclinical hyperthyroidism.

Management of subclinical hyperthyroidism in patients receivingl-T₄ replacement therapy is straightforward. The dosage should be titrated to maintain a serum TSH value within the normal range. In patients taking suppressive doses ofl-T₄ for goiter reduction or thyroid cancer, in whom a low TSH is the goal of therapy, the administered dosage should be the lowest necessary to keep serum TSH concentrations in the target level.

Treatment of endogenous subclinical hyperthyroidism should be considered based on the individual situation. Factors such as age, preexisting medical conditions (i.e., coronary artery disease, osteoporosis, hypertension, arrhythmias), and the likelihood of becoming overtly hyperthyroid should be taken into account. A trial of ATDs to normalize the TSH is reasonable to determine if symptoms possibly related to subclinical hyperthyroidism may improve. RAI therapy may be the best option in patients with a multinodular goiter.

[edit] THYROID NODULES

Nodular thyroid disease is the most common endocrinopathy. The prevalence of clinically apparent nodules is 4% to 7% in the United States, with the frequency increasing throughout adult life. When ultrasound and autopsy data are included, the prevalence of thyroid nodules approaches 50% by age 60. As with other forms of thyroid disease, nodules are more frequent in women. Nodules have been estimated to develop at a rate of 0.1% per year. In individuals exposed to ionizing radiation, the rate of nodule development is twentyfold higher. Although the presence of a nodule raises the question of a malignancy, only 8% to 10% of patients with thyroid nodules have thyroid cancer. There are about 14,000 new cases of thyroid cancer diagnosed annually, with about 1000 deaths from the disease per year. However, many more people have clinically silent thyroid cancer: up to 35% of thyroids removed at autopsy or at surgery harbor a small (under 1 cm), clinically silent papillary cancer.

The mechanism underlying nodule growth and development in most cases remains unknown. Thyroid cancer is more frequent in patients exposed to ionizing radiation, such as radiation treatments for acne, tonsillitis, enlarged thymus, or cheloid scars or exposure to nuclear fallout (i.e., Chernobyl, Three Mile Island, Nevada atomic bomb tests). In the latter situation, the risk is highest in children exposed to nuclear fallout, with little increased risk observed in adults who were exposed. Nodules in general are more frequent in patients exposed to ionizing radiation, as are multiple nodules in a single exposed patient. In addition, nodules are more frequent in individuals residing in regions of endemic iodine deficiency.

The vast majority (over 90%) of thyroid nodules are benign lesions (Table 97-6). The most common benign nodule is the colloid, or adenomatous, nodule, followed by follicular adenomas. Thyroiditis is unusual in a solitary nodule but common in a multinodular gland. Of the malignant nodules, papillary cancer is most common, followed by follicular and then anaplastic carcinoma. Medullary carcinoma occurs most often over the age of 40, with about 20% of cases being associated with the familial multiple endocrine neoplasia type IIA (MEN IIA) and mutations in the RET proto-oncogene. Cysts make up 15% to 25% of all nodules and include simple cysts, hemorrhagic adenomas, parathyroid cysts, and necrotic papillary cancers. Rare causes of a solitary thyroid nodule include metastaticcarcinoma and fungal or parasitic infection in the immunocompromised patient.

Table 97-6 Differential Diagnosis of Thyroid Nodules

[edit] Patient Evaluation

Nodules that occur at the extremes of age are more likely to be malignant. Rapid growth and symptoms of local invasion (i.e., vocal cord paralysis, dysphagia) are poor prognostic signs, but few patients present with these symptoms. The most common presentation is that of a nodule discovered incidentally during a physical examination performed for other reasons. Once the nodule is discovered, the patient should be asked about symptoms of hyperthyroidism, exposure to radiation, and family history of medullary or papillary thyroid cancer or familial polyposis (Gardner's syndrome).

Physical examination should reveal nodules larger than 1 cm unless they lie deep in the neck. The physical characteristics may give clues as to the malignant potential of the nodule. However, a hard, firm nodule can be seen in Hashimoto's thyroiditis and a cystic papillary carcinoma may be soft and mobile. Cancers are more often found in patients with solitary nodules, although when examined by ultrasound or at surgery multiple nodules are found in up to two thirds of thyroid cancer patients. Most thyroid cancers metastasize locally, so the presence of suspicious lymph nodes in the cervical and supraclavicular regions should be noted.

[edit] Diagnosis

In the absence of signs of hyperthyroidism, thyroid function tests are usually normal. Serum TSH measurement is often the only test needed. Management principles are outlined in Box 97-8. If medullary carcinoma is suspected, serum calcitonin should be measured. Once a diagnosis of medullary carcinoma is confirmed, testing for mutations in the RET proto-oncogene should be performed to identify hereditary disease. Mutations in the RET proto-oncogene are present in 90% to 95% of hereditary disease and 25% of sporadic disease.

[edit] Fine-needle Aspiration Biopsy.

The most cost-effective initial test in the nontoxic patient with a thyroid nodule is fine-needle aspiration biopsy (FNAB), which is a safe and accurate method to diagnose the presence of a thyroid malignancy. Es