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Thyroid
Overview of Thyroid Disease
The thyroid gland synthesizes both T 4 and T 3 , which are essential for normal human growth and development and for normal physiologic function during adult life. Thyroid hormone levels are genetically set in each individual and are regulated by a negative feedback loop that allows for exquisite control. Disorders of thyroid hormone production, including both hypothyroidism and hyperthyroidism, have diverse causes, are exceedingly common, and present important therapeutic challenges for clinicians who are caring for these patients. Patients who have goiters can be hypothyroid, hyperthyroid, or euthyroid. Thyroid nodules, which have the potential to be malignant, are extremely common in the general population. A systematic approach is critical to discern which nodules must be evaluated further but also to avoid unnecessary therapy, including thyroid surgery.
Pathobiology
The thyroid gland is an essential endocrine organ whose principal function is to secrete two thyroid hormones: 3,5,3′,5′–l-tetraiodothyronine (also known as thyroxine or T 4 ) and 3,5,3′–l-triiodothyronine (also known as T 3 ) from thyroid follicular cells. The gland itself also contains parafollicular or C cells that produce the hormone calcitonin, which plays little role in normal human physiology but can be used pharmacologically to treat hypercalcemia. T 4 and T 3 are absolutely required for normal development of the human fetus, and lack of thyroid hormones either early in utero or immediately after birth has severe neurologic consequences. After birth, thyroid hormone is critical for normal growth and development through adulthood and is also responsible for the control of many aspects of normal physiologic function, including cardiac contractility and heart rate, free water clearance, and regulation of body weight and energy expenditure.
T 3 is the principal biologic congener of the thyroid hormones, whereas T 4 functions as a pro-hormone that is converted to T 3. The actions of T 3 are mediated by a family of thyroid hormone receptors that exert their actions primarily in the cell nucleus to regulate physiology by changing gene expression.
The thyroid gland develops in the first trimester of pregnancy from the anterior endoderm. Mutations in key transcription factors that are responsible for this development can lead to congenital hypothyroidism, which is found in 1 per 3500 births. Thyroid follicular cells, which are derived from embryonic stem cells, also can be derived from induced pluripotent stem cells. The thyroid gland weighs approximately 10 to 20 grams in adults and is shaped like a butterfly, with a right lobe and left lobe that are each approximately 4 cm in height and 2 cm in width with an isthmus that bridges the two lobes. In a small percentage of patients, a vestigial pyramidal lobe, which extends off either the right or left lobe, is a remnant of the embryonic tract of the gland from the pharynx to its position in the neck. Because of this tract, ectopic thyroid tissue can be located behind the tongue or anywhere in the neck region. Histologically the gland is composed of thyroid follicular cells, which organize themselves into follicular units that surround a colloid center. C cells, which derive through a separate process from pharyngeal ectoderm, are interspersed in between the thyroid follicular units and have a distinct histological appearance.
Thyroid Hormone Synthesis and Secretion
Thyroid hormones are the only iodinated proteins in humans, and their synthesis is dependent on the appropriate dietary intake of iodine (approximately 150 ug/day). In many regions of the world, iodine intake is below the threshold, thereby leading to thyroid growth, or goiter, as the gland is stimulated by the pituitary gland to try to compensate for the deficiency of thyroid hormone production. Circulating iodine is actively concentrated in the thyroid follicular cell by the sodium-iodide symporter, which is a 13-member transmembrane protein located at the junction between the circulation and the thyroid follicular cell. After iodine enters the cell, it moves to the apical membrane where it is effluxed into the colloid space by specific transporters. When it is out of the thyroid follicular cell, iodide is oxidized by the enzyme thyroid peroxidase, which requires the production of hydrogen peroxide in the colloid space. The oxidized iodide is then coupled to tyrosyl residues present on the 660-KD protein thyroglobulin. Specific residues on thyroglobulin can either be monodeiodinated or diiodinated, thereby allowing for the formation of T 4 or T 3 . When it is back in the thyroid follicular cell, the thyroglobulin backbone is lysosomally digested, and mature thyroid hormones are secreted into the blood stream. The human thyroid secretes T 4 and T 3 in a ratio of 14:1. Genetic defects in any of the key enzymatic processes (e.g., mutations in thyroid peroxidase) can lead to congenital hypothyroidism ( E-Fig. 207-1 ).
Thyroid Hormone Transport and Metabolism
Once secreted, circulating T 4 and T 3 are tightly bound to plasma proteins, especially thyroxine binding globulin. The ratio of T 4 to T 3 in the circulation is 60:1 because T 4 is more tightly bound to thyroxine binding globulin and thus has a longer half-life than T 3 (5 to 7 days compared with about 24 hours). To mediate their genomic effects, thyroid hormones first enter target cells via specific thyroid hormone transporters that are differentially expressed across cells. The most well known of these transporters is the monocarboxylate 8 transporter, which is mutated in Allen-Herndon Dudley syndrome, a rare X-linked neurologic syndrome of devastating consequences caused by the inability of thyroid hormones to cross the blood-brain barrier in utero. In addition to allowing the transport of thyroid hormones into cells, the monocarboxylate 8 transporter is also responsible for allowing T 4 to be secreted by the thyroid follicular cell into the circulation.
After thyroid hormones enter target cells, local T 3 availability is regulated by a family of deiodinases that can either activate T 4 to T 3 or inactivate T 4 to the inert reverse T 3 or inactivate T 3 to T 2 . The deiodinase family contains three members. Type 1 deiodinase is highly expressed in the liver, has both activating and inactivating properties, but preferentially converts T 4 to T 3 . Type 2 deiodinase, which also is an activating deiodinase, is highly expressed in the pituitary, central nervous system (CNS), and skeletal muscle. In contrast, type 3 deiodinase is an inactivating enzyme that is highly expressed during development in the CNS and in sensory organs ( E-Fig. 207-2 ).
