THYROID

ANATOMY OF THE THYROID AND PARATHYROID GLANDS

Located between the larynx and the trachea medially and the carotid sheath and the sternomastoid muscles laterally, the thyroid gland weighs 15 to 25 g. The lateral thyroid lobes are 3 to 4 cm long and 1.5 to 2 cm wide; the isthmus is 1.2 to 2 cm long and 2 cm wide and crosses the trachea between the I and II rings. In Plate 2-1 ( upper image ), the skin, subcutaneous fat, and platysma muscle have been excised, exposing, on the right half of the neck, the anterior or first cervical fascia. This fascia envelops the external and anterior jugular veins and the transverse cervical nerves. The subcutaneous fat and platysma muscle contain a rich blood supply, so that wide surgical exposures may be obtained, without sacrificing skin, by raising flaps of skin, subcutaneous fat, and platysma. The veins and nerves thus exposed are left initially in situ to be moved later with the muscles beneath.

On the left side of the neck ( Plate 2-1 , upper image ), the first cervical fascia, the external jugular vein, the transverse nerves, and the sternocleidomastoid muscle have been excised. This excision shows the positions of the omohyoid muscle, the ansa hypoglossal nerve, the important limiting insertion of the shorter inner pretracheal muscle, the sternothyroid muscle, and the entire course of the longer thyrohyoid muscle. The same fascial layer has been incised down the midline, exposing the medial borders of the sternohyoid muscle. These muscles, normally meeting together in the midline, have been partially retracted to expose the thyroid and cricoid cartilages, the isthmus of the thyroid, and the upper trachea lying beneath.

The anterior jugular veins supplement the external jugular vein in returning the blood from the pharynx and upper neck. They also receive tributaries throughout their length: first, from the platysma superficial to them; second, from the pretracheal muscles (sternohyoid, sternothyroid, and omohyoid) deep to them; and third, at the level of the larynx, particularly at the notch, from several fine tributaries from the upper larynx near the midline. In exposing the thyroid and parathyroid glands and the trachea, it is important to save as many of these vessels as possible by retracting them, rather than dividing them, to avoid unnecessary edema of the upper neck and larynx. These anterior veins may be greatly dilated when tumors of the thyroid or other organs deep in the neck have pressed on either internal jugular vein.

The sensory transverse cervical nerves may be severed because they will regenerate. However, this is not true for the two lower branches of the facial nerve—transection of the marginal mandibular branch is followed by drooping of the lower lip on the paralyzed side. The ansa hypoglossal nerve, lying along the anterior medial aspect of the carotid sheath, should be preserved. In exposing the nerve, it is helpful to remember that a small branch of the superior thyroid artery comes down just in front of the nerve, delivering branches to the posterior edge of the muscle as well as supplying the nerve. Division of this nerve renders swallowing more difficult after operation.

The lymphatic vessels in the superficial fascia, anterior to the prethyroid muscles, are not prominent. Lymph nodes are rare; the first one consistently encountered lies immediately in front of the thyroid isthmus in the midline between the pretracheal muscles, deep to the anterior fasciae and superficial to the second or middle cervical fasciae, the false capsule of the thyroid. This node drains the pharynx or larynx but not the thyroid gland or deeper tissues beneath. It is thus enlarged in patients with acute pharyngitis and laryngitis but not in those with thyroiditis or tracheitis.

Exposure of the thyroid, parathyroid, and thymus glands is achieved by retracting the pretracheal or prethyroid muscles. The widest exposure is obtained if the muscles are cut transversely and the ends retracted up and down. A good view of the upper thyroid pole often requires transection of the inner muscle.

The position of the esophagus, shown slightly to the right of midline ( Plate 2-1 , lower image ), is adjacent to the usually larger right lobe of the thyroid.

The Plate 2-2 ( upper image ) depicts the organs of the neck and anterior superior mediastinum with the anterior neck muscles and the bones of the upper thorax removed. When the thyroid, parathyroid, and thymus glands are first exposed, they lie enveloped on their anterior, lateral, and posterior surfaces by an ill-defined loose areolar fascia (also called the false capsule of the thyroid), which permits the glands, larynx, and trachea to rise and fall with swallowing. Indeed, nearly the entire anterior surface of both thyroid lobes can be palpated when the patient is instructed to swallow.

The normal thyroid gland is nearly always asymmetric. The right lobe may be even twice as large as the left lobe. The right upper pole extends higher up in the neck, and the lower pole extends lower. In a patient with dextrocardia, the lobe size is reversed.

