Basic and Clinical Endocrinology 7th International student edition Edition


The Thyroid Gland

Francis S. Greenspan MD

The thyroid gland is the largest organ specialized for endocrine function in the human body. The major function of the thyroid follicular cells is to secrete a sufficient amount of thyroid hormones, primarily 3,5,3′,5′-l-tetraiodothyronine (T4), and a lesser quantity of 3,5,3′-l-triiodothyronine (T3). Thyroid hormones promote normal growth and development and regulate a number of homeostatic functions, including energy and heat production. In addition, the parafollicular cells of the human thyroid gland secrete calcitonin, which is important in calcium homeostasis (Chapter 8).


The thyroid gland originates as an outpouching in the floor of the pharynx, which grows downward anterior to the trachea, bifurcates, and forms a series of cellular cords. These form tiny balls or follicles and develop into the two lateral lobes of the thyroid connected by a thin isthmus. The origin of the gland at the base of the tongue is evident as the foramen cecum. The course of its downward migration is marked by the thyroglossal duct, remnants of which may persist in adult life as thyroglossal duct cysts. These are mucus-filled cysts, lined with squamous epithelium, and are usually found in the anterior neck between the thyroid cartilage and the base of the tongue. A remnant of the caudal end of the thyroglossal duct is found in the pyramidal lobe, attached to the isthmus of the gland (Figure 7-1).

The isthmus of the thyroid gland is located just below the cricoid cartilage, midway between the apex of the thyroid cartilage (“Adam's apple”) and the suprasternal notch. Each lobe is pear-shaped and measures about 2.5–4 cm in length, 1.5–2 cm in width, and 1–1.5 cm in thickness. The weight of the gland in the normal individual, as determined by ultrasonic examination, varies depending on dietary iodine intake, age, and body weight but in adults is approximately 10–20 g. Upward growth of the thyroid gland is limited by the attachment of the sternothyroid muscle to the thyroid cartilage; however, posterior and downward growth is unhampered, so that thyroid enlargement, or goiter, will frequently extend posteriorly and inferiorly or even substernally.

Transverse section of the neck at the level of the thyroid isthmus shows the relationships of the thyroid gland to the trachea, esophagus, carotid artery, and jugular vein (Figure 7-2). Ultrasonography, CT scans, or MRI reveals these relationships in vivo.

The thyroid gland has a rich blood supply (Figure 7-3). The superior thyroid artery arises from the common or external carotid artery, the inferior thyroid artery from the thyrocervical trunk of the subclavian artery, and the small thyroid ima artery from the brachiocephalic artery at the aortic arch. Venous drainage is via multiple surface veins coalescing into superior, lateral, and inferior thyroid veins. The blood flow to the thyroid gland is about 5 mL/g/min; in hyperthyroidism, the blood flow to the gland is markedly increased, and a whistling sound, or bruit, may be heard over the lower poles of the gland and may even be felt in the same areas as a vibration, or thrill. Other important anatomic considerations include the two pairs of parathyroid glands that usually lie behind the upper and middle thyroid lobes and the recurrent laryngeal nerves, which course along the trachea behind the thyroid gland.

On microscopic examination, the thyroid gland is found to consist of a series of follicles of varying sizes. The follicles contain a pink-staining material (with hematoxylin-eosin stain) called “colloid” and are surrounded by a single layer of thyroid epithelium. Tissue culture studies suggest that each follicle may represent an individual clone of cells. These cells become columnar when stimulated by TSH and flattened when resting (Figure 7-4). The follicle cells synthesize thyroglobulin, which is extruded into the lumen of the follicle. The biosynthesis of T4and T3 occurs within thyroglobulin at the cell-colloid interface. Numerous microvilli project from the surface of the follicle into the lumen; these are involved in endocytosis of thyroglobulin, which is then hydrolyzed in the cell to release thyroid hormones (Figure 7-5).



Thyroid hormones are unique in that they contain 59–65% of the trace element iodine. The structures of the thyroid hormones, T4 and T3, are shown in Figure 7-6. The iodinated thyronines are derived from iodination of the phenolic rings of tyrosine residues in thyroglobulin to form mono- or diiodotyrosine, which are coupled to form T3 or T4 (see below).


Iodine* enters the body in food or water in the form of iodide or iodate ion, the iodate ion being converted to iodide in the stomach. In the course of millennia, iodine




has been leached from the soil and washed down into the oceans, so that in mountainous and inland areas the supply of iodine may be quite limited, whereas the element is plentiful in coastal areas. The thyroid gland concentrates and traps iodide and synthesizes and stores thyroid hormones in thyroglobulin, which compensates for the scarcity of iodine.


Figure 7-1. Gross anatomy of the human thyroid gland (anterior view).


Figure 7-2. Cross section of the neck at the level of T1, showing thyroid relationships. (Reproduced, with permission, from Lindner HH: Clinical Anatomy. McGraw-Hill, 1989.)


Figure 7-3. Arteries and veins related to the thyroid gland. (Reproduced, with permission, from Lindner HH: Clinical Anatomy. McGraw-Hill, 1989.)

The recommendations of the World Health Organization for optimal daily iodide intake are as follows: for adults, 150 ľg; during pregnancy and lactation, 200 ľg; for the first year of life, 50 ľg; for ages 1–6, 90 ľg; and for ages 7–12, 120 ľg. If iodide intake is below 50 ľg/d, the gland is unable to maintain adequate hormonal secretion, and thyroid hypertrophy (goiter) and hypothyroidism result. In the United States, the average daily iodide intake increased from a range of 100–200 ľg/d in the 1960s to 240–740 ľg/d in the 1980s. This was largely due to the introduction of iodate as a dough conditioner, though other sources of dietary iodine included iodized salt, vitamin and mineral preparations, iodine-containing medications, and iodinated contrast media. In the 1990s, bromine salts replaced iodine in the baking industry, and iodine intake has fallen considerably, indicating the need for continued monitoring.

An approximation of iodine turnover in subjects on a high-iodine diet is depicted in Figure 7-7. Iodide, like chloride, is rapidly absorbed from the gastrointestinal tract and distributed in extracellular fluids as well as in salivary, gastric, and breast secretions. Although the concentration of inorganic iodide in the extracellular fluid pool will vary directly with iodide intake, extracellular fluid I- is usually quite low because of the rapid clearance of iodide from extracellular fluid by thyroidal uptake and renal clearance. In the example shown, the basal I-concentration in extracellular fluid is only 0.6 ľg/dL, or a total of 150 ľg of I- in an extracellular pool of 25 L despite a daily oral intake of 500 ľg I-. In the thyroid gland there is active transport of I- from the serum across the basement membrane of the thyroid cell (see below). The thyroid gland takes up about 115 ľg of I- per 24 hours, or, in this example, about 18% of the available I-. About 75 ľg of I- is utilized for hormone synthesis and stored in thyroglobulin; the remainder leaks back into the extracellular fluid pool. The thyroid pool of organified iodine is very large, averaging 8–10 mg, and represents a store of hormone and iodinated tyrosines, protecting the organism against a period of iodine lack. From this storage pool, about 75 ľg of hormonal iodide is released into the circulation


daily. This hormonal iodide is mostly bound to serum thyroxine-binding proteins, forming a circulating pool of about 600 ľg of hormonal I-(as T3 and T4). From this pool, about 75 ľg of I- as T3 and T4 is taken up and metabolized by tissues. About 60 ľg of I- is returned to the iodide pool and about 15 ľg of hormonal I- is conjugated with glucuronide or sulfate in the liver and excreted into the stool. Since most of the dietary iodide is excreted in the urine, a 24-hour urinary iodide excretion is an excellent index of dietary intake. The 24-hour radioactive iodine uptake (RAIU) by the thyroid gland is inversely proportionate to the size of the inorganic iodide pool and directly proportionate to thyroidal activity. Typical RAIU curves are shown in Figure 7-8. In the USA, the 24-hour thyroidal radioiodine uptake has decreased from about 40–50% in the 1960s to about 8–30% in the 1990s because of increased dietary iodide intake.


Figure 7-4. A: Normal rat thyroid. A single layer of cuboidal epithelial cells surrounds PAS-positive material in the follicular space (colloid). The larger, lighter-staining cells indicated by the arrows (I) are C cells that produce calcitonin. (F, follicular cells.) B: Inactive rat thyroid several weeks after hypophysectomy. The follicular lumens are larger and the follicular cells flatter. C: Rat thyroid under intensive TSH stimulation. The animal was fed an iodine-deficient diet and injected with propylthiouracil for several weeks. Little colloid is visible. The follicular cells are tall and columnar. Several mitoses (m) are visible. (Reproduced, with permission, from Halmi NS in: Histology. Greep RO, Weiss L [editors]. McGraw-Hill, 1973.)


The synthesis of T4 and T3 by the thyroid gland involves six major steps: (1) active transport of I- across the basement membrane into the thyroid cell (trapping of iodide); (2) oxidation of iodide and iodination of tyrosyl residues in thyroglobulin; (3) coupling of iodotyrosine molecules within thyroglobulin to form T3 and T4; (4) proteolysis of thyroglobulin, with release of free iodothyronines and iodotyrosines; (5) deiodination of iodotyrosines within the thyroid cell, with conservation and reuse of the liberated iodide; and (6) under certain circumstances, intrathyroidal 5′-deiodination of T4 to T3.

Thyroid hormone synthesis involves a unique glycoprotein, thyroglobulin, and an essential enzyme, thyroperoxidase (TPO). This process is summarized in Figure 7-9.


Thyroglobulin is a large glycoprotein molecule containing 5496 amino acids, with a molecular weight of about 660,000 and a sedimentation coefficient of 19S. It contains about 140 tyrosyl residues and about 10% carbohydrate in the form of mannose, N-acetylglucosamine, galactose, fucose, sialic acid, and chondroitin sulfate. The 19S thyroglobulin compound is a dimer of two identical 12S subunits, but small amounts of the 12S monomer and a 27S tetramer are often present. The iodine content of the molecule can vary from 0.1% to 1% by weight. In thyroglobulin containing 0.5% iodine (26 atoms of iodine per 660-kDa molecule), there would be 5 molecules of monoiodotyrosine (MIT), 4.5 molecules of diiodotyrosine (DIT), 2.5 molecules of


thyroxine (T4), and 0.7 molecules of triiodothyronine (T3). About 75% of the thyroglobulin monomer consists of repetitive domains with no hormonogenic sites. There are four tyrosyl sites for hormonogenesis on the thyroglobulin molecule: One site is located at the amino terminal end of the molecule, and the other three are located in a sequence of 600 amino acids at the carboxyl terminal end. There is a surprising homology between this area of the thyroglobulin molecule and the structure of acetylcholinesterase, suggesting conservation in the evolution of these proteins.


Figure 7-5. Processes of synthesis and iodination of thyroglobulin (left) and its reabsorption and digestion (right). These events occur in the same cell. (Reproduced, with permission, from Junqueira LC, Carneiro J, Kelley R: Basic Histology, 7th ed. McGraw-Hill, 1992.)

The human thyroglobulin (hTg) gene lies on the long arm of chromosome 8 distal to the c-myc oncogene. TSH stimulates the transcription of the thyroglobulin gene, and hypophysectomy or T3 therapy decreases its transcription. The thyroglobulin gene contains about 8500 nucleotides, which encode the prethyroglobulin (pre-Tg) monomer. The pre-thyroglobulin monomer contains a 19-amino-acid signal peptide, followed by a 2750-amino-acid chain that constitutes the thyroglobulin monomer. The mRNA is translated in the rough endoplasmic reticulum, and thyroglobulin chains are glycosylated during transport to the Golgi apparatus (Figure 7-5). In the Golgi apparatus, the thyroglobulin dimers are incorporated into exocytotic vesicles that fuse with the basement membrane and release the thyroglobulin into the follicular lumen. There, at the apical-colloid border, tyrosines within thyroglobulin are iodinated and stored in colloid.

Thyroidal Peroxidase

Thyroidal peroxidase is a membrane-bound glycoprotein with a molecular weight of about 102,000 and a heme compound as the prosthetic group of the enzyme. This enzyme mediates both the oxidation of iodide ions and the incorporation of iodine into tyrosine residues of thyroglobulin. Thyroidal peroxidase is synthesized in the rough endoplasmic reticulum (RER). After insertion into the membrane of RER cisternae, it is transferred


to the apical cell surface through Golgi elements and exocytic vesicles. Here, at the cell colloid interface, it is available for iodination and hormonogenesis in thyroglobulin. Thyroidal peroxidase biosynthesis is stimulated by TSH.


Figure 7-6. Structure of thyroid hormones and related compounds. (Reproduced, with permission, from Murray RK et al: Harper's Biochemistry, 24th ed. McGraw-Hill, 1996.)

Iodide Transport (the Iodide Trap)

I- is transported across the basement membrane of the thyroid cell by an intrinsic membrane protein called the Na+/I- symporter (NIS). At the apical border, a second I- transport protein called pendrin moves iodine into the colloid where it is involved in hormonogenesis (Figure 7-10). The NIS derives its energy from Na+-K+ ATPase, which drives the transport process. This active transport system allows the human thyroid gland to maintain a concentration of free iodide 30–40 times that in plasma. The NIS is stimulated by TSH and by the TSH receptor-stimulating antibody found in Graves' disease. It is saturable with large amounts of iodide and inhibited by ions such as ClO4-, SCN-, NO3-, and TcO4-. Some of these ions have clinical utility. Sodium perchlorate will discharge nonorganified iodide from the NIS and has been used to diagnose organification defects (Figure 7-11) and in the treatment of iodide-induced hyperthyroidism. Sodium pertechnetate Tc99m, which has a 6-hour half-life and a 140-keV gamma emission, is used for rapid visualization of the thyroid gland for size and functioning nodules. Pendrin, encoded by the Pendred syndrome gene (PDS), is a transporter of chloride and iodide. Mutations in the PDS gene have been found in patients with goiter and congenital deafness (Pendred's syndrome). Although iodide is concentrated by salivary, gastric, and breast tissue, these tissues do not organify or store I- and are not stimulated by TSH.

Iodination of Tyrosyl in Thyroglobulin

Within the thyroid cell, at the cell-colloid interface, iodide is rapidly oxidized by H2O2, catalyzed by thyroperoxidase, and converted to an active intermediate which is incorporated into tyrosyl residues in thyroglobulin. H2O2 is probably generated by a dihydronicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the presence of Ca2+; this process is stimulated by TSH. The iodinating intermediate may be iodinium ion (I+), hypoiodate, or an iodine-free radical. The site of iodination at the apical (colloid) border of the thyroid cell can be demonstrated by autoradiography.

Thyroidal peroxidase will catalyze iodination of tyrosyl molecules in proteins other than thyroglobulin, such as albumin or thyroglobulin fragments. However, no thyroactive hormones are formed in these proteins. The metabolically inactive protein may be released into the circulation, draining thyroidal iodide reserves.

Coupling of Iodotyrosyl Residues in Thyroglobulin

The coupling of iodotyrosyl residues in thyroglobulin is also catalyzed by thyroperoxidase. It is thought that this is an intramolecular mechanism involving three steps: (1) oxidation of iodotyrosyl residues to an activated form by thyroperoxidase; (2) coupling of activated iodotyrosyl residues within the same thyroglobulin molecule to form a quinol ether intermediate; and (3) splitting of the quinol ether to form iodothyronine, with conversion of the alanine side chain of the donor iodotyrosine to dehydroalanine (Figure 7-12). For this process to occur, the dimeric structure of thyroglobulin is essential: Within the thyroglobulin molecule, two




molecules of DIT may couple to form T4, and an MIT and a DIT molecule may couple to form T3. Thiocarbamide drugs—particularly propylthiouracil, methimazole, and carbimazole—are potent inhibitors of thyroperoxidase and will block thyroid hormone synthesis (Figure 7-13). These drugs are clinically useful in the management of hyperthyroidism.


Figure 7-7. Iodine metabolism. The values indicated are representative of those that might be found in a healthy subject ingesting 500 ľg of iodine a day. The actual iodine intake varies considerably among different individuals.


Figure 7-8. Typical curves of 24-hour radioiodine uptake in normal subjects and in patients with thyroid disease. A “high-turnover” curve may be seen in patients taking an iodine-deficient diet or with a defect in hormone synthesis.


Figure 7-9. Thyroid hormone synthesis in a thyroid follicle.


Figure 7-10. The iodide transporter in the thyroid cell. The large solid circle represents the Na+/I- symporter actively transporting I-into the cell; the large open circle represents Na+-K+ ATPase supplying the ion gradient which drives the reaction. I- is transported across the apical membrane by pendrin. Hormone synthesis takes place in the colloid at the colloid-apical membrane, catalyzed by thyroperoxidase (TPO).


Figure 7-11. Perchlorate discharge of thyroidal inorganic iodine. Two to 3 hours after administration of a tracer dose of radioactive iodide, perchlorate is administered orally, blocking further active transport of iodide into the thyroid cell. In the normal subject (solid line), no significant decrease in radioactivity is detectable over the thyroid gland. In the representative example shown by the dashed line, there is a significant discharge of thyroidal iodide, indicating that iodide organification has been incomplete. (ClO4-, perchlorate.)

Proteolysis of Thyroglobulin & Thyroid Hormone Secretion

The pattern of proteolysis of thyroglobulin and secretion of thyroid hormones is illustrated in Figure 7-5. Lysosomal enzymes are synthesized by the rough endoplasmic reticulum and packaged by the Golgi apparatus into lysosomes. These structures, surrounded by membrane, have an acidic interior and are filled with proteolytic enzymes, including proteases, endopeptidases, glycoside hydrolyases, phosphatases, and other enzymes. At the cell-colloid interface, colloid is engulfed into a colloid vesicle by a process of macropinocytosis or micropinocytosis and is absorbed into the thyroid cell. The lysosomes then fuse with the colloid vesicle and hydrolysis of thyroglobulin occurs, releasing T4, T3, DIT, MIT, peptide fragments, and amino acids. T3 and T4 are released into the circulation, while DIT and MIT are deiodinated and the I- is conserved. Thyroglobulin with a low iodine content is hydrolyzed more rapidly than thyroglobulin with a high iodine content, which may be beneficial in geographic areas where natural iodine intake is low. The mechanism of transport of T3 and T4 through the thyroid cell is not known, but it may involve a specific hormone carrier. Thyroid hormone secretion is stimulated by TSH, which activates adenylyl cyclase, and by the cAMP analog Bu2cAMP, suggesting that it is cAMP-dependent.


Thyroglobulin proteolysis is inhibited by excess iodide (see below) and by lithium, which, as lithium carbonate, is used for the treatment of bipolar disorders. A small amount of unhydrolyzed thyroglobulin is also released from the thyroid cell; this is markedly increased in certain situations such as subacute thyroiditis, hyperthyroidism, or TSH-induced goiter (Figure 7-9). Thyroglobulin (perhaps modified) may also be synthesized and released by certain thyroid malignancies such as papillary or follicular thyroid cancer and may be useful as a marker for metastatic disease.


Figure 7-12. Hypothetical coupling scheme for intramolecular formation of T4 within the thyroglobulin molecule. The major hormonogenic site at tyrosyl residue 5 is indicated. (Reproduced, with permission, from Taurog A: Thyroid hormone synthesis. Thyroid iodine metabolism. In: Werner and Ingbar's The Thyroid, 7th ed. Braverman LE, Utiger RD [editors]. Lippincott, 1996.)

Intrathyroidal Deiodination

MIT and DIT formed during the synthesis of thyroid hormone are deiodinated by intrathyroidal deiodinase (Figure 7-9). This enzyme is an NADPH-dependent flavoprotein found in mitochondria and microsomes. It acts on MIT and DIT but not on T3 and T4. The iodide released is mostly reutilized for hormone synthesis; a small amount leaks out of the thyroid into the body pool (Figure 7-7). The 5′-deiodinase that converts T4 to T3 in peripheral tissues is also found in the thyroid gland. In situations of iodide deficiency, the activity of this enzyme may increase the amount of T3 secreted by the thyroid gland, increasing the metabolic efficiency of hormone synthesis.


Inherited Metabolic Defects (Dyshormonogenesis)

Inherited metabolic defects may involve any phase of hormonal biosynthesis. These result in “dyshormonogenesis,” or impaired hormonal synthesis. Patients present with thyroid enlargement, or goiter, mild to severe hypothyroidism, low serum T3 and T4, and elevated serum TSH. The defects are described in more detail in the section on nontoxic goiter, below.

Effect of Iodide Deficiency on Hormone Biosynthesis

A diet very low in iodine reduces intrathyroidal iodine content, increases the intrathyroidal ratio of MIT to DIT, increases the ratio of T3 to T4, decreases the secretion of T4, and increases serum TSH. In the adult, this results in goiter, with a high iodine uptake and mild to severe hypothyroidism; in the neonate, it may result in cretinism (see below). The adaptations that occur involve the increased synthesis of T3relative to T4 and the increased intrathyroidal 5′-deiodination of T4 to T3 to produce a more active hormone mixture.


Figure 7-13. Thiocarbamide inhibitors of thyroidal iodide organification.



Effect of Iodine Excess on Hormone Biosynthesis

Increasing doses of iodide given to iodide-deficient rats initially induce increased iodide organification and hormone formation until a critical level is reached, whereupon inhibition of organification occurs and hormonogenesis decreases. This Wolff-Chaikoff effect (Figure 7-14) is probably due to inhibition of H2O2 generation by the high intrathyroidal I- content. The most striking observation was that the effect is transient and that the normal thyroid gland “escapes” from the I- effect. This is due to inhibition of the transport of I- with reduction in intrathyroidal iodide, allowing hormonogenesis to proceed. If the gland is unable to make this adaptation—as may occur in patients with autoimmune thyroiditis or in some patients with dyshormonogenesis—iodide-induced hypothyroidism will ensue. In some patients, an iodide load will induce hyperthyroidism (“jodbasedow” effect). This may develop in patients with latent Graves' disease, in those with multinodular goiters, or occasionally in those with previously normal thyroid glands.


Figure 7-14. The Wolff-Chaikoff block. As increasing doses of iodide are administered to rats, there is an initial increase in iodide organification. At a critical concentration, however, higher doses of iodide given to the animals block iodide organification. The effect of increasing doses of iodide on thyroid hormone synthesis is therefore biphasic. Concomitantly with the increase in the organification block, the intracellular inorganic iodide concentration rises. As the amount of stable iodide injected is increased, there is a decrease in thyroidal uptake of radioactive iodide. (Reproduced, with permission, from DeGroot LJ, Stanbury JB: The Thyroid and Its Diseases, 4th ed. Wiley, 1975.)


Thyroid hormones are transported in serum bound to carrier proteins. Although only 0.04% of T4 and 0.4% of T3 are “free,” it is the free fraction that is responsible for hormonal activity (Figure 7-15). There are three major thyroid hormone transport proteins: thyroxine-binding globulin (TBG); thyroxine-binding prealbumin (TBPA), or transthyretin; and albumin (Figure 7-16).

Thyroxine-Binding Globulin (TBG)

TBG, a single 54-kDa polypeptide chain, is synthesized in the liver. It contains four carbohydrate chains, representing 23% of the molecule by weight, and has homology with α1-antichymotrypsin and α1-antitrypsin. Normally, there are about ten sialic acid residues per molecule. Pregnancy or estrogen therapy increases the sialic acid content of the molecule, resulting in decreased metabolic clearance and elevated serum levels of TBG. Each molecule of TBG has a single binding site for T4 or T3. The serum concentration of TBG is 15–30 ľg/mL, or 280–560 nmol/L. The affinity constant (Ka) for T4 is 1 × 1010 M-1, and for T3 it is 5 × 108 M-1. The high affinity for T3 and T4 allows TBG to carry about 70% of the circulating thyroid hormones. When fully saturated, TBG can carry about 20 ľg of T4 per deciliter.

Congenital TBG deficiency is an X-linked trait with a frequency of 1:2500 live births. One variant occurs in African Pygmies, Panamanians, African blacks, Micronesians, and Indonesians. Another variant occurs in 40% of Australian aborigines. Despite the low circulating T4 and T3levels, the free hormone levels are normal and the patients are not hypothyroid. Congenital TBG


deficiency is often associated with congenital corticosteroid-binding globulin (CBG) deficiency (Chapter 9). Congenital TBG excess is rare; it presents with elevated total T4 and T3 concentrations but normal free hormone levels and normal TSH.


Figure 7-15. Representation of free T4 (and free T3) as the biologically active hormone at the level of the pituitary and the peripheral tissues. Most of the thyroid hormones circulating in plasma are protein-bound and have no biologic activity. This pool of bound hormone is in equilibrium with the free hormone pool. (Reproduced, with permission, from DeGroot LJ, Stanbury JB: The Thyroid and Its Diseases, 4th ed. Wiley, 1975.)

Androgenic steroids and glucocorticoids lower TBG levels, as does major systemic illness as well Table 7-1. Drugs such as salicylates, phenytoin, phenylbutazone, and diazepam may bind to TBG, displacing T4 and T3, in effect producing a low-TBG state. Heparin stimulates lipoprotein lipase, releasing free fatty acids, which displace T3 and T4 from TBG. This can occur in vivo and also in vitro, eg, in blood drawn through a heparin Heplock, where even minute quantities of heparin will increase the measured levels of free T4 and T3.

Thyroxine-Binding Prealbumin

Transthyretin, or thyroxine-binding prealbumin (TBPA), is a 55-kDa globular polypeptide consisting of four identical subunits, each containing 127 amino acids. It binds about 10% of circulating T4. Its affinity for T3 is about tenfold lower than for T4, so that it mostly carries T4. The dissociation of T4 and T3 from TBPA is rapid, so that TBPA is a source of readily available T4. There are binding sites on TBPA for retinol-binding protein, but the transport of T4 is independent of the transport of retinol-binding protein. The concentration of TBPA in serum is 120–240 mg/L, or 2250–4300 nmol/L.


Figure 7-16. Diagrammatic representation of the distribution of radioactive T4 and T3 among serum thyroid hormone-binding proteins.Top: Paper electrophoretic pattern of serum proteins. Middle: Radioactive T4 was added to serum and was then subjected to paper electrophoresis. The peaks represent the mobility of radioactive T4 bound to different serum proteins. (TBG, thyroid hormone-binding globulin; TBPA, thyroxine-binding prealbumin.) Bottom: Radioactive T3 was added to serum and subjected to paper electrophoresis. The peaks indicate the relative distribution of protein-bound radioactive T3. The figures above each peak indicate the relative hormone distribution among the binding proteins in a normal adult. (Reproduced, with permission, from Rosenfield RL et al: Pediatric Nuclear Medicine. James AE Jr, Wagner HN Jr, Cooke RE [editors]. Saunders, 1974.)

Table 7-1. Factors influencing the concentration of protein-bound thyroid hormones in serum.

1. Increased TBG concentration

1. Congenital

2. Hyperestrogenic states: pregnancy, estrogen therapy

3. Diseases: acute infectious hepatitis, hypothyroidism

2. Decreased TBG concentration

1. Congenital

2. Drugs: androgenic steroids, glucocorticoids

3. Major systemic illness: Protein malnutrition, nephrotic syndrome, cirrhosis, hyperthyroidism

3. Drugs affecting thyroid hormone binding to normal concentrations of binding protein

1. Phenytoin

2. Salicylates

3. Phenylbutazone

4. Mitotane

5. Diazepam

6. FFA released by heparin stimulation of lipoprotein lipase



Increased levels of TBPA may be familial and may occur in patients with glucagonoma or pancreatic islet cell carcinoma. These patients have an elevated total T4 but a normal free T4. Abnormal TBPA has been described in familial amyloidotic polyneuropathy, associated with a low total T4 but normal free hormone levels.


Albumin has one strong binding site for T4 and T3 and several weaker ones. Because of its high concentration in serum, albumin carries about 15% of circulating T4 and T3. The rapid dissociation rates of T4 and T3 from albumin make this carrier a major source of free hormone to tissues. Hypoalbuminemia, as occurs in nephrosis or in cirrhosis of the liver, is associated with a low total T4 and T3, but the free hormone levels are normal.

Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant inherited disorder in which 25% of the albumin exhibits high-affinity T4 binding, resulting in an elevated total T4 level but normal free T4 and euthyroidism. Affinity for T3 may be elevated but is usually normal.

Kinetics of Thyroid Hormone Binding to Transport Proteins

The kinetics of thyroid hormone binding to the thyroid binding proteins can be expressed by conventional equilibrium equations. Thus, for T4:

where (T4) represents free (unbound) hormone, (TBG) is TBG not containing T4, and (TBG - T4) is TBG-bound T4. This can be expressed by the mass action relationship:

where K is the equilibrium constant for the interaction. Rearranging:

From this equation, it can be seen that T4 exists in plasma in both free and bound forms, and the free hormone level is inversely proportionate to the free binding sites on TBG and the binding affinity for the hormone. The same relationships exist for the other thyroid hormone-binding proteins.

The effect of a change in the concentration of thyroid hormone-binding protein is shown in Figure 7-17. The levels of free thyroid hormone are normal in states where there are primary or secondary changes in plasma binding, because TSH release is controlled by the free thyroid hormone level and adjusts to normalize it irrespective of how much hormone is bound by the plasma proteins.

There has been much speculation on the role of the thyroid hormone transport proteins. The three major hypotheses are as follows: (1) they form a storage pool of readily available free hormone; (2) they allow the delivery of T3 and T4 to all tissues because the tiny free hormone pool is continually replenished as the hormones are absorbed by tissues; and (3) they protect tissues from massive hormone release. Thus, although the transport proteins are not essential for thyroid hormone activity, they may make the system more efficient.


The daily secretion of the normal thyroid gland is about 100 nmol of T4, about 5 nmol of T3, and less than 5 nmol of metabolically inactive reverse T3 (rT3) (Figure 7-18). Most of the plasma pool of T3 is derived from peripheral metabolism (5′-deiodination) of T4. The biologic activity of thyroid hormones is greatly dependent on the location of the iodine atoms Table 7-2. Deiodination of the outer ring of T4 (5′-deiodination) produces 3,5,3′-triiodothyronine (T3), which is three to eight times more potent than T4. On the other hand, deiodination of the inner ring of T4 (5-deiodination) produces 3,3′,5′-triiodothyronine (reverse T3, or


rT3), which is metabolically inert. The deiodinative pathways of thyroxine metabolism are presented in Figure 7-19. Monodeiodination of the outer ring of thyroxine is a “step up” process, increasing the metabolic activity of the resultant compound, while monodeiodination of the inner ring is a “step down” or inactivation process. Further deiodination of the molecule abolishes hormonal activity.


Figure 7-17. The effect of an increase in thyroid hormone-binding protein concentration on the free and protein-bound hormone concentrations. The initial increase in binding protein concentration (as may occur with estrogen administration) increases the amount of bound hormone and transiently decreases the free hormone concentration. There follows a transient increase in thyroid hormone secretion under the stimulus of TSH to replenish the free hormone pool. Another contributing factor is a transient decrease in the metabolic clearance rate of thyroid hormone. A new steady state is attained in which the free hormone secretion, metabolism, and plasma concentration are the same as initially except that the free hormone is now in equilibrium with a larger pool of bound hormone. In subjects receiving thyroid hormone medication, the same daily dose of thyroid hormone is necessary to maintain euthyroidism irrespective of the size of the bound hormone pool.

At least three enzymes catalyze these monodeiodination reactions: type 1 5′-deiodinase; type 2 5′-deiodinase; and type 3 tyrosyl ring deiodinase, or 5-deiodinase. They differ in tissue localization, substrate specificity, and effect of disease. The properties of these deiodinases are summarized in Table 7-3.


Figure 7-18. Major pathways of thyroxine metabolism in normal adult humans. Rates are expressed in nmol/24 h and are approximations based upon available data. 100 nmol of T4 is equivalent to approximately 75 ľg. (rT3, reverse T3; TETRAC, tetraiodothyroacetic acid.) (Reproduced, with permission, from Cavalieri RR, Rapoport B: Impaired peripheral conversion of thyroxine to triiodothyronine. Ann Rev Med 1977;28:5765.)

Type 1 5′-deiodinase is the most abundant deiodinase and is found largely in liver and kidney and in lesser quantity in the thyroid gland, skeletal muscle, heart muscle, and other tissues. Molecular cloning of type 1 5′-deiodinase has revealed that it contains selenocysteine and that this is probably the active deiodinating site. The major function of type 1 5′-deiodinase is to provide T3 to the plasma. It is increased in hyperthyroidism and decreased in hypothyroidism. The increased activity in hyperthyroidism accounts in part for the high T3 levels in this syndrome. The enzyme is inhibited by propylthiouracil but not methimazole, which explains why propylthiouracil is more effective than methimazole in reducing T3 levels in severe hyperthyroidism. Inhibition of type 1 5′-deiodinase activity results in impaired conversion of T4to T3. Some conditions associated with decreased conversion of T4 to T3 are listed in Table 7-4. Note that only propylthiouracil, amiodarone, and ipodate impair intracellular conversion of T4 to T3; the other conditions may modify the ratio of T4 to T3 in serum, requiring interpretation of thyroid tests (see below), but they do not change intracellular T3 production. Dietary deficiency of selenium also impairs conversion of T4 to T3. In the presence of






iodine deficiency, repletion of selenium causes increased type 1 5′-deiodinase activity, an acceleration of T4 metabolism, and a worsening of hypothyroidism, since the iodine-deficient gland cannot compensate for the increased T4 metabolism.

Table 7-2. Chemical structures and biologic activity of thyroid hormones.



Common Name

Biologic Activity



L-Thyroxine; T4








Reverse T3; rT3

< 1




< 1–3










L-3,5,3′,5′-Tetraiodothyro-acetic acid


? 10–50


L-3,5,3′-Triiodothyroacetic acid


? 25–35


Figure 7-19. The deiodinative pathway of thyroxine metabolism. The monodeiodination of T4 to T3 represents a “step up” in biologic potency, whereas the monodeiodination of T4 to reverse T3 has the opposite effect. Further deiodination of T3 essentially abolishes hormonal activity.

Table 7-3. Iodothyronine deiodinases.1


Type 1 (5′)

Type 2 (5′)

Type 3 (5)

Physiologic role

Provides T3 to plasma

Provides intracellular T3

Inactivates T3 and T4

Tissue location

Liver, kidney, muscle, thyroid

CNS, pituitary, brown fat, placenta

Placenta, CNS, skin, fetal liver


rT3 >> T4 > T3

T4 = rT3

T3 > T4

Km for T4

1 × 10-6 M

1 × 10-9 M

6 × 10-9 M (T3), 37 × 10-9M (T4)

Deiodination site

Outer and inner ring

Outer ring

Inner ring

Kinetic mechanism








Ki for PTU

5 × 10-7 M (sensitive)

4 × 10-3 M (resistant)

? > 10-3 M (resistant)

Active site




Ipanoic acid












1Adapted and modified, with permission, from Larsen PR, Ingbar SH. The thyroid gland. In: Williams Textbook of Endocrinology, 8th ed. Wilson JW, Foster DW (editors). Saunders, 1992.

Table 7-4. Conditions or factors associated with decreased conversion of T4 or T3.

1. Fetal life

2. Caloric restriction

3. Hepatic disease

4. Major systemic illness

5. Drugs:
      Propranolol (mild effect)
      Iodinated x-ray contrast agents (iopanoic acid, ipodate sodium)

6. Selenium deficiency

Type 2 5′-deiodinase is found largely in the brain and pituitary gland. It is resistant to propylthiouracil but very sensitive to circulating T4. The major effect of the enzyme is to maintain a constant level of intracellular T3 in the central nervous system. Reduction in circulating T4results in a rapid increase in the amount of the enzyme in brain and pituitary cells, probably by altering the rate of enzyme degradation and inactivation, maintaining the level of intracellular T3 and cellular function. High levels of serum T4 reduce type 2 5′-deiodinase, protecting brain cells from excessive T3. This may be the mechanism whereby the hypothalamus and pituitary monitor the levels of circulating T4. Other metabolic products of T4 metabolism such as rT3 can also modify the levels of type 2 5′-deiodinase in the brain and the pituitary gland, and alpha-adrenergic compounds stimulate type 2 5′-deiodinase in brown fat. The physiologic significance of these reactions is not clear.

Type 3 5-deiodinase, or tyrosyl ring deiodinase, is found in placental chorionic membranes and glial cells in the central nervous system. It inactivates T4 by converting it to rT3 and T3 by converting it to 3,3′-diiodothyronine (3,3′-T2) (Figure 7-19). It is elevated in hyperthyroidism and decreased in hypothyroidism. Thus, it may help to protect the fetus and the brain from excess or deficiency of T4.

Overall, the functions of the deiodinases may be threefold: (1) they may provide a means for local tissue and cellular control of thyroidal activity; (2) they may allow the organism to adapt to changing environmental states such as iodine deficiency or chronic illness; and (3) they have an important role in the early development of many vertebrates, including amphibia and mammals.

About 80% of T4 is metabolized by deiodination, 35% to T3 and 45% to rT3 (Figure 7-18). The remainder is inactivated mostly by glucuronidation in the liver and secretion into bile, or to a lesser extent by sulfonation and deiodination in the liver or kidney. Other metabolic reactions include deamination of the alanine side chain, forming thyroacetic acid derivatives of low biologic activity Table 7-2; or decarboxylation or cleavage of the ether bridge, forming inactive compounds.

Representative iodothyronine kinetic values are summarized in Table 7-5. The volume of distribution is the quantity of plasma that would contain the equivalent of the total extrathyroidal pool of the compound. Thus, for T4, the serum concentration is about 100 nmol/L; the volume of distribution is about 10 L; and the body pool is about 1000 nmol. The metabolic clearance rate for T4 is only about 10% per day (100 nmol), and the half-life of T4 in plasma is about 7 days. The body pool of T3 is much smaller and the turnover more rapid, with a plasma half-life of 1 day. The total body pool of rT3 is about the same size as that of T3, but rT3 has a much more rapid turnover, with a plasma half-life of only 0.2 day. The rapid clearance of T3 and rT3 is due to lower binding affinity for thyroid binding proteins.

Table 7-5. Representative iodothyronine kinetic values in a euthyroid human.





Serum levels

   Total, ľg/dL (nmol/L)

8 (103)

0.12 (1.84)

0.04 (0.51)

   Free, ng/dL (pmol/L)

1.5 (19)

0.28 (4.3)

0.24 (3.69)

Body pool, ľg (nmol)

800 (1023)

46 (70.7)

40 (61.5)

Distribution volume (L)




Metabolic clearance rate (MCR) (L/d)




Production (disposal) rate. MCR X serum concentration, ľg/d (nmol/d)

80 (103)

26 (34)

36 (46)

Half-life in plasma (t˝) (days)




(Note: T4 ľg/dL × 12.87 = nmol/L; T3 ľg/dL × 15.38 = nmol/L)




The growth and function of the thyroid gland and the peripheral effects of thyroid hormones are controlled by at least four mechanisms: (1) the classic hypothalamic-pituitary-thyroid axis (Figure 7-20), in which hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and release of anterior pituitary thyroid-stimulating hormone (TSH), which in turn stimulates growth and hormone secretion by the thyroid gland; (2) the pituitary and peripheral deiodinases, which modify the effects of T4 and T3; (3) autoregulation of hormone synthesis by the thyroid gland itself in relationship to its iodine supply; and (4) stimulation or inhibition of thyroid function by TSH receptor autoantibodies. In addition, the effects of T3 may be modified by the status of the T3 receptor (repressor or activation) and potentially by nonthyroidal T3 receptor agonists or antagonists.


Figure 7-20. The hypothalamic-hypophysial-thyroidal axis. TRH produced in the hypothalamus reaches the thyrotrophs in the anterior pituitary by the hypothalamic-hypophysial-portal system and stimulates the synthesis and release of TSH. In both the hypothalamus and the pituitary, it is primarily T3 that inhibits TRH and TSH secretion. T4 undergoes monodeiodination to T3 in neural and pituitary as well as in peripheral tissues.

Thyrotropin-Releasing Hormone

Thyrotropin-releasing hormone (TRH) is a tripeptide, pyroglutamyl-histidyl-prolineamide, synthesized by neurons in the supraoptic and supraventricular nuclei of the hypothalamus (Figure 7-21). It is stored in the median eminence of the hypothalamus and then transported via the pituitary portal venous system down the pituitary stalk to the anterior pituitary gland, where it controls synthesis and release of TSH. TRH is also found in other portions of the hypothalamus, the brain, and the spinal cord, where it may function as a neurotransmitter. The gene for human preproTRH, located on chromosome 3, contains a 3.3-kb transcription unit that encodes six TRH molecules. The gene also encodes other neuropeptides that may be biologically significant. In the anterior pituitary gland, TRH binds to specific membrane receptors on thyrotrophs and prolactin-secreting cells, stimulating synthesis and release of both TSH and prolactin. Thyroid hormones cause a slow depletion of pituitary TRH receptors, diminishing TRH response; estrogen increases TRH receptors, increasing pituitary sensitivity to TRH.

The response of the pituitary thyrotroph to TRH is bimodal: First, it stimulates release of stored hormone; and second, it stimulates gene activity, which increases hormone synthesis. The TRH receptor (TRH-R) is a member of the seven-transmembrane-spanning, GTP-binding, protein-coupled receptor family (Table 3-1; Figure 3-2). The TRHR gene is located on chromosome 8. Large glycoprotein hormones such as TSH and LH bind to the extracellular portions of their receptors, but TRH, a small peptide, binds to the transmembrane helix 3 of the TRH-R. After binding to its receptor on the thyrotroph, TRH activates a G protein, which in turn activates phospholipase c to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3). IP3 stimulates the release of intracellular Ca2+, which causes the first burst response


of hormone release. Simultaneously, there is generation of 1,2-diacylglycerol, which activates protein kinase C, thought to be responsible for the second and sustained phase of hormone secretion. The increases in intracellular Ca2+ and in protein kinase C may be involved in increased transcription of TSH. TRH also stimulates the glycosylation of TSH, which is necessary for full biologic activity of the hormone. Thus, patients with hypothalamic tumors and hypothyroidism may have measurable TSH, which is not glycosylated and is biologically inactive.


Figure 7-21. Chemical structure of thyrotropin-releasing hormone (TRH).

Elegant studies in vitro and in vivo demonstrated that T3 directly inhibits the transcription of preproTRH gene and thus the synthesis of TRH in the hypothalamus. Since T4 is converted to T3 within peptidergic neurons, it is also an effective inhibitor of TRH synthesis and secretionTable 7-6.

TRH is rapidly metabolized, with a half-life of intravenously administered hormone of about 5 minutes. Plasma TRH levels in normal subjects are very low, ranging from 25 to 100 pg/mL.

TRH-stimulated TSH secretion occurs in a pulsatile fashion throughout the 24 hours (Figure 7-22). Normal subjects have a mean TSH pulse amplitude of about 0.6 ľU/mL and an average frequency of one pulse every 1.8 hours. In addition, normal subjects show a circadian rhythm, with a peak serum TSH at night, usually between midnight and 4 AM. This peak is unrelated to sleep, eating, or the secretion of other pituitary hormones. This rhythm is presumably controlled by a hypothalamic neuronal “pulse generator” driving TRH synthesis in the supraoptic and supraventricular nuclei. In hypothyroid patients, the amplitude of the pulses and the nocturnal surge are much larger than normal, and in patients with hyperthyroidism both the pulses and the nocturnal surge are markedly suppressed.

In experimental animals and in the newborn human, exposure to cold increases TRH and TSH secretion, but this is not noted in the adult human.

Certain hormones and drugs may modify TRH synthesis and release. TRH secretion is stimulated by decreased serum T4 or T3 (with decreased intraneuronal T3), by alpha-adrenergic agonists, and by arginine vasopressin. Conversely, TRH secretion is inhibited by increased serum T4 or T3 (with increased intraneuronal T3) and alpha-adrenergic blockade Table 7-6.

TRH administered intravenously to humans in a bolus dose of 200–500 ľg results in a rapid threefold to fivefold rise in serum TSH, peaking at about 30 minutes and lasting for 2–3 hours (see Figure 5-14). In patients with primary hypothyroidism—in whom basal TSH is elevated—there is an exaggerated response. The response is suppressed in patients with hyperthyroidism, in those who have nodular goiters with autonomously functioning nodules, in patients on high-dose thyroxine therapy, and in patients with pituitary hypothyroidism. In a patient with a hypothalamic lesion, a partial TSH response to TRH injection would indicate an intact pituitary. TRH and its dipeptide metabolite cyclo(HisPro) are also found in the islet cells of the pancreas, the gastrointestinal tract, the placenta, the heart, and in the prostate, testes, and ovaries. TRH mRNA in these peripheral tissues is not inhibited by T3, and the role of TRH in these tissues has not yet been determined.

Table 7-6. Factors controlling the secretion of thyroid hormones.

1. HYPOTHALAMIC: Synthesis and release of TRH
      Decreased serum T4 and T3, and intraneuronal T3
      Neurogenic: Pulsatile secretion and circadian rhythm
      Exposure to cold (animals and human newborn)
      Alpha-adrenergic catecholamines
      Arginine vasopressin
      Increased serum T4 and T3, and intraneuronal T3
      Alpha-adrenergic blockers
      Hypothalamic tumors

2. ANTERIOR PITUITARY: Synthesis and release of TSH
      Decreased serum T4 and T3, and intrathyrotrope T3
      Decreased activity Type 2 5′-deiodinase
      Estrogen: increased TRH binding sites
      Increased serum T4 and T3, and intrathyrotrope T3
      Increased activity Type 2 5′-deiodinase
      Dopamine, dopamine agonists: bromocriptine
      Chronic illness
      Pituitary tumors

3. THYROID: Synthesis and release of thyroid hormones
  TSH-R stimulating antibodies
      TSH-R blocking antibodies
      Iodide excess
      Lithium therapy


Thyroid-stimulating hormone, or thyrotropin (TSH), is a glycoprotein synthesized and secreted by the thyrotrophs of the anterior pituitary gland. It has a molecular


weight of about 28,000 and is composed of two noncovalently linked subunits, α and β. The α subunit is common to the two other pituitary glycoproteins, FSH and LH, and also to the placental hormone hCG; the β subunit is different for each glycoprotein hormone and confers specific binding properties and biologic activity. The human α subunit has an apoprotein core of 92 amino acids and contains two oligosaccharide chains; the TSH β subunit has an apoprotein core of 112 amino acids and contains one oligosaccharide chain. The α and β subunit amino acid chains of TSH each form three loops which are intertwined into a knot-like structure called a “cystine knot” (Figure 7-23). Mutations of the amino acids in either chain can result in either decreased or increased TSH activity. Glycosylation takes place in the rough endoplasmic reticulum and the Golgi of the thyrotroph, where glucose, mannose, and fucose residues and terminal sulfate or sialic acid residues are linked to the apoprotein core. The function of these carbohydrate residues is not entirely clear, but it is likely that they enhance TSH biologic activity and modify its metabolic clearance rate. For example, deglycosylated TSH will bind to its receptor, but its biologic activity is markedly decreased and its metabolic clearance rate is markedly increased.


Figure 7-22. Serum TSH in two normal subjects demonstrating spontaneous pulses and the circadian rhythm of TSH secretion. (0 time is 0900; Stars indicate significant pulses.) (Reproduced, with permission, from Greenspan SL et al: Pulsatile secretion of TSH in man. J Clin Endocrinol Metabol 1986;63:664. Copyright Š 1986 by The Endocrine Society.)

The gene for the human α subunit is located on chromosome 6 and the gene for the human β subunit on chromosome 1. Several kindreds have been reported with a point mutation in the TSHβ gene, resulting in a TSH-β subunit that did not combine with the α subunit to produce biologically active TSH. The disorders were autosomal recessive, and the clinical picture was that of nongoitrous hypothyroidism.


Figure 7-23. Schematic configuration of the TSH-TSHR complex. The central portion of the figure represents the ribbon-like structure of TSH within the TSH receptor. The dark blue line represents the β subunit and the light blue line the α subunit. See also Figure 7-24. (Reproduced, with permission, from Szkudlinski MW et al: Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 2002;82:473.)





TSH is the primary factor controlling thyroid cell growth and thyroid hormone synthesis and secretion. It achieves this effect by binding to a specific TSH receptor (TSH-R) on the thyroid cell membrane and activating both the G protein-adenylyl cyclase-cAMP and the phospholipase C signaling systems. The human TSH receptor (TSH-R) gene is located on chromosome 14q3. The TSH-R is a single-chain glycoprotein containing 764 amino acids. Like the TRH receptor of the anterior pituitary, the TSH-R in the thyroid follicular cell is a member of the seven-membrane spanning, GTP-binding protein-coupled receptor family. Structurally, it can be divided into two subunits: subunit A, containing 397 amino acids, representing the ectodomain which is involved in ligand binding; and subunit B, which includes the intramembrane and intracellular portion of the receptor involved in activation of thyroid cell growth, thyroid hormone synthesis, and release of the hormone (Figure 7-24). The TSH-R is unique in that it has binding sites not only for TSH but also for TSH receptor-stimulating antibodies (TSH-R Ab [stim]), which are found in patients with autoimmune hyperthyroidism (Graves' disease), and also for autoantibodies that bind to the TSH receptor and block the action of TSH (TSH-R Ab [block]). These latter antibodies are found in patients with severe hypothyroidism due to autoimmune atrophic thyroiditis and in some infants with neonatal hypothyroidism.

Mutations in the TSH-R have been associated with either spontaneous activation of the receptor and clinical hyperthyroidism or with resistance to TSH. Activating mutations involving the B subunit of the TSH-R have been found in solitary autonomous adenomas and in multinodular goiters as well as in rare cases of sporadic familial hyperthyroidism. Resistance to TSH due to mutations in either subunit of the receptor is associated with elevated serum TSH levels and euthyroidism or hypothyroidism.

Effects of TSH on the Thyroid Cell

TSH has many actions on the thyroid cell. Most of its actions are mediated through the G protein-adenylyl cyclase-cAMP system, but activation of the phosphatidylinositol (PIP2) system with increase in intracellular calcium may also be involved. The major actions of TSH include the following:


TSH rapidly induces pseudopods at the cell-colloid border, accelerating thyroglobulin resorption. Colloid content is diminished. Intracellular colloid droplets are formed and lysosome formation is stimulated, increasing thyroglobulin hydrolysis (Figure 7-5).


Individual thyroid cells increase in size (Figure 7-4); vascularity is increased; and, over a period of time, thyroid enlargement, or goiter, develops.


TSH stimulates all phases of iodide metabolism, from increased iodide uptake and transport to increased iodination of thyroglobulin and increased secretion of thyroid hormones. The increase in cAMP mediates increased iodide transport, while PIP2 hydrolysis and increased intracellular Ca2+ stimulate the iodination of thyroglobulin. The TSH effect on iodide transport is biphasic: Initially, it is depressed (iodide efflux); and then, after a lag of several hours, iodide uptake is increased. The efflux of iodide may be due to the rapid increase in hydrolysis of thyroglobulin with release of hormone and leakage of iodide out of the gland.


Other effects include increase in mRNA for thyroglobulin and thyroperoxidase, with an increase in incorporation of I- into MIT, DIT, T3 and T4; and increased lysosomal activity, with increased secretion of T4 and T3 from the gland. There is also increased activity of type 1 5′-deiodinase, conserving intrathyroidal iodine.

TSH has still other effects on the thyroid gland, including stimulation of glucose uptake, oxygen consumption, CO2 production, and an increase in glucose oxidation via the hexosemonophosphate pathway and the Krebs cycle. There is accelerated turnover of phospholipids and stimulation of synthesis of purine and pyrimidine precursors, with increased synthesis of DNA and RNA.

Serum TSH

Normally, only α subunit and intact TSH are present in the serum. The level of α subunit is about 0.5–2 ľg/L; it is elevated in postmenopausal women and in patients with TSH-secreting pituitary tumors (see below). The serum level of TSH is about 0.5–5 mU/L; it is increased in hypothyroidism and decreased in hyperthyroidism, whether endogenous or from excessive oral intake of thyroid hormones. The plasma half-life of TSH is about 30 minutes, and the daily production rate is about 40–150 mU/d.

Control of Pituitary TSH Secretion

The two major factors controlling the synthesis and release of TSH are the level of intrathyrotroph T3, which


controls mRNA for TSH synthesis and release; and TRH, which controls glycosylation, activation, and release of TSH Table 7-6.


Figure 7-24. Schematic representation of the TSH receptor. The A subunit is the ligand-binding portion of the receptor and the B subunit is the activation portion. The ligands which bind to the receptor include TSH, TSH-stimulating antibody, and TSH-blocking antibody. There are two cleavage sites which allow breakage of the receptor and loss of the A subunit into the serum. (Reproduced, with permission, from Rapoport R et al: The thyrotropin (TSH)-receptor: interaction with TSH and autoantibodies. Endocr Rev 1998;19:673.)

TSH synthesis and release are inhibited by high serum levels of T4 and T3 (hyperthyroidism) and stimulated by low levels of thyroid hormone (hypothyroidism). In addition, certain hormones and drugs inhibit TSH secretion. These include somatostatin, dopamine, dopamine agonists such as bromocriptine, and glucocorticoids. Acute or chronic disease may cause inhibition of TSH secretion during active illness, and there may be a rebound rise in TSH as the patient recovers. The magnitude of these effects is variable; thus, the drugs mentioned above will suppress serum TSH, but it will usually be detectable. In contrast, hyperthyroidism will turn off TSH secretion entirely. These observations are important clinically in interpreting serum TSH levels in patients receiving these medications.

Destructive lesions or tumors of the hypothalamus or anterior pituitary gland may impair TRH and TSH secretion by destruction of secretory cells. This will result in “secondary hypothyroidism” due to pituitary thyrotroph destruction or “tertiary hypothyroidism” due to destruction of TRH-secreting neurons. Differential diagnosis of these lesions is discussed below (see Thyroid Tests).

Other Thyroid Stimulators & Inhibitors

The thyroid follicle has a rich supply of capillaries that carry noradrenergic nerve fibers from the superior cervical ganglion and acetylcholine esterase-positive nerve fibers derived from the vagal nodose and thyroid ganglia. The parafollicular C cells secrete both calcitonin and calcitonin gene-related peptide (CGRP). In experimental animals, these and other neuropeptides modify thyroid blood flow and hormone secretion. In addition, growth factors such as insulin, IGF-I, and EGF and the autocrine actions of prostaglandins and cytokines may modify thyroid cell growth and hormone production. However, it is not yet clear how important these effects are in clinical situations.

Role of Pituitary & Peripheral Deiodinases

Pituitary type 2 5′-deiodinase converts T4 to T3 in the brain and pituitary, providing the main source of intracellular T3. Its increased activity in hypothyroidism


helps to maintain cerebral intracellular T3 in the presence of falling serum T4 concentrations. In hyperthyroidism, the decrease in its activity helps to prevent overloading of pituitary and neural cells with thyroid hormone. In contrast, type 1 5′-deiodinase is decreased in hypothyroidism, conserving T4, and increased in hyperthyroidism, accelerating T4 metabolism Table 7-3.

Thyroidal Autoregulation

Autoregulation may be defined as the capacity of the thyroid gland to modify its function to adapt to changes in the availability of iodine, independent of pituitary TSH. Thus, humans can maintain normal thyroid hormone secretion with iodide intakes varying from 50 ľg to several milligrams per day. Some of the effects of iodide deficiency or excess are discussed above. The major adaptation to low iodide intake is the preferential synthesis of T3 rather than T4, increasing the metabolic effectiveness of the secreted hormone. Iodide excess, on the other hand, inhibits many thyroidal functions, including I- transport, cAMP formation, H2O2 generation, hormone synthesis and secretion, and the binding of TSH and TSH-R Ab to the TSH receptor. Some of these effects may be mediated by the formation of intrathyroidal iodinated fatty acids. The ability of the normal thyroid to“escape” from these inhibitory effects (Wolff-Chaikoff effect) allows the gland to continue to secrete hormone despite a high dietary iodide intake. It is important to note that this is different from the therapeutic effect of iodide in the treatment of Graves' disease. Here, the high levels of iodide inhibit thyroglobulin endocytosis and lysosomal activity, decreasing thyroid hormone release and lowering circulating hormone levels. In addition, the inhibition of TSH-R Ab [stim] activity reduces the vascularity of the gland, with beneficial consequences during surgery. This effect is also transient, lasting about 10 days to 2 weeks.