Thyroid Hormone Set Points
Circulating levels of thyroid hormones are the tip of the iceberg, because variations in both transport and deiodination can substantially alter intracellular concentrations of T 3 . Nevertheless, the amount of circulating thyroid hormone is controlled tightly by the hypothalamic-pituitary thyroid axis, by which negative feedback of thyroid hormones determines the appropriate set point ( E-Fig. 207-3 ). In the paraventricular nucleus of the hypothalamus, the tripeptide thyrotropin-releasing hormone (TRH) is synthesized and released via the median eminence to the pituitary, where it targets pituitary thyrotropes to synthesize and release thyroid-stimulating hormone (TSH). TSH is released into the circulation, where it binds to its receptor on thyroid follicular cells to stimulate the production of thyroid hormone. Critically, circulating T 4 and T 3 feed back at the level of the hypothalamus to regulate the production of TRH and at the level of the pituitary to regulate the synthesis and secretion of TSH. In this way, TSH levels rise when thyroid hormone levels are low and are suppressed when thyroid hormone levels are high, thereby making TSH the most useful screening test for disorders of thyroid function. Importantly, TSH and thyroid hormone levels remain quite constant through a person’s lifetime, thereby suggesting a genetic set point for the thyroid axis.
T 3 engages its cognate nuclear receptors, which are members of the nuclear receptor family that includes receptors for vitamin D, estrogen, and androgen. All members of the family possess a modular structure that includes a DNA-binding domain and a specific ligand or hormone binding domain. The three thyroid hormone receptor isoforms have similar functions, but their actions differ based on where they are expressed. For example, TRβ2 is highly expressed in the hypothalamus and pituitary, where it controls the secretion of TSH, whereas TRβ1 is the principal isoform expressed in the liver, where it regulates the metabolism of cholesterol and fatty acids. In contrast, TRα1 is expressed in the heart, the gastrointestinal tract, and bone, where it is an important regulator of cardiac function, heart rate, intestinal motility, bone metabolism, and growth. Patients with TRβ mutations present with inappropriately high thyroid hormone levels because they cannot properly regulate the secretion of TSH. In contrast, patients with TRα mutations have a normal HPT axis but have issues with bone length and gastrointestinal motility, and they are relatively bradycardic.
Clinical Manifestations and Diagnosis
Patients with thyroid disease can present with symptoms or signs of hyperthyroidism, hypothyroidism, or a goiter. Oftentimes, however, the first manifestation is an abnormal thyroid function test or a palpable goiter or one or more thyroid nodules.
Physical Examination
Physical examination of the thyroid gland starts with an inspection of the appearance of the anterior neck for visible thyroid nodules, goiter, deviation, or lymphadenopathy. The patient should be seated or standing with the neck in a neutral position. The lower anterior neck between the cricoid cartilage and the suprasternal notch is then palpated using the fingertips, with the examiner standing either in front of or posterior to the patient. When using an anterior approach, all four fingers of the right hand are used to palpate the right thyroid lobe, whereas the left thyroid lobe should be palpated with the fingers of the left hand. The size and symmetry of the gland should be noted. A normal thyroid is symmetric, nontender, weighs 10 to 20 grams, has a soft (rather than rubbery or firm) texture, and should move upward with swallowing. The size, location, texture, tenderness, and mobility of any thyroid nodules should be determined, and the presence of cervical lymphadenopathy should be assessed. To gauge the presence of a substernal goiter in the setting of thyroid enlargement or when the inferior margins of the gland cannot be palpated, the patient should be asked to raise both arms with forearms against the side of the face. Substantial substernal extension of the thyroid will cause narrowing of the thoracic inlet when the goiter shifts upward, thereby resulting in the rapid development of facial plethora and distention of the neck veins. In some patients with a diffuse goiter from Graves disease, increased thyroid vascularity causes an audible bruit over the thyroid gland on auscultation.
Laboratory Testing
Serum TSH is a sensitive screening test for primary thyroid dysfunction and should be obtained in all patients who have symptoms or signs that are concerning for thyroid disease. The reference range for the serum TSH level is typically approximately 0.5 to 4.5 mIU/L, but it is lower (about 0.1 to 4.0 mIU/L) in early pregnancy. Serum TSH values also may increase somewhat with normal aging, but age-specific TSH reference ranges have not been defined. Serum TSH levels alone cannot be used to diagnose thyroid gland dysfunction in the presence of pituitary disease ( Chapter 205 ).
Although subtle shifts in thyroid function are better detected by serum TSH values than by levels of peripheral thyroid hormones, measurement of peripheral thyroid hormones is needed to determine the degree of thyroid dysfunction when the serum TSH level is abnormal. The vast majority (>99%) of circulating T 4 and T 3 is bound to thyroxine binding globulin (TBG) and other binding proteins, and it is only the tiny unbound (free) fraction that is bioactive. Commercial assays for free T 4 are reliable in most settings. However, accurate measurement of free T 3 , which is present at much lower levels, is challenging, so total T 3 levels are often used instead. Overt hypothyroidism is defined as an elevated serum TSH level with a low free T 4 level, and subclinical hypothyroidism is defined as an elevated serum TSH level with a normal free T 4 level.
Measurement of both T 3 and free T 4 is useful in the evaluation of potentially thyrotoxic patients. Overt hyperthyroidism is defined as a low serum TSH level with elevated peripheral thyroid hormone levels, whereas subclinical hyperthyroidism is defined as a low serum TSH level with normal peripheral hormone levels. In Graves disease and nodular autonomy, the thyroid gland often preferentially secretes T 3 , so the ratio of circulating T 3 : T 4 is higher (above 20:1) than in thyroiditis, where the lower T 3 : T 4 ratio reflects the ratio of hormones stored in the thyroid gland. However, a number of conditions and medications can interfere with the results of thyroid function tests ( Table 207-1 ).
TABLE 207-1
CAUSES OF SPURIOUS OR MISLEADING THYROID FUNCTION TESTS
| CAUSE | THYROID FUNCTION TEST EFFECT | |
|---|---|---|
| Laboratory artifacts | Biotin (in some assays, in patients taking biotin doses >100 mg/day) | Artifactually decreased TSH and increased free and total T 4 and T 3 . Results normalize after stopping biotin. supplements for 2-3 days. |
| Heterophile antibody | Artifactually increased TSH. No effect on T 4 or T 3 . Most assays incorporate blocking agents to eliminate this interference. | |
| Thyroid hormone autoantibody | Artifactually increased total and free T 4 and/or T 3 . No effect on TSH. If suspected, compare against measurements by equilibrium dialysis. | |
| Macro TSH (large bioinactive circulating form of TSH composed of TSH complexed with autoimmune anti-TSH antibodies) | Artifactually elevated TSH. No effect on T 4 or T 3 . If suspected, polyethylene glycol can be used in the laboratory to precipitate the macro TSH. | |
| Alterations in thyroid hormone binding | Increased thyroxine binding globulin levels
|
Elevated total, but not free, T 4 and T 3 levels. No effect on TSH. |
Increased binding to albumin
|
Elevated total and sometimes free T 4 . T 3 unaffected. No effect on TSH. | |
Decreased thyroxine binding globulin levels
|
Decreased total, but not free, T 4 and T 3 levels. No effect on TSH. | |
Competition with T 4 and T 3 Binding Sites on Thyroid Hormone Binding Proteins
|
Increased free T 4 and T 3 . No effect on TSH. | |
| Inhibition of 5′-deiodination (activation from T 4 to T 3 ) | Amiodarone | Slightly high total and free T 4 , slightly low total and free T 3 . No effect on TSH. |
T3 = triiodothyronine; T4 = thyroxine; TBG = thyroid-binding globulin; TSH = thyroid-stimulating hormone.