Four developmental anomalies are to be noted. A pyramidal lobe persists in at least 15% of the population, becoming enlarged if the thyroid is enlarged by a diffuse process. It is occasionally the site or origin of thyroid neoplasia. The second anomaly is the failure of thyroid tissue to be contained within the main thyroid mass posteriorly, which occurs in at least 5% of people. The noncontiguous nature may be palpable on physical examination, giving rise to suspicion of a tumor. The third and fourth anomalies are the failure of the isthmus to fuse in the midline and the absence of a substantial part of the lateral lobe, notably the lower half of the left lobe. These anomalies are rare, occurring in less than 1% of the population. When the isthmus fails to fuse, the medial aspects of the lateral lobes may feel like tumors, but palpating the tracheal rings where the isthmus should be will give the clue. Similarly, absence of the lower half of a lateral lobe may lead to the mistaken impression that the upper half is a thyroid nodule.

The lower image on Plate 2-2 is a lateral view of the organs of the right side of the neck, with the neck muscles, right clavicle, and sternum removed. The position and size of the normal parathyroids are variable. Usually, there are four glands, two upper and two lower. Rarely, there is a fifth, which the surgeon may need to find if it is adenomatous and the source of parathyroid hormone hypersecretion or if it is involved in hyperplasia (e.g., in multiple endocrine neoplasia type 1). The upper glands are more constant and circumscribed in position than the lower glands, often significantly larger, and therefore easier to find. They lie in the plane behind the thyroid, from the upper thyroid pole to the lower branches of the inferior thyroid artery. When enlarged by disease, they may be displaced downward into the posterior mediastinum. The lower glands, arising from a branchial cleft higher than the upper glands and associated, in their embryologic descent, with the thymus, are found over a much wider extent—above or behind the thyroid and down into the anterior mediastinum as far as thymic tissue is found.

The lymphatic vessels and nodes, in the upper image on Plate 2-2 , follow a consistent pattern. The most readily felt and the first encountered are those in the midline in front. The uppermost, just above the thyroid isthmus, in front of the cricoid cartilage, and medial to a pyramidal lobe, if present, is a constant node group of one to five nodes, which has been termed the Delphian node . If involved in thyroid cancer or Hashimoto thyroiditis, it may be felt preoperatively. The pretracheal nodes below the thyroid isthmus are harder to identify because they are embedded in fat and not so constant in position as the Delphian. The other node groups, in order of operative importance, are those on the lateral thyroid surface along the lateral thyroid vein, the nodes along the upper stretch of the recurrent laryngeal nerve behind the thyroid lobe, those at the angle of the jaw, those along the carotid sheath (jugular chain), and the more lateral nodes in the supraclavicular fossa. The sentinel nodes of Virchow are the lowermost of the jugular chain at the upper end of the thoracic duct. These nodes may be involved with thyroid and parathyroid carcinoma, as well as with metastases from carcinomas localized outside of the neck.

The laryngeal motor nerves are well depicted in both images on Plate 2-2 . The superior nerve carries the motor branch to the cricothyroid muscle. This muscle tenses the vocal cord by drawing the front of the thyroid cartilage down on the cricoid. Fuzziness of the voice follows section of the nerve, particularly if the injury is bilateral.

The different sites of origin of the two inferior or recurrent laryngeal nerves induce a different course for the nerve on either side. The right nerve passes diagonally from lateral to medial on its upward course, but the left is thrown by the aortic arch, at its inception, against the trachea and esophagus and comes straight up in the tracheoesophageal groove. This constant course makes it the easier of the two to find.

DEVELOPMENT OF THE THYROID AND PARATHYROID GLANDS

PHARYNX

By the beginning of the second month of embryonic development, the portion of the originally tubular entodermal foregut caudal to the buccopharyngeal (oral) membrane has differentiated into the pharynx. At this time, the pharynx is relatively wide; compressed dorsoventrally; and has on each side a series of four lateral outpocketings, the pharyngeal pouches (see Plate 2-3, A and B ). Each pouch is in close relationship to an aortic arch and is situated opposite a branchial cleft (gill furrow) (see Plate 2-3A ).

In certain aquatic species, the tissue in the depths of the branchial clefts and at the extremities of the pharyngeal pouches disintegrates to produce communications (the gill slits) between the pharyngeal cavity and the surface of the body. Persistent gill slits can occur in humans; the anomaly may be a slender, epithelially lined tract (branchial or cervical fistula) that extends from the pharyngeal cavity to an opening near the auricle (first pouch) or onto the neck (second and third pouches) (see Plate 2-4 ). When the anomaly is less extensive, it is either a cervical diverticulum or an epithelially lined cervical cyst. A blind diverticulum may extend either outward from the pharynx, for a variable distance, or inward from the neck. A cyst may be located at one site or another in the depths of the neck, causing no trouble unless it becomes infected or filled with fluid in postnatal life.