Autoimmune Regulation

The ability of B lymphocytes to synthesize TSH receptor antibodies that can either block the action of TSH or mimic TSH activity by binding to different areas on the TSH receptor provides a form of thyroid regulation by the immune system.


Thus, the synthesis and secretion of thyroid hormones are controlled at three different levels: (1) the level of the hypothalamus, by modifying TRH secretion; (2) the pituitary level, by inhibition or stimulation of TSH secretion; and (3) the level of the thyroid, by autoregulation and blockade or stimulation of the TSH receptor Table 7-6.


  1. The Thyroid Hormone Receptor

Thyroid hormones, T3 and T4, circulate in plasma largely bound to protein but in equilibrium with the free hormone. It is the free hormone that is transported, either by passive diffusion or by specific carriers, through the cell membrane, through the cell cytoplasm, to bind to a specific receptor in the cell nucleus. Within the cell, T4 is converted to T3 by 5′ deiodinase, suggesting that T4 is a prohormone and T3 the active form of the hormone. The nuclear receptor for T3 has been cloned. It is one of a“family” of receptors, all similar to the receptor for the retrovirus that causes erythroblastosis in chickens, v-erbA, and to the nuclear receptors for glucocorticoids, mineralocorticoids, estrogens, progestins, vitamin D3, and retinoic acid (Figure 3-13).

In the human, there are two genes for the thyroid hormone receptor, alpha and beta. TRα is located on chromosome 17 and TRβ on chromosome 3. Each gene produces at least two products, TRα 1 and 2 and TRβ 1 and 2. The structure and characteristics of these products are portrayed in Figure 7-25. Each has three domains: a ligand-independent domain at the amino terminal, a centrally located DNA binding area with two cysteine-zinc “fingers,” and a ligand-binding domain at the carboxyl terminal (Figures 3-12 and 3-13). Note that TRα2 does not bind T3 and may actually inhibit T3 action. The concentration of these receptors in tissue varies with the stage of development and the tissue. For example, the brain contains mostly TRα, the liver mostly TRβ, and cardiac muscle contains both. The binding affinity of T3analogs is directly proportionate to the biologic activity of the analog. Point mutations in the ligand-binding domain of the TRβ gene are responsible for the syndrome of generalized resistance to thyroid hormone (GRTH—Refetoff's syndrome; see below).

The thyroid hormone receptors may bind to the specific thyroid hormone response element (TRE) sites on DNA even in the absence of T3(Figure 7-26)—unlike the steroid hormone receptors). The TREs are located near—generally upstream with respect to the start of transcription—to the promoters where transcription of specific thyroid hormone-responsive genes is initiated. T3 binding to the receptors results in stimulation—in some cases inhibition—of the transcription of these genes with consequent changes in the levels of the mRNAs transcribed from them. The changes in mRNA levels alter the levels of the protein product of these




genes. These proteins then mediate the thyroid hormone response. These receptors often function as heterodimers with other transcription factors such as the retinoid X receptor and the retinoic acid receptor (Figure 7-26).


Figure 7-25. Deduced protein structure of the thyroid hormone receptor α and β gene products. The receptor protein has three domains: a DNA-binding domain with a high degree of similarity among the different types of receptors, a carboxyl terminal triiodothyronine (T3) binding domain, and an amino terminal domain that is not required for full function. The numbers above the structures represent amino acid numbers. The properties of the receptors with respect to their ability to bind T3 and bind to a T3-response element of DNA are shown on the right. Identical shading of receptor domains indicates identical amino acid sequences. (TR, thyroid hormone receptor.) (Reproduced, with permission, from Brent GA: The molecular basis of thyroid hormone action. N Engl J Med 1994;331:847.)


Figure 7-26. Model of the interaction of T3 with the T3 receptor. Panel A, Inactive Phase: The unliganded T3 receptor dimer bound to the TRE along with corepressors acts as a suppressor of gene transcription. Panel B, Active Phase: T3 and T4 circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within the cytoplasm, T4 is converted to T3 by 5′-deiodinase and T3 moves into the nucleus. There it binds to the ligand-binding domain of the TR monomer. This promotes disruption of the TR homodimer and heterodimerization with RXR on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads to alteration in protein synthesis and cellular phenotype. (TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; TRE, thyroid hormone response element; TBPs, thyroxine-binding proteins; T3, triiodothyronine; T4, tetraiodothyronine, L-thyroxine; 5′DI, 5′-deiodinase.

  1. Physiologic Effects of Thyroid Hormones

The transcriptional effects of T3 characteristically demonstrate a lag time of hours or days to achieve full effect. These genomic actions result in a number of effects, including those on tissue growth, brain maturation, and increased heat production and oxygen consumption, which is due in part to increased activity of Na+-K+ ATPase and in part to production of increased beta-adrenergic receptors. Some actions of T3 are not genomic, such as reduction of pituitary type 2 5′-deiodinase and increase in glucose and amino acid transport. Some specific effects of thyroid hormones are summarized in what follows.

Effects on Fetal Development

The thyroid and the anterior pituitary TSH system begin to function in the human fetus at about 11 weeks. Prior to this time, the fetal thyroid does not concentrate 123I. Because of the high placental content of type 3 5-deiodinase, most maternal T3 and T4 are inactivated in the placenta, and very little free hormone reaches the fetal circulation. This small amount of free hormone from the mother may be important for early fetal brain development. However, after 11 weeks of gestation, the fetus is largely dependent on its own thyroidal secretion. Although some fetal growth occurs in the absence of fetal thyroid hormone secretion, brain development and skeletal maturation are markedly impaired, resulting in cretinism (mental retardation and dwarfism).

Effects on Oxygen Consumption, Heat Production, & Free Radical Formation

T3 increases O2 consumption and heat production in part by stimulation of Na+-K+ ATPase in all tissues except the brain, spleen, and testis. This contributes to the increased basal metabolic rate (O2 consumption by the whole animal at rest) and the increased sensitivity to heat in hyperthyroidism—and the converse in hypothyroidism. Thyroid hormones also decrease superoxide dismutase levels, resulting in increased superoxide anion free radical formation. This may contribute to the deleterious effects of chronic hyperthyroidism.

Cardiovascular Effects

T3 stimulates transcription of myosin heavy chain α and inhibits myosin heavy chain β, improving cardiac muscle contractility. T3 also increases transcription of Ca2+ ATPase in the sarcoplasmic reticulum, increasing diastolic tone of the heart; alters isoforms of Na+-K+ATPase genes; and increases beta-adrenergic receptors and the concentration of G proteins. Thus, thyroid hormones have marked positive inotropic and chronotropic effects on the heart. This accounts for the increased cardiac output and marked increase in heart rate in hyperthyroidism and the reverse in hypothyroidism.

Sympathetic Effects

As noted above, thyroid hormones increase the number of beta-adrenergic receptors in heart muscle, skeletal muscle, adipose tissue, and lymphocytes. They also decrease myocardial alpha-adrenergic receptors. In addition, they may amplify catecholamine action at a postreceptor site. Thus, sensitivity to catecholamines is markedly increased in hyperthyroidism, and therapy with beta-adrenergic blocking agents may be very helpful in controlling tachycardia and arrhythmias.

Pulmonary Effects

Thyroid hormones maintain normal hypoxic and hypercapnic drive in the respiratory center. In severe hypothyroidism, hypoventilation occurs, occasionally requiring assisted ventilation.

Hematopoietic Effects

The increased cellular demand for O2 in hyperthyroidism leads to increased production of erythropoietin and increased erythropoiesis. However, blood volume is usually not increased because of hemodilution and increased red cell turnover. Thyroid hormones increase the 2,3-diphosphoglycerate content of erythrocytes, allowing increased O2 dissociation from hemoglobin and increasing O2 availability to tissues. The reverse occurs in hypothyroidism.

Gastrointestinal Effects

Thyroid hormones stimulate gut motility, which can result in increased motility and diarrhea in hyperthyroidism and slowed bowel transit and constipation in hypothyroidism. This may also contribute to the modest weight loss in hyperthyroidism and weight gain in hypothyroidism.



Skeletal Effects

Thyroid hormones stimulate increased bone turnover, increasing bone resorption and, to a lesser degree, bone formation. Thus, chronic hyperthyroidism may result in significant osteopenia and, in severe cases, modest hypercalcemia, hypercalciuria, and increased excretion of urinary hydroxyproline and pyridinium cross-links.

Neuromuscular Effects

Although thyroid hormones stimulate increased synthesis of many structural proteins, in hyperthyroidism there is increased protein turnover and loss of muscle tissue, or myopathy. This may be associated with spontaneous creatinuria. There is also an increase in the speed of muscle contraction and relaxation, noted clinically in the hyperreflexia of hyperthyroidism—or the reverse in hypothyroidism. As noted above, thyroid hormones are essential for normal development and function of the central nervous system, and failure of fetal thyroid function results in severe mental retardation. In the adult, hyperactivity in hyperthyroidism and sluggishness in hypothyroidism can be striking.

Effects on Lipid & Carbohydrate Metabolism

Hyperthyroidism increases hepatic gluconeogenesis and glycogenolysis as well as intestinal glucose absorption. Thus, hyperthyroidism will exacerbate underlying diabetes mellitus. Cholesterol synthesis and degradation are both increased by thyroid hormones. The latter effect is due largely to an increase in the hepatic low-density lipoprotein (LDL) receptors, so that cholesterol levels decline with thyroid overactivity. Lipolysis is also increased, releasing fatty acids and glycerol. Conversely, cholesterol levels are elevated in hypothyroidism.

Endocrine Effects

Thyroid hormones increase the metabolic turnover of many hormones and pharmacologic agents. For example, the half-life of cortisol is about 100 minutes in the normal individual, about 50 minutes in a hyperthyroid patient, and about 150 minutes in a hypothyroid patient. The production rate of cortisol will increase in the hyperthyroid patient with normal adrenal function, thus maintaining a normal circulating hormone level. However, in a patient with adrenal insufficiency, the development of hyperthyroidism or thyroid hormone treatment of hypothyroidism may unmask the adrenal disease. Ovulation may be impaired in both hyperthyroidism and hypothyroidism, resulting in infertility, which will be corrected by restoration of the euthyroid state. Serum prolactin levels are increased in about 40% of patients with hypothyroidism, presumably a manifestation of increased TRH release; this will revert to normal with T4 therapy. Other endocrine effects will be discussed in appropriate sections elsewhere in this chapter.


Thyroid Function in the Fetus

Prior to the development of independent fetal thyroid function, the fetus is dependent on maternal thyroid hormones for early neural development. However, by the 11th week of gestation, the hypophysial portal system has developed, and measurable TSH and TRH are present. At about the same time, the fetal thyroid begins to trap iodine. The secretion of thyroid hormone probably begins in mid gestation (18–20 weeks). TSH increases rapidly to peak levels at 24–28 weeks, and T4 levels peak at 35–40 weeks. T3 levels remain low during gestation; T4 is converted to rT3 by type 3 5-deiodinase during fetal development. At birth, there is a sudden marked rise in TSH, a rise in T4, a rise in T3, and a fall in rT3. These parameters gradually return to normal over the first month of life.

Thyroid Function in Pregnancy

The striking change in thyroid parameters during pregnancy is the rise in TBG and consequent rise in total T4 and total T3 in the serum. The rise in TBG is due to estrogen-induced hepatic glycosylation of TBG with N-acetylgalactosamine, which prolongs the metabolic clearance rate of TBG. There is usually no change in thyroxine-binding prealbumin and little change in albumin. Although total T4 and T3 are increased, a new equilibrium develops between free and bound thyronines, and the levels of free T4 and free T3 are normal. Other changes in pregnancy include an increase in iodide clearance, which, in areas of low iodine intake, may result in impaired hormone synthesis and a fall in T4, a rise in TSH, and thyroid enlargement. hCG, which peaks near the end of the first trimester, has a weak TSH agonist activity and may be responsible for the slight thyroid enlargement that occurs at that time. Maternal I- crosses the placenta and supplies the fetal requirement; in large amounts, I- can inhibit fetal thyroid function. Maternal TSH-R Ab [stim] and TSH-R Ab [block] can also cross the placenta and may be responsible for thyroid dysfunction in the fetus. As noted above, most maternal T3 and T4 are deiodinated by placental type 3 5-deiodinase and do not reach the fetus.


However, antithyroid drugs such as propylthiouracil and methimazole do cross the placenta and in large doses will block fetal thyroid function (Chapter 16).

Changes in Thyroid Function with Aging

Thyroxine turnover is highest in infants and children and gradually falls to adult levels after puberty. The T4 turnover rate is then stable until after age 60, when it again drops slightly. Thus, replacement doses of levothyroxine will vary with age and other factors, and patients taking the drug must be monitored regularly (see below and Chapter 23).

Effects of Acute & Chronic Illness on Thyroid Function (Euthyroid Sick Syndrome)

Acute or chronic illness may have striking effects on circulating thyroid hormone levels by modifying the peripheral metabolism of T4 or by interference with T4 binding to TBG. These effects can be classified as (1) the low T3 syndrome or (2) the low T3-T4 syndrome.

The peripheral metabolism of T4 is diagrammed in Figure 7-19. Inhibition of outer ring type 1 5′-deiodinase or activation of type 3 5-deiodinase accelerates conversion of T4 to rT3 and conversion of T3 to 3,3′-T2. These reactions will markedly lower the circulating level of T3, resulting in the low T3 syndrome. This occurs physiologically in the fetus and pathologically in circumstances of carbohydrate restriction, as in malnutrition, starvation, anorexia nervosa, and diabetes mellitus, and in patients with hepatic disease or major acute or chronic systemic illnesses Table 7-4. Drugs that inhibit type 1 5′-deiodinase also lower the circulating levels of T3; corticosteroids, amiodarone, and iodinated dyes are the most effective, and propylthiouracil and propranolol are relatively weak. The pathogenesis of the low T3 syndrome when associated with acute or chronic illness is thought to involve cytokines such as tumor necrosis factor, secreted by inflammatory cells, which inhibit type 1 5′-deiodinase, accelerating inner ring deiodination of T4.

Serum thyroid hormone levels in the low T3 syndrome are presented diagrammatically in Figure 7-27. T3 levels are low; total T4 levels are normal or slightly elevated; free T4 (by dialysis) often is slightly elevated; and rT3 is elevated. TSH is normal. True hypothyroidism can be ruled out by the normal T4, FT4, and TSH and by the elevated rT3.

Patients with the low T3-T4 syndrome are usually much sicker, and indeed the mortality rate in this group of patients may approach 50%. Serum T3 and T4 levels are both low; FT4 (by dialysis) is usually normal; and rT3 is elevated. TSH is usually normal, though it may be low if the patient is receiving dopamine or corticosteroids, which suppress TSH. The pathogenesis of this syndrome is thought to involve the liberation of unsaturated fatty acids, such as oleic acid, from anoxic or injured tissue, which inhibits the binding of T4 to TBG. The syndrome can be differentiated from true hypothyroidism by the normal levels of free T4 and TSH.

These abnormalities normalize when the patient recovers. Recovery is frequently accompanied by a transient elevation of the serum TSH that may be misinterpreted as hypothyroidism. In this setting, in the absence of clinically apparent hypothyroidism, it is best to avoid thyroid hormone therapy and to reevaluate


at a later time following recovery. It is possible that intracellular hypothyroidism exists in these patients, but administration of T3 or T4does not benefit the patient and may worsen the situation. Thus, these changes may represent a protective adaptation on the part of the organism to severe illness. For example, one effect would be to reduce oxygen and other metabolic demands.


Figure 7-27. A schematic representation of the changes in serum thyroid hormone values with increasing severity of nonthyroidal illness. A rapidly rising mortality rate accompanies the fall in serum total T4 (TT4) and free T4 (FT4) values. (Reproduced, with permission, from Nicoloff JT: Abnormal measurements in nonendocrine illness. In: Medicine for the Practicing Physician, 2nd ed. Hurst JW [editor]. Butterworth-Heinemann, 1991.)


Autoimmune mechanisms are involved in the pathogenesis of many thyroid diseases, including the hyperthyroidism, ophthalmopathy, and dermopathy associated with Graves' disease; the nontoxic goiter or atrophic hypothyroidism associated with Hashimoto's thyroiditis; neonatal Graves' disease and some forms of neonatal hypothyroidism; and postpartum hyperthyroidism or hypothyroidism. Thus, it is important that we understand how the immune system works and how thyroid disease develops (see Chapter 4).

Immunologic defense against foreign substances and neoplastic cells involves macrophages that ingest and digest the foreign material and present peptide fragments on the cell surface in association with a class II protein coded by the HLA-DR region of the MHC gene complex. This complex is recognized by a T cell receptor on a CD4 helper T cell, which stimulates the release of cytokines such as interleukin-2 (IL-2). These cytokines amplify the response by inducing T cell activation and division, induction of killer cell activity in CD8 suppressor cells, and stimulation of antibody formation against the foreign antigen by B lymphocytes. Eventually, the activation process is muted by the action of the CD8 suppressor cells.

In 1956, three major observations suggested the possibility that immunologic reactions could develop involving the thyroid gland: (1) Rose and Witebsky produced thyroiditis in one lobe of a rabbit thyroid by immunization of the animal with a suspension of the other lobe in Freund's adjuvant; (2) Roitt and Doniach demonstrated the presence of precipitating human thyroglobulin antibodies in the serum of patients with thyroiditis; and (3) Adams and Purves demonstrated the presence of a long-acting thyroid stimulator (later proved to be an antibody to the TSH receptor) in the serum of patients with Graves' disease. Thus, the concept of autoimmune thyroid disease was born.

There are three major thyroidal autoantigens: thyroglobulin (Tg), thyroperoxidase (TPO), and the TSH receptor (TSH-R). Autoantibodies to these antigens are useful as markers for the presence of autoimmune thyroid disease. However, the pathogenesis of the thyroid disease probably involves lymphocyte sensitization to these and possibly other thyroidal antigens. Thyroid cells have the capacity to ingest antigen (eg, thyroglobulin) and, when stimulated by cytokines such as gamma interferon, will express cell surface class II molecules (eg, HLA-DR4) to present these antigens to T lymphocytes. Whereas the presence of both the antigen and the class II molecule may be required for autoimmune thyroid disease to develop, other unknown factors also are critical. Active inquiry is under way into whether the process is initiated or promoted either by external antigens that lead to antibody and cellular immune responses through cross-reactivity with thyroid gland antigens or by primary or secondary immunologic imbalances—or by both mechanisms. Clues to the pathogenesis may come from understanding the roles of both genetic and environmental factors now known to be associated with autoimmune thyroid disease.

Genetic factors play a large role in the autoimmune process. HLA typing in patients with Graves' disease reveals a high incidence of HLA-B8 and HLA-DR3 in Caucasians, HLA-Bw46 and HLA-B5 in Chinese, and HLA-B17 in blacks. In Caucasians, atrophic thyroiditis has been associated with HLA-B8 and goitrous Hashimoto's thyroiditis with HLA-DR5. These associations are of limited diagnostic or prognostic value but illustrate the genetic predisposition to autoimmune thyroid disease. It has been suggested that a genetically induced antigen-specific defect in suppressor T lymphocytes may be the basis for autoimmune thyroid disease.

Environmental factors may also play a role in the pathogenesis of autoimmune thyroid disease. Viruses infecting human thyroid cell cultures induce the expression of HLA-DR4 on the follicle cell surface, probably as an effect of a cytokine such as alpha interferon. The increased incidence of autoimmune thyroid disease in postpubertal and premenopausal women, as well as the occurrence of postpartum thyroiditis, implies a role for sex hormones in the pathogenesis of autoimmune thyroid disease. The gram-negative bacillus Yersinia enterocolitica, which can cause chronic enterocolitis in humans, has a saturable binding site for mammalian thyrotropin as well as antigens that cross-react with human thyroid antigens. It has been postulated that antibodies against Y. enterocolitica could cross-react with the TSH-R on the thyroid cell membrane and trigger an episode of Graves' disease. A high iodine intake may result in more highly iodinated thyroglobulin, which is more immunogenic and would favor the development of autoimmune thyroid disease. Therapeutic doses of lithium, used for the treatment of manic-depressive psychoses, can interfere with suppressor cell function and precipitate autoimmune thyroid disease. Thus, there are a number of environmental and genetic factors that could contribute to the development of this disorder.




The function of the thyroid gland may be evaluated in many different ways: (1) tests of thyroid hormones in blood, (2) evaluation of the hypothalamic-pituitary-thyroid axis, (3) assessment of iodine metabolism, (4) estimation of gland size, (5) thyroid biopsy, (6) observation of the effects of thyroid hormones on peripheral tissues, and (7) measurement of thyroid autoantibodies.


The total serum T4 and total serum T3 are measured by radioimmunoassay or immunofluorescent assay. If the concentration of serum thyroid hormone binding proteins is normal, these measurements provide a reasonably reliable index of thyroid gland activity. However, changes in serum concentration of thyroid-binding proteins or the presence of drugs that modify the binding of T4 or T3 to TBP Table 7-1 will modify the total T4 and T3 but not the amount of free hormone. Thus, further tests must be performed to assess the free hormone level that determines biologic activity (Figure 7-15).

Serum free thyroxine (FT4) can be estimated using the free thyroxine index (FT4I). This is the product of the total T4 multiplied by the percentage of free T4 as estimated by the amount of T4 which binds to resin or charcoal added to the system. A more precise estimate of free thyroxine is obtained by a two-step chemiluminescent immunoassay in which the thyroxine antibody system is modified to react with the free hormone. The normal range for FT4 by this assay is 0.7–1.85 ng/dL (9–24 pmol/L). Although the FT4I or the FT4 is valid for normal subjects, these assays may not be valid in subjects with dysproteinemias and abnormal thyroxine-binding proteins (TBPs)—or in subjects taking medications modifying TBP (see Table 7-1)—or in subjects with the euthyroid sick syndrome. In these subjects, free thyroxine by equilibrium dialysis (FT4D) will more accurately reflect the level of free thyroxine. Note that FT4 does not measure T3, so that patients receiving high oral doses of T3 or with T3 hyperthyroidism (early Graves' disease or toxic nodular goiter), FT4 may be low despite the hyperthyroid state (T3 toxicosis). Antiepileptic drugs such as phenytoin and carbamazepine and the antituberculous drug rifampin increase hepatic metabolism of T4, resulting in a low total T4, a low free T4, and a low FT4I. However, serum T3 and serum TSH levels are normal, indicating that patients receiving these drugs are euthyroid. As noted above, T4 and FT4I may be low in severe illness, but FT4D and TSH are usually normal, which will distinguish these very ill patients from patients who are hypothyroid.

At times, FT4I and FT4D will be inappropriately elevated. For example, drugs such as iodinated contrast media, amiodarone, glucocorticoids, and propranolol Table 7-4 inhibit type 1 5′-deiodinase and the conversion of T4 to T3 in peripheral tissues, resulting in elevation of total T4,FT4I, and FT4D and depression of T3. Hyperthyroidism is ruled out by the low T3 and normal TSH. FT4I and FT4D are inappropriately elevated in the rare syndrome of generalized resistance to thyroid hormone (see below). The presence of heparin in serum, even in the tiny amounts that would be found in a patient with a “heparin lock” indwelling intravenous catheter, will cause a spurious increase in FT4D. This occurs in the test tube, since heparin activates lipoprotein lipase, releasing free fatty acids that displace T4 from TBG.

Total T3 can be measured in serum by immunoassay with specific T3 antisera. The normal range in adults is 70–132 ng/dL (1.1–2 nmol/L). The measurement of total T3 is most useful in the differential diagnosis of hyperthyroidism, because T3 is preferentially secreted in early Graves' disease or toxic nodular goiter. For example, the normal ratio of serum T3 in ng/dL to T4 in ľg/dL is less than 20 (eg, T3 120 ng/dL, T4 8 ľg/dL: ratio = 15). In hyperthyroidism, this ratio will usually be well over 20, and it will be even higher in T3 thyrotoxicosis. T3 levels are often maintained in the normal range in hypothyroidism because TSH stimulation increases the relative secretion of T3; thus, serum T3 is not a good test for hypothyroidism.

T3 is bound to TBG, and the total T3 concentration in serum will vary with the level of TBG Table 7-1. Serum free T3 (FT3) can be measured by immunoassay or more precisely by equilibrium dialysis; the normal adult FT3 is 230–420 pg/dL (3.5–6.5 pmol/L).

Reverse T3 (rT3) can be measured by radioimmunoassay. The serum concentration of rT3 in adults is about one-third of the total T3concentration, with a range of 25–75 ng/dL (0.39–1.15 nmol/L). RT3 can be used to differentiate chronic illness from hypothyroidism becauserT3 levels are elevated in chronic illness and low in hypothyroidism. However, this differential diagnosis can be made by determination of TSH (see below), so that it is rarely necessary to measure rT3.

Thyroglobulin(Tg) can be measured in serum by double antibody radioimmunoassay. The normal range will vary with method and laboratory, but generally the normal range is less than 40 ng/mL (< 40 ľg/L) in the euthyroid individual and less than 2 ng/mL (< 2 ľg/L) in a totally thyroidectomized individual. The major problem with the test is that endogenous thyroglobulin antibodies interfere with the assay procedure and, depending on the method, may result in spuriously low or


spuriously high values. Serum thyroglobulin is elevated in situations of thyroid overactivity such as Graves' disease and toxic multinodular goiter; in subacute or chronic thyroiditis, where it is released as a consequence of tissue damage; and in patients with large goiters, in whom the thyroglobulin level is proportionate to the size of the gland. Serum thyroglobulin determinations have been most useful in the management of patients with papillary or follicular thyroid carcinoma. Following thyroidectomy and 131I therapy, thyroglobulin levels should be very low. In such a patient, serum thyroglobulin greater than 2 ng/dL (> 2 ľg/L) indicates the presence of metastatic disease, and a rise in serum thyroglobulin in a patient with known metastases indicates progression of the disease.


The hypothalamic-pituitary-thyroid axis is illustrated in Figure 7-20. It has not been clinically feasible to measure TRH in the peripheral circulation in humans. However, very sensitive methods for the measurement of TSH have been developed using monoclonal antibodies against human TSH. The general principle is this: One monoclonal TSH antibody is fixed to a solid matrix to bind serum TSH, and a second monoclonal TSH antibody labeled with isotope or enzyme or fluorescent tag will bind to a separate epitope on the TSH molecule. The quantity of TSH in the serum is thus proportionate to the quantity of bound second antibody. The earlier TSH radioimmunoassays, which could detect about 1 ľU of TSH/mL, were adequate for the diagnosis of elevated TSH in hypothyroidism but could not detect suppressed TSH levels in hyperthyroidism. The “second generation” of“sensitive” TSH assays, using monoclonal antibodies, can detect about 0.1 ľU/mL, and the “third generation” of “supersensitive”assays are sufficiently sensitive to detect about 0.01 ľU/mL. This has allowed measurement of TSH well below the normal range of 0.5–5 ľU/mL (0.5–5 mU/L) and has enabled the clinician to detect partially and totally suppressed serum TSH levels. The level of FT4 is inversely related to the logarithm of the TSH concentration (Figure 7-28A). Thus, a small change in FT4 may result in a large change in TSH. The relationship between TSH and FT4 in various situations is demonstrated in Figure 7-28A and 7-28B. Serum TSH below 0.1 ľU/mL (0.1 mU/L) and an elevated FT4 or FT4I is indicative of hyperthyroidism. This may be due to Graves' disease, toxic nodular goiter, or high-dose thyroxine therapy. In the rare case of hyperthyroidism due to a TSH-secreting pituitary tumor, FT4I or FT4 will be elevated and TSH will not be suppressed but will actually be normal or slightly elevated. An elevated TSH (> 10 ľU/mL; 10 mU/L) and a lowFT4 or FT4I is diagnostic of hypothyroidism. In patients with hypothyroidism due to a pituitary or hypothalamic tumor (central hypothyroidism), FT4I or FT4 will be low and TSH will not be elevated. This diagnosis can be confirmed by demonstrating the failure of serum TSH to increase following an injection of TRH. The TRH test is performed as follows: 200 ľg of TRH is administered intravenously. Serum TSH is determined prior to the injection and at 30 and 60 minutes afterward. The absence of a rise in TSH indicates either pituitary insufficiency or suppression. A modest or delayed rise may be seen in patients with hypothalamic disease and hypothyroidism. The test can also be used to differentiate the hyperthyroxinemia of the T3 resistance syndrome from thyrotoxicosis due to a TSH-secreting pituitary tumor. TRH will produce a rise in TSH in the patient with a thyroid hormone resistance syndrome, whereas TSH-secreting tumors will not respond to TRH. Note that corticosteroids and dopamine inhibit TSH secretion Table 7-6, which will modify the interpretation of serum TSH levels in patients taking these drugs.