The presence of elevated TSH receptor stimulating antibody titers is highly sensitive and specific for the diagnosis of Graves disease. Elevated levels of serum thyroperoxidase and thyroglobulin antibody may be useful to confirm the diagnosis of autoimmune thyroiditis. Serum thyroglobulin is useful as a tumor marker for differentiated thyroid cancers, as is the serum calcitonin level for medullary thyroid cancer. The erythrocyte sedimentation rate is used in the diagnosis of subacute thyroiditis.
Imaging
Ultrasonography, which is the best imaging modality for evaluating thyroid structure, can’ determine the thyroid gland’s size and echotexture. For example, the thyroid gland has a distinctively heterogeneous echotexture in individuals who have autoimmune thyroiditis, whereas vascularity as assessed by Doppler ultrasonography is typically increased in Graves disease and absent in inflammatory thyroiditis. Ultrasonography also can characterize the size and location of thyroid nodules, as well as whether they are solid or cystic. Although thyroid malignancy usually cannot be diagnosed based on ultrasound alone, ultrasonographic risk stratification (based on the size, shape, echogenicity, and margins of the nodule, as well as the presence of microcalcifications) can guide decision making regarding the need for fine-needle aspiration biopsy. Ultrasound is also a sensitive tool for assessing cervical lymphadenopathy. Other forms of anatomic imaging, including computed tomographic (CT) scans and magnetic resonance imaging (MRI), are less frequently used to assess the thyroid gland, but they may be helpful in establishing the presence of a substernal goiter or determining whether a goiter is causing tracheal narrowing. Positron emission tomography ( 18 FDG-PET) scanning may be used to localize metastatic thyroid cancer.
Although radioactive iodine-123 (I 123 ) uptake scanning can differentiate among various causes of thyrotoxicosis (e.g., I 123 uptake is diffusely increased in Graves disease but is low or absent in inflammatory thyroiditis), highly sensitive and specific TSH receptor-stimulating antibody assays have largely replaced scanning for this indication. However, I 123 scanning is still used to distinguish among hyperfunctioning (“hot”), hypofunctioning (“cold”), or isofunctioning nodules. I 123 scans also are useful in patients with hyperthyroidism when the physical examination or ultrasound findings indicate the presence of thyroid nodularity. In addition, whole-body I 123 scans may be used in patients with thyroid cancer to identify recurrent or metastatic disease. Radioactive iodine scanning is not effective in the setting of a recent large iodine load (e.g., from exposure to iodinated contrast media) because the gland will already be saturated with non-radioactive iodine so the uptake of the I 123 will be low. In this setting, pertechnetate scanning is an alternative. The use of all thyroid scintigraphy is contraindicated during pregnancy.
Differential Diagnosis
The diagnosis of hypothyroidism ( Table 207-2 ), hyperthyroidism ( Table 207-3 ), or a thyroid nodule must prompt a search for the specific cause. Of note is that some conditions (e.g., various forms of thyroiditis) can cause transient hyperthyroidism followed by hypothyroidism. Goiters can be associated with hyperthyroidism (e.g., Graves disease, toxic multinodular goiter) or hypothyroidism (e.g., iodine deficiency) or be seen in euthyroid patients.
TABLE 207-2
CAUSES OF HYPOTHYROIDISM
| THYROID DESTRUCTION Autoimmune Post-radioactive iodine or external neck radiation Sclerosing (Reidel) thyroiditis †
MEDICATIONS
Hypothalamic disorders
|
∗ Can also cause transient hyperthyroidism before later causing hypothyroidism.
TABLE 207-3
CAUSES OF TRANSIENT OR SUSTAINED HYPERTHYROIDISM
| SUSTAINED HYPERTHYROIDISM |
| Primary Thyroid Disease |
| Graves disease † Toxic multinodular goiter † Thyroid adenoma † Functioning thyroid carcinoma † Struma ovarii McCune Albright syndrome |
| Secondary Thyroid Disease |
| TSH-secreting pituitary adenoma Tumors secreting human chorionic gonadotropin Ingestion of excess thyroid hormone, sometimes in dietary supplements |
| TRANSIENT HYPERTHYROIDISM |
| Gestational thyrotoxicosis Postpartum thyroiditis ∗ , † Sporadic painless thyroiditis ∗ , † Subacute (de Quervain thyroiditis) ∗ , † Iodine administration (Jod-Basedow phenomenon in the setting of a previously euthyroid multinodular goiter) † |
TSH = thyroid-stimulating hormone.
Hypothyroidism
Definition
Hypothyroidism refers to conditions in which levels of circulating thyroid hormones are lower than their genetic set point. Hypothyroidism can be classified as primary, when the function of the thyroid gland itself is impaired, or secondary (central), when an abnormality in the pituitary gland’s secretion of TSH prevents normal synthesis and secretion of thyroid hormones by the thyroid gland. Primary hypothyroidism is further classified into overt or subclinical hypothyroidism. In overt hypothyroidism, circulating levels of T 4 and T 3 are below normal laboratory cutoffs, the TSH level is usually above 20 mIU/L, and patients typically manifest some of the symptoms of hypothyroidism. In subclinical hypothyroidism, circulating T 4 and T 3 levels are within the normal range of the general population but, because they are lower than the individual’s targeted set point, lead to an elevation of the TSH level (usually less than 10 mIU/L but occasionally as high as 20 mIU/L). Importantly, patients with subclinical hypothyroidism are often identified by routine laboratory testing, not because of clinical symptoms.