The central lumen of the embryonic pharynx gives rise to the adult pharynx (see Plate 2-4 ). The first, or most cephalic, pair of pharyngeal pouches gives rise to the auditory (eustachian) tubes, to the tympanic (middle ear) cavities, and to the mucous membrane lining the inner surface of each tympanum. The first branchial clefts, located opposite the first pouches, give rise to the external acoustic (auditory) meatuses and to the outer epithelial lining of each eardrum. The second pouches give rise to the epithelium lining the palatine tonsils. The latter pouches are, for the most part, absorbed into the pharyngeal wall, persisting only as pharyngeal outpocketings by contributing to the formation of the supratonsillar fossae (see Plate 2-4 ).

THYROID GLAND

At a level between the first and second pharyngeal pouches, a saclike entodermal diverticulum (the thyroid sac) appears in the midline of the ventral surface of the pharynx. This sac, destined to give rise to the parenchyma of the thyroid gland (see Plate 2-3A ), is the first glandular derivative of the pharynx. When it appears, near the end of the fourth gestational week, it almost immediately becomes bilobated, and a narrow, hollow neck connects the two lobes. This neck is known as the thyroglossal duct because its pharyngeal attachment is located where the ventral floor of the pharynx contributes to the formation of the tongue. The duct becomes a solid stalk and begins to atrophy by the sixth gestational week; however, its pharyngeal connection results in a permanent pit, the foramen cecum, at the apex of the V-shaped sulcus terminalis on the dorsum of the tongue (see Plate 2-3C and 2-4 ).

The thyroid sac is converted into a solid mass of cells by the time the thyroglossal stalk disappears. By the end of the seventh week, the developing thyroid becomes crescentic in shape and is relocated to a position at the level of the developing trachea (see Plate 2-3C ). This relocation occurs because the thyroid is left behind as the pharynx grows forward. At this time, the thyroid's two (lateral) lobes, one on each side of the trachea, are connected in the midline by a very narrow isthmus of developing thyroid tissue (see Plate 2-3C ).

The formation of thyroid follicles begins during the eighth week of development. They acquire colloid by the third month. By the end of the fourth month, new follicles arise only by the budding and subdivision of those already present. The mesenchyma, surrounding the thyroid primordium, differentiates into the stroma of the gland and its thin proper fiber-elastic capsule.

The thyroglossal duct may persist either as an epithelial tract, which is open from the foramen cecum of the tongue to the level of the larynx, or as a series of blind pockets (thyroglossal duct cysts) (see Plates 2-4 and 2-5 ).

Persistent portions of the duct or stalk may give rise to accessory thyroids or to a median fistula that opens onto the neck. When a portion of thyroglossal duct persists at the level of the hyoid bone, it passes through the body of the bone (see Plate 2-4 ).

The variably occurring “pyramidal lobe of the thyroid” results from the retention and growth of the lower end of the stalk. A ligament or a band of muscle, usually located to the left of the midline, may connect the pyramidal lobe either to the thyroid cartilage or to the hyoid bone. The pyramidal lobe undergoes gradual atrophy; therefore, it is found more often in children than in adults.

Other variations of the thyroid gland are found. For example, the isthmus may be voluminous, rudimentary, or absent. The lateral lobes may be of different sizes, or both may be absent, with only the isthmic portion present. The shape of the gland may be more like that of an “H” than that of a “horseshoe.” Rarely, the gland may be located at the base of the tongue (lingual thyroid) or deep to the sternum. Complete absence of the gland or failure of the gland to function is seldom noticed until a few weeks after birth because fetuses are supplied, through the placenta, with sufficient maternal thyroid hormone to permit normal development. If proper hormonal treatment is not instituted after birth, the result is congenital hypothyroidism

CONGENITAL ANOMALIES OF THE THYROID GLAND

Aberrant, or abnormal, locations of thyroid tissue may be explained on the basis of abnormal embryologic migration of the thyroid and of its close association with lateral thyroid anlagen. These abnormal settings of thyroid tissue can better be understood if one considers the embryology of the thyroid gland, which, in humans, arises about the seventeenth day of gestation and is derived from the alimentary tract. The median part of the thyroid is formed from the ventral evagination of the floor of the pharynx at the level of the first and second pharyngeal pouches. The lateral thyroid anlage, from the area of the fourth pouch, becomes incorporated into the median thyroid anlage to contribute a small proportion of the final thyroid parenchyma. The thyroid anlage becomes elongated and enlarges laterally, with the pharyngeal region contracting to become a narrow stalk—the thyroglossal tract or duct. This subsequently atrophies, leaving at its point of origin on the tongue a depression known as the foramen cecum. Normally, the thyroid continues to grow and simultaneously migrates caudally.