Serum TSH levels reflect the anterior pituitary gland sensing the level of circulating FT4. High FT4 levels suppress TSH and low FT4 levels increase TSH release. Thus, the ultrasensitive measurement of TSH has become the most sensitive, most convenient, and most specific test for the diagnosis of both hyperthyroidism and hypothyroidism. Indeed, a suppressed TSH correlates so well with impaired pituitary response to TRH that the simple measurement of serum TSH has replaced the TRH test in the diagnosis of hyperthyroidism.


Radioactive iodine allows assessment of the turnover of iodine by the thyroid gland in vivo. Iodine-123 is the ideal isotope for this purpose: It has a half-life of 13.3 hours and releases a 28-keV x-ray and a 159-keV gamma photon but no beta emissions. Thus, it is easily measured and causes little tissue damage. It is usually administered orally in a dose of 100–200 ľCi, and radioactivity over the thyroid area is measured with a scintillation counter at 4 or 6 hours and again at 24 hours (Figure 7-8). The normal radioactive iodine uptake (RAIU) will vary with the iodide intake. In areas of low iodide intake and endemic goiter, the 24-hour RAIU may be as high as 60–90%. In the USA—a country with a relatively high iodide intake—the normal uptake at 6 hours is 5–15% and at 24 hours 8–30%. In thyrotoxicosis due to Graves' disease or toxic nodular goiter, the 24-hour RAIU is markedly elevated,


though if the iodide turnover is very rapid, the 5-hour uptake may be even higher than the 24-hour uptake (Figure 7-8). Thyrotoxicosis with a very low thyroidal RAIU occurs in the following situations: (1) in subacute thyroiditis; (2) during the active phase of Hashimoto's thyroiditis, with release of preformed hormone, causing “spontaneously resolving thyrotoxicosis”; (3) in thyrotoxicosis factitia due to oral ingestion of a large amount of thyroid hormone; (4) as a result of excess iodide intake (eg, amiodarone therapy), inducing thyrotoxicosis in a patient with latent Graves' disease or multinodular goiter, the low uptake being due to the huge iodide pool; (5) in struma ovarii; and (6) in ectopic functioning metastatic thyroid carcinoma after total thyroidectomy.


Figure 7-28. A: Relationship between serum free thyroxine by dialysis (FT4) ng/dL and log10 TSH in euthyroid, hyperthyroid, hypothyroid, and L-T4-suppressed euthyroid individuals. Note that for each unit change in T4 there is a logarithmic change in TSH.

In normal individuals, administration of 75–100 ľg of T3 in divided doses daily for 5 days will reduce the 24-hour RAIU by more than 50% (suppression test). Failure of the thyroid to suppress on this treatment indicates autonomous thyroid function, as in Graves' disease, or autonomously functioning thyroid nodules.

The efficiency of the thyroid organification process may be tested with the “perchlorate discharge test.” As noted above, KClO4 will displace I-from the iodide trap. Thus, oral administration of 0.5 g KClO4 to a normal individual will block further uptake of 123I, but not more


than 5% of the previously accumulated radioiodine will be released. Conversely, if there is an organification defect, not only is further uptake blocked but I- diffuses out of the gland or is “discharged.” Positive tests are seen in some patients with congenital iodide organification defects, Hashimoto's thyroiditis, Graves' disease after 131I therapy, or patients receiving inhibitors of iodide organification such as methimazole or propylthiouracil. The perchlorate discharge test is rarely used clinically, but it can be very helpful in understanding the pathophysiology of some of the above illnesses (see Figure 7-11).


Figure 7-28. B: Relationship between FT4 by dialysis and log10 TSH in normal subjects and subjects with various illnesses including primary hypothyroidism, central hypothyroidism and non-levothyroxine-suppressed TSH, levothyroxine-treated congenital hypothyroidism, TSH-secreting tumors, thyroid hormone resistance, nonthyroidal illness, and nonpituitary hyperthyroidism. (Reproduced, with permission, from Kaptein EM: Clinical applications of free thyroxine determinations. Clin Lab Med 1993;13:654.)


  1. Radionuclide Imaging

123I and technetium Tc 99m pertechnetate (99mTc as TcO4) are useful for determining the functional activity


of the thyroid gland. 123I is administered orally in a dose of 200–300 ľCi, and a scan of the thyroid is obtained at 8–24 hours. 99mTcO4 is administered intravenously in a dose of 1–10 mCi, and the scan is obtained at 30–60 minutes. Images can be obtained with either a rectilinear scanner or a gamma camera. The rectilinear scanner moves back and forth over the area of interest; it produces a life-size picture, and special areas, such as nodules, can be marked directly on the scan (Figure 7-29). The gamma camera has a pinhole collimator, and the scan is obtained on a fluorescent screen and recorded on Polaroid film or a computer monitor. The camera has greater resolution, but special areas must be identified with a radioactive marker for clinical correlation (Figure 7-30). Radionuclide scans provide information about both the size and shape of the thyroid gland and the geographic distribution of functional activity in the gland. Functioning thyroid nodules are called “hot” nodules, and nonfunctioning ones are called “cold” nodules. The incidence of malignancy in hot nodules is about 1%, but they may become toxic, producing enough hormone to suppress the rest of the gland and induce thyrotoxicosis. About 16% of surgically removed cold nodules are malignant. Occasionally, a nodule will be hot with 99mTcO4 and cold with 123I, and a few of these nodules have been malignant. For large substernal goiters or for distant metastases from a thyroid cancer, 131I is the preferred isotope because of its long half-life (8 days) and its 0.72 MeV gamma emission.


Figure 7-29. Rectilinear sodium 123I scan performed 6 hours after the ingestion of 100 ľCi of sodium 123I. (Courtesy of RR Cavalieri.)


Figure 7-30. Scintiphoto (pinhole collimator) thyroid scan performed 6 hours after the ingestion of 100 ľCi of sodium 1231. (Courtesy of RR Cavalieri.)

  1. Fluorescent Scanning

The iodine content can be determined and an image of the thyroid gland can be obtained by fluorescent scanning without administration of a radioisotope. An external source of americium-241 is beamed at the thyroid gland, and the resulting emission of 28.5 keV x-ray from iodide ions is recorded, producing an image of the thyroid gland similar to that obtained with 123I (Figure 7-29). The advantage of this procedure is that the patient receives no radioisotope and the gland can be imaged even when it is loaded with iodine—as, for example, after intravenous contrast media. The disadvantage of this study is that it requires specialized equipment that may not be generally available.


A rough estimate of thyroid size and nodularity can be obtained from radionuclide scanning, but much better detail can be obtained by thyroid ultrasonography or MRI.

Thyroid ultrasonography is particularly useful for measuring the size of the gland or individual nodules and for evaluating the results of therapy (Figure 7-31). It is useful also for differentiating solid from cystic lesions and to guide the operator to a deep nodule during fine-needle thyroid aspiration biopsy (see below). Thyroid


ultrasonography is limited to thyroid tissue in the neck, ie, it cannot be used for substernal lesions.


Figure 7-31. Ultrasound of the normal thyroid gland. Tr, trachea; LL, left lobe of thyroid; RL, right lobe of thyroid; Is, isthmus; CA, carotid artery; JV, jugular vein; STM, sternothyroid muscle. (Courtesy of RA Filly.)

MRI provides an excellent image of the thyroid gland, including posterior or substernal extension of a goiter or malignancy. Both transverse and coronal images of the gland can be obtained, and lymph nodes as small as 1 cm can be visualized. MRI is invaluable for the demonstration of tracheal compression from a large goiter, tracheal invasion or local extension of a thyroid malignancy, or metastases to local or mediastinal lymph nodes.


Fine-needle aspiration biopsy of a thyroid nodule has proved to be the best method for differentiation of benign from malignant thyroid disease. It is performed as an outpatient procedure and requires no preparation. The skin over the nodule is cleansed with alcohol, and, if desired, a small amount of 1% lidocaine can be injected intracutaneously for local anesthesia. A No. 25 one and one-half-inch needle is then inserted into the nodule and moved in and out until a small amount of bloody material is seen in the hub of the needle; the needle is then removed, and with a syringe the contents of the needle are expressed onto a clean slide. A second clean slide is placed on top of the first slide, and a thin smear is obtained by drawing the slides apart quickly. Alternatively, a 10 mL or 20 mL syringe in an appropriate syringe holder can be used with a No. 23 one-inch needle to sample the nodule or to evacuate cystic contents.

The slides are fixed—either dry and stained with Wright's or Giemsa's stain, or fixed in alcohol and stained with Papanicolaou stain. The sensitivity (true-positive results divided by total cases of disease) is about 95%, and the specificity (true-negative results divided by total cases of no disease) is also about 95%. For best results, fine-needle aspiration biopsy requires an adequate tissue sample and a specially trained cytologist to interpret it.


The definitive test of thyroid function would be a test of the effect of thyroid hormones on body tissues. Thyroid hormones increase heat production and oxygen consumption. A measurement of this basal oxygen in the intact organism became one of the first tests of thyroid function, the basal metabolic rate (BMR). However, this test is nonspecific and insensitive and is rarely used today. The speed of muscle contraction and relaxation is increased in hyperthyroidism and decreased in hypothyroidism. The contraction and relaxation time of the Achilles tendon has been standardized and measured by an instrument called the photomotogram. However, there is considerable overlap between normal


subjects and patients with thyroid dysfunction, limiting the usefulness of this procedure.

Cardiac muscle contractility can also be measured as an index of thyroid hormone action. With echocardiography, it is relatively easy to measure such indices as the preejection period (PEP), the time from onset of the QRS complex to the opening of the aortic valve; or the left ventricular ejection time (LVET). These are prolonged in hypothyroidism and shortened in hyperthyroidism. Although these measurements are modified by coexistent cardiac disease, they may be the best objective tests for measuring the peripheral effects of thyroid hormone action.

Thyroid hormones influence the concentration of a number of enzymes and blood constituents. For example, serum cholesterol is usually lowered in hyperthyroidism and elevated in hypothyroidism. Serum creatine kinase and lactic dehydrogenase, probably of skeletal muscle origin, are elevated in hypothyroidism—and indeed, isoenzyme determination may be required to differentiate the enzyme changes occurring in myocardial infarction from those occurring in myxedema.

Sex hormone-binding globulin (SHBG) and angiotensin-converting enzyme are also increased in hyperthyroidism and decreased in hypothyroidism. However, none of these biochemical or enzyme changes are sensitive or specific enough for diagnostic use.


Thyroid autoantibodies include (1) thyroglobulin antibody (Tg Ab); (2) thyroperoxidase antibody (TPO Ab), formerly called microsomal antibody; and (3) TSH receptor antibody, either stimulating (TSH-R Ab [stim]) or blocking (TSH-R Ab [block]). Tg Ab and TPO Ab have been measured by hemagglutination, enzyme-linked immunosorbent assay (ELISA), or radioimmunoassay (RIA). The hemagglutination technique is much less sensitive than the ELISA or RIA methods. For example, in the Whickham study of a normal population in northeastern England, TPO antibodies were found in about 8% of young women (aged 18–24) and 13.7% of older women (aged 45–54). In a similar study of normal blood donors and using radioimmunoassay, TPO antibodies were found in 10.6% of younger and in 30.3% of older women. The incidence of positive TPO antibodies in normal men (by hemagglutination) was low—about 2%—and did not increase with age. On the other hand, high Tg Ab and TPO Ab titers by RIA are found in 97% of patients with Graves' disease or Hashimoto's thyroiditis. Thyroglobulin antibodies are often high early in the course of Hashimoto's thyroiditis and decrease with time; TPO antibodies are usually measurable for the life of the patient. The titers of both Tg and TPO antibodies will decrease with time following institution of T4 therapy in Hashimoto's thyroiditis or with antithyroid therapy in Graves' disease. A strongly positive test for either of these antibodies is an indication of the presence of autoimmune thyroid disease but is not specific for the type of disease, ie, hyperthyroidism, hypothyroidism, or goiter.

The thyroid receptor stimulating antibody (TSH-R Ab [stim]) is characteristic of Graves' disease (see above). It was originally measured by demonstrating prolonged discharge of radioiodine from the thyroid gland of the mouse after injection of serum from a patient with Graves' disease; it was then called long-acting thyroid stimulator (LATS). This laborious assay has been replaced by a bioassay using human thyroid cells in culture or culture of hamster ovary cells into which the human TSH receptor gene has been introduced. Then, the increase in thyroid cAMP is measured following incubation with serum or IgG. The test is positive in 80–90% of patients with Graves' disease and undetectable in healthy subjects or patients with Hashimoto's thyroiditis (without ophthalmopathy), nontoxic goiter, or toxic nodular goiter. It is most useful for the diagnosis of Graves' disease in patients with euthyroid ophthalmopathy or in predicting neonatal Graves' disease in the newborn of a mother with active or past Graves' disease.

The same type of assay can be used to detect TSH receptor-blocking antibody (TSH-R Ab [block]). In this assay, the increase in cAMP induced by TSH added to a human thyroid cell culture or the culture of hamster ovary cells containing the TSH-R gene is blocked by concurrent incubation with the patient's serum. The TSH-binding inhibition assay (TBII) measures the ability of serum IgG to inhibit the binding of labeled TSH to a thyroid cell membrane preparation containing the TSH receptor. This technique is not as satisfactory as the bioassay because there are a variety of nonspecific interfering substances, such as thyroglobulin, which inhibit TSH binding. However, a modification of the TSH-binding inhibition assay using recombinant human TSH receptor has proved to be more reliable. Detection of a TSH receptor-blocking antibody in maternal serum may be very helpful in predicting the occurrence of congenital hypothyroidism in newborns of mothers with autoimmune thyroid disease.


The diagnosis of thyroid disease has been greatly simplified by the development of sensitive assays for TSH and free thyroxine. The estimate of free thyroxine, either


FT4I or FT4, and a sensitive TSH determination are used both for the diagnosis of thyroid disease and for following patients receiving T4replacement or antithyroid drug therapy. An elevated TSH and low free thyroxine establish the diagnosis of hypothyroidism, and a suppressed TSH and elevated FT4 establish the diagnosis of hyperthyroidism.

Other tests are available for special uses. In hypothyroidism, Tg Ab or TPO Ab tests will clarify the cause of the illness, and in hyperthyroidism elevation of free T3, abnormal radioiodine uptake and scan, and a positive test for TSH-R Ab [stim] may be useful. In patients with nodules or goiter, fine-needle aspiration biopsy will rule out malignancy; radioiodine scan may help to determine function; and thyroid ultrasound or MRI may be helpful in following the size or growth of the goiter. Patients with known thyroid cancer are followed with serial thyroglobulin determinations, and 131I scan or MRI may be useful for detection of metastatic disease.


Patients with thyroid disease will usually complain of (1) thyroid enlargement, which may be diffuse or nodular; (2) symptoms of thyroid deficiency, or hypothyroidism; (3) symptoms of thyroid hormone excess, or hyperthyroidism; or (4) complications of a specific form of hyperthyroidism—Graves' disease—which may present with striking prominence of the eyes (exophthalmos) and, rarely, thickening of the skin over the lower legs (thyroid dermopathy).


The history should include evaluation of symptoms related to the above complaints, discussed in more detail below. Exposure to ionizing radiation in childhood has been associated with an increased incidence of thyroid disease, including cancer. Iodide ingestion in the form of kelp or iodide-containing cough preparations or intravenous iodide-containing contrast media used in angiography or CT scanning may induce goiter, hypothyroidism, or hyperthyroidism. Lithium carbonate, used in the treatment of manic-depressive psychiatric disorder, can also induce hypothyroidism and goiter or hyperthyroidism. Residence in an area of low dietary iodide is associated with iodine deficiency goiter (“endemic goiter”). Although dietary iodide is generally adequate in developed countries, there are still areas low in natural iodine (ie, developing countries in Africa, Asia, South America, and inland mountainous areas). Finally, the family history should be explored with particular reference to goiter, hyperthyroidism, hypothyroidism, or thyroid cancer as well as immunologic disorders such as diabetes, rheumatoid disease, pernicious anemia, alopecia, vitiligo, or myasthenia gravis, which may be associated with an increased incidence of autoimmune thyroid disease. Multiple endocrine neoplasia type 2A (Sipple's syndrome) with medullary carcinoma of the thyroid gland is an autosomal dominant condition.

Physical Examination

Physical examination of the thyroid gland is illustrated in Figure 7-32. The thyroid is firmly attached to the anterior trachea midway between the sternal notch and the thyroid cartilage; it is often easy to see and to palpate. The patient should have a glass of water for comfortable swallowing. There are three maneuvers: (1) With a good light coming from behind the examiner, the patient is instructed to swallow a sip of water. Observe the gland as it moves up and down. Enlargement and nodularity can often be noted. (2) Palpate the gland anteriorly. Gently press down with one thumb on one side of the gland to rotate the other lobe forward, and palpate as the patient swallows. (3) Palpate the gland from behind the patient with the middle three fingers on each lobe while the patient swallows. An outline of the gland can be traced on the skin of the neck and measured (Figure 7-32D). Nodules can be measured in a similar way. Thus, changes in the size of the gland or in nodules can easily be followed.

On physical examination, the palpable bulbous portion of each lobe of the normal thyroid gland measures about 2 cm in vertical dimension and about 1 cm in horizontal dimension above the isthmus. An enlarged thyroid gland is called goiter. Generalized enlargement is termed diffuse goiter; irregular or lumpy enlargement is called nodular goiter.


Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormones, which in turn results in a generalized slowing down of metabolic processes. Hypothyroidism in infants and children results in marked slowing of growth and development, with serious permanent consequences including mental retardation. Hypothyroidism with onset in adulthood causes a generalized slowing down of the organism, with deposition of glycosaminoglycans in intracellular spaces, particularly in skin and muscle, producing the clinical picture of myxedema. The symptoms of hypothyroidism in adults are largely reversible with therapy.



Etiology & Incidence Table 7-7


Figure 7-32. Examination of the thyroid gland. A: Observe the neck, especially as the patient swallows. B: Examine from the front, rotating the gland slightly with one thumb while palpating the other lobe with the other thumb. C: Examine from behind, using three fingers and the same technique. D: The size of each lobe or of thyroid nodules can be measured by first drawing an outline on the skin.

Hypothyroidism may be classified as (1) primary (thyroid failure), (2) secondary (to pituitary TSH deficit), or (3) tertiary (due to hypothalamic deficiency of TRH)—or may be due to (4) peripheral resistance to the action of thyroid hormones. Hypothyroidism can also be classified as goitrous or nongoitrous, but this classification is probably unsatisfactory, since Hashi-moto's thyroiditis (autoimmune thyroiditis) may produce hypothyroidism with or without goiter.

The incidence of various causes of hypothyroidism will vary depending on geographic and environmental factors such as dietary iodide and goitrogen intake, the genetic characteristics of the population, and the age distribution of the population (pediatric or adult). The causes of hypothyroidism, listed in approximate order of frequency in the USA, are presented in Table 7-7. Hashimoto's thyroiditis is probably the most common cause of hypothyroidism. In younger patients, it is more likely to be associated with goiter; in older patients, the gland may be totally destroyed by the immunologic process, and the only trace of the disease


will be a persistently positive test for TPO (thyroperoxidase) autoantibodies. Similarly, the end stage of Graves' disease may be hypothyroidism. This is accelerated by destructive therapy such as administration of radioactive iodine or subtotal thyroidectomy. Thyroid glands involved in autoimmune disease are particularly susceptible to excessive iodide intake (eg, ingestion of kelp tablets, iodide-containing cough preparations, or the antiarrhythmic drug amiodarone) or intravenous administration of iodide-containing radiographic contrast media. The large amounts of iodide block thyroid hormone synthesis, producing hypothyroidism with goiter in the patient with an abnormal thyroid gland; the normal gland usually “escapes” from the iodide block (see above). Although the process may be temporarily reversed by withdrawal of iodide, the underlying disease will often progress, and permanent hypothyroidism will usually supervene. Hypothyroidism may occur during the late phase of subacute thyroiditis; this is usually transient, but it is permanent in about 10% of patients. Iodide deficiency is rarely a cause of hypothyroidism in the USA but may be more common in developing countries. Certain drugs can block hormone synthesis and produce hypothyroidism with goiter; at present, the most common pharmacologic causes of hypothyroidism (other than iodide) are lithium carbonate, used for the treatment of manic-depressive states, and amiodarone. Chronic therapy with the antithyroid drugs propylthiouracil and methimazole will do the same. Inborn errors of thyroid hormone synthesis result in severe hypothyroidism if the block in hormone synthesis is complete, or mild hypothyroidism if the block is partial. Pituitary and hypothalamic deficiencies as causes of hypothyroidism are quite rare and are usually associated with other symptoms and signs of pituitary insufficiency (Chapter 5). Peripheral resistance to thyroid hormones is discussed below.

Table 7-7. Etiology of hypothyroidism.


1. Hashimoto's thyroiditis:

1. With goiter.

2. “Idiopathic” thyroid atrophy, presumably end-stage autoimmune thyroid disease, following either Hashimoto's thyroiditis or Graves' disease.

3. Neonatal hypothyroidism due to placental transmission of TSH-R blocking antibodies.

2. Radioactive iodine therapy for Graves' disease.

3. Subtotal thyroidectomy for Graves' disease or nodular goiter.

4. Excessive iodide intake (kelp, radiocontrast dyes).

5. Subacute thyroiditis.

6. Rare causes in the USA:

1. Iodide deficiency.

2. Other goitrogens such as lithium; antithyroid drug therapy.

3. Inborn errors of thyroid hormone synthesis.

Secondary: Hypopituitarism due to pituitary adenoma, pituitary ablative therapy, or pituitary destruction.
Tertiary: Hypothalamic dysfunction (rare).
Peripheral resistance to the action of thyroid hormone.


Thyroid hormone deficiency affects every tissue in the body, so that the symptoms are multiple. Pathologically, the most characteristic finding is the accumulation of glycosaminoglycans—mostly hyaluronic acid—in interstitial tissues. Accumulation of this hydrophilic substance and increased capillary permeability to albumin account for the interstitial edema that is particularly evident in the skin, heart muscle, and striated muscle. The accumulation is due not to excessive synthesis but to decreased destruction of glycosaminoglycans.

Clinical Presentations & Findings


The term cretinism was originally applied to infants—in areas of low iodide intake and endemic goiter—with mental retardation, short stature, a characteristic puffy appearance of the face and hands, and (frequently) deaf mutism and neurologic signs of pyramidal and extrapyramidal tract abnormalities (Figure 7-33). In the USA, neonatal screening programs have revealed that in the white population the incidence of neonatal hypothyroidism is 1:5000, while in the black population the incidence is only 1:32,000. Neonatal hypothyroidism may result from failure of the thyroid to descend during embryonic development from its origin at the base of the tongue to its usual site in the lower anterior neck, which results in an “ectopic thyroid” gland that functions poorly. Placental transfer to the embryo of TSH-R Ab [block] from a mother with Hashimoto's thyroiditis may result in agenesis of the thyroid gland and “athyreotic cretinism.” Inherited defects in thyroid hormone biosynthesis induce neonatal hypothyroidism and goiter. Rare causes of neonatal hypothyroidism include administration during pregnancy of iodides, antithyroid drugs, or radioactive iodine for thyrotoxicosis.

The symptoms of hypothyroidism in newborns include respiratory difficulty, cyanosis, jaundice, poor feeding, hoarse cry, umbilical hernia, and marked retardation


of bone maturation. The proximal tibial epiphysis and distal femoral epiphysis are present in almost all full-term infants with a body weight over 2500 g. Absence of these epiphyses strongly suggests hypothyroidism. The introduction of routine screening of newborns for TSH or T4has been a major achievement in the early diagnosis of neonatal hypothyroidism. A drop of blood obtained by heel stick 24–48 hours after birth is placed on filter paper and sent to a central laboratory. A serum T4 under 6 ľg/dL or a serum TSH over 25 ľU/mL is suggestive of neonatal hypothyroidism. The diagnosis can then be confirmed by radiologic evidence of retarded bone age. Note that euthyroid infants born to hypothyroid mothers inadequately treated during pregnancy may have symptoms of mild mental retardation later in life—emphasizing the importance of maintaining the mother in a euthyroid state throughout pregnancy.


Figure 7-33. A 9-month-old infant with hypothyroidism (cretinism). Note the puffy face, protuberant abdomen, umbilical hernia, and muscle weakness (infant cannot sit up unassisted).


Hypothyroidism in children is characterized by retarded growth and evidence of mental retardation. In the adolescent, precocious puberty may occur, and there may be enlargement of the sella turcica in addition to short stature. This is not due to pituitary tumor but probably to pituitary hypertrophy associated with excessive TSH production.


In adults, the common features of hypothyroidism include easy fatigability, coldness, weight gain, constipation, menstrual irregularities, and muscle cramps. Physical findings include a cool, rough, dry skin, puffy face and hands, a hoarse, husky voice, and slow reflexes (Figure 7-34). Reduced conversion of carotene to vitamin A and increased blood levels of carotene may give the skin a yellowish color.

  1. Cardiovascular signs—Hypothyroidism is manifested by impaired muscular contraction, bradycardia, and diminished cardiac output. The ECG reveals low voltage of QRS complexes and P and T waves, with improvement in response to therapy. Cardiac enlargement may occur, due in part to interstitial edema, nonspecific myofibrillary swelling, and left ventricular dilation but often due to pericardial effusion (Figure 7-35). The degree of pericardial effusion can easily be determined by echocardiography. Although cardiac output is reduced, congestive heart failure and pulmonary edema are rarely noted. There is controversy about whether myxedema induces coronary artery disease, but coronary artery disease is more common in patients with hypothyroidism, particularly in older patients. In patients with angina pectoris, hypothyroidism may protect the heart from ischemic stress, and replacement therapy may aggravate the angina.
  2. Pulmonary function—In the adult, hypothyroidism is characterized by shallow, slow respirations and impaired ventilatory responses to hypercapnia or hypoxia. Respiratory failure is a major problem in patients with myxedema coma.
  3. Intestinal peristalsis—Peristalsis is markedly slowed, resulting in chronic constipation and occasionally severe fecal impaction or ileus.
  4. Renal function—Renal function is impaired, with decreased glomerular filtration rate and impaired ability to excrete a water load. This predisposes the myxedematous patient to water intoxication if excessive free water is administered.
  5. Anemia—There are at least four mechanisms that may contribute to anemiain patients with hypothyroidism: (1) impaired hemoglobin synthesis as a result of


thyroxine deficiency; (2) iron deficiency from increased iron loss with menorrhagia, as well as impaired intestinal absorption of iron; (3) folate deficiency from impaired intestinal absorption of folic acid; and (4) pernicious anemia, with vitamin B12-deficient megaloblastic anemia. The pernicious anemia is often part of a spectrum of autoimmune diseases, including myxedema due to chronic thyroiditis associated with thyroid autoantibodies, pernicious anemia associated with parietal cell autoantibodies, diabetes mellitus associated with islet cell autoantibodies, and adrenal insufficiency associated with adrenal autoantibodies (Schmidt's syndrome; see Chapter 4).