Epidemiology
In the United States and Europe, the prevalence of hypothyroidism is about 5% in the general population, with the majority of cases being subclinical hypothyroidism. Additionally, most of the hypothyroidism is primary, with secondary hypothyroidism likely only comprising 1% of all cases. The incidence of hypothyroidism is much higher in women than in men, and the risk increases with age, with women over age 70 years at highest risk. The incidence of hypothyroidism is, not surprisingly, doubled in persons who have another autoimmune disease, given that the most common cause of hypothyroidism is autoimmunity. In the United States, the prevalence of hypothyroidism is highest in Whites and lowest in Blacks.
Pathobiology
In 1 per 3500 births, defects in the transcription factors needed for the development of thyroid follicular cells or in the transporters or enzymes needed for the synthesis of thyroid hormone cause congenital hypothyroidism and devastating neurological consequences. Iodine deficiency also can lead to profound hypothyroidism and severe developmental abnormalities, but iodine fortification of food, particularly salt, in most countries has dramatically reduced the prevalence of iodine deficiency.
The most frequent cause of failure of the thyroid gland is an autoimmune disease, Hashimoto thyroiditis, which can occur in isolation or in conjunction with other autoimmune conditions and as a component of polyglandular autoimmune syndromes ( Chapter 212 ). The use of immune checkpoint inhibitors and tyrosine kinase inhibitors also increases the incidence of autoimmune thyroid disease.
Hashimoto thyroiditis is characterized by a lymphocytic infiltration that is mediated by aberrantly activated T cells and by inflammation and fibrosis, which lead to failure of follicular units. Autoimmune thyroid disease is highly heritable, and gene variants in a variety of immunomodulatory genes lead to increased susceptibility. The T-cell immune attack on the thyroid also leads to the measurable production of antibodies directed against both thyroid-peroxidase and thyroglobulin. However, although the titer of these antibodies can be helpful in predicting the progression from mild to severe thyroid failure, these autoantibodies themselves do not appear to be the cause of Hashimoto thyroiditis because they can also be found in patients without thyroid dysfunction.
Another common cause of primary hypothyroidism (see Table 207-2 ) is thyroid surgery for thyroid nodular disease, cancer, or Graves disease. Even removal of only one lobe of the thyroid can lead to hypothyroidism in a small proportion of patients, especially in the presence of antithyroid-peroxidase or antithyroglobulin antibodies. The thyroid also can be damaged by parathyroid surgery or in other significant head and neck surgery procedures. Radioactive iodine therapy for Graves disease is a frequent cause of hypothyroidism, and external beam radiotherapy for head and neck cancer can also destroy the thyroid unless it is specifically protected.
Both painless and subacute thyroiditis can lead to permanent hypothyroidism. Rarer causes of primary hypothyroidism include infiltrative diseases such as Reidel thyroiditis, which is characterized by a fibrous infiltration of the thyroid gland, sometimes with extension to the recurrent laryngeal nerve or the parathyroid glands. Hemochromatosis ( Chapter 196 ) and amyloidosis ( Chapter 174 ) can cause primary hypothyroidism by infiltrating the thyroid gland.
Drugs can lead to hypothyroidism by affecting the synthesis of thyroid hormone. Amiodarone, which is likely the most common agent to affect the thyroid, can cause both hypothyroidism and thyrotoxicosis. Its induction of hypothyroidism is because the large amounts of iodine contained in the drug stimulate the gland reflexively to decrease the synthesis of thyroid hormone. Amiodarone-induced hypothyroidism can be permanent, especially in patients who have autoimmune thyroid disease. Additionally, amiodarone is an inhibitor of the type 1 deiodinase, so it decreases the conversion of T 4 to T 3 . Lithium therapy can also lead to hypothyroidism by affecting the synthesis and release of thyroid hormone.
Acquired secondary or central hypothyroidism (see Table 207-2 ) is most commonly due to a pituitary tumor, either a primary adenoma or metastatic tumor, that impairs the function of the pituitary cells that synthesize TSH. In these conditions, other pituitary hormones are also affected, so hypothyroidism is essentially always accompanied by hypogonadism and adrenal insufficiency ( Chapter 205 ). Tumors that invade the hypothalamus ( Chapter 204 ) can impair the release of TRH, impair the production of TSH, and thereby reduce the production of thyroid hormone. Infiltrative diseases such as sarcoidosis ( Chapter 83 ) can impair the hypothalamic-pituitary TSH-producing axis. Radiation therapy to the area can also lead to pituitary failure. The anticancer agent bexarotene is a retinoid that directly inhibits the synthesis of TSH and causes central hypothyroidism.
Clinical Manifestations
Overt hypothyroidism with frankly low thyroid hormone levels and subclinical hypothyroidism may be associated with few symptoms, and the diagnosis is often made by the appearance of a mildly elevated TSH on routine blood work. The clinical manifestations of hypothyroidism are nonspecific, highly variable, and most dependent upon the degree of decrease in the levels of circulating thyroid hormones. Overt hypothyroidism is characterized by symptoms of fatigue, lethargy, weight gain, a decrease in mental acuity, cold intolerance, hair loss, and dry skin in both men and women. Women can have menstrual irregularities, most commonly prolonged heavy menses. The disease can be present for a long period before diagnosis, and the appearance or recognition of new symptoms can be difficult.
The physical findings in hypothyroidism can be myriad and relate to the cause and degree of hypothyroidism. An elevated TSH level leads to an enlarged thyroid gland, except in some individuals with Hashimoto and Riedel thyroiditis, in which the gland may be small because of fibrosis. Bradycardia may be detected, and diastolic hypertension can be seen. Hypothermia usually is present only in severe hypothyroidism. Other classic signs of hypothyroidism include loss of the outer eyebrows and general hair loss or thinning. The skin may be dry and cool, and nonpitting edema may be present peripherally. Delayed return of deep tendon reflexes is considered the most sensitive clinical finding in hypothyroidism and is probably best assessed using the ankle jerk reflex. The nails may be brittle. In severe hypothyroidism, a pericardial effusion ( Chapter 62 ) can be present, so muffled heart sounds may be noted on the physical examination. Because of the chronic nature of the effusion, signs or symptoms of pericardial tamponade ( Chapter 62 ) are distinctly unusual.
If thyroid hormone levels are profoundly reduced for a long period of time or if patients experience a secondary systemic insult, significant hypothermia, hypotension, bradycardia, and profound neurologic manifestations, including coma, can be seen. This syndrome, which is termed myxedema coma, is a medical emergency.