The anatomic sites for the location of anomalously formed thyroid tissue range from the posterior tongue down into the region of the heart, within the mediastinum. Persistence of thyroid tissue on the posterior tongue is a fairly uncommon anomaly known as lingual thyroid. This may be the only source of thyroid tissue in the individual. It can often be demonstrated with radioactive iodine scintigraphy, revealing the localization of radioiodine only within the lingual thyroid without any thyroid tissue being demonstrated in the neck.

Intralingual and sublingual rests of thyroid tissue have been described, but these are quite uncommon. The thyroglossal tract that persists usually atrophies completely. However, it may fail to atrophy, remaining as a cystic mass in the midline of the neck, somewhere between the base of the tongue and the hyoid bone. A thyroglossal cyst should therefore be considered in any individual presenting with an enlarging cystic mass immediately beneath the chin in the midline. Occasionally, such cysts may be associated with thyroid tissue capable of concentrating radioactive iodine.

Substernal aberrant thyroid, tissue in the mediastinum, is rarely the consequence of abnormal development, representing glandular rests remaining from the time of the caudal descent of the thyroid. However, most often, substernal thyroid tissue is the result of downward growth of a nodular goiter. Prelaryngeal thyroid tissue may exist, being attached to a very long pyramidal lobe or to a thyroglossal cyst. Intratracheal thyroid rests have also been reported, although infrequently. The “lateral aberrant thyroid” may represent original branchial tissue that did not fuse with the median thyroid. However, the demonstration of microscopic carcinoma in the thyroids of some patients with so-called “lateral aberrant thyroid tissue” suggests that, in most instances, these may actually be metastases from a low-grade, well-differentiated thyroid papillary thyroid carcinoma.

The medical significance of aberrant thyroid tissue is quite limited. Occasionally, an inflammatory change or, rarely, enlargement and consequent thyrotoxicity will call for surgical or radiotherapeutic intervention. The exact interpretation of these lesions necessitates an understanding of their embryologic derivation.

EFFECTS OF THYROTROPIN ON THE THYROID GLAND

The hypothalamic–pituitary unit has an indispensable role in the regulation of thyroid function. Hypothalamic dysfunction or anterior pituitary failure leads to diminished thyroid mass and decreased production and secretion of thyroid hormones. The pituitary hormone that targets the thyroid gland is the glycoprotein thyrotropin (thyroid-stimulating hormone [TSH]), which is secreted by pituitary thyrotrophs. TSH is the main regulator of the structure and function of the thyroid gland. TSH is composed of an α subunit and a β subunit. The α subunit consists of 92 amino acids, and it is identical to the α subunit of luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin. The β subunit of glycoprotein hormones confers specificity. The β subunit synthesized in thyrotrophs is an 112-amino acid protein. Hypothalamic thyrotropin-releasing hormone (TRH) is a modified tripeptide (pyroglutamyl-histidyl-proline-amide) that increases the transcription of both subunits, and thyroid hormones (thyroxine [T ₄ ] and triiodothyronine [T ₃ ]) suppress the transcription of both subunits. In healthy persons, the serum TSH concentration is between 0.3 and 5.0 mIU/L. TSH concentrations are increased in primary hypothyroidism, increased in secondary hyperthyroidism (e.g., TSH-secreting pituitary tumor), and decreased in primary hyperthyroidism. Blood TSH concentrations vary in both a pulsatile and a circadian manner—a nocturnal surge precedes the onset of sleep.

Both T ₄ and T ₃ mediate feedback regulation of TRH and TSH secretion. A linear inverse relationship exists between the serum free T ₄ concentration and the log of the TSH. Thus, the serum TSH concentration is a very sensitive indicator of the thyroid state of patients with intact hypothalamic-pituitary function.

A TSH receptor is expressed on thyroid cells. The TSH receptor is a member of the glycoprotein G protein–coupled receptor family. The TSH receptor couples to Gs and induces a signal via the phospholipase C and intracellular calcium pathways that regulate iodide efflux, H ₂ O ₂ production, and thyroglobulin iodination. Signaling by the protein kinase A pathways mediated by cyclic adenosine monophosphate regulates iodine uptake and transcription of thyroglobulin, thyroperoxidase, and the sodium-iodide symporter mRNAs, leading to thyroid hormone production. In addition to TSH, the TSH receptor also binds thyroid-stimulating antibody (increased in the setting of Graves disease) and thyroid-blocking antibodies (increased in the setting of Hashimoto thyroiditis). At high concentrations, the closely related glycoprotein hormones—luteinizing hormone and chorionic gonadotropin—also bind to and activate TSH receptor signaling and can cause physiologic hyperthyroidism of early pregnancy.