  1. Neuromuscular system—Many patients complain of symptoms referable to the neuromuscular system, eg, severe muscle cramps, paresthesias, and muscle weakness.
  2. Central nervous system symptoms—Symptoms may include chronic fatigue, lethargy, and inability to concentrate. Hypothyroidism impairs the conversion of estrogen precursors to estrogens, resulting in altered FSH and LH secretion and in anovulatory cycles and infertility. This may also be associated with severe menorrhagia. Patients with myxedema are usually quite placid but can be severely depressed or even extremely agitated (“myxedema madness”).

Figure 7-34. Hypothyroidism in adult (myxedema). Note puffy face, puffy eyes, frowsy hair, and dull and apathetic appearance.


The combination of a low serum FT4 or FT4I and an elevated serum TSH is diagnostic of primary hypothyroidism (Figure 7-36). Serum T3levels are variable and may be within the normal range. A positive test for thyroid autoantibodies suggests underlying Hashimoto's thyroiditis. In patients with pituitary myxedema, the FT4I or FT4 will be low but serum TSH will not be elevated. It may then be necessary to differentiate pituitary from hypothalamic disease, and for this the TRH test is most helpful (see above). Absence of TSH response to TRH indicates pituitary deficiency. A partial or “normal” type response indicates that pituitary function is intact but that a defect exists in hypothalamic secretion of TRH. The patient may be taking thyroid medication (levothyroxine or desiccated thyroid tablets) when first seen. A palpable or enlarged thyroid gland and a positive test for thyroid autoantibodies would suggest underlying Hashimoto's thyroiditis, in which case the medication should be continued. If antibodies are absent, the medication should be withdrawn for 6 weeks and determinations made for FT4I or FT4 and for TSH. The 6-week period of withdrawal is necessary because of the long half-life of thyroxine (7 days) and to allow the pituitary gland to recover after a long period of suppression. The pattern of recovery of thyroid function after withdrawal of T4 is noted in Figure 7-37. In hypothyroid individuals, TSH becomes markedly elevated at 5–6 weeks and T4 remains subnormal, whereas both are normal after 6 weeks in euthyroid controls.

The clinical picture of fully developed myxedema is usually quite clear, but the symptoms and signs of mild hypothyroidism may be very subtle. Patients with hypothyroidism will at times present with unusual features: neurasthenia with symptoms of muscle cramps, paresthesias, and weakness; refractory anemia; disturbances in reproductive function, including infertility, delayed puberty, or menorrhagia; idiopathic edema or pleuropericardial effusions; retarded growth; obstipation; chronic rhinitis or hoarseness due to edema of nasal mucosa or vocal cords; and severe depression progressing to emotional instability or even frank paranoid psychosis. In the elderly, hypothyroidism may present with apathy and withdrawal, often attributed to senility (Chapter 23). In such cases, the diagnostic studies outlined above will confirm or rule out hypothyroidism as a contributing factor.



Myxedema coma is the end stage of untreated hypothyroidism. (See Chapter 24.) It is characterized by progressive weakness, stupor, hypothermia, hypoventilation,




hypoglycemia, hyponatremia, water intoxication, shock, and death. Although rare now, in the future it may occur more frequently in association with the increasing use of radioiodine for the treatment of Graves' disease, with resulting permanent hypothyroidism. Since it occurs most frequently in older patients with underlying pulmonary and vascular disease, the mortality rate is extremely high.


Figure 7-35. Top: Chest x-ray studies of patient with hypothyroid cardiomyopathy. Left: Before therapy, showing pronounced cardiomegaly. Right: Six months after institution of thyroxine therapy, the heart size has returned to normal. (Reproduced, with permission, from Reza MJ, Abbasi AS: Congestive cardiomyopathy in hypothyroidism. West J Med 1975;123:228.) Bottom:Echocardiogram of a 29-year-old woman with hypothyroidism (A) before and (B) after 2 months of therapy with levothyroxine sodium. (CW, chest wall; RVW, right ventricular wall; RVC, right ventricular cavity; IVS, interventricular septum; LVC, left ventricular cavity; PWLV, posterior wall left ventricle.) Note disappearance of pericardial effusion following levothyroxine therapy. (Reproduced, with permission, from Sokolow M, Mcilroy MB: Clinical Cardiology, 4th ed. McGraw-Hill, 1986.)


Figure 7-36. Diagnosis of hypothyroidism. Either free thyroxine (FT4) or free thyroxine index (FT4I) may be used with TSH for evaluation.

The patient (or a family member if the patient is comatose) may recall previous thyroid disease, radioiodine therapy, or thyroidectomy. The medical history is of gradual onset of lethargy progressing to stupor or coma. Examination reveals bradycardia and marked hypothermia, with body temperature as low as 24 °C (75 °F). The patient is usually an obese elderly woman with yellowish skin, a hoarse voice, a large tongue, thin hair, puffy eyes, ileus, and slow reflexes. There may be signs of other illnesses such as pneumonia, myocardial infarction, cerebral thrombosis, or gastrointestinal bleeding. Laboratory clues to the diagnosis of myxedema coma include lactescent serum, high serum carotene, elevated serum cholesterol, and increased cerebrospinal fluid protein. Pleural, pericardial, or abdominal effusions with high protein content may be present. Serum tests will reveal a low FT4 and a markedly elevated TSH. Thyroidal radioactive iodine uptake is low, and thyroid autoantibodies are usually strongly positive, indicating underlying chronic thyroiditis. The ECG shows sinus bradycardia and low voltage. If laboratory studies are not readily available, which is frequently the case, the diagnosis must be made clinically.

The pathophysiology of myxedema coma involves three major aspects: (1) CO2 retention and hypoxia, (2) fluid and electrolyte imbalance, and (3) hypothermia. CO2 retention and hypoxia are probably due in large part to a marked depression in the ventilatory responses to hypoxia and hypercapnia, though factors such as obesity, heart failure, ileus, immobilization, pneumonia, pleural or peritoneal effusions, central nervous system depression, and weak chest muscles may also contribute. Failure of the myxedema patient to respond to hypoxia or hypercapnia may be due to hypothermia. Impairment of ventilatory drive is often severe, and assisted respiration is almost always necessary in patients with myxedema coma. Thyroid hormone therapy in patients with myxedema corrects the hypothermia and markedly improves the ventilatory response to hypoxia. The major fluid and electrolyte disturbance is water intoxication due to reduced renal perfusion and impaired free water clearance. This presents as hyponatremia and is managed by water restriction. Hypothermia is frequently not recognized, because the ordinary clinical thermometer only goes down to about 34 °C (93 °F); a laboratory type thermometer that registers a broader scale must be used to obtain accurate body temperature readings. Active rewarming of the body is contraindicated, because it may induce vasodilation and vascular collapse. A rise in


body temperature is a useful indication of therapeutic effectiveness of thyroxine.


Figure 7-37. Changes in T4, T3, TSH, and TRH response following abrupt withdrawal of suppressive thyroxine therapy. Note that in euthyroid individuals the T4 may not return to normal until 6 weeks after withdrawal of therapy and that serum TSH is never elevated. In hypothyroid patients, TSH may be elevated as early as 2 weeks after withdrawal of therapy, and TRH response is exaggerated. (LLN, lower limit of normal; ULN, upper limit of normal.) (Reproduced, with permission, from Wood LC: Controversial questions in thyroid disease. Workshop in the Thyroid, American Thyroid Association, Nov 1979, as adapted from Vagenakis AG et al: Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid suppression therapy. N Engl J Med 1975;293:681.)

Disorders that may precipitate myxedema coma include heart failure, pneumonia, pulmonary edema, pleural or peritoneal effusions, ileus, excessive fluid administration, or administration of sedative or narcotic drugs to a patient with severe hypothyroidism. Adrenal insufficiency occurs occasionally in association with myxedema coma, but it is relatively rare and usually associated with either pituitary myxedema or concurrent autoimmune adrenal insufficiency (Schmidt's syndrome). Seizures, bleeding episodes, hypocalcemia, or hypercalcemia may be present. It is important to differentiate pituitary myxedema from primary myxedema. In pituitary myxedema, glucocorticoid replacement is essential. Clinical clues to the presence of pituitary myxedema include the following: a history of amenorrhea or impotence; scanty pubic or axillary hair; and normal serum cholesterol and normal or low TSH levels. CT scan or MRI may reveal an enlarged sella turcica. The treatment of myxedema coma is discussed below.


In the past, treatment of patients with myxedema and heart disease, particularly coronary artery disease, was very difficult, because levothyroxine replacement was frequently associated with exacerbation of angina, heart failure, or myocardial infarction. Now that coronary angioplasty and coronary artery bypass surgery are available, patients with myxedema and coronary artery disease can be treated surgically first, and more rapid thyroxine replacement therapy will then be tolerated.


Hypothyroidism is often associated with depression, which may be quite severe. More rarely, myxedematous patients may become confused, paranoid, or even manic (“myxedema madness”). Screening of psychiatric admissions with FT4 and TSH is an efficient way to find these patients, who will frequently respond to levothyroxine therapy alone or in combination with psychopharmacologic agents. The effectiveness of levothyroxine therapy in disturbed hypothyroid patients has given rise to the hypothesis that the addition of T3 or T4 to psychotherapeutic regimens for depressed patients may be helpful in patients without demonstrable thyroid disease. Further work needs to be done to establish this concept as standard treatment.



Hypothyroidism is treated with levothyroxine (T4), which is available in pure form and is stable and inexpensive.


Intracellularly, levothyroxine is converted to T3, so that both hormones become available even though only one is administered. Desiccated thyroid is unsatisfactory because of its variable hormone content, and triiodothyronine (as liothyronine) is unsatisfactory because of its rapid absorption, short half-life, and transient effects. The half-life of levothyroxine is about 7 days, so it need be given only once daily. It is well absorbed, and blood levels are easily monitored by following FT4I or FT4 and serum TSH levels. There is a rise in T4 or FT4I of about 1–2 ľg/dL (13–26 nmol/L) and a concomitant fall in TSH of 1–2 ľU/mL (1–2 mU/L) beginning about 2 hours and lasting about 8–10 hours after an oral dose of 0.1–0.15 mg of levothyroxine (Figure 7-38). It is best, therefore, to take the daily dose of levothyroxine in the morning to avoid symptoms such as insomnia if the medication is taken at bedtime. In addition, when monitoring serum thyroxine levels, it is important that blood be drawn fasting or before the daily dose of the hormone in order to obtain consistent data.


Replacement doses of levothyroxine in adults range from 0.05 to 0.2 mg/d, with a mean of 0.125 mg/d. The dose of levothyroxine varies according to the patient's age and body weight Table 7-8. Young children require a surprisingly high dose of levothyroxine compared with adults. In adults, the mean replacement dose of T4 is about 1.7 ľg/kg/d, or about 0.8 ľg/lb/d. In older adults, the replacement dose is lower, about 1.6 ľg/kg/d, or about 0.7 ľg/lb/d. For TSH suppression in patients with nodular goiters or cancers of the thyroid gland, the average dose of levothyroxine is about 2.2 ľg/kg/d (1 ľg/lb/d). In younger patients with mild hypothyroidism, one can begin treatment with one-half of the estimated dose requirement for 4–6 weeks and then adjust the final dose based on the FT4 and TSH. In older patients or patients with severe hypothyroidism, it is best to start with a low dose of levothyroxine, eg, 0.025 mg daily, and increase the dose at 4- to 6-week intervals based on FT4 and TSH measurements. Malabsorptive states or concurrent administration of aluminum preparations, cholestyramine, calcium, or iron compounds will modify T4 absorption. In these patients, levothyroxine should be given before breakfast, when the stomach is empty, and the other compounds taken 2–4 hours later. Levothyroxine has a sufficiently long half-life (7 days) so that if the patient is unable to take medications by mouth for a few days, omitting levothyroxine therapy will not be detrimental. If the patient is being managed by sustained parenteral therapy, the parenteral dose of T4 is about 75–80% of the usual oral dose.

Table 7-8. Replacement doses of levothyroxine.1


Dose of Levothyroxine (ľg/kg/d)

0–6 mo


7–11 mo


1–5 yr


6–10 yr


11–20 yr




1Adapted and modified, with permission, from Foley TP Jr. Congenital hypothyroidism. In: Werner and Ingbar's The Thyroid, 7th ed. Braverman LE, Utiger RD (editors). Lippincott, 1996.


Figure 7-38. Rise in serum free thyroxine index (FT4I) and fall in serum TSH following an oral dose of 0.15 mg levothyroxine.


Myxedema coma is an acute medical emergency and should be treated in the intensive care unit. Blood gases must be monitored regularly, and the patient usually requires intubation and mechanical ventilation. Associated illnesses such as infections or heart failure must be sought for and appropriately treated. Intravenous fluids should be administered with caution, and excessive free


water intake must be avoided. Because patients with myxedema coma absorb all drugs poorly, it is imperative to give levothyroxine intravenously. These patients have marked depletion of serum thyroxine with a large number of empty binding sites on thyroxine-binding globulin and therefore should receive an initial loading dose of 300–400 ľg of levothyroxine intravenously, followed by 50 ľg intravenously daily. The clinical guides to improvement are a rise in body temperature and the return of normal cerebral and respiratory function. If the patient is known to have had normal adrenal function before the onset of coma, adrenal support is probably not necessary. If, however, no data are available, the possibility of concomitant adrenal insufficiency (due to autoimmune adrenal disease or pituitary insufficiency) does exist. In this case, a cosyntropin stimulation test should performed (Chapter 9). Full adrenal support should then be administered, eg, hydrocortisone hemisuccinate, 100 mg intravenously, followed by 50 mg intravenously every 6 hours, tapering the dose over 7 days. Adrenal support can be withdrawn sooner if the pretreatment plasma cortisol is 30 ľg/dL or greater or if results of a cosyntropin stimulation test are within normal limits. When giving levothyroxine intravenously in large doses, there is an inherent risk of precipitating angina, heart failure, or arrhythmias in older patients with underlying coronary artery disease. Thus, this type of therapy is not recommended for ambulatory patients with myxedema; in these patients, it is better to start slowly and build up the dose as noted below. (See also Chapter 24.)


In long-standing hypothyroidism or in older patients—particularly those with known cardiovascular disease—it is imperative to start treatment slowly. Levothyroxine is given in a dosage of 0.025 mg/d for 2 weeks, increasing by 0.025 mg every 2 weeks until a daily dose of 0.075 mg is reached. This dose is continued for about 6 weeks. TSH is then measured and the dosage adjusted accordingly. It usually takes about 2 months for a patient to come into equilibrium on full dosage. In these patients, the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or cardiac arrhythmia develops, it is essential to reduce the dose of thyroxine immediately.

Toxic Effects of Levothyroxine Therapy

There are no reported instances of allergy to pure levothyroxine, though it is possible that a patient may develop an allergy to the coloring dye or some component of the tablet. The major toxic reactions to levothyroxine overdosage are symptoms of hyperthyroidism—particularly cardiac symptoms—and, in postmenopausal women, osteoporosis. The most common thyrotoxic cardiac symptom is arrhythmia, particularly paroxysmal atrial tachycardia or fibrillation. Insomnia, tremor, restlessness, and excessive warmth may also be troublesome. Simply omitting the daily dose of levothyroxine for 3 days and then reducing the dosage will correct the problem.

Increased bone resorption and severe osteoporosis have been associated with long-standing hyperthyroidism and will develop in postmenopausal women chronically overtreated with levothyroxine. This can be prevented by regular monitoring and by maintaining normal serum FT4 and TSH in patients receiving long-term replacement therapy. In patients receiving TSH-suppressive therapy for nodular goiter or thyroid cancer, if FT4I or FT4 is kept in the upper range of normal—even if TSH is suppressed—the adverse effects of T4 therapy on bone will be minimal (Chapter 23). In addition, concomitant administration of estrogen or bisphosphonate to postmenopausal women receiving high-dose thyroxine therapy will minimize bone resorption.

Course & Prognosis

The course of untreated myxedema is one of slow deterioration, leading eventually to myxedema coma and death. With appropriate treatment, however, the long-term prognosis is excellent. Because of the long half-life (7 days) of thyroxine, it takes time to establish equilibrium on a fixed dose. Therefore, it is important to monitor the FT4I or FT4 and the serum TSH every 4–6 weeks until equilibrium is reached. Thereafter, FT4 and TSH can be monitored once a year. The dose of T4 must be increased about 25% during pregnancy. Older patients metabolize T4 more slowly, and the dose will gradually decrease with age (Chapter 23).

The mortality rate of myxedema coma was about 80% at one time. The prognosis has been vastly improved as a result of recognition of the importance of mechanically assisted respiration and the use of intravenous levothyroxine. At present, the outcome probably depends upon how well the underlying disease problems can be managed.


Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormone. In most instances, thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism. Occasionally, thyrotoxicosis may be due to other causes such as excessive ingestion of thyroid hormone or excessive secretion of thyroid hormone from


ectopic sites. The various forms of thyrotoxicosis are listed in Table 7-9. These syndromes will be discussed individually below.

  1. Diffuse Toxic Goiter (Graves' Disease)

Graves' disease is the most common form of thyrotoxicosis and may occur at any age, more commonly in females than in males. The syndrome consists of one or more of the following features: (1) thyrotoxicosis, (2) goiter, (3) ophthalmopathy (exophthalmos), and (4) dermopathy (pretibial myxedema).


Graves' disease is currently viewed as an autoimmune disease of unknown cause. There is a strong familial predisposition in that about 15% of patients with Graves' disease have a close relative with the same disorder, and about 50% of relatives of patients with Graves' disease have circulating thyroid autoantibodies. Females are involved about five times more commonly than males. The disease may occur at any age, with a peak incidence in the 20- to 40-year age group. (See section on thyroid autoimmunity, above.)


In Graves' disease, T lymphocytes become sensitized to antigens within the thyroid gland and stimulate B lymphocytes to synthesize antibodies to these antigens. (See Chapter 4. See also the section on thyroid autoimmunity, above, and Figure 7-39.) One such antibody is directed against the TSH receptor site in the thyroid cell membrane and has the capacity to stimulate the thyroid cell to increased growth and function (TSH-R Ab [stim]). The presence of this circulating antibody is positively correlated with active disease and with relapse of the disease. There is an underlying genetic predisposition, but it is not clear what “triggers” the acute episode. Some factors that may incite the immune response of Graves' disease are (1) pregnancy, particularly the postpartum period; (2) iodide excess, particularly in geographic areas of iodide deficiency, where the lack of iodide may hold latent Graves' disease in check; (3) lithium therapy, perhaps by modifying immune responsiveness; (4) viral or bacterial infections; and (5) glucocorticoid withdrawal. It has been postulated that “stress” may trigger an episode of Graves' disease, but there is no evidence to support this hypothesis. The pathogenesis of ophthalmopathy may involve cytotoxic lymphocytes


(killer cells) and cytotoxic antibodies sensitized to a common antigen such as the TSH-R found in orbital fibroblasts, orbital muscle, and thyroid tissue (Figure 7-39). Cytokines from these sensitized lymphocytes would cause inflammation of orbital fibroblasts and orbital myositis, resulting in swollen orbital muscles, proptosis of the globes, and diplopia as well as redness, congestion, and conjunctival and periorbital edema (thyroid ophthalmopathy; Figures 7-40 and 7-41). The pathogenesis of thyroid dermopathy (pretibial myxedema) (Figure 7-42) and the rare subperiosteal inflammation on the phalanges of the hands and feet (thyroid osteopathy) (Figure 7-43) may also involve lymphocyte cytokine stimulation of fibroblasts in these locations.

Table 7-9. Conditions associated with thyrotoxicosis.

1. Diffuse toxic goiter (Graves' disease)

2. Toxic adenoma (Plummer's disease)

3. Toxic multinodular goiter

4. Subacute thyroiditis

5. Hyperthyroid phase of Hashimoto's thyroiditis

6. Thyrotoxicosis factitia

7. Rare forms of thyrotoxicosis: ovarian struma, metastatic thyroid carcinoma (follicular), hydatidiform mole,“hamburger thyrotoxicosis,” TSH-secreting pituitary tumor, pituitary resistance to T3 and T4


Figure 7-39. One theory of the pathogenesis of Graves' disease. There is a defect in suppressor T lymphocytes (Ts) that allows helper T lymphocytes (TH) to stimulate B lymphocytes (B) to synthesize thyroid autoantibodies. The thyroid-stimulating immunoglobulin (TSI) is the driving force for thyrotoxicosis. The inflammatory process in the orbital muscles may be due to sensitization of cytotoxic T lymphocytes (Tc), or killer cells, to orbital antigens in association with cytotoxic antibodies. The thyroid and the eye are linked by a common antigen, the TSH-R, found in thyroid follicular cells and orbital fibroblasts. It is not yet clear what triggers this immunologic cascade. (Tg Ab, thyroglobulin antibody; TPO Ab, thyroperoxidase or microsomal antibody; Ag, antigen; Ab, antibody.)

Many symptoms of thyrotoxicosis suggest a state of catecholamine excess, including tachycardia, tremor, sweating, lid lag, and stare. Circulating levels of epinephrine are normal; thus, in Graves' disease, the body appears to be hyperreactive to catecholamines. This may be due in part to a thyroid hormone-mediated increase in cardiac catecholamine receptors.

Clinical Features


In younger individuals, common manifestations include palpitations, nervousness, easy fatigability, hyperkinesia, diarrhea, excessive sweating, intolerance to heat, and preference for cold. There is often marked weight loss without loss of appetite. Thyroid enlargement, thyrotoxic eye signs (see below), and mild tachycardia commonly occur. Muscle weakness and loss of muscle mass may be so severe that the patient cannot rise from a chair without assistance. In children, rapid growth with accelerated bone maturation occurs. In patients over age 60, cardiovascular and myopathic manifestations predominate; the most common presenting complaints are palpitation, dyspnea on exertion, tremor, nervousness, and weight loss (Chapter 23).


Figure 7-40. Patient with mild ophthalmopathy of Graves' disease. Left: Before radioactive iodine therapy. Note white sclera visible above and below the iris as well as mild periorbital edema. Classification Table 7-10: class 1, mild; class 2, mild: class 3, mild. Right:After radioactive iodine therapy. Marked improvement is noted.

The eye signs of Graves' disease have been classified by Werner as set forth in Table 7-10. This classification is useful in describing the extent of the eye involvement, but it is not helpful in following the progress of the illness since one class does not always progress into the next. The first letters of each class form the mnemonic “NO SPECS.” Class 1 involves spasm of the upper lids associated with active thyrotoxicosis and usually resolves spontaneously when the thyrotoxicosis is adequately controlled. Classes 2–6 represent true infiltrative disease involving orbital muscles and orbital tissues (Figures 7-40 and 7-41). Class 2 is characterized by soft tissue involvement with periorbital edema, congestion or redness of the conjunctiva, and swelling of the conjunctiva (chemosis). Class 3 consists of proptosis as measured by the Hertel exophthalmometer. This instrument consists of two prisms with a scale mounted


on a bar. The prisms are placed on the lateral orbital ridges, and the distance from the orbital ridge to the anterior cornea is measured on the scale (Figure 7-44). The upper limits of normal according to race are listed in the footnote to Table 7-10. Class 4 consists of muscle involvement. The muscle most commonly involved in the infiltrative process is the inferior rectus, limiting upward gaze. The muscle next most commonly involved is the medial rectus, impairing lateral gaze. Class 5 is characterized by corneal involvement (keratitis) and class 6 loss of vision from optic nerve involvement. As noted above, thyroid ophthalmopathy is due to infiltration of the extraocular muscles with lymphocytes and edema fluid in an acute inflammatory reaction. The orbit is a cone enclosed by bone, and swelling of the extraocular muscles within this closed space causes proptosis of the globe and impaired muscle movement, resulting in diplopia. Ocular muscle enlargement can be demonstrated by orbital CT scanning or MRI (Figure 7-45). When muscle swelling occurs posteriorly, toward the apex of the orbital cone, the optic nerve is compressed, which may cause loss of vision.


Figure 7-41. Severe ophthalmopathy of Graves' disease. Note marked periorbital edema, injection of corneal blood vessels, and proptosis. There was also striking limitation of upward and lateral eye movements and reduced visual acuity. Classification Table 7-10: class 1, severe; class 2, severe; class 3, severe; class 4, severe; class 5, none; class 6, mild.

Thyroid dermopathy consists of thickening of the skin, particularly over the lower tibia, due to accumulation of glycosaminoglycans (Figure 7-42). It is relatively rare, occurring in about 2–3% of patients with Graves' disease. It is usually associated with ophthalmopathy and with a very high serum titer of TSH-R Ab [stim]. The skin is markedly thickened and cannot be picked up between the fingers. Sometimes the dermopathy involves the entire lower leg and may extend onto the feet. Bony involvement (osteopathy), with subperiosteal bone formation and swelling, is particularly evident in the metacarpal bones (Figure 7-43). This too is a relatively rare finding. A more common finding in Graves' disease is separation of the fingernails from their beds, or onycholysis (Figure 7-46).


Figure 7-42. Dermopathy of Graves' disease. Marked thickening of the skin is noted, usually over the pretibial area. Thickening will occasionally extend downward over the ankle and the dorsal aspect of the foot but almost never above the knee.


The laboratory findings in hyperthyroidism are summarized in Figure 7-47. Essentially, the combination of an elevated FT4 and a suppressed TSH makes the diagnosis of hyperthyroidism. If eye signs are present, the diagnosis of Graves' disease can be made without further tests. If eye signs are absent and the patient is hyperthyroid with or without a goiter, a radioiodine uptake test should be done. An elevated uptake is diagnostic of Graves' disease or toxic nodular goiter. A low uptake is seen in patients with spontaneously resolving hyperthyroidism, as in subacute thyroiditis or a flare-up of Hashimoto's thyroiditis. Low uptakes will


also be found in patients who are iodine-loaded or are on T4 therapy—or, rarely, in association with a struma ovarii. If both FT4 and TSH are elevated and radioiodine uptake is also elevated, consider a TSH-secreting pituitary tumor or generalized or pituitary resistance syndromes. If FT4 is normal and TSH is suppressed, check FT3, which will be elevated in early Graves' disease or in T3-secreting toxic nodules. Low FT3will be found in the euthyroid sick syndrome or in patients receiving corticoids or dopamine.


Figure 7-43. X-ray of hand of patient with thyroid osteopathy. Note marked periosteal thickening of the proximal phalanges.

Thyroid autoantibodies—Tg Ab and TPO Ab—are usually present in both Graves' disease and Hashimoto's thyroiditis, but TSH-R Ab [stim] is specific for Graves' disease. This may be a useful diagnostic test in the “apathetic” hyperthyroid patient or in the patient who presents with unilateral exophthalmos without obvious signs or laboratory manifestations of Graves' disease. The 123I or technetium scan is useful to evaluate the size of the gland or the presence of “hot” or “cold” nodules. Since the ultrasensitive TSH test will detect TSH suppression, TRH tests (see above) are rarely indicated. CT and MRI scans of the orbit have revealed muscle enlargement in most patients with Graves' disease even when there is no clinical evidence of ophthalmopathy. In patients with ophthalmopathy, orbital muscle enlargement may be striking (Figure 7-45).

Table 7-10. Classification of eye changes in Graves' disease.1




No signs or symptoms.


Only signs, no symptoms. (Signs limited to upper lid retraction, stare, lid lag.)


Soft tissue involvement (symptoms and signs).


Proptosis (measured with Hertel exophthalmometer).2


Extraocular muscle involvement.


Corneal involvement.


Sight loss (optic nerve involvement).

1Reproduced, with permission, from Werner SC: Classification of the eye changes of Graves' disease. J Clin Endocrinol Metab 1969;29:782 and 1977;44:203.
2Upper limits of normal according to race: 18 mm; white, Asian, 20 mm; black, 22 mm. Increase in proptosis of 3–4 mm is mild involvement; 5–7 mm, moderate involvement; and over 8 mm, severe involvement. Other classes can be similarly graded as mild, moderate, or severe.