In addition to abnormalities on thyroid function testing, hypothyroidism can be associated with other suggestive laboratory findings. Probably most sensitive is an unexplained elevation in the serum cholesterol level ( Chapter 190 ), and in particular the low-density lipoprotein (LDL) fraction, given the major role of thyroid hormone signaling in regulating cholesterol metabolism. Significant hypothyroidism can be associated with a macrocytic anemia ( Chapter 145 ), and hypothyroidism should be in the differential diagnosis whenever a patient has an elevated mean corpuscular volume. Hyponatremia ( Chapter 102 ) can also be seen because thyroid hormones are needed for free water clearance. The muscle dysfunction of hypothyroidism may be associated with otherwise unexplained elevations in serum levels of creatine kinase and aspartate aminotransferase.
Diagnosis
The biochemical diagnosis of primary hypothyroidism is heralded by a TSH level that is above the laboratory’s normal range, which is usually greater than 4.5 mU/L. An elevated TSH level always warrants measurement of circulating thyroid hormone levels, especially a free T 4 level ( Fig. 207-1 ). Rarely, both the TSH and the free T 4 are elevated, thereby suggesting either peripheral resistance to thyroid hormone or a TSH-secreting pituitary tumor. If the TSH is only mildly elevated (between 4.5 and 20 mU/L), the free T 4 can be within the normal limits, and the diagnosis is subclinical hypothyroidism. If the TSH level is elevated and the free T 4 level is low, the diagnosis is almost always overt primary hypothyroidism.
Once the biochemical diagnosis of primary subclinical hypothyroidism or overt hypothyroidism is made, the physical examination often can establish a presumptive diagnosis. Primary hypothyroidism should be considered in patients who have another autoimmune disease. The thyroid gland may be either enlarged or nonpalpable in Hashimoto thyroiditis, which is the most common cause. Antithyroid peroxidase or antithyroglobulin antibodies can often confirm the diagnosis of Hashimoto thyroiditis, but they are not positive in all cases. Higher titers of antithyroid peroxidase or antithyroglobulin antibodies often may be helpful in predicting which cases of subclinical hypothyroidism will progress to overt hypothyroidism. By comparison, iodine deficiency is associated with a palpable goiter.
The classic finding in secondary hypothyroidism is a low, normal, or just mildly elevated TSH level despite low circulating levels of free T 4 . If such patients have no history of a mass, surgery, or radiation therapy to the area of the hypothalamus or pituitary gland, it is reasonable to obtain a pituitary MRI and to measure other hormone levels.
Treatment
Overt Hypothyroidism
l -Thyroxine (which is available in tablets of 25 μg, 50 μg, 75 μg, 88 μg, 100 μg, 112 μg, 125 μg, 137 μg, 150 μg, 175 μg, 200 μg, and 300 μg) is typically prescribed because its long half-life allows for stable dosing and a constant supply of T 4 , which can then be converted to T 3 within the circulation and in target cells. Combination T 4 /T 3 therapy more closely simulates normal physiology, but current guidelines recommend against its use.
The goal of therapy in primary hypothyroidism is to return the TSH level to the normal range, unless TSH should be suppressed, as in aggressive thyroid cancers. The average required dose of l -thyroxine is 1.6 ug/kg. A major concern is that the bioavailability of l -thyroxine varies among formulations, so patients should try to remain on the same formulation if possible. If the formulation is switched, a TSH level should be evaluated 6 weeks after the change. l -Thyroxine should be taken on an empty stomach, because it is absorbed in the small intestine, where food may impair absorption. A number of other medications ( Table 207-4 ), including iron tablets and calcium carbonate, can impair the absorption of l -thyroxine, so a spacing of a few hours is recommended between l -thyroxine and any of these medications. Very rarely, l -thyroxine can be malabsorbed, but the usual explanation for a poor response is nonadherence.
TABLE 207-4
INTERFERENCE WITH THYROXINE REPLACEMENT THERAPY
| FACTORS CONTRIBUTING TO UNDERREPLACEMENT |
| Inadequate prescribed dose Limited compliance Decreased absorption due to ingestion of agents that bind thyroxine
Increased metabolism of thyroxine
Diminishing residual thyroid function |
| FACTORS CONTRIBUTING TO OVERREPLACEMENT |
| Excessive prescribed dose Factitious ingestion of additional doses Decreased metabolism of thyroxine due to aging Increasing residual thyroid function Changing formulations |
l -Thyroxine dosing can usually be begun at the predicted weight-based dose, with its effectiveness assessed by changes in clinical signs and symptoms, and by measuring the TSH level no earlier than the interval required for it to reach its new steady state (5 weeks after beginning the medication or after a change in dose). Aging is associated with a decreased l -thyroxine requirement, probably due to decreased tissue demand both centrally and peripherally. In patients in whom an increase in energy expenditure or demand could cause issues, in particular in older patients or in patients who have significant coronary artery disease, a smaller starting dose (i.e., 25 μg) should be chosen, and careful up-titration can be undertaken with changes to the dose every 6 weeks.
The most common problem with l -thyroxine is over-replacement that leads to mild hyperthyroidism with a suppressed TSH level. In patients who have secondary hypothyroidism and in whom the TSH level cannot be used as a measure of efficacy, a reasonable practice is to titrate the dose based on the free T 4 and aim for it to be in the upper half of the normal range.
Combination T 4 /T 3 Therapy
Although the vast majority of patients treated with l -thyroxine do well, up to 15% of patients experience persistent symptoms of hypothyroidism despite normal TSH levels. Because the thyroid gland secretes both T 4 and T 3 and because l -thyroxine monotherapy results in low T 3 levels, some patients may have cellular hypothyroidism despite a normal TSH level. Although more than a dozen randomized trials have failed to show a benefit of combination therapy compared with l -thyroxine monotherapy, uncertainty persists regarding the potential benefit of combination therapy specifically in patients who are dissatisfied with monotherapy, especially if T 3 and T 4 are administered in their ideal physiologic ratios. If combination therapy is used, the dose of l -thyroxine should be decreased and replaced by 2.5 to 10 μg of T 3 daily, ideally given as a divided dose twice daily.
Subclinical Hypothyroidism
Although the treatment of overt hypothyroidism with l -thyroxine is clearly beneficial, the benefit of treatment is uncertain in patients who have mildly elevated TSH levels but a normal free T 4 level. For example, the treatment of subclinical hypothyroidism does not improve symptoms or quality of life in persons over age 65 years. In large population-based studies, however, l -thyroxine appears to be beneficial if the TSH level is above 10 mU/L, perhaps in part because it lowers LDL cholesterol levels. One approach is to defer treatment and recheck the TSH and free T 4 levels annually. Another is to treat individuals who have TSH levels greater than 10 mU/L or have elevated serum LDL cholesterol levels. A third approach is to treat individuals whose TSH level is in the 5 to 10 mIU/L range if they have symptoms potentially attributable to hypothyroidism or elevated titers of thyroid peroxidase antibodies.