With an intact hypothalamic–pituitary–thyroid axis, the thyroid gland mass is normal, thyroid follicle cells appear cuboidal, TSH concentration is in the reference range, free T ₄ and total T ₃ concentrations are in the reference range, and radioactive iodine uptake is normal. In the setting of hypothalamic or pituitary dysfunction, secondary hypothyroidism is manifest by decreased thyroid gland mass (which may not be palpable on physical examination), flat-appearing thyroid follicle cells, low TSH concentration (or inappropriately low for the low thyroid hormone levels), free T ₄ and total T ₃ concentrations below the reference range, and low radioactive iodine uptake. However, in a patient with a TSH-secreting pituitary tumor, the thyroid gland mass is increased and is usually evident as a firm goiter on physical examination, thyroid follicle cells appear columnar and the colloid is diminished, TSH concentration is inappropriately within or slightly above the reference range, free T ₄ and total T ₃ concentrations are above the reference range, and radioactive iodine uptake is increased.

PHYSIOLOGY OF THYROID HORMONES

The role of the thyroid gland in the total body economy comprises the synthesis, storage, and secretion of thyroid hormones, which are necessary for growth, development, and normal body metabolism. These thyroid functions can be considered almost synonymous with iodine metabolism. Iodination of the tyrosine molecule leads to synthesis of thyroxine (tetraiodothyronine [T ₄ ]) and triiodothyronine (T ₃ ).

Inorganic iodine (I ⁻ ) is rapidly absorbed in the gastrointestinal (GI) tract and circulates as iodide, until it is either trapped by the thyroid or salivary glands or excreted by the urinary tract. The thyroid extracts iodine from the plasma, against a 25-fold concentration gradient, by virtue of the sodium–iodide symporter (NIS). The function of NIS requires a sodium gradient across the basolateral membrane—the transport of 2 Na ⁺ ions allows the transport of 1 iodide atom. NIS also transports TcO ₄ ⁻ , which is used clinically for thyroid scintigraphy, and potassium perchlorate (KClO ₄ ⁻ ), which can block thyroid iodide uptake. NIS gene transcription and protein half-life are enhanced by thyrotropin (thyroid-stimulating hormone [TSH]). Intrafollicular cell iodide is also generated by the action of iodotyrosine dehalogenase 1 isoenzyme (Dhal-1) that deiodinates monoiodotyrosine (MIT) and diiodotyrosine (DIT).

Pendrin is a glycoprotein expressed on the apical border of the thyroid follicular cell, where it facilitates the transfer of iodide into the follicular colloid. After the pendrin-facilitated iodide transfer to the colloid, iodide is oxidized by thyroid peroxidase (TPO) to facilitate the iodination of tyrosine to MIT and DIT. Antithyroid drugs (e.g., propylthiouracil, methimazole, carbimazole) inhibit the function of TPO. TPO requires H ₂ O ₂ that is generated by thyroid oxidase 2 (THOX2), a step that is inhibited by iodide excess. The organic compounds of iodine are stored in the thyroid as part of thyroglobulin (Tg; molecular weight, 660 kDa). TPO also serves to catalyze the coupling of 2 molecules of DIT to form T ₄ and 1 molecule of MIT and 1 molecule of DIT to form T ₃ . T ₄ and T ₃ are stored in the colloid as part of the Tg molecule—there are 3 to 4 T ₄ molecules in each molecule of Tg. TSH stimulates the retrieval of Tg from the colloid by micropinocytosis to form phagolysosomes, where proteases free T ₄ , T ₃ , DIT, and MIT within the phagolysosome. T ₄ and T ₃ are then transported from the phagolysosome across the basolateral cell membrane and into the circulation. This action is inhibited by large amounts of iodine, a finding that can be used therapeutically in the treatment of patients with hyperthyroidism caused by Graves disease. DIT and MIT are deiodinated by Dhal-1, and the iodide is returned to the follicular lumen.

The ratio of T ₄ to T ₃ in Tg is approximately 15 to one, and when released from the follicular cell, it is approximately 10 to one (the difference reflecting the action of a 5′-deiodination). The deiodination step can be inhibited by propylthiouracil. T ₄ is produced only in the thyroid gland. Although T ₃ is released from the thyroid, 75% of T ₃ in the body is derived from peripheral 5′-deiodination of one of the outer ring iodine atoms in T ₄ . T ₄ and T ₃ can be inactivated by inner ring (5-deiodination) to form reverse T ₃ and diiodothyronine (T ₂ ), respectively. The presence of these deiodinases in various cell types provides for local regulation of thyroid hormone effect.