Differential Diagnosis

Graves' disease occasionally presents in an unusual or atypical fashion, in which case the diagnosis may not be obvious. Marked muscle atrophy may suggest severe myopathy that must be differentiated from primary neurologic disorder. Thyrotoxic periodic paralysis usually occurs in Asian males and presents with a sudden attack of flaccid paralysis and hypokalemia. The paralysis usually subsides spontaneously and can be prevented by K+ supplementation and beta-adrenergic blockade. The illness is cured by appropriate treatment of the thyrotoxicosis (see Chapter 24). Patients with thyrocardiac disease present primarily with symptoms of heart involvement—especially refractory atrial fibrillation insensitive to digoxin—or with high-output heart failure. About 50% of these patients have no evidence of underlying heart disease, and the cardiac problems are cured by treatment of the thyrotoxicosis. Some older patients will present with weight loss, small goiter, slow atrial fibrillation, and severe depression, with none of the clinical features of increased catecholamine reactivity. These placid patients have apathetic hyperthyroidism. Finally, some young women may present with amenorrhea or infertility as the primary symptom.


In all of these instances, the diagnosis of hyperthyroidism can usually be made on the basis of the clinical and laboratory studies described above.


Figure 7-44. A: Hertel exophthalmometer. B: Proper use of the exophthalmometer. The edges of the instrument are placed on the lateral orbital ridges, and the distance from the orbital bone to the anterior cornea is read on the scale contained within the prisms.

In the syndrome called familial dysalbuminemic hyperthyroxinemia, an abnormal albumin-like protein is present in serum that preferentially binds T4 but not T3. This results in elevation of serum T4 and FT4I, but free T4, T3, and TSH are normal. It is important to differentiate this euthyroid state from hyperthyroidism. In addition to the absence of clinical features of hyperthyroidism, a normal serum T3and a normal TSH level will rule out hyperthyroidism.


Figure 7-45. Orbital CT scan in a patient with severe ophthalmopathy and visual failure. Note the marked enlargement of extraocular muscles posteriorly, with compression of the optic nerve at the apex of the orbital cone.


Figure 7-46. Onycholysis (separation of the nail from its bed) in Graves' disease usually resolves spontaneously as the patient improves.


Figure 7-47. Laboratory tests useful in the differential diagnosis of hyperthyroidism. (See text for details.)




Thyrotoxic crisis (thyroid storm) is the acute exacerbation of all of the symptoms of thyrotoxicosis, often presenting as a syndrome that may be of life-threatening severity. (See Chapter 24.) Occasionally, thyroid storm may be mild and present simply as an unexplained febrile reaction after thyroid surgery in a patient who has been inadequately prepared. More commonly, it occurs in a more severe form after surgery, radioactive iodine therapy, or parturition in a patient with inadequately controlled thyrotoxicosis—or during a severe, stressful illness or disorder such as uncontrolled diabetes, trauma, acute infection, severe drug reaction, or myocardial infarction. The clinical manifestations of thyroid storm are marked hypermetabolism and excessive adrenergic response. Fever ranges from 38 to 41 °C and is associated with flushing and sweating. There is marked tachycardia, often with atrial fibrillation and high pulse pressure and occasionally with heart failure. Central nervous system symptoms include marked agitation, restlessness, delirium, and coma. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and jaundice. A fatal outcome will be associated with heart failure and shock.

At one time it was thought that thyroid storm was due to sudden release or “dumping” of stored thyroxine and triiodothyronine from the thyrotoxic gland. Careful studies have revealed, however, that the serum levels of T4 and T3 in patients with thyroid storm are not higher than in thyrotoxic patients without this condition. There is no evidence that thyroid storm is due to excessive production of triiodothyronine. There is evidence that in thyrotoxicosis the number of binding sites for catecholamines increases, so that heart and nerve tissues have increased sensitivity to circulating catecholamines. In addition, there is decreased binding to TBG, with elevation of free T3 and T4. The present theory is that in this setting, with increased binding sites available for catecholamines, an acute illness, infection, or surgical stress triggers an outpouring of catecholamines which, in association with high levels of free T4 and T3, precipitates the acute problem.

The most striking clinical diagnostic feature of thyrotoxic crisis is hyperpyrexia out of proportion to other findings. Laboratory findings include elevated serum T4, FT4, and T3 as well as a suppressed TSH (see Chapter 24).

Treatment of Graves' Disease

Although autoimmune mechanisms are responsible for the syndrome of Graves' disease, management has been largely directed toward controlling the hyperthyroidism. Three good methods are available: (1) antithyroid


drug therapy, (2) surgery, and (3) radioactive iodine therapy.


In general, antithyroid drug therapy is most useful in young patients with small glands and mild disease. The drugs (propylthiouracil or methimazole) are given until the disease undergoes spontaneous remission. This occurs in 20–40% of patients treated for 6 months to 15 years. Although this is the only therapy that leaves an intact thyroid gland, it does require a long period of observation, and the incidence of relapse is high, perhaps 50–60% even in selected patients. There may be a genetic predisposition to the failure to respond to antithyroid drug therapy. Antithyroid drug therapy is generally started with large divided doses; when the patient becomes clinically euthyroid, maintenance therapy may be achieved with a lower single morning dose. A common regimen consists of giving propylthiouracil, 100 mg every 6 hours initially, and then in 4–8 weeks reducing the dose to 50–200 mg once or twice daily. Propylthiouracil has one advantage over methimazole in that it partially inhibits the conversion of T4 to T3, so that it is effective in bringing down the levels of activated thyroid hormone more quickly. However, me-thimazole has a longer duration of action and is more useful if a single daily dose is desirable. A typical program would start with a 40-mg dose of methimazole each morning for 1–2 months; this dose would then be reduced to 5–20 mg each morning for maintenance therapy. The laboratory tests of most value in monitoring the course of therapy are serum FT4 and TSH.

An alternative method of therapy utilizes the concept of a total block of thyroid activity. The patient is treated with methimazole until euthyroid (about 3–6 months), but instead of continuing to taper the dose of methimazole, at this point levothyroxine is added in a dose of about 0.1 mg/d. The patient then continues to receive the combination of methimazole 10 mg/d and levothyroxine 0.1 mg/d for another 12–24 months. At the end of this time, or when the size of the gland has returned to normal, methimazole is discontinued. This combined therapy will prevent the development of hypothyroidism due to excessive doses of methimazole, but the incidence of relapse is about the same as after treatment with methimazole alone.

  1. Duration of therapy—The duration of therapy with antithyroid drugs in Graves' disease is quite variable and can range from 6 months to 20 years or more. A sustained remission may be predicted in about 80% of treated patients in the following circumstances: (1) if the thyroid gland returns to normal size; (2) if the disease can be controlled with a relatively small dose of antithyroid drugs; (3) if TSH-R Ab [stim] is no longer detectable in the serum; and (4) if the thyroid gland becomes normally suppressible following the administration of liothyronine.
  2. Reactions to antithyroid drugs—Allergic reactions to antithyroid drugs involve either a rash (about 5% of patients) or agranulocytosis (about 0.5% of patients). The rash can be managed by simply administering antihistamines, and unless it is severe it is not an indication for discontinuing the medication. Agranulocytosis requires immediate cessation of all antithyroid drug therapy, institution of appropriate antibiotic therapy, and shifting to an alternative therapy, usually radioactive iodine. Agranulocytosis is usually heralded by sore throat and fever. Thus, all patients receiving antithyroid drugs are instructed that if sore throat or fever develops, they should stop the drug, obtain a white blood cell and differential count, and see their physician. If the white blood cell count is normal, the antithyroid drug can be resumed. Cholestatic jaundice, angioneurotic edema, hepatocellular toxicity, and acute arthralgia are serious but rare side effects that also require cessation of drug therapy.

Subtotal thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters. The patient is prepared with antithyroid drugs until euthyroid (about 6 weeks). In addition, starting 2 weeks before the day of operation, the patient is given saturated solution of potassium iodide, 5 drops twice daily. This regimen has been shown empirically to diminish the vascularity of the gland and to simplify surgery.

There is disagreement about how much thyroid tissue should be removed. Total thyroidectomy is usually not necessary unless the patient has severe progressive ophthalmopathy (see below). However, if too much thyroid tissue is left behind, the disease will relapse. Most surgeons leave 2–3 g of thyroid tissue on either side of the neck. Many patients, however, require thyroid supplementation following thyroidectomy for Graves' disease.

Hypoparathyroidism and recurrent laryngeal nerve injury occur as complications of surgery in about 1% of cases.


In the USA, sodium iodide 131I is the preferred treatment for most patients over age 21. In many patients without underlying heart disease, radioactive iodine may be given immediately in a dosage of 80–150 ľCi/g of thyroid weight estimated on the basis of physical examination and sodium 123I rectilinear scan. The dosage is corrected for iodine uptake according to the following formula:



Following the administration of radioactive iodine, the gland will shrink and the patient will become euthyroid over a period of 6–12 weeks.

In elderly patients and in those with underlying heart disease or other medical problems, severe thyrotoxicosis, or large glands (> 100 g), it is desirable to achieve a euthyroid state prior to 131I therapy. For this purpose, pretreatment with methimazole rather than propylthiouracil is preferable because propylthiouracil may inhibit radioiodine uptake for weeks or months after discontinuation, whereas the inhibitory effect of methimazole on radioiodine uptake may dissipate in 24 hours. Patients usually are treated with methimazole until they are euthyroid; medication is then stopped for 5–7 days; and a dose of 100–150 mCi 131I per gram of estimated thyroid weight (corrected for uptake) is calculated as described above. Because it is usually desirable to destroy most of the gland in patients with underlying medical problems, the dose of 131I may be slightly larger than is ordinarily given.

The major complication of radioactive iodine therapy is hypothyroidism, which ultimately develops in 80% or more of patients who are adequately treated. However, this complication may indeed be the best assurance that the patient will not have a recurrence of hyperthyroidism. Serum FT4 and TSH levels should be followed, and when hypothyroidism develops, prompt replacement therapy with levothyroxine, 0.05–0.2 mg daily, is instituted.

Hypothyroidism may occur after any type of therapy for Graves' disease—even after antithyroid drug therapy; in some patients,“burned-out” Graves' disease may be an end result of autoimmune thyroid disease. Accordingly, all patients with Graves' disease require lifetime follow-up to be certain that they remain euthyroid.


During the acute phase of thyrotoxicosis, beta-adrenergic blocking agents are extremely helpful. Propranolol, 10–40 mg every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. This drug is gradually withdrawn as serum thyroxine levels return to normal. Adequate nutrition, including multivitamin supplements, is essential. Barbiturates accelerate T4 metabolism, and phenobarbital may be helpful both for its sedative effect and to lower T4 levels. Ipodate sodium or iopanoic acid has been shown to inhibit both thyroid hormone synthesis and release as well as peripheral conversion of T4 to T3. Thus, in a dosage of 1 g daily, this drug may help to rapidly restore the euthyroid state. It leaves the gland saturated with iodide, so it should not be used before 131I therapy or antithyroid drug therapy with propylthiouracil or methimazole. Cholestyramine, 4 g orally three times daily, will lower serum T4 by binding it in the gut. In a patient with a large toxic goiter and a severe allergic reaction to antithyroid drugs, ipodate sodium and beta blockade can be used effectively as preparation for surgery.

Choice of Therapy

Choice of therapy will vary with the nature and severity of the illness and prevailing customs. For example, in the USA, radioiodine therapy has been the preferred treatment for the average patient, whereas in Europe and Asia, antithyroid drug therapy is preferred. In the opinion of this author, most patients should be treated with antithyroid drugs until euthyroid. If there is a prompt response and the gland begins to shrink, the option of long-term antithyroid drug therapy with or without simultaneous levothyroxine therapy should be considered. If large doses of antithyroid drugs are required for control and the gland does not shrink in response to therapy, radioiodine would be the treatment of choice. If the gland is very large (> 150 g) or multi-nodular—or if the patient wishes to become pregnant very soon—thyroidectomy is a reasonable option. A serious allergic reaction to an antithyroid drug is an indication for radioiodine therapy.

Treatment of Complications


Thyrotoxic crisis (thyroid storm) requires vigorous management. Propranolol, 1–2 mg slowly intravenously or 40–80 mg every 6 hours orally, is helpful in controlling arrhythmias. In the presence of severe heart failure or asthma and arrhythmia, cautious intravenous administration of verapamil in a dose of 5–10 mg may be effective. Hormone synthesis is blocked by the administration of propylthiouracil, 250 mg every 6 hours. If the patient is unable to take medication by mouth, methimazole in a dose of 60 mg every 24 hours or propylthiouracil, 400 mg every 6 hours, can be given by rectal suppository or enema.* After administration


of an antithyroid drug, hormone release is retarded by the administration of sodium iodide, 1 g intravenously over a 24-hour period, or saturated solution of potassium iodide, 10 drops twice daily. Ipodate sodium, 1 g daily given orally, or iohexol given intravenously may be used instead of sodium iodide, but this will block the definitive use of radioiodine therapy for 3–6 months. The conversion of T4 to T3 is blocked by the administration of ipodate sodium or iohexol and also by the combination of propranolol and propylthiouracil. The administration of hydrocortisone hemisuccinate, 50 mg intravenously every 6 hours, is additive. Supportive therapy includes a cooling blanket and acetaminophen to help control fever. Aspirin is probably contraindicated because of its tendency to bind to TBG and displace thyroxine, rendering more thyroxine available in the free state. Fluids, electrolytes, and nutrition are important. For sedation, phenobarbital is probably best because it accelerates the peripheral metabolism and inactivation of thyroxine and triiodothyronine, ultimately bringing these levels down. Oxygen, diuretics, and digitalis are indicated for heart failure. Finally, it is essential to treat the underlying disease process that may have precipitated the acute exacerbation. Thus, antibiotics, anti-allergy drugs, and postoperative care are indicated for management of these problems. As an extreme measure (rarely needed) to control thyrotoxic crisis, plasmapheresis or peritoneal dialysis may be used to remove high levels of circulating thyronines. (See Chapter 24.)


Management of ophthalmopathy due to Graves' disease involves close cooperation between the endocrinologist and the ophthalmologist. The thyroid disease may be managed as outlined above, but in the opinion of this author, total surgical excision of the thyroid gland or total ablation of the thyroid gland with radioactive iodine is indicated. Although there is controversy over the need for total ablation, removal or destruction of the thyroid gland certainly prevents exacerbations and relapses of thyrotoxicosis, which may reactivate residual ophthalmopathy. Prednisone begun 24 hours after radioiodine in a dose of 40 mg/d, tapering the dose 10 mg every 2 weeks, will protect against exacerbation of ophthalmopathy following 131I therapy. Keeping the patient's head elevated at night will diminish periorbital edema. For the severe acute inflammatory reaction, a short course of corticosteroid therapy is frequently effective, eg, prednisone, 100 mg daily orally in divided doses for 7–14 days, then every other day in gradually diminishing dosage for 6–12 weeks. If corticosteroid therapy is not effective, external x-ray therapy to the retrobulbar area may be helpful. The dose is usually 2000 cGy in ten fractions given over a period of 2 weeks. The lens and anterior chamber structures must be shielded.

In very severe cases where vision is threatened, orbital decompression can be used. One type of orbital decompression involves a transantral approach through the maxillary sinus, removing the floor and the lateral walls of the orbit. In the alternative anterior approach, the orbit is entered under the globe, and portions of the floor and the walls of the orbit are removed. Both approaches have been extremely effective, and exophthalmos can be reduced by 5–7 mm in each eye by these techniques. After the acute process has subsided, the patient is frequently left with double vision or lid abnormalities owing to muscle fibrosis and contracture. These can be corrected by cosmetic lid surgery or eye muscle surgery.


Thyrotoxicosis during pregnancy presents a special problem. Radioactive iodine is contraindicated because it crosses the placenta freely and may injure the fetal thyroid. Two good alternatives are available. If the disease is detected during the first trimester, the patient can be prepared with propylthiouracil, and subtotal thyroidectomy can be performed safely during the mid trimester. It is essential to provide thyroid supplementation during the balance of the pregnancy. Alternatively, the patient can be treated with antithyroid drugs throughout the pregnancy, postponing the decision regarding long-term management until after delivery. The dosage of antithyroid drugs must be kept to the minimum necessary to control symptoms, because these drugs cross the placenta and may affect the function of the fetal thyroid gland. If the disease can be controlled by initial doses of propylthiouracil of 250 mg/d (in divided doses) or less and maintenance doses of 25–100 mg/d, the likelihood of fetal hypothyroidism is extremely small. The FT4I or FT4 should be maintained in the upper range of normal by appropriately reducing the propylthiouracil dosage. Supplemental thyroxine is not necessary. Breast feeding is not contraindicated, because propylthiouracil is not concentrated in the milk.

Graves' disease may occur in the newborn infant (neonatal Graves' disease). There seem to be two forms of the disease. In both types, the mother has a current or recent history of Graves' disease. In the first type, the child is born small, with weak muscles, tachycardia, fever, and frequently respiratory distress or neonatal jaundice. Examination reveals an enlarged thyroid gland and occasionally prominent, puffy eyes. The heart rate is rapid, temperature is elevated, and heart failure may ensue. Laboratory studies reveal an elevated FT4I or FT4, a markedly elevated T3, and usually a low TSH—in contrast to normal infants, who have elevated


TSH at birth. Bone age may be accelerated. TSH-R Ab [stim] is usually found in the serum of both the infant and the mother. The pathogenesis of this syndrome is thought to involve transplacental transfer of TSH-R Ab [stim] from mother to fetus, with subsequent development of thyrotoxicosis. The disease is self-limited and subsides over a period of 4–12 weeks, coinciding with the fall in the child's TSH-R Ab [stim]. Therapy for the infant includes propylthiouracil in a dose of 5–10 mg/kg/d (in divided doses at 8-hour intervals); strong iodine (Lugol's) solution, 1 drop (8 mg potassium iodide) every 8 hours; and propranolol, 2 mg/kg/d in divided doses. In addition, adequate nutrition, antibiotics for infection if present, sedatives if necessary, and supportive therapy are indicated. If the child is very toxic, corticosteroid therapy (prednisone, 2 mg/kg/d) will partially block conversion of T4 to T3 and may be helpful in the acute phase. The above medications are gradually reduced as the child improves and can usually be discontinued by 6–12 weeks.

A second form of neonatal Graves' disease occurs in children from families with a high incidence of that disorder. Symptoms develop more slowly and may not be noted until the child is 3–6 months old. This syndrome is thought to be a true genetic inheritance of defective lymphocyte immunoregulation. It is much more severe, with a 20% mortality rate and evidence of persistent brain dysfunction even after successful treatment. The hyperthyroidism may persist for months or years and requires prolonged therapy.

Maternal sera may contain TSH-R blocking antibodies that can cross the placenta and produce transient hypothyroidism in the infant. This condition may need to be treated with T4 supplementation for a short time.

Course & Prognosis

In general, the course of Graves' disease is one of remissions and exacerbations over a protracted period of time unless the gland is destroyed by surgery or radioactive iodine. Although some patients may remain euthyroid for long periods after treatment, many eventually develop hypothyroidism. Lifetime follow-up is therefore indicated for all patients with Graves' disease.

  1. Other Forms of Thyrotoxicosis

Toxic Adenoma (Plummer's Disease)

A functioning adenoma hypersecreting T3 and T4 will cause hyperthyroidism. These lesions start out as a “hot nodule” on the thyroid scan, slowly increase in size, and gradually suppress the other lobe of the gland (Figure 7-48). The typical patient is an older individual (usually over 40) who has noted recent growth of a long-standing thyroid nodule. Symptoms of weight loss, weakness, shortness of breath, palpitation, tachycardia, and heat intolerance are noted. Infiltrative ophthalmopathy is never present. Physical examination reveals a definite nodule on one side, with very little thyroid tissue on the other side. Laboratory studies usually reveal suppressed TSH and marked elevation in serum T3 levels, often with only borderline elevation of thyroxine levels. The scan reveals that the nodule is “hot.” Toxic adenomas are almost always follicular adenomas and almost never malignant. They are easily managed by administration of antithyroid drugs such as propyl-thiouracil, 100 mg every 6 hours, or methimazole, 10 mg every 6 hours, followed by treatment with radioactive iodine or unilateral lobectomy. Sodium 131I in doses of 20–30 mCi is usually required to destroy the benign neoplasm. Radioactive iodine is preferable for smaller toxic nodules, but larger ones are best managed surgically.

Toxic Multinodular Goiter

This disorder usually occurs in older patients with long-standing multinodular goiter. Ophthalmopathy is extremely rare. Clinically, the patient presents with tachycardia,


heart failure, or arrhythmia and sometimes weight loss, nervousness, weakness, tremors, and sweats. Physical examination reveals a multinodular goiter that may be small or quite large and may even extend substernally. Laboratory studies reveal a suppressed TSH and striking elevation in serum T3 levels, with less striking elevation of serum T4. Radioiodine scan reveals multiple functioning nodules in the gland or occasionally an irregular, patchy distribution of radioactive iodine (Figure 7-49).


Figure 7-48. Solitary toxic nodule as it appears on 99mTc pertechnetate scan. Note suppression of contralateral lobe (left) by toxic nodule (right).

Hyperthyroidism in patients with multinodular goiters can often be precipitated by the administration of iodides (often called“jodbasedow phenomenon,” or iodide-induced hyperthyroidism). Some thyroid adenomas do not develop the Wolff-Chaikoff effect (see above) and cannot adapt to an iodide load. Thus, they are driven to excess hormone production by a high level of circulating iodide. This is one mechanism for the development of hyperthyroidism after administration of the antiarrhythmic drug amiodarone (see below).


Figure 7-49. Toxic multinodular goiter as it appears on 99mTc pertechnetate scan. Note multiple functioning thyroid nodules. (Courtesy of JM Lowenstein.)

The management of toxic nodular goiter is difficult. Control of the hyperthyroid state with antithyroid drugs followed by subtotal thyroidectomy would seem to be the therapy of choice, but often these patients are elderly and have other illnesses that make them poor candidates for surgery. The toxic nodules can be destroyed with 131I, but the multinodular goiter will remain, and other nodules may become toxic, requiring repeated doses of 131I.

Amiodarone is an antiarrhythmic drug that contains 37.3% iodine. In the body, it is stored in fat, myocardium, liver, and lung and has a half-life of about 50 days. About 2% of patients treated with amiodarone develop amiodarone-induced thyrotoxicosis. In some patients, the thyrotoxicosis is due to the excess iodine; in others, it is due to an amiodarone-induced thyroiditis with dumping of stored hormone. Thyroid ultrasound with doppler examination of the thyroid circulation may be helpful in differentiating the two syndromes: The circulation is increased in iodide-induced hyperthyroidism and diminished in the chemically induced thyroiditis. Treatment is difficult. Iodide-induced thyrotoxicosis can be controlled with methimazole, 40–60 mg/d, and beta-adrenergic blockade. In addition, potassium perchlorate in a dose of 250 mg every 6 hours may be added to block further iodide uptake. However, long-term potassium chloride has been associated with aplastic anemia and requires monitoring. The chemical thyroiditis responds to prednisone therapy, which may be continued for several months. Total thyroidectomy is curative but is feasible only if the patient can withstand the stress of surgery. (See Chapter 24.)

Subacute or Chronic Thyroiditis

These entities will be discussed in a separate section, but it should be mentioned here that thyroiditis, either subacute or chronic, may present with an acute release of T4 and T3, producing symptoms of mild to severe thyrotoxicosis. These illnesses can be differentiated from other forms of thyrotoxicosis in that the radioiodine uptake is markedly suppressed, and the symptoms usually subside spontaneously over a period of weeks or months.

Thyrotoxicosis Factitia

This is a psychoneurotic disturbance in which the patient ingests excessive amounts of thyroxine or thyroid hormone, usually for purposes of weight control. The individual is often someone connected with the field of medicine who can easily obtain thyroid medication. Features of thyrotoxicosis, including weight loss, nervousness, palpitation, tachycardia, and tremor, may be present, but no goiter or eye signs. Characteristically, TSH is suppressed, serum T4 and T3 levels are elevated, serum thyroglobulin is low, and radioactive iodine uptake is nil. Management requires careful discussion of the hazards of long-term thyroxine therapy, particularly cardiovascular damage, muscle wasting, and osteoporosis. Formal psychotherapy may be necessary.



Rare Forms of Thyrotoxicosis


In this syndrome, a teratoma of the ovary contains thyroid tissue that becomes hyperactive. Mild features of thyrotoxicosis result, such as weight loss and tachycardia, but there is no evidence of goiter or eye signs. Serum FT4 and T3 are mildly elevated, serum TSH is suppressed, and radioiodine uptake in the neck is nil. Body scan reveals uptake of radioiodine in the pelvis. The disease is curable by removal of the teratoma.


Carcinoma of the thyroid, particularly follicular carcinoma, may concentrate radioactive iodine, but only rarely does it retain the ability to convert this iodide into active hormone. Only a few cases of metastatic thyroid cancer have presented with hyperthyroidism. The clinical picture consists of weakness, weight loss, palpitation, and a thyroid nodule but no ophthalmopathy. Body scan with 131I reveals areas of uptake usually distant from the thyroid, eg, bone or lung. Treatment with large doses of radioactive iodine may destroy the metastatic deposits.


Hydatidiform moles produce chorionic gonadotropin, which has intrinsic TSH-like activity. This may induce thyroid hyperplasia, increased iodine turnover, suppressed TSH, and mild elevation of serum T4 and T3 levels. It is rarely associated with overt thyrotoxicosis and is totally curable by removal of the mole.


An epidemic of thyrotoxicosis in the midwestern United States was traced to hamburger made from “neck trim,” the strap muscles from the necks of slaughtered cattle that contained beef thyroid tissue. The United States Department of Agriculture has now prohibited the use of this material for human consumption.


A group of patients have been reported with elevated serum free thyroxine concentrations in association with elevated serum immunoreactive TSH. This has been called the “syndrome of inappropriate TSH secretion.” Two types of problems are found: (1) TSH-secreting pituitary adenoma and (2) nonneoplastic pituitary hypersecretion of TSH.

Patients with TSH-secreting pituitary adenomas usually present with mild thyrotoxicosis and goiter, often with evidence of gonadotropic hormone deficiency such as amenorrhea or impotence. There are no eye signs of Graves' disease. Study reveals elevated total and free serum T4 and T3. Serum TSH, usually undetectable in Graves' disease, is within the normal range or even elevated. The TSH α subunit secretion from these tumors is markedly elevated; a molar ratio of α subunit:TSH greater than 5.7 is usually diagnostic of the presence of a TSH-secreting pituitary adenoma.* In addition, there is no hormonal response to TRH, and the increased radioactive iodine uptake is not suppressible with exogenous thyroid hormone. Visual field examination may reveal temporal defects, and CT or MRI of the sella usually reveals a pituitary tumor. Management usually involves control of the thyrotoxicosis with antithyroid drugs and removal of the pituitary tumor via transsphenoidal hypophysectomy. These tumors are often quite aggressive and may extend widely out of the sella. If the tumor cannot be completely removed, it may be necessary to treat residual tumor with radiation therapy and to control thyrotoxicosis with radioactive iodine. Long-acting somatostatin (octreotide) will suppress TSH secretion in many of these patients and may even inhibit tumor growth in some.

Nonneoplastic pituitary hypersecretion of TSH is essentially a form of pituitary (and occasionally peripheral) resistance to T3 and T4. This is discussed below.


Several forms of resistance to thyroid hormones have been reported: (1) generalized resistance to thyroid hormones (GRTH), (2) selective pituitary resistance to thyroid hormones (PRTH), and possibly (3) a selective peripheral resistance to thyroid hormones (perRTH).