Myxedema Coma
Because of the high mortality associated with myxedema coma, treatment with parental l -thyroxine is imperative. The usual approach is an intravenous loading dose of 200 to 300 μg followed by 1.6 μg/kg intravenously every 24 hours. Since the conversion of T 4 to T 3 may be impaired, parenteral T 3 (5 to 10 μg T 3 every 8 to 12 hours) may be added until clinical improvement is seen. High-dose glucocorticoids (100 mg of hydrocortisone every 6 hours until adrenal insufficiency is excluded) are usually added prior to starting l -thyroxine because of the concern of associated adrenal insufficiency. Hypothermia should be treated with passive rather than active rewarming to prevent further hypotension.
Pregnancy
The required dose of l -thyroxine increases during pregnancy ( Chapter 221 ) because of an increase in thyroxine binding globulin, fetal demand (especially during the first trimester), and placental metabolism of thyroid hormones. In euthyroid pregnant patients, human chorionic gonadotropin acts as a TSH receptor stimulator and allows the endogenous thyroid to increase production of thyroid hormones. If the pregnant patient has no thyroid reserve (i.e., a surgically removed thyroid gland), then a dose adjustment of up to 33 to 50% of the baseline dose may be required. If partial thyroid reserve is present (i.e., some patients with Hashimoto thyroiditis), a dose increase of 25% may be necessary. Because undetected hypothyroidism in early pregnancy has been linked to poorer fetal neurologic outcomes, it is important to increase the l -thyroxine dose as soon as pregnancy is confirmed. A simple approach is to increase the thyroxine dose from 7 tablets to 9 tablets weekly (i.e., add a second tablet on two of the days of the week). The TSH level can be evaluated 3 weeks later to ensure that it is in the target range (<2.5 mIU/L during gestation) and should be monitored every 4 weeks until mid-gestation.
Prognosis
Treatment of hypothyroidism with l -thyroxine is highly effective. Once an ideal dose is found and the TSH level is normalized, patients can be followed annually with a TSH level to ensure stability. Patients should be counseled continually regarding taking their l -thyroxine on an empty stomach and being aware of other medications that can impair its absorption. Additionally, women who are considering pregnancy must know to contact their physician to increase their l -thyroxine dose and be monitored closely as soon as they know they are pregnant.
Hyperthyroidism
Definition
Hyperthyroidism is a clinical syndrome in which circulating thyroid hormone levels are either frankly elevated, and thereby suppress TSH levels, or are within the normal range but are too high for that person’s set point, thereby at least partially suppressing TSH levels. The latter syndrome is termed subclinical hyperthyroidism. The degree of signs and symptoms depend on the cause of the hyperthyroidism as well as on the levels of circulating T 4 and T 3 . Importantly, hyperthyroidism includes all syndromes related to the endogenous overproduction of thyroid hormone by the thyroid gland, whereas thyrotoxicosis includes all causes of elevated thyroid hormone levels.
Epidemiology
The prevalence of hyperthyroidism is 1 to 2% in women and 0.1 to 0.2% in men, including both overt and subclinical hyperthyroidism. In younger populations (ages 12 to 49 years), the prevalence of hyperthyroidism is higher in Black persons as compared with White or Hispanic persons. Graves disease, which is the most common cause of hyperthyroidism, is four-fold more common in women. Its environmental triggers may include iodine, smoking, stress, and potentially infection because epitopes on Yersinia enterolitica ( Chapter 288 ) overlap with that of the TSH receptor. Additionally, drugs (e.g., interferon-α and immune checkpoint inhibitors) and the recovery from lymphopenia seen in immune reconstitution inflammatory syndrome ( Chapter 357 ) can lead to Graves disease. Genetic predisposition is limited to autoimmune susceptibility genes. Long-standing iodine deficiency is associated with higher rates of toxic nodular goiter.
Pathobiology
Thyrotoxicosis can result from the overproduction and release of thyroid hormones directly from the gland itself, from an ectopic source, or from exogenous ingestion of thyroid hormone (see Table 207-3 ). The release of thyroid hormones from the gland itself can be due to intrinsic synthesis of excess thyroid hormone independent of TSH stimulation, excess release of stored hormone from the thyroid gland because of inflammatory thyroiditis, excess TSH, or the stimulation of the thyroid gland by substances other than TSH, as occurs during pregnancy when elevated levels of human chorionic gonadotropin bind to the TSH receptor on the follicular cell.
Graves disease is caused when a circulating antibody binds to and activates the TSH receptor, thereby leading to growth of the gland and overproduction of T 4 and T 3 . These antibodies can also target antigens behind the eye and in skin, thereby leading to ophthalmopathy and pretibial myxedema. In addition to thyrotropin receptor autoantibodies, many patients with Graves disease will also have antithyroid peroxidase and antithyroglobulin antibodies, thereby indicating an overlap in immune dysregulation between Graves and Hashimoto diseases.
During pregnancy, the human chorionic gonadotropin–mediated rise in thyroid hormone levels in the first trimester is necessary to meet fetal demand and to maintain stable levels of free thyroid hormones in the setting of excess thyroxine-binding globulin. A potential side effect, however, is that excess thyroid stimulation, especially coincident with hyperemesis gravidarum, can lead to significant clinical hyperthyroidism ( Chapter 221 ).
Thyroid nodular disease can also lead to hyperthyroidism. Solitary nodules can have mutations in the TSH receptor or its downstream components, thereby leading to constitutive activation, nodular growth, and hyperthyroidism. A multinodular gland can also cause hyperthyroidism, especially in the presence of excess iodine, which often results from the use of contrast agents or amiodarone. Finally, rare TSH-producing pituitary adenomas can lead to hyperthyroidism with a TSH level that is inappropriately normal or elevated.
Exogenous causes of thyrotoxicosis include ectopic production of T 4 and T 3 in rare ovarian teratomas (termed struma ovarii) or from widely metastatic follicular thyroid carcinoma. Most commonly, however, exogenous thyrotoxicosis is secondary to over-replacement with thyroid hormone preparations or the ingestion of food (e.g., hamburger thyrotoxicosis from improperly processed meat) or supplements that contain excessive thyroid hormones.