T ₄ and T ₃ are poorly water soluble and circulate bound to plasma proteins—thyroxine-binding globulin (TBG), T ₄ -binding prealbumin (transthyretin), and albumin. TBG has one iodothyronine binding site per molecule. The affinity of TBG for T ₃ is 20-fold less than that for T ₄ .

From the thyroxine-binding proteins, T ₄ and T ₃ enter the body cells, where they exert their metabolic actions, which are, predominantly, calorigenic (raising the basal metabolic rate). Thyroid hormones act by binding to the thyroid hormone receptor, which, in turn, binds to DNA. T ₃ has a 15-fold higher binding affinity for the thyroid hormone receptor than does T ₄ .

Both T ₄ and T ₃ are metabolized by kidney and liver tissue to their pyruvic acid and acetic acid derivatives and, eventually, to iodide. These metabolites are concentrated and conjugated in the liver to glucuronic acid, excreted with the bile, hydrolyzed in the small bowel, and reabsorbed.

The thyroid gland is unique with regard to the amount of stored hormone. There is approximately 250 μg of T ₄ for every gram of thyroid gland—approximately 5 mg of T ₄ in a 20-g thyroid. Thus, it is not surprising that thyrotoxicosis is common when the thyroid gland is acutely damaged by inflammation (e.g., subacute thyroiditis).

GRAVES DISEASE

Graves disease is an eponym that describes a thyroid autoimmune syndrome characterized by hyperthyroidism, goiter, ophthalmopathy, and occasionally an infiltrative dermopathy (pretibial or localized myxedema). Graves disease and hyperthyroidism are not synonymous because some patients with Graves disease have ophthalmopathy but not hyperthyroidism. Also, in addition to Graves disease, hyperthyroidism has several other causes. The hyperthyroidism in Graves disease is caused by autoantibodies to the thyrotropin (thyroid-stimulating hormone [TSH]) receptor that activate the receptor and stimulate the synthesis and secretion of thyroid hormones (thyroxine [T ₄ ] and triiodothyronine [T ₃ ]) and thyroid gland growth.

Graves disease occurs more commonly in females than in males (8 :1) and more frequently during the childbearing years, although it may occur as early as in infancy and in extreme old age. Although this malady's primary signs are an enlarged thyroid gland and prominent eyes, along with cardiovascular symptoms, it actually involves most systems of the body and is thus a systemic disease. The thyroid is diffusely enlarged (goiter) and is anywhere from two to several times its normal size. Some asymmetry may be observed, the right lobe being somewhat larger than the left. The pyramidal lobe is usually enlarged. Rarely in a patient with Graves disease, there is no palpable enlargement of the thyroid gland. The gland has an increased vascularity, as evidenced by a bruit that can be heard with a stethoscope and sometimes by a thrill felt on palpation, which may be demonstrated over the upper poles. Histologically, the gland shows follicular hyperplasia with a marked loss of colloid from the follicles and an increased cell height, with high columnar acinar cells that may demonstrate papillary infolding into the follicles. Late in the disease, there may be multifocal lymphocytic (primarily T cells) infiltration throughout the thyroid gland, and, occasionally, even lymph follicles (primarily B cells) may be seen within the thyroid parenchyma.

The hyperplastic thyroid functions at a markedly accelerated pace, evidenced by an increased uptake and turnover of radioactive iodine and increased levels of T ₄ and T ₃ , which cause an increased rate of oxygen consumption or increased basal metabolic rate and decreased serum total and high-density lipoprotein cholesterol concentrations. The increased levels of T ₄ and T ₃ cause a variety of physical and psychologic manifestations. Patients with this malady are usually nervous; agitated; restless; and experience insomnia, personality changes, and emotional lability. Behavioral findings include difficulty concentrating, confusion, and poor immediate recall.

On physical examination, patients with Graves disease present a fine tremor that may not be obvious but is best demonstrated by placing a paper towel on the extended fingers. The increased levels of T ₄ and T ₃ and the increased levels of oxygen consumption, with concomitant generalized vasodilatation, result in increased cardiac output, presenting with palpitation and sinus tachycardia. The increased stimulus to the heart action may result in atrial fibrillation and heart failure.