Generalized resistance to thyroid hormones was first described in 1967 by Refetoff and coworkers as a familial syndrome of deaf mutism, stippled epiphyses, goiter, and abnormally high thyroid hormone levels with normal TSH. The clinical presentation in the more than 500 cases that have been reported has been variable; while most patients are euthyroid, many present with goiter, stunted growth, delayed maturation, attention deficits, hyperactivity disorders, and resting tachycardia. Seventy-five percent of reported cases are familial. Inheritance is autosomal dominant. Laboratory tests reveal elevated T4, FT4, T3, and normal or elevated TSH. Dynamic tests to distinguish generalized resistance to thyroid hormones from TSH-secreting adenomas usually reveal an increase in TSH after administration of TRH, a fall in TSH with T3 suppression, and a molar


ratio of α subunit:TSH of less than 1. In addition, in patients with GRTH, pituitary MRI fails to demonstrate a microadenoma. Molecular studies have revealed point mutations in the carboxyl terminal ligand-binding portion of the human thyroid receptor beta gene (TRβ), which produces a defective thyroid hormone receptor (TR) that fails to bind T3 but retains the ability to bind to DNA. In addition, the mutant TR occupies the TRE as an inactive dimer or heterodimer, perhaps inducing sustained gene repression (Figures 7-25 and 7-26). Different point mutations in different families may account in part for the differences in clinical expression of the syndrome. Furthermore, identification of the mutation in affected individuals may allow the use of molecular screening methods for the diagnosis of the syndrome in some families.

In most patients with generalized resistance to thyroid hormones, the increased levels of T3 and T4 will compensate in part for the receptor defect, and treatment is not necessary. In some children, administration of thyroid hormone may be necessary to correct defects in growth or mental development.

Selective pituitary resistance to thyroid hormones is less common and usually presents with symptoms of mild hyperthyroidism, goiter, elevated serum T4 and T3, and normal or elevated serum TSH. In this syndrome, T3 receptors in peripheral tissues are normal, but there is a failure of T3 to inhibit pituitary TSH secretion, resulting in inappropriate TSH secretion and TSH-induced hyperthyroidism. Differentiation from TSH-secreting pituitary adenoma can be made using the dynamic tests and MRI of the pituitary as outlined above.

This syndrome may be due in part to some abnormality in the pituitary type 2 5′-deiodinase with failure to convert intrapituitary T4 to T3, leading to PTHR. Ablation of the thyroid gland with 131I or treatment with antithyroid drugs may lead to pituitary hyperplasia. However, administration of triiodothyroacetic acid (TRIAC) has been reported to suppress TSH, reduce the size of the goiter, lower serum T4, and correct the hyperthyroidism.

Only one case of suspected selective peripheral resistance to T3 has been reported, and it is not yet clear that this is a distinct entity.

TSH Receptor Gene Mutations

Mutations in the TSH receptor gene can produce a variety of clinical syndromes. Somatic mutations in the seven-transmembrane loop of the TSH-R may activate the receptor, producing solitary or multiple hyperfunctioning adenomas, whereas germline mutations may result in congenital hyperthyroidism in the newborn. Mutations in the extracellular amino terminal of the TSH-R produce resistance to TSH with uncompensated or compensated hypothyroidism. The patient reported by Refetoff had normal FT4 and FT3 and normal growth and development but persistently elevated serum TSH. The patients reported by Medeiros-Neto were severely hypothyroid (cretinoid), with lowFT4 levels, elevated TSH, and no response to exogenous TSH. In this group, the defect may be in the coupling of TSH-R and the Gs protein necessary for activation of adenylyl cyclase.



Nontoxic goiter usually represents enlargement of the thyroid gland from TSH stimulation, which in turn results from inadequate thyroid hormone synthesis. Table 7-11 lists some of the causes of nontoxic goiter.

Iodine deficiency was the most common cause of nontoxic goiter or “endemic goiter”; with the widespread use of iodized salt and the introduction of iodides into fertilizers, animal feeds, and food preservatives, iodide deficiency in developed countries has become relatively rare. It does not exist in the United States. However, there are large areas such as central Africa, the mountainous areas of central Asia, the Andes of central South America, and Indonesia (particularly New Guinea), where iodine intake is still markedly deficient. Optimal iodine requirements for adults are in the range of 150–300 ľg/d. In endemic goiter areas, the daily intake (and urinary excretion) of iodine falls below 50 ľg/d; in areas where iodine is extremely scarce, excretion falls below 20 ľg/d. It is in these areas that 90% of the population will have goiters, and 5–15% of infants will be born with myxedematous or neurologic changes of cretinism. The variability in the extent of goiter in these areas may be related to the presence of other, unidentified goitrogens.

Dietary goitrogens are a rare cause of goiter, and of these the most common is iodide itself. Large amounts of iodide, as in amiodarone or kelp tablets, may in susceptible individuals produce goiter and hypothyroidism


(see above). Withdrawal of iodide reverses the process. Other goitrogens include lithium carbonate and some vegetable foodstuffs such as goitrin, found in certain roots and seeds; and cyanogenic glycosides, found in cassava and cabbage, that release thiocyanates which may cause goiter, particularly in the presence of iodide deficiency. In addition, compounds such as phenols, phthalates, pyridines, and polyaromatic hydrocarbons found in industrial waste water are weakly goitrogenic. The role of these vegetable and pollutant goitrogens in the production of goiter is not clearly established.

Table 7-11. Etiology of nontoxic goiter.

1. Iodine deficiency

2. Goitrogen in the diet

3. Hashimoto's thyroiditis

4. Subacute thyroiditis

5. Inadequate hormone synthesis due to inherited defect in thyroidal enzymes necessary for T4 and T3biosynthesis

6. Generalized resistance to thyroid hormone (rare)

7. Neoplasm, benign or malignant

The most common cause of thyroid enlargement in developed countries is chronic thyroiditis (Hashimoto's thyroiditis; see below). Subacute thyroiditis causes thyroid enlargement with exquisite tenderness (see below).

Nontoxic goiter may be due to impaired hormone synthesis resulting from genetic deficiencies in enzymes necessary for hormone biosynthesis (thyroid dyshor-monogenesis, or familial goiter). These effects may be complete, resulting in a syndrome of cretinism with goiter; or partial, resulting in nontoxic goiter with mild hypothyroidism. At least five separate biosynthetic abnormalities have been reported: (1) impaired transport of iodine; (2) deficient peroxidase with impaired oxidation of iodide to iodine and failure to incorporate iodine into thyroglobulin; (3) impaired coupling of iodinated tyrosines to triiodothyronine or tetraiodothyronine; (4) absence or deficiency of iodotyrosine deiodinase, so that iodine is not conserved within the gland; and (5) excessive production of metabolically inactive iodoprotein by the thyroid gland (Figure 7-9). The latter may involve impaired or abnormal thyroglobulin synthesis. In all of these syndromes, impaired production of thyroid hormones presumably results in TSH release and goiter formation.

Finally, thyroid enlargement can be due to a benign lesion, such as adenoma, or to a malignant one such as carcinoma.


The development of nontoxic goiter in patients with dyshormonogenesis or severe iodine deficiency involves impaired hormone synthesis and, secondarily, an increase in TSH secretion. TSH induces diffuse thyroid hyperplasia, followed by focal hyperplasia with necrosis and hemorrhage, and finally the development of new areas of focal hyperplasia. Focal or nodular hyperplasia usually involves a clone of cells that may or may not be able to pick up iodine or synthesize thyroglobulin. Thus, the nodules will vary from “hot” nodules that can concentrate iodine to “cold” ones that cannot, and from colloid nodules that can synthesize thyroglobulin to microfollicular ones that cannot. Initially, the hyperplasia is TSH-dependent, but later the nodules become TSH-independent, or autonomous. Thus, a diffuse nontoxic TSH-dependent goiter progresses over a period of time to a multinodular toxic or nontoxic TSH-independent goiter.

The mechanism for the development of autonomous growth and function of thyroid nodules may involve mutations that occur with TSH-induced cell division in an oncogene that activates the Gs protein in the cell membrane. Mutations of this oncogene, called the gsp oncogene, have been found in a high proportion of nodules from patients with multinodular goiter. Chronic activation of the Gs protein would result in thyroid cell proliferation and hyperfunction even when TSH is suppressed.

Clinical Features


Patients with nontoxic goiter usually present with thyroid enlargement, which, as noted above, may be diffuse or multinodular. The gland may be relatively firm but is often extremely soft. Over a period of time, the gland becomes progressively larger, so that in long-standing multinodular goiter, huge goiters may develop and extend inferiorly to present as substernal goiter. Facial flushing and dilation of cervical veins on lifting the arms over the head is a positive Pemberton sign and indicates obstruction. The patient may complain of pressure symptoms in the neck, particularly on moving the head upward or downward, and of difficulty in swallowing. Vocal cord paralysis due to recurrent laryngeal nerve involvement is rare. There may be symptoms of mild hypothyroidism, but most of these patients are euthyroid. Thyroid enlargement probably represents compensated hypothyroidism.


Laboratory studies will reveal a low or normal free thyroxine and, usually, normal levels of TSH. The increased mass of thyroid tissue compensates for inefficient synthesis of hormone. In patients with dyshormonogenesis due to abnormal iodoprotein synthesis, PBI and serum thyroglobulin may be elevated out of proportion to serum T4, because of secretion of nonhormonal organic iodide compounds. Radioiodine uptake may be high, normal, or low, depending upon the iodide pool and the TSH drive.


Isotope scanning usually reveals a patchy uptake, frequently with focal areas of increased uptake corresponding to “hot”nodules and areas of decreased uptake corresponding to “cold” nodules. Radioactive iodine uptake of the “hot” nodules may not be suppressible on administration of thyroid hormones such


as liothyronine. Thyroid ultrasound is a simple way to follow the growth of the goiter and in addition may reveal cystic changes in one or more of the nodules, representing previous hemorrhage and necrosis.

Differential Diagnosis

The major problem in differential diagnosis is to rule out cancer. This will be discussed in the section on thyroid carcinoma.


With the exception of those due to neoplasm, the current management of nontoxic goiters consists simply of giving thyroid hormone until TSH is suppressed to 0.1–0.4 ľU/L (normal range is 0.5–5 ľU/L). This requires levothyroxine in doses of 0.1–0.2 mg (approximately 2.2 ľg/kg, or 1 ľg/lb) daily. This will correct hypothyroidism and often result in slow regression of the goiter. Long-standing goiters may have areas of necrosis, hemorrhage, and scarring as well as autonomously functioning nodules that will not regress on thyroxine therapy. However, the lesions will usually grow more slowly while the patient is taking thyroxine. In older patients with multinodular goiters, administration of levothyroxine must be done very cautiously since the “hot” nodules are autonomous and the combination of endogenous and exogenous hormone will rapidly produce toxic symptoms.

Surgery is indicated for goiters that continue to grow despite TSH suppression with T4 or those that produce obstructive symptoms. Substernal extension of a goiter is usually an indication for surgical removal. The gross appearance of a multinodular goiter at the time of surgery is presented in Figure 7-50. Note that the left lobe of the gland extends downward from the middle of the thyroid cartilage to just above the clavicle. The pressure of this enlargement has caused deviation of the trachea to the right. The surface of the gland is irregular, with many large and small nodules. Although these multinodular goiters are rarely malignant, the size of the mass with resulting pressure symptoms requires subtotal thyroidectomy.

If the patient is not a suitable candidate for surgery, radioiodine ablation of functioning thyroid tissue may provide palliative relief of obstructive symptoms. An adequate dose of radioiodine will reduce the size of the goiter about 30%, but the residual tissue may regrow, with recurrence of symptoms.

Course & Prognosis

Patients with nontoxic goiter must usually take levothyroxine for life. They should avoid iodides, which may induce either hyperthyroidism or, in the absence of thyroxine therapy, hypothyroidism. Occasionally, single adenomas or several adenomas will become hyperfunctional, producing a toxic nodular goiter (discussed above). Nontoxic goiter is often familial, and other members of the family should be examined and observed for the possible development of goiter.


Figure 7-50. Multinodular goiter at the time of surgery. The asymmetric enlargement and the nodularity are apparent, as is the rightward deviation of the trachea resulting from marked enlargement of the lobe.


  1. Subacute Thyroiditis

Subacute thyroiditis (De Quervain's thyroiditis, or granulomatous thyroiditis) is an acute inflammatory disorder of the thyroid gland most likely due to viral infection. A number of viruses, including mumps virus, coxsackievirus, and adenoviruses, have been implicated, either by finding the virus in biopsy specimens taken from the gland or by demonstration of rising titers of viral antibodies in the blood during the course of the infection. Pathologic examination reveals moderate thyroid enlargement and a mild inflammatory reaction involving the capsule. Histologic features include destruction of thyroid parenchyma and the presence of many large phagocytic cells, including giant cells.



Clinical Features


Subacute thyroiditis usually presents with fever, malaise, and soreness in the neck, which may extend up to the angle of the jaw or toward the ear lobes on one or both sides of the neck. Initially, the patient may have symptoms of hyperthyroidism, with palpitations, agitation, and sweats. There is no ophthalmopathy. On physical examination, the gland is exquisitely tender, so that the patient will object to pressure upon it. There are no signs of local redness or heat suggestive of abscess formation. Clinical signs of toxicity, including tachycardia, tremor, and hyperreflexia, may be present.


Laboratory studies will vary with the course of the disease (Figure 7-51). Initially, T4 and T3 are elevated, whereas serum TSH and thyroid radioactive iodine uptake are extremely low. The erythrocyte sedimentation rate is markedly elevated, sometimes as high as 100 mm/h by the Westergren scale. Thyroid autoantibodies are usually not detectable in serum. As the disease progresses, T4 and T3 will drop, TSH will rise, and symptoms of hypothyroidism are noted. Later, radioactive iodine uptake will rise, reflecting recovery of the gland from the acute insult.


Figure 7-51. Changes in serum T4 and radioactive iodine uptake in patients with subacute thyroiditis. In the initial phase, serum T4 is elevated and the patient may have symptoms of thyrotoxicosis, but radioactive iodine uptake is markedly suppressed. The illness may pass through phases of euthyroidism and hypothyroidism before remission. (Data adapted, with permission, from Woolf PD, Daly R: Thyrotoxicosis with painless thyroiditis. Am J Med 1976;60:73.)

Differential Diagnosis

Subacute thyroiditis can be differentiated from other viral illnesses by the involvement of the thyroid gland. It is differentiated from Graves' disease by the presence of low thyroid radioiodine uptake associated with elevated serum T3 and T4 and suppressed serum TSH and by the absence of thyroid antibodies.


In most cases, only symptomatic treatment is necessary, eg, acetaminophen, 0.5 g four times daily. If pain, fever, and malaise are disabling, a short course of a nonsteroidal anti-inflammatory drug or a glucocorticoid such as prednisone, 20 mg three times daily for 7–10 days, may be necessary to reduce the inflammation. Levothyroxine, 0.1–0.15 mg once daily, is indicated during the hypothyroid phase of the illness in order to prevent reexacerbation of the disease induced by the rising TSH levels. In about 10% of patients, permanent hypothyroidism ensues and long-term levothyroxine therapy is necessary.

Course & Prognosis

Subacute thyroiditis usually resolves completely and spontaneously over weeks or months. Occasionally, the disease may begin to resolve and then suddenly get worse, sometimes involving first one lobe of the thyroid gland and then the other (migrating thyroiditis). Exacerbations often occur when the T4 levels have fallen, the TSH level has risen, and the gland is starting to recover function. Rarely, the course may extend over several years, with repeated bouts of inflammatory disease.

  1. Chronic Thyroiditis

Chronic thyroiditis (Hashimoto's thyroiditis, lymphocytic thyroiditis) is probably the most common cause of hypothyroidism and goiter in the United States. It is certainly the major cause of goiter in children and young adults and is probably the major cause of “idiopathic myxedema,” which represents an end stage of Hashimoto's thyroiditis, with total destruction of the gland. Riedel's struma is probably a variant of Hashimoto's thyroiditis, with extensive fibrosis extending outside the gland and involving overlying muscle and surrounding tissues. Riedel's struma presents as a stony-hard mass that must be differentiated from thyroid cancer.



Etiology & Pathogenesis

Hashimoto's thyroiditis is thought to be an immunologic disorder in which lymphocytes become sensitized to thyroidal antigens and autoantibodies are formed that react with these antigens (see thyroid autoimmunity, above). In Hashimoto's thyroiditis, the three most important thyroid autoantibodies are thyroglobulin antibody (Tg Ab), thyroperoxidase antibody (TPO Ab), and TSH receptor blocking antibody (TSH-R Ab [block]). During the early phases of Hashimoto's thyroiditis, Tg Ab is markedly elevated and TPO Ab is slightly elevated. Later, Tg Ab may disappear, but TPO Ab will be present for many years. TSH-R Ab [block] is found in patients with atrophic thyroiditis and myxedema and in mothers giving birth to infants with no detectable thyroid tissue (athyreotic cretins). The pathology of Hashimoto's thyroiditis involves a heavy infiltration of lymphocytes totally destroying normal thyroidal architecture. Lymphoid follicles and germinal centers may be formed. The follicular epithelial cells are frequently enlarged and contain a basophilic cytoplasm (Hurthle cells). Destruction of the gland results in a fall in serum T3 and T4 and a rise in TSH. Initially, TSH may maintain adequate hormonal synthesis by the development of thyroid enlargement or goiter, but often the gland fails, and hypothyroidism with or without goiter ensues.

Hashimoto's thyroiditis is part of a spectrum of thyroid diseases that includes Graves' disease at one end and idiopathic myxedema at the other (Figure 7-52). It is familial and may be associated with other autoimmune diseases such as pernicious anemia, adrenocortical insufficiency, idiopathic hypoparathyroidism, myasthenia gravis, and vitiligo. Schmidt's syndrome consists of Hashimoto's thyroiditis, idiopathic adrenal insufficiency, hypoparathyroidism, diabetes mellitus, and ovarian insufficiency. Schmidt's syndrome represents destruction of multiple endocrine glands on an autoimmune basis (Chapter 4).

Clinical Features


Hashimoto's thyroiditis usually presents with goiter in a patient who is euthyroid or has mild hypothyroidism. The sex distribution is about four females to one male. The process is painless, and the patient may be unaware of the goiter unless it becomes very large. Older patients may present with severe hypothyroidism with only a small, firm atrophic thyroid gland (idiopathic myxedema).


There are multiple defects in iodine metabolism. Peroxidase activity is decreased, so that organification of iodine is impaired. This can be demonstrated by a positive perchlorate discharge test (Figure 7-11). In addition, iodination of metabolically inactive protein material occurs, so that there will be a disproportionately high serum PBI and serum globulin compared with serum T4. Radioiodine uptake may be high, normal, or low. Circulating thyroid hormone levels are usually normal or low, and if low, TSH will be elevated.

The most striking laboratory finding is the high titer of autoantibodies to thyroidal antigens in the serum. Serum tests for either Tg Ab or TPO Ab are positive in most patients with Hashimoto's thyroiditis. Another diagnostic test that may be helpful is the fine-needle aspiration biopsy, which reveals a large infiltration of lymphocytes as well as the presence of Hurthle cells.

Differential Diagnosis

Hashimoto's thyroiditis can be differentiated from other causes of nontoxic goiter by serum antibody studies and, if necessary, by fine-needle aspiration biopsy.


Figure 7-52. Spectrum of autoimmune disease of the thyroid gland. The clinical manifestations of autoimmune disease of the thyroid gland range from idiopathic myxedema, through nontoxic goiter, to diffuse toxic goiter, or Graves' disease. Progression of autoimmune disease from one form to another in the same patient can occasionally occur.



Complications & Sequelae

The major complication of Hashimoto's thyroiditis is progressive hypothyroidism. Although only 10–15% of young patients presenting with goiter and hypothyroidism seem to progress to permanent hypothyroidism, the high incidence of permanent hypothyroidism in older patients with positive antibody tests and elevated TSH levels suggests that long-term treatment is desirable. Rarely, a patient with Hashimoto's thyroiditis may develop lymphoma of the thyroid gland, but whether the two conditions are causally related is not clear. Thyroid lymphoma is characterized by rapid growth of the gland despite continued thyroid hormone therapy; the diagnosis of lymphoma must be made by surgical biopsy (see below).

There is no evidence that adenocarcinoma of the thyroid gland occurs more frequently in patients with Hashimoto's thyroiditis, but the two diseases—chronic thyroiditis and carcinoma—can coexist in the same gland. Cancer must be suspected when a solitary nodule or thyroid mass grows or fails to regress while the patient is receiving maximal tolerated doses of thyroxine. Fine-needle aspiration biopsy is helpful in this differential diagnosis.


The indications for treatment of Hashimoto's thyroiditis are goiter or hypothyroidism; a positive thyroid antibody test does not require therapy. Sufficient levothyroxine is given to suppress TSH and allow regression of the goiter. Surgery is rarely indicated.

Course & Prognosis

Without treatment, Hashimoto's thyroiditis will usually progress from goiter and hypothyroidism to myxedema. The goiter and the myxedema are totally corrected by adequate thyroxine therapy. Hashimoto's thyroiditis may go through periods of activity when large amounts of T4and T3 are released or “dumped,” resulting in transient symptoms of thyrotoxicosis. This syndrome, which has been called spontaneously resolving hyperthyroidism, is characterized by low radioiodine uptake. However, it can be differentiated from subacute thyroiditis in that the gland is not tender, the erythrocyte sedimentation rate is not elevated, autoantibodies to thyroidal antigens are strongly positive, and fine-needle aspiration biopsy reveals lymphocytes and Hurthle cells. Therapy is symptomatic, usually requiring only propranolol, until symptoms subside; T4 supplementation may then be necessary.

Because Hashimoto's thyroiditis may be part of a syndrome of multiple autoimmune diseases (Chapter 4), the patient should be monitored for other autoimmune diseases such as pernicious anemia, adrenal insufficiency, hypothyroidism, or diabetes mellitus. Patients with Hashimoto's thyroiditis may also develop true Graves' disease, occasionally with severe ophthalmopathy or dermopathy (Figure 7-52). The chronic thyroiditis may blunt the severity of the thyrotoxicosis, so that the patient may present with eye or skin complications of Graves' disease without marked thyrotoxicosis, a syndrome often called euthyroid Graves' disease. The thyroid gland will invariably be nonsuppressible, and this, plus the presence of thyroid autoantibodies, will help to make the diagnosis. The ophthalmopathy and dermopathy are treated as if thyrotoxic Graves' disease were present.

  1. Other Forms of Thyroiditis

The thyroid gland may be subject to acute abscess formation in patients with septicemia or acute infective endocarditis. Abscesses cause symptoms of pyogenic infection, with local pain and tenderness, swelling, and warmth and redness of the overlying skin. Needle aspiration will confirm the diagnosis and identify the organism. Treatment includes antibiotic therapy and occasionally incision and drainage. A thyroglossal duct cyst may become infected and present as acute suppurative thyroiditis. This too will respond to antibiotic therapy and occasionally incision and drainage.


Ionizing radiation can induce both acute and chronic thyroiditis. Thyroiditis may occur acutely in patients treated with large doses of radioiodine and may be associated with release of thyroid hormones and an acute thyrotoxic crisis. Such an occurrence is extremely rare, however, and pretreatment with antithyroid drugs to bring the patient to a euthyroid state prior to 131I therapy will completely prevent this type of radiation thyroiditis.

External radiation was used many years ago for the treatment of respiratory problems in the newborn, thought to be due to thymic hyperplasia, and for the treatment of benign conditions such as severe acne and chronic tonsillitis or adenoiditis. This treatment was often associated with the later development of nodular goiter, hypothyroidism, or thyroid cancer. Another source of radiation exposure is fallout from atomic bomb testing or a nuclear reactor accident.

The incidence of thyroid lesions after irradiation is summarized in Table 7-12. As little as 6.5 cGy (1 cGy = 1 rad) to the thyroid gland received during the radiation


treatment of tinea capitis has been reported to cause cancer in 0.11% of exposed children; the incidence of thyroid cancer in sibling controls was 0.02%. Radiation therapy to the thymus delivered to the thyroid dosages of 100–400 cGy, and the incidence of thyroid cancer attributed to this source ranged from 0.5% to 5%. X-ray therapy to the neck and chest given to children or adolescents for acne or chronic upper respiratory infections delivered thyroid doses ranging from 200 cGy to 1500 cGy, resulting in the development of nodular goiter in about 27% and thyroid cancer in 5–7% of the patients so treated. These tumors developed 10–40 years after radiation was administered, with a peak incidence at 20–30 years. Radiation fallout with a thyroid dose of 700–1400 cGy has produced nodular goiter in approximately 40% of exposed victims and thyroid cancer in about 6%. However, radioiodine therapy, which exposes the thyroid to a dosage of around 10,000 cGy, was rarely associated with the development of thyroid cancer, presumably because the thyroid gland is largely destroyed by these doses of radioiodine, so that—although the incidence of postradiation hypothyroidism is high—the incidence of thyroid cancer is extremely low. Ninety percent of patients with radiation-induced thyroid cancer develop papillary carcinoma; the remainder develop follicular carcinoma. Medullary carcinoma and anaplastic carcinomas have been rare following radiation exposure. Although the overall incidence of thyroid carcinoma in irradiated patients is low, data from several large series suggest that the incidence of cancer in a patient who presents with a solitary cold nodule of the thyroid gland and a history of therapeutic radiation of the head, neck, or chest is around 50%.

Table 7-12. Thyroid lesions after irradiation.

Areas Treated

Estimated Dose to Thyroid (cGy)

Incidence (%)


Nodular Goiter






Modan et al (1974)

   Total group




Hemplemann et al (1975)






Neck, chest




Favus et al (1975)
Refetoff et al (1975)

Radiation fallout

< 50
> 50
175 (γ) and 700–1400 (β)



Parker et al (1974)
Sampson et al (1969)
Conrad et al (1970)

131I therapy

≈ 10,000



Dobyns et al (1974)

The most recent episode of radiation-induced thyroid neoplasia was the Chernobyl disaster in April 1986, at which time huge amounts of radioactive material, especially radioiodine, were released. As early as 4 years later, a striking increase in the incidence of thyroid nodules and thyroid cancer was noted in children in Gomel, an area in the Republic of Belarus, close to Chernobyl and heavily contaminated. A high proportion of the cancers arose in young children and developed after a very short latency period. The sex distribution was equal. Most of the cancers were papillary carcinomas and were very aggressive, with intraglandular, capsular, local, and lymph node invasion.

Patients who have been exposed to ionizing radiation should be followed carefully for life. Annual studies should include physical examination of the neck for goiter or nodules, and FT4 or TSH determinations to rule out hypothyroidism. Periodic thyroid ultrasound may detect nodules that are not palpable. If a nodule is found, it should be scanned with 123I, and if cold, fine-needle aspiration biopsy should be done. If the nodule is malignant, the patient should have total thyroidectomy; if benign, the patient should be treated with levothyroxine in a dose sufficient to suppress TSH. If the nodule persists or grows while T4 therapy is being given, the thyroid gland should be surgically removed.


In 95% of cases, thyroid cancer presents as a nodule or lump in the thyroid. In occasional instances, particularly in children, enlarged cervical lymph nodes are the first sign of the disease, though on careful examination a small primary focus in the form of a thyroid nodule


can often be felt. Rarely, distant metastasis in lung or bone is the first sign of thyroid cancer. Thyroid nodules are extremely common, particularly among women. The prevalence of thyroid nodules in the USA has been estimated to be about 4% of the adult population, with a female:male ratio of 4:1. In young children, the prevalence is less than 1%; in persons aged 11–18 years, about 1.5%; and in persons over age 60, about 5%.

In contrast to thyroid nodules, thyroid cancer is a rare condition, with a prevalence of 0.004% per year according to the Third National Cancer Survey. Thus, most thyroid nodules are benign, and it is important to identify those that are likely to be malignant.

  1. Benign Thyroid Nodules


Benign conditions that can produce nodularity in the thyroid gland are listed in Table 7-13. They include focal areas of chronic thyroiditis, a dominant portion of a multinodular goiter, a cyst involving thyroid tissue, parathyroid tissue, or thyroglossal duct remnants, and agenesis of one lobe of the thyroid, with hypertrophy of the other lobe presenting as a mass in the neck. It is usually the left lobe of the thyroid that fails to develop, and the hypertrophy occurs in the right lobe. Scarring in the gland following surgery—or regrowth of the gland after surgery or radioiodine therapy—can present with nodularity. Finally, benign neoplasms in the thyroid include follicular adenomas such as colloid or macrofollicular adenomas, fetal adenomas, embryonal adenomas, and Hurthle cell or oxyphil adenomas. Rare types of benign lesions include teratomas, lipomas, and hemangiomas. Except for thyroid hyperplasia of the right lobe of the gland in the presence of agenesis of the left lobe—and some follicular adenomas—all of the above lesions present as “cold” nodules on isotope scanning.