The symptoms and signs of hyperthyroidism are directly attributable to the effects of thyroid hormones on target cells via their genomic and nongenomic actions, including activation of the sympathetic nervous system, the cardiovascular system, and the systems that regulate energy expenditure. Thyroid hormones likely activate pathways that mediate activation of the adrenergic response. Thyroid hormones also have a catabolic effect on muscle.
Clinical Manifestations
The clinical presentation of hyperthyroidism depends on both the level of circulating thyroid hormones and the duration of the hyperthyroidism. In mild subclinical hyperthyroidism, patients may have no clinical symptoms, whereas patients with florid Graves disease may develop hemodynamic crisis and even death, often termed thyroid storm. In general, the clinical signs and symptoms of hyperthyroidism are more apparent in younger patients, whereas elderly patients may have “apathetic” hyperthyroidism without classic hyperadrenergic symptoms.
Patients with significant hyperthyroidism often report heat intolerance, weight loss despite a vigorous appetite, palpitations, and a tremor, which may manifest as difficulty with fine motor control, including handwriting. Additional symptoms can include emotional lability, enhanced gastrointestinal motility, diarrhea, and muscle weakness. General signs on physical examination include the presence of tachycardia or atrial arrhythmias, systolic hypertension, a stare and lid lag (when the eye lags behind the upper lid on movement up or down) due to activation of sympathetic tone, tremor, and proximal muscle weakness.
Specific signs that can suggest the cause of hyperthyroidism include thyroid enlargement (goiter), which is diffuse in Graves disease but also can be due to an autonomously functioning single large nodule or multiple nodules. The diffuse enlargement in Graves disease can also be associated with a systolic bruit heard directly over the gland with the bell of the stethoscope. Although all causes of hyperthyroidism can cause lid lag, specific bulging or inflammation around the eyes is distinctive of Graves ophthalmopathy ( Fig. 207-2 ). Similarly, peripheral nonpitting edema or redness on the extensor surfaces of the shins is consistent with pretibial myxedema that is specific to Graves disease. Rarely, clubbing of the nails ( Fig. 39-9 ) and swelling of the distal digits of the hands, termed thyroid acropachy, can also be seen with Graves disease.
Diagnosis
Thyroid function testing makes or excludes the diagnosis ( Fig. 207-3 ). In overt hyperthyroidism, both circulating T 4 and T 3 levels will be frankly elevated, whereas the TSH level is completely suppressed. In subclinical hyperthyroidism, circulating T 4 and T 3 levels will be within the normal range, while the TSH level is either fully or partially suppressed. In women of childbearing age, a pregnancy test should be performed to exclude pregnancy-induced hyperthyroidism ( Chapter 221 ).
The absolute levels of total T 4 and total T 3 can also be helpful. For example, Graves disease and nodular thyroid disease are likely to have a T 3 : T 4 ratio of over 20 : 1, whereas the ratio will be less in thyroiditis.
The diagnosis of Graves disease can be confirmed by directly measuring TSH-receptor antibody levels. The uptake of radioactive iodine is useful when the cause of hyperthyroidism otherwise cannot be discerned ( Table 207-5 ). Since the uptake of iodine into the thyroid gland is entirely regulated by TSH, the uptake of radioactive iodine in the thyroid should be close to zero when the TSH level is suppressed, as in thyroiditis or an exogenous or ectopic source of thyroid hormone. In contrast, the uptake of radioactive iodine will be diffusely inappropriately normal or elevated in Graves disease and focally increased in nodular causes of hyperthyroidism, including multinodular goiter and single autonomous nodules. A radioactive iodine scan is unlikely to be helpful in the presence of excess nonradioactive iodine, such as with the administration of amiodarone. Technetium scanning also can show diffuse excess uptake in Graves disease and focal uptake in nodular hyperthyroidism. Thyroid ultrasound can confirm the presence or absence of thyroid nodules and, using Doppler, identify a relative increase in blood flow, which is suggestive of Graves disease and nodular forms of hyperthyroidism.
TABLE 207-5
RADIOGRAPHIC EVALUATION OF SUSPECTED THYROTOXICOSIS
From Jonklaas J, Cooper DS. Thyroid. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine , 26th ed. Philadelphia: Elsevier; 2020:1462-1476.
| ETIOLOGY | FRACTIONAL 24-HOUR RADIOIODINE UPTAKE (%) | THYROID SCAN APPEARANCE |
|---|---|---|
| Graves disease | 35-95 | Diffuse increased homogeneous uptake; visible pyramidal lobe extending from isthmus |
| Toxic adenoma | 20-60 | Solitary focus of intense uptake; suppression of uptake in remainder of thyroid |
| Toxic multinodular goiter | 20-60 | Patchy heterogeneous foci of increased uptake interspersed with regions of diminished uptake |
| Subacute thyroiditis | 0-2 | Minimal to absent uptake |
| Autoimmune thyroiditis | 0-2 | Minimal to absent uptake; patchy heterogeneous uptake during recovery |
| Iodine-induced hyperthyroidism | 0-2 | Minimal to absent uptake |
| Exogenous thyroid hormone intoxication | 0-2 | Minimal to absent uptake |
| Metastatic differentiated thyroid cancer | 0-5 | Focal uptake in metastases |
| TSH-secreting pituitary adenoma | 30-80 | Diffuse increased homogeneous uptake |
TSH = thyroid-stimulating hormone.
Laboratory abnormalities associated with hyperthyroidism include elevated liver aminotransferase levels, because excess thyroid hormone signaling increases hepatocyte stress. The alkaline phosphatase level can also be elevated, likely reflecting bone resorption caused by excess thyroid hormones. The serum calcium level can be mildly elevated, sometimes associated with hypercalciuria and even nephrolithiasis ( Chapter 111 ). Graves disease also can present with neutropenia and a lymphocytosis. Because antithyroid drugs used to treat hyperthyroidism can also cause neutropenia and abnormalities in liver enzymes, baseline values should be obtained before starting treatment.
Treatment
The treatment of hyperthyroidism ( Table 207-6 ) depends on its underlying cause and severity. However, the basic approach is similar for all causes.