The skin of patients with this disease is warm and velvety (because of a decrease in the keratin layer); it may also be flushed and is often associated with marked perspiration caused by increased calorigenesis. Occasionally, vitiligo—another autoimmune manifestation—is observed. Onycholysis (known as Plummer nails)—loosening of the nails from the nail bed and softening of the nails—occurs in a minority of patients with Graves disease. Infiltrative dermopathy (pretibial myxedema) is the skin change that sometimes occurs in the lower extremities or on the forearms in patients with severe progressive ophthalmopathy. This is associated with a brawny, nonpitting thickening of the skin. It presents as a rubbery, nonpitting swelling of the cutaneous and subcutaneous tissues, with a violaceous discoloration of the skin on the lower third of the legs. Usually, it is predominant in the outer half of the leg. Nodules (as large as 1 cm in diameter) over the tibia, extending up as high as the knees, may be associated with classic localized pretibial myxedema. This lesion may also occur on the forearms, and it has been known to involve the feet and even the toes. Characteristically, hair does not grow in such myxedematous sites, but the occasional presence of hair follicles, producing hair at the site, does not exclude the diagnosis. When localized myxedema occurs, it is almost always in patients who have severe and progressive ophthalmopathy. Graves disease is also associated with clubbing of the fingers and of the toes (thyroid acropachy).

Sympathetic overactivity results in a stare and eyelid lag in most patients with hyperthyroidism. Eyelid lag is demonstrated by having the patient follow the examiner's finger through a vertical arc—the sclera can usually be seen above the iris as the patient looks down. Unique to Graves disease is ophthalmopathy (see Plate 2-10 ).

The increased metabolic rate and calorigenesis of these patients leads to a loss of weight despite a good to increased appetite, and to wasting of certain muscles, which is associated with muscular weakness. Hyperthyroidism has mixed effects on glucose metabolism, but affected patients typically have fasting hyperglycemia. Severe hyperthyroidism may be associated with hyperdefecation and malabsorption.

In women, the total serum estradiol concentrations are increased because of increased serum sex hormone–binding globulin concentrations. However, free estradiol concentrations are low, and serum luteinizing hormone concentrations are increased—factors that lead to oligomenorrhea or even amenorrhea, which is corrected by restoring the euthyroid state. The increase in serum sex hormone–binding globulin concentrations is also observed in hyperthyroid men, reflected in high serum total testosterone concentrations, low serum free testosterone concentrations, and mild increases in serum luteinizing hormone concentrations. The aromatization of testosterone to estradiol is increased, frequently resulting in gynecomastia, decreased libido, and sexual dysfunction.

Patients with Graves disease manifest the symptoms and signs of profound muscle changes known as thyroid myopathy. Atrophy of the temporal muscles, the muscles of the shoulder girdle, and the muscles of the lower extremities—notably the quadriceps femoris group—is typical. Muscular weakness is present, and these patients are often unable to climb steps or to lift their own weight from a chair. The muscular weakness may also contribute to dyspnea. Characteristically, these patients have a tremor, and when asked to extend a leg, they manifest a marked trembling and are usually unable to hold the leg in the extended position for more than 1 minute.

Excess T ₄ and T ₃ stimulate bone resorption, which reduces trabecular bone volume and increases the porosity of cortical bone. The effect on cortical bone density is usually greater than that on trabecular bone density. The high bone turnover state can be confirmed by measurement of increased blood concentrations of osteocalcin and bone-specific alkaline phosphatase. In some patients, the increased bone resorption leads to hypercalcemia. The hypercalcemia inhibits parathyroid hormone secretion and the genesis of 1,25-dihydroxyvitamin D, which leads to impaired calcium absorption and increased urinary calcium excretion. Thus, patients with long-standing hyperthyroidism are at increased risk for bone fracture and osteoporosis.

The earliest descriptions of Graves disease concerned patients who had goiters and some degree of heart failure. Characteristically, patients with hyperthyroidism report a variety of cardiac symptoms and signs. An increased heart rate is usually present. Cardiac output is increased, and those who develop heart failure present the manifestations of high-output failure characterized by a shorter than normal circulation time despite elevated venous pressure. Systolic hypertension is frequently present. Enlargement of the heart is unusual except in a case of frank heart failure or in a patient with previous heart disease. The heart does not show any characteristic anatomic or microscopic changes that can be attributed to hyperthyroidism. The stimulus to cardiac output has been attributed to the elevated basal metabolic rate and the increased oxygen demands of the body. The usual cardiac effects of the catecholamines are accentuated by thyroid hormones, and all sympathetic activity is exaggerated in hyperthyroidism. Atrial fibrillation occurs in approximately 15% of patients and is more common in patients older than age 60 years. In most patients, the atrial fibrillation spontaneously converts to normal sinus rhythm when euthyroidism is established. Thus, a peripheral β-adrenergic blocker will control most of the circulatory manifestations, reduce sweating, and diminish eyelid retraction—all independent of any effect on circulating levels of T ₄ and T ₃ .