Table 7-13. Etiology of benign thyroid nodules.

1. Focal thyroiditis

2. Dominant portion of multinodular goiter

3. Thyroid, parathyroid, or thyroglossal cysts

4. Agenesis of a thyroid lobe

5. Postsurgical remnant hyperplasia or scarring

6. Postradioiodine remnant hyperplasia

7. Benign adenomas:

1. Follicular:
    Colloid or macrofollicular
    Hürthle cell

2. Rare: Teratoma, lipoma, hemangioma

Differentiation of Benign & Malignant Lesions

Risk factors that predispose to benign or malignant disease are set forth in Table 7-14 and discussed below.


A family history of goiter suggests benign disease, as does residence in an area of endemic goiter. However, a family history of medullary carcinoma or a history of recent thyroid growth, hoarseness, dysphagia, or obstruction strongly suggests cancer. The significance of exposure to ionizing radiation is discussed above.


Physical characteristics associated with a low risk for thyroid cancer include older age, female sex, soft thyroid nodules, and the presence of a multinodular goiter. Individuals at higher risk for thyroid cancer include children, young adults, and males. A solitary firm or dominant nodule that is clearly different from the rest of the gland signifies an increased risk of malignancy. Vocal cord paralysis, enlarged lymph nodes, and suspected metastases are strongly suggestive of malignancy.


A high titer of thyroid autoantibodies in serum suggests chronic thyroiditis as the cause of thyroid enlargement but does not rule out an associated malignancy. However, an elevated serum calcitonin, particularly in patients with a family history of medullary carcinoma, strongly suggests the presence of thyroid cancer. Elevated serum thyroglobulin following total thyroidectomy for papillary or follicular thyroid cancer usually indicates metastatic disease, but serum thyroglobulin is not usually helpful in determining the nature of a thyroid nodule.


Scanning procedures can be used to identify “hot” or “cold” nodules, ie, those that take up more or less radioactive iodine than surrounding tissue. Hot nodules are almost never malignant, whereas cold ones may be. Scintillation camera photographs with 99mTc pertechnetate give the best resolution (Figure 7-53). Thyroid ultrasound can distinguish cystic from solid lesions. A pure cyst is almost never malignant. Cystic lesions that have internal septa or solid lesions on ultrasound may be benign or malignant. CT scanning or MRI may be


helpful in defining substernal extension or deep thyroid nodules in the neck.

Table 7-14. Risk factors useful in distinguishing benign from malignant thyroid lesions.


More Likely Benign

More Likely Malignant


Family history of benign goiter
Residence in endemic goiter area

Family history of medullary cancer of thyroid
Previous therapeutic irradiation of head or neck
Recent growth of nodule
Hoarseness, dysphagia, or obstruction

Physical characteristics

Older woman
Soft nodule
Multinodular goiter

Child, young adult, male
Solitary, firm nodule clearly different from rest of gland (“dominant nodule”)
Vocal cord paralysis, firm lymph nodes, distant metastases

Serum factors

High titer of thyroid autoantibodies

Elevated serum calcitonin

Scanning techniques
 123I or 99mTcO4

“Hot nodule”

“Cold nodule”

   Echo scan

Cyst (pure)

Solid or semicystic

Biopsy (needle)

Benign appearance on cytologic examination

Malignant or suggestion of malignancy

Levothyroxine therapy (TSHsuppression for 3–6 months)


No regression


The major advance in management of the thyroid nodule in recent years has been the fine-needle aspiration biopsy (see above). Large-needle core aspiration biopsies of thyroid nodules have been available since about 1930, but they are limited to large nodules and are relatively traumatic. Söderström in 1952 introduced the technique of fine-needle aspiration biopsy, which is simple, safe, reliable, and well-tolerated (Figure 7-54).


Fine-needle aspiration biopsy separates thyroid nodules into three groups: (1) Malignant thyroid nodules: The technique is diagnostic in about 95% of all types of thyroid malignancies. (2) Follicular neoplasms: About 15% of these lesions are malignant and about 85% are benign, but these two groups cannot be distinguished by cytology. Thus, a diagnosis of follicular neoplasm is always suspicious for malignancy. On isotope scan, a “hot” follicular neoplasm is benign, and a “cold” follicular neoplasm may be benign or malignant. (3) Benign thyroid nodules. About 5% of fine-needle aspiration readings are false-positives and about 5% false-negatives. Thus, results are accurate in about 90% of cases, as demonstrated by subsequent surgery or long-term follow-up of patients with lesions originally reported to be benign. The results of the biopsy study must be interpreted by the clinician but are extremely useful for the diagnosis of malignancy in thyroid nodules.


Figure 7-53. Demonstration of resolution obtained utilizing different scanning techniques: A: 123I scintiscan with rectilinear scanner.B: Fluorescent scan with rectilinear scanner. C: 99mTc pertechnetate scan with the pinhole collimated gamma camera. Note the presence of two “cold” nodules, one in each lobe of the thyroid, easily detected in C but not clearly delineated in the other two scans. The lesion in the right lobe was palpable, about 1 cm in diameter, and was shown to be follicular carcinoma on needle biopsy. The lesion in the left lobe was either a metastatic tumor or a second primary follicular carcinoma. (Courtesy of MD Okerlund.)


Figure 7-54. Decision matrix for workup of a thyroid nodule. See text for details. (FNA, fine-needle aspiration.)


Benign lesions may undergo spontaneous involution and regression, and some may be sufficiently TSH-dependent to shrink in response to thyroxine therapy. Some studies have shown no regression of solitary nodules following T4 therapy, while others have shown a 20–30% reduction in size, particularly in multinodular goiters. However, malignant lesions are unlikely to regress either spontaneously or in response to T4 therapy.

Management of Thyroid Nodules

A decision matrix for management of a thyroid nodule is presented in Figure 7-54. A patient with a thyroid nodule should have a serum TSH and fine-needle aspiration biopsy as the initial screening tests. If TSH is abnormal, appropriate therapy should be instituted. The


biopsy will be reported as malignant, follicular neoplasm, benign, or unsatisfactory. If unsatisfactory, it should be repeated. If the nodule is malignant, the patient is referred directly to the surgeon. If the cytologic report shows that the nodule is benign, the patient is given thyroxine, and if the lesion regresses the patient is maintained on thyroxine indefinitely at a dose sufficient to suppress serum TSH. If there is no regression, the lesion is biopsied again—or, if it grows or changes in consistency, it may be excised. In patients who are reported to have follicular neoplasms, radionuclide scan is obtained. If the scan reveals the nodule to be hot, the patient is simply observed, with or without thyroxine therapy. If the lesion is cold and there is an increased chance of malignancy (large lesion over 2 cm in diameter, firm nodule, young patient), the patient might be referred directly to the surgeon. If the risk is low (small lesion 1 cm or less in diameter, soft nodule, older patient), the patient is given thyroxine. If thyroxine does not induce regression in the latter case, the lesion should probably be excised.

There are two groups that represent special problems: patients with thyroid cysts and patients who have received radiation therapy. Although thyroid cysts are almost always benign, cancer is occasionally found in the wall of the cyst. For this reason, recurrent cysts should be studied with ultrasonography, and if there is evidence of a septate lesion or growth in the wall of the lesion, surgical removal is indicated. In patients who have received radiation therapy, there may be multiple lesions, some benign and some malignant. Therefore, the presence of a cold nodule in a patient who has had radiation exposure is an indication for surgical removal.

If this protocol is followed, there will be a marked reduction in surgery for benign thyroid nodules, and the incidence of malignancy at the time of surgery will be about 40%. The cost savings is enormous, since unnecessary surgery is eliminated and the cost of the thyroid nodule workup is cut in half. In addition, there is no delay in making the diagnosis and referring the patient with thyroid cancer for appropriate therapy.

  1. Thyroid Cancer


The types and approximate frequency of malignant thyroid tumors are listed in Table 7-15.


Papillary carcinoma of the thyroid gland usually presents as a nodule that is firm, solitary, “cold” on isotope scan, solid on thyroid ultrasound, and clearly different from the rest of the gland. In multinodular goiter, the cancer will usually be a“dominant nodule”—larger, firmer, and (again) clearly different from the rest of the gland. About 10% of papillary carcinomas, especially in children, present with enlarged cervical nodes, but careful examination will often reveal a “cold” nodule in the thyroid. Rarely, there will be hemorrhage, necrosis, and cyst formation in the malignant nodule, but on thyroid ultrasound of these lesions, clearly defined internal echoes will differentiate the semicystic malignant lesion from the nonmalignant “pure cyst.” Finally, papillary carcinoma may be found incidentally as a microscopic focus of cancer in the middle of a gland removed for other reasons such as Graves' disease or multinodular goiter.

Table 7-15. Approximate frequency of malignant thyroid tumors.

Papillary carcinoma (including mixed papillary and follicular)


Follicular carcinoma


Medullary carcinoma


Undifferentiated carcinomas


Miscellaneous (including lymphoma, fibrosarcoma, squamous cell carcinoma, malignant hemangioen-dothelioma, teratomas, and metastatic carcinomas)


Microscopically, the tumor consists of single layers of thyroid cells arranged in vascular stalks, with papillary projections extending into microscopic cyst-like spaces. The nuclei of the cells are large and pale and frequently contain clear, glassy intranuclear inclusion bodies. About 40% of papillary carcinomas form laminated calcified spheres—often at the tip of a papillary projection—called “psammoma bodies,” which are usually diagnostic of papillary carcinoma. These cancers usually extend by intraglandular metastasis and by local lymph node invasion. They grow very slowly and remain confined to the thyroid gland and local lymph nodes for many years. In older patients, they may become more aggressive and invade locally into muscles and trachea. In later stages, they can spread to the lung. Death is usually due to local disease, with invasion of deep tissues in the neck; less commonly, death may be due to extensive pulmonary metastases. In some older patients, a long-standing, slowly growing papillary carcinoma will begin to grow rapidly and convert to undifferentiated or anaplastic carcinoma. This “late anaplastic shift” is another cause of death from papillary carcinoma. Many papillary carcinomas secrete thyroglobulin, which can be used as a marker for recurrence or metastasis of the cancer.


Follicular carcinoma is characterized by the presence of small follicles, though colloid formation is poor. Indeed,


follicular carcinoma may be indistinguishable from follicular adenoma except by capsular or vascular invasion. The tumor is somewhat more aggressive than papillary carcinoma and can spread either by local invasion of lymph nodes or by blood vessel invasion with distant metastases to bone or lung. Microscopically, the cells are cuboidal, with large nuclei, arranged around follicles that frequently contain dense colloid. These tumors often retain the ability to concentrate radioactive iodine, to form thyroglobulin, and, rarely, to synthesize T3 and T4. Thus, the rare “functioning thyroid cancer” is almost always a follicular carcinoma. This characteristic makes these tumors more likely to respond to radioactive iodine therapy. In untreated patients, death is due to local extension or to distant bloodstream metastasis with extensive involvement of bone, lungs, and viscera.

A variant of follicular carcinoma is the “Hörthle cell” carcinoma, characterized by large individual cells with pink-staining cytoplasm filled with mitochondria. They behave like follicular cancer except that they rarely take up radioiodine. Mixed papillary and follicular carcinomas behave more like papillary carcinoma. Thyroglobulin secretion by follicular carcinomas can be used to follow the course of disease.


Medullary cancer is a disease of the C cells (parafollicular cells) derived from the ultimobranchial body and capable of secreting calcitonin, histaminase, prosta-glandins, serotonin, and other peptides. Microscopically, the tumor consists of sheets of cells separated by a pink-staining substance that has characteristics of amyloid. This material stains with Congo red. Amyloid consists of chains of calcitonin laid down in a fibrillary pattern—in contrast to other forms of amyloid, which may have immunoglobulin light chains or other proteins deposited in a fibrillary pattern.

Medullary carcinoma is somewhat more aggressive than papillary or follicular carcinoma but not as aggressive as undifferentiated thyroid cancer. It extends locally into lymph nodes and into surrounding muscle and trachea. It may invade lymphatics and blood vessels and metastasize to lungs and viscera. Calcitonin and carcinoembryonic antigen (CEA) secreted by the tumor are clinically useful markers for diagnosis and follow-up.

About 80% of medullary carcinomas are sporadic, and the remainder are familial. There are three familial patterns: (1) familial medullary carcinoma without associated endocrine disease (FMTC); (2) MEN 2A, consisting of medullary carcinoma, pheochromocytoma, and hyperparathyroidism; and (3) MEN 2B, consisting of medullary carcinoma, pheochromocytoma, and multiple mucosal neuromas. There is also a variant of MEN 2A with cutaneous lichen amyloidosis, a pruritic skin lesion located on the upper back. The genes responsible for the familial syndromes have been mapped to the centromeric region of chromosome 10, which is the location of the ret proto-oncogene (a receptor-linked protein kinase gene), and mutations in exon 10, 11, or 16 of this proto-oncogene have been found in these syndromes (see below and Chapter 22).

If medullary carcinoma is diagnosed by fine-needle aspiration biopsy or at surgery, it is essential that the patient be screened for the other endocrine abnormalities found in MEN 2 and that family members be screened for medullary carcinoma and MEN 2 as well. Screening involves measurement of serum calcitonin after calcium infusion in patients who have demonstrated mutations in the ret proto-oncogene on DNA analysis (see below). Calcium gluconate is administered intravenously in a dose of 2 mg/kg given over 1 minute, and blood for calcitonin determination is obtained at 1, 2, 3, and 5 minutes after the infusion. Peak values occur 1–2 minutes after injection. Peak values of > 100 pg/mL in females and > 300 pg/mL in males are considered abnormal.


Undifferentiated thyroid gland tumors include small cell, giant cell, and spindle cell carcinomas. They usually occur in older patients with a long history of goiter in whom the gland suddenly—over weeks or months—begins to enlarge and produce pressure symptoms, dysphagia, or vocal cord paralysis. Death from massive local extension usually occurs within 6–36 months. These tumors are very resistant to therapy.

  2. Lymphoma—The only type of rapidly growing thyroid cancer that is responsive to therapy is the lymphoma, which may develop as part of a generalized lymphoma or may be primary in the thyroid gland. Thyroid lymphoma occasionally develops in a patient with long-standing Hashimoto's thyroiditis and may be difficult to distinguish from chronic thyroiditis. It is characterized by lymphocyte invasion of thyroid follicles and blood vessel walls, which helps to differentiate thyroid lymphoma from chronic thyroiditis. If there is no systemic involvement, the tumor may respond dramatically to radiation therapy.
  3. Cancer metastatic to the thyroid—Systemic cancers that may metastasize to the thyroid gland include cancers of the breast and kidney, bronchogenic carcinoma, and malignant melanoma. The primary site of involvement is usually obvious. Occasionally, the diagnosis is made by needle biopsy or open biopsy of a rapidly enlarging cold thyroid nodule. The prognosis is that of the primary tumor.



  1. Molecular biology of thyroid neoplasms—Extensive studies have revealed evidence of gene mutations in both benign and malignant thyroid neoplasms (Figure 7-55). Activating mutations in the gsponcogene or TSH-R in the thyroid follicular cell have been associated with increased growth and function in the “hot” or “toxic” thyroid nodule. Aberrant DNA methylation, activation of the rasoncogene and mutation of the MEN1 gene located at 11q13 are associated with benign follicular adenomas. Loss of the 3P suppressor gene may then result in the development of follicular carcinoma, and further loss of suppressor gene P53 may allow progression to an anaplastic carcinoma. Mutations in the ret and trk oncogenes are associated with the development of papillary carcinomas—and again, loss of P53suppressor gene may allow progression to anaplastic carcinoma. This hypothesis suggests a progression from benign to malignant lesions and from differentiated to undifferentiated carcinoma. Indeed, in pathology specimens from older patients with long-standing goiters and recent rapid enlargement, we may see a transition from papillary or follicular thyroid carcinoma to anaplastic carcinoma, a phenomenon termed “late anaplastic shift.”

As noted above, activating mutations of the ret proto-oncogene on chromosome 10 have been shown to be associated with MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The ret oncogene encodes a receptor-linked tyrosine kinase. About 85–90% of the mutations found in MEN 2A and FMTC occur in exons 10 and 11, whereas about 95% of the mutations associated with MEN 2B are found in exon 16 of the ret oncogene. These mutations can be demonstrated in DNA from peripheral white blood cells utilizing the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). In patients with MEN 2 or FMTC who do not demonstrate a mutation in the ret oncogene, family unit linkage analysis may be used to identify gene carriers. Thus, families can be screened for the carrier state, and early diagnosis and treatment can be instituted (Figure 7-56). Somatic mutations in the ret oncogene occur in about 30% of sporadic MTC tumor cells, but this does not occur in white blood cells and does not represent a germline mutation. (See also Chapter 22.)


Figure 7-55. Molecular defects associated with development and progression of human thyroid neoplasms. The hypothetical role of specific mutational events in thyroid tumorigenesis is inferred from their prevalence in the various thyroid tumor phenotypes. (Reproduced, with permission, from Fagin JA: Genetic basis of endocrine disease 3: Molecular defects in thyroid gland neoplasia. J Clin Endocrinol Metab 75:1398, 1992.)

Management of Thyroid Cancer (Figure 7-57)


These patients may be classified into low-risk and high-risk groups. The low-risk group includes patients under age 45 with primary lesions under 2 cm and no evidence of intra- or extraglandular spread. For these patients, lobectomy is adequate therapy. All other patients should be considered high-risk, and for these total thyroidectomy and—if there is evidence of lymphatic spread—a modified neck dissection are indicated. In the absence of evidence of lymphatic spread, prophylactic neck dissection is not necessary. However, for the high-risk group, postoperative radioiodine ablation of residual thyroid remnant is essential. After recovery from surgery, the patient receives liothyronine, 50–100 ľg daily in divided doses for 4 weeks; the medication is then stopped for 2 weeks, and the patient is placed on a low-iodine diet. At the end of the 2-week period, the serum thyroglobulin level is determined and the patient is scanned at 24 and 72 hours after a dose of 2–4 mCi of 131I. Liothyronine is used for replacement therapy because it is cleared from the blood rapidly; after 2 weeks off therapy, serum TSH is usually over 50 mU/L, which is necessary for good scanning studies. If there is evidence of residual radioactive iodine uptake in the neck or elsewhere or if there is a rise in serum thyroglobulin greater than 4 ng/mL, radioactive iodine (131I) is effective treatment. (Therapeutic doses of 131I range from 30 mCi to 200 mCi.) The scan is repeated at intervals of 12 months until serum thyroglobulin levels remain under 4 ng/mL and no further uptake is observed; the patient is then maintained on maximum replacement therapy with levothyroxine, 0.15–0.3 mg daily, to suppress serum TSH to undetectable levels. Once a negative scan has been achieved, recombinant human TSH (rhTSH) can be used instead of thyroxine withdrawal for follow-up evaluation. The patient continues to take the appropriate dose of levothyroxine but follows a low-iodine diet for at least 1


week prior to the study. Then on day 1, blood is drawn for thyroglobulin (Tg) determination, and 0.9 mg of rhTSH is administered intramuscularly. On day 2, the patient receives rhTSH, 0.9 mg intramuscularly; on day 3, 4 mCi 131I is given orally; and on day 5, blood is drawn for Tg determination and a neck scan and whole body scan are obtained. If serum Tg is < 2 ng/mL and the scans are negative, the study is negative for recurrence. If serum Tg rises above 4 ng/mL or if the scan is positive, the patient has persistent disease and should be treated with 131I following the schedule of levothyroxine withdrawal as set forth above. If Tg is > 4 ng/mL and the scan is negative, thyroid ultrasound, CT, or MRI examination may reveal recurrent tumor that may be approached surgically.


Figure 7-56. Decision matrix for the management of medullary thyroid carcinoma. See text for details. FNA, fine-needle aspiration biopsy; PE, physical examination.

Follow-up at intervals of 6–12 months should include careful examination of the neck for recurrent masses. If a lump is noted, needle biopsy is indicated to confirm or rule out cancer. Serum TSH should be checked to be certain it is adequately suppressed, and serum Tg should be < 2 ng/mL (2 ľg/L). A rise in serum Tg to > 4 ng/mL (10 ľg/L) while TSH is suppressed suggests recurrence of the malignancy, which may be treated with 131I as above.

Thyroglobulin antibodies in the patient's serum interfere with the thyroglobulin assay and may negate the value of the serum thyroglobulin determination. These patients may have to be followed with periodic visualization studies such as thyroid ultrasound or MRI. The patient with a rising thyroglobulin and a negative 131I scan presents a difficult problem. Administration of a large dose of 131I after appropriate preparation has been tried, but there is little evidence of long-term benefit. For patients with bone or brain metastases, combined external radiation and 131I therapy may be effective. Chemotherapeutic programs are being studied, but no clearly effective protocol has yet been developed.


Patients with medullary carcinoma should be followed in a similar way, except that the marker for recurrent medullary cancer is serum calcitonin or carcinoembryonic


antigen (CEA). Family members of patients with a genetic ret oncogene mutation should be screened for the mutation as noted above (Figure 7-56). Histaminase and other peptides are also secreted by these tumors, but assays for these substances are not generally available. If a patient has a persistently elevated serum calcitonin concentration after total thyroidectomy and regional node dissection, MRI of the neck and chest or selective venous catheterization and sampling for serum calcitonin may reveal the location of the metastases. Metastatic medullary carcinoma foci may be revealed by PET scan, indium-labeled somatostatin (octreotide), or sestamibi scan. If this fails to localize the lesion (as is often the case), the patient must be followed until the metastatic lesion shows itself as a palpable mass or a shadow on chest x-ray or MRI. Metastatic medullary carcinoma cannot be treated with 131I; therefore, initial thorough surgical excision and postoperative levothyroxine




therapy are essential. Chemotherapy for medullary carcinoma has not been effective.


Table 7-16. Tumor (T), lymph node (N), and distant metastasis (M) classification and staging of thyroid cancer.1


Figure 7-57. Decision matrix for the management of papillary, follicular, or anaplastic thyroid carcinoma. See text for details. FNA, fine-needle aspiration biopsy; PE, physical examination.


Anaplastic carcinoma of the thyroid has a very poor prognosis. Treatment consists of isthmusectomy (to confirm the diagnosis and to prevent tracheal compression) and palliative x-ray therapy (Figure 7-57). Thyroid lymphomas are quite responsive to x-ray therapy; giant cell, squamous cell, spindle cell, and anaplastic carcinomas are unresponsive. Chemotherapy is not very effective for anaplastic carcinomas. Doxorubicin, 75 mg/m2 as a single injection or divided into three consecutive daily injections repeated at 3-week intervals, has been useful in some patients with disseminated thyroid cancer unresponsive to surgery, TSH suppression, or radiation therapy. This drug is quite toxic; side effects include cardiotoxicity, myelosuppression, alopecia, and gastrointestinal symptoms.


Local x-ray therapy has been useful in the treatment of solitary metastatic lesions, particularly follicular or papillary tumors, that do not concentrate radioactive iodine. It is particularly effective in isolated nonfunctional bone metastases.

Course & Prognosis

The staging of cancer has been a useful method for prediction of the outcome of therapy. The International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) have proposed the TNM (tumor, nodes, metastases) system for staging thyroid cancer Table 7-16.

In this system, papillary and follicular thyroid carcinomas are grouped together and the staging is directly related to the age of the patient at the time of diagnosis. The cause-specific 5-year mortality rates in a group of 1500 patients studied by Hay were as follows: stage 1, 0%; stage 2, 0.6%; stage 3, 5.3%; and stage 4, 77%. Similarly, DeGroot and coworkers demonstrated 80–90% survival for stage 1 and stage 2 patients followed for up to 38 years; about 50% survival for stage 3 patients followed for 20 years; and 0% survival for stage 4 patients followed for 10 years. The TNM system may


underestimate the risk of recurrence and death in younger patients with aggressive disease. This is particularly true for patients under age 7 with local invasion or distant metastases, who should probably be grouped in stage 3 or stage 4. However, the system recognizes that for most younger patients, papillary and follicular thyroid carcinomas are relatively indolent and thus can be classified as stage 1 or stage 2.


Figure 7-58. Improved survival in patients with papillary or follicular thyroid carcinoma following total or near-total thyroidectomy compared to less than near total thyroidectomy. (Reproduced, with permission, from Mazzaferri EL, Jhiang SM: Long term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418.)

Outcome is also dependent upon adequate therapy. There has been controversy over the extent of initial surgery for papillary and follicular thyroid cancer. As noted above, lesions under 1 cm with no evidence of local or distant metastases (T1, N0, M0) can probably be treated with lobectomy alone. However, in all other groups, total thyroidectomy and modified regional neck dissection (if gross evidence of spread is noted at the time of surgery) is indicated for two reasons: (1) it removes all local disease, and (2) it sets the stage for 131I therapy and follow-up utilizing serum thyroglobulin measurements. Total or near-total thyroidectomy must be performed by an experienced thyroid surgeon to minimize the complications of surgery. The improvement in outcome following total thyroidectomy is presented in Figure 7-58.

A second factor in survival is the use of radioiodine for ablation of residual thyroid tissue after thyroidectomy and the treatment of residual or recurrent disease. Low doses of 30–50 mCi 131I are used to ablate residual thyroid tissue, but larger doses of 100–200 mCi are necessary for the treatment of metastatic disease. Acute adverse effects of the larger doses include radiation sickness, sialitis, gastritis, and transient oligospermia. Cumulative doses of 131I above 500 mCi may be associated with infertility in the female and azoospermia in the male, pancytopenia in about 4%, and leukemia in about 0.3% of patients. Radiation pneumonitis may occur in patients with diffuse pulmonary metastases, but this is minimized by utilization of high-dose treatment


no more than once a year. The effectiveness of 131I therapy in reducing cancer mortality is presented in Figure 7-59.


Figure 7-59. Cancer death rates after thyroid remnant ablation, thyroid hormone therapy alone, or no postoperative medical therapy. (Modified and reproduced, with permission, from Mazzaferri EL: Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997;7:265.)

A third factor in survival is the adequate use of TSH suppression therapy. T4 in a dose of 2.2 ľg/kg/d (1 ľg/lb/d) will usually suppress TSH to 0.1 mU/L or less, which removes a major growth factor for papillary or follicular thyroid cancer (Figure 7-59). However, high-dose T4therapy is not without risk: angina, tachycardia, or heart failure in older patients or tachycardia and nervousness in younger patients. In addition, there is an increased risk of osteoporosis in postmenopausal women. Estrogen or bisphosphonate therapy may prevent bone loss in these patients, but the treatment program must be individualized.

Medullary carcinoma is more aggressive. It is most aggressive in patients with MEN 2B, less in the sporadic type, and least virulent in MEN 2A and FMTC. Early and adequate initial surgery is the best therapy; once the disease has started to metastasize, it is very difficult to control, though the more favorable types often progress very slowly. Anaplastic thyroid carcinomas have a very poor prognosis, with death anticipated to occur within 1 year.



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*In this chapter, the words “iodine” and “iodide” are used interchangeably.

*Preparation of rectal methimazole: Dissolve 1200 mg methimazole in 12 mL of water to which has been added a mixture of 2 drops of Span 80 in 52 mL of cocoa butter warmed to 37 °C. Stir the mixture to form a water-oil emulsion, pour into 2.6 mL suppository molds, and cool. Each suppository will supply approximately 60 mg methimazole absorbed dose (Nabil et al, 1982). Preparation of rectal propylthiouracil: Dissolve 400 mg propyl-thiouracil in 60 mL of Fleet Mineral Oil for the first dose and then dissolve 400 mg propylthiouracil in 60 mL of Fleet Phospho-Soda for subsequent enemas.

*The α subunit: TSH molar ratio is calculated as follows: α subunit in ľg/L divided by TSH in ľU/L × 10. Normal range (for a patient with normal TSH and gonadotrophins) is < 5.7.