TABLE 207-6
TREATMENT OF GRAVES DISEASE
Adapted from Jonklaas J, Cooper DS. Thyroid. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine , 26th ed. Philadelphia: Elsevier; 2020:1462-1476.
| TREATMENT | OUTCOME |
|---|---|
| Antithyroid drugs: methimazole, propylthiouracil | About 50% remission rate; hypothyroidism unusual |
| Radioactive iodine ( 131 I) | About 75 to 90% cure rate (euthyroid or hypothyroid) after one dose; up to 80% risk of hypothyroidism at 1 year |
| Surgical total thyroidectomy | Definitive cure and universal hypothyroidism, except in very rare cases of ectopic thyroid tissue |
If thyroid hormones are being overproduced by the gland because of Graves disease or other causes, treatment must inhibit the synthesis of thyroid hormone (by removing the gland surgically, by inactivating it biologically with radioactive iodine or antithyroid drugs) potentially coupled with β-adrenergic antagonists to block the peripheral actions of the thyroid hormone if the clinical symptoms are significant. In contrast, if the problem is over-release of preformed thyroid hormone because of damage to the gland, then the only focus should be blocking the actions of thyroid hormones ( Fig. 207-4 ).
Blocking Thyroid Hormone Action
Symptomatic control of the hyperadrenergic and cardiovascular symptoms (e.g., tremor, tachycardia, and the ventricular response rate of atrial fibrillation) of hyperthyroidism can be achieved quickly with nonselective β-blockade. The preferred β-blocker is propranolol, which inhibits type 1 deiodinase and can reduce serum T 3 by 20% at a daily dose of 80 mg. The usual starting dose of propranolol is 20 mg every 6 to 8 hours, depending on the severity of the hyperthyroidism, titrated upwards to a maximum of 240 mg over 24 hours. If propranolol is a concern or causes complications in patients with asthma or chronic obstructive lung disease, selective β-blockers (e.g., atenolol [25 to 50 mg] or metoprolol [25 to 50 mg]) can be used; these drugs do not block the activity of type 1 deiodinase but nevertheless are efficacious for treating the clinical symptoms of thyrotoxicosis.
Reducing Thyroid Hormone Levels
Antithyroid Drugs
The thionamides, methimazole and propylthiouracil, block the activity of thyroid peroxidase and, as a result, the synthesis of thyroid hormone. They may also have immunosuppressive effects, thereby blunting the autoimmune process itself. Propylthiouracil also inhibits the activation of type 1 deiodinase.
Methimazole is the recommended agent of choice for hyperthyroidism except for thyroid storm, when T 3 levels must be lowered quickly, or the first trimester of pregnancy. The usual starting dose is 20 to 30 mg given either once a day or divided into two doses. Propylthiouracil must be given two to three times per day, and 400 mg of propylthiouracil is equivalent to 30 mg of methimazole.
About 1 to 5% of patients on either medication develop a rash or urticaria, which can be treated with the use of an antihistamine (e.g., diphenhydramine 25 to 50 mg) or by switching to the other drug. More rare (about 1/1000 with either drug) is agranulocytosis, which can be idiosyncratic but is more likely in the first few months of therapy, especially in older patients and with higher doses. Monitoring of the neutrophil count is not useful because of the rapidity of onset of the process, so patients should be instructed to stop the drug and call their physician immediately if they develop fever, sore throat, or any other symptoms suggestive of infection. Recovery from the neutropenia is usual, but severe infections may require hospitalization, broad-spectrum antibiotics ( Chapter 260 ), and the administration of growth factors ( Chapter 153 ) to stimulate white cell growth. If this side effect does occur, neither drug can ever be given again. Another rare but serious side effect is fulminant hepatic necrosis, which is seen primarily with propylthiouracil and is a common cause of drug-related liver failure ( Chapter 136 ). Methimazole also can cause a drug-induced hepatitis or, more commonly, cholestasis.
Treatment with methimazole or propylthiouracil will usually lower the T 4 and T 3 levels to normal within 4 to 6 weeks. As the T 4 and T 3 levels fall toward normal, their dose can be titrated down to maintain euthyroidism. The TSH level cannot be used to follow the regression of hyperthyroidism because it may remain suppressed for weeks even after T 4 and T 3 levels fall into the normal range.
In Graves disease, medical antithyroid drug therapy can induce a remission and restore the euthyroid state. If therapy for 12 to 18 months results in normalization of thyrotropin receptor autoantibody levels, remission is likely and medical therapy can be discontinued. If thyrotropin receptor autoantibody levels remain elevated, however, more definitive therapy with radioactive iodine or surgery can be pursued, although another option is to continue medical therapy for several years to see if thyrotropin receptor autoantibody levels eventually return to normal.
Iodine and Other Agents
Supraphysiologic doses of iodine are usually used only after starting antithyroid drug therapy in patients who have severe thyrotoxicosis, but they also can be utilized alone in patients who are intolerant to antithyroid drugs. Iodine is administered as a saturated solution of potassium iodide (SSKI) or as Lugol solution. Lithium also blocks thyroid hormone release and can be utilized short term to control hyperthyroidism in patients intolerant to antithyroid drugs and iodine. Cholestyramine enhances the metabolism of T 4 by the liver and can effectively lower thyroid hormone levels in severe cases.
Radioactive Iodine Therapy
Radioactive iodine kills follicular cells, thereby reducing or eliminating the production of thyroid hormone. Radioactive iodine is highly effective in the treatment of Graves disease, autonomous hyperfunctioning thyroid nodules, and toxic multinodular goiters. The goal of radioactive iodine therapy is to ablate the thyroid gland and cause hypothyroidism. For Graves disease, radioactive iodine ameliorates hyperthyroidism in 90% of patients within 6 months but may increase the risk of cancer slightly. Radioactive iodine may worsen Graves ophthalmopathy and is contraindicated in patients who have significant Graves ophthalmopathy unless patients receive concomitant high doses of corticosteroid therapy for 4 to 6 weeks after the administration of radioactive iodine. Radioactive iodine treatment also may cause radiation thyroiditis and induce the release of preformed thyroid hormone, thereby transiently worsening hyperthyroidism. Pretreatment with an antithyroid drug, to deplete the gland of stored thyroid hormone and prevent radiation thyroiditis, for 5 to 6 weeks prior to the administration of radioactive iodine can be helpful in patients who have significant hyperthyroidism, who are elderly, or who are at risk of decompensation with continued hyperthyroidism (e.g., patients with cardiovascular disease). If given, antithyroid drugs should be discontinued 5 days prior to giving radioiodine so that its uptake will not be impacted.
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