GRAVES OPHTHALMOPATHY

Graves ophthalmopathy is an autoimmune disease of the retro-orbital tissues, and the eye signs, of which proptosis and periorbital edema are the most common, vary in degree from mild to extremely severe and progressive.

Most patients with hyperthyroidism (regardless of the cause) have retraction of the eyelids (caused by contraction of the eyelid levator palpebrae muscles), which leads to widened palpebral fissures and a stare. Although the stare may give the appearance of proptosis, it must be confirmed with an exophthalmometer (see following text). Frequently, an eyelid lag can be demonstrated. This is a failure of the upper eyelid to maintain its position relative to the globe as the gaze is directed downward. There also may be globe lag—the eyelid moves upward more rapidly than does the globe as the patient looks upward. The eyelid retraction and eyelid lag regress after correction of the hyperthyroidism.

Graves ophthalmopathy includes varying degrees of additional findings such as true proptosis, conjunctival injection, conjunctival edema (chemosis), periorbital edema, weakness of convergence, and palsy of one or more extraocular muscles. Patients often report increased lacrimation (aggravated by bright light, wind, or cold air), a sandy feeling in the eyes, and an uncomfortable sense of fullness in the orbits. When the patient is requested to look in one direction or another, a significant weakness of one or more of the extraocular muscles may be noted. The patient may complain of blurred vision, or even of diplopia on looking either upward or to the side.

If the distance, measured with an exophthalmometer, from the canthus to the front of the cornea exceeds 20 mm in white patients and 22 mm in black patients, proptosis is present. The proptosis may be asymmetric, and it may be masked by periorbital edema. Testing the eye and the orbital contents for resiliency to pressure is also useful. This is done by applying the fingers to the eyeball over the closed eyelid and attempting to move the eyeball backward. Normally, the eyeball can be pushed back easily and without resistance; in patients with severe ophthalmopathy, however, a significant decrease in resiliency is evident, and in some patients, it is impossible to push the eyeball back at all—a poor prognostic sign of progressive ophthalmopathy. The progression may be so rapid and extensive that the eyelids cannot be closed over the eyes, so that ulcerations of the cornea may result. These ulcerations may become infected and may even lead to loss of the eye. Rarely, the optic nerve may be involved by papilledema, papillitis, or retrobulbar neuritis, causing blindness.

The pathogenesis of Graves ophthalmopathy is related to an increased volume in the retro-orbital space—the extraocular muscles and retro-orbital connective and adipose tissues—because of inflammation and the accumulation of hydrophilic glycosaminoglycans (GAGs) (e.g., hyaluronic acid). As GAGs accumulate in these tissues, a change in osmotic pressure and an increase in fluid content displace the globes forward and compromise the function of the extraocular muscles. The extraocular muscles are swollen and infiltrated with T lymphocytes—the latter also probably play a key role in the pathogenesis of this disorder. T cells appear to be activated by the thyrotropin (thyroid-stimulating hormone [TSH]) receptor antigen. There is a positive correlation between the severity of ophthalmopathy and serum TSH receptor antibody concentrations.

In addition to a high titer of TSH receptor antibodies, several other risk factors for the development of ophthalmopathy in patients with Graves disease have been identified. Graves eye disease is more common in women, as is hyperthyroidism. However, when present, men appear to have more severe ophthalmopathy than women. Cigarette smoking has been clearly shown to increase both the risk for and the severity of ophthalmopathy. Cigarette smoke appears to increase GAG production and adipogenesis. Radioiodine therapy for hyperthyroidism appears to trigger or worsen ophthalmopathy more than subtotal thyroidectomy or antithyroid drug therapy. Although treating hyperthyroidism decreases the eyelid retraction, it does not improve Graves ophthalmopathy. Finally, there is a temporal relationship between the Graves eye disease and the onset of hyperthyroidism. Ophthalmopathy appears before the onset of hyperthyroidism in 20% of patients, concurrently in 40%, when hyperthyroidism is treated in 20%, and in the 6 months after diagnosis in 20%.

Most patients can be successfully treated by raising the head of the bed at night, using saline eye drops frequently through the day, and wearing sunglasses when outside. In patients with more severe symptoms (e.g., chemosis, diplopia), glucocorticoid therapy should be considered. Orbital decompression surgery should be considered if the ophthalmopathy progresses despite glucocorticoid therapy, if vision is threatened, or if there is a cosmetic reason in patients with severe proptosis.