C h a p t e r 65The Thyroid Gland

Vivien BonertTheodore C. Friedman

593

The thyroid gland secretes thyroxine (T4) and tri-iodothyronine (T3), both of which modulate energy

utilization and heat production and facilitate growth.The gland consists of two lateral lobes joined by anisthmus. The weight of the adult gland is 10 to 20g.Microscopically, the thyroid is composed of several fol-licles containing colloid surrounded by a single layer ofthyroid epithelium. The follicular cells synthesize thy-roglobulin, which is then stored as colloid. Biosynthesisof T4 and T3 occurs by iodination of tyrosine moleculesin thyroglobulin.

Thyroid Hormone PhysiologyTHYROID HORMONE SYNTHESISDietary iodine is essential for synthesis of thyroid hormones. Iodine, after conversion to iodide in thestomach, is rapidly absorbed from the gastrointestinaltract and distributed in the extracellular fluids. Afteractive transport from the blood stream across the fol-licular cell basement membrane, iodide is enzymaticallyoxidized by thyroid peroxidase, which also mediates the iodination of the tyrosine residues in thyroglobulinto form monoiodotyrosine and diiodotyrosine. Theiodotyrosine molecules couple to form T4 (3,5,3¢,5¢-tetraiodothyronine) or T3 (3,5,3¢-triiodothyronine).Once iodinated, thyroglobulin containing newly formedT4 and T3 is stored in the follicles. Secretion of free T4 and T3 into the circulation occurs after proteolyticdigestion of thyroglobulin, which is stimulated bythyroid-stimulating hormone (TSH). Deiodination ofmonoiodotyrosine and diiodotyrosine by iodotyrosinedeiodinase releases iodine, which then reenters thethyroid iodine pool.

THYROID HORMONE TRANSPORTT4 and T3 are tightly bound to serum carrier proteins:thyroxine-binding globulin (TBG), thyroxine-bindingpre-albumin, and albumin. The unbound or free frac-tions are the biologically active fractions and representonly 0.04% of the total T4 and 0.4% of the total T3.

PERIPHERAL METABOLISM OF THYROID HORMONESThe normal thyroid gland secretes T4, T3, and reverseT3, a biologically inactive form of T3. Most of the

circulating T3 is derived from 5¢-deiodination of circu-lating T4 in the peripheral tissues. Deiodination of T4

can occur at the outer ring (5¢-deiodination), producingT3 (3,5,3¢-triiodothyronine), or at the inner ring, pro-ducing reverse T3 (3,3,5¢-triiodothyronine).

CONTROL OF THYROID FUNCTIONHypothalamic thyrotropin-releasing hormone (TRH) istransported through the hypothalamic-hypophysialportal system to the thyrotrophs of the anterior pitu-itary gland, stimulating synthesis and release of TSH(Fig. 65–1). TSH, in turn, increases thyroidal iodideuptake and iodination of thyroglobulin, releases T3 andT4 from the thyroid gland by increasing hydrolysis ofthyroglobulin, and stimulates thyroid cell growth.Hypersecretion of TSH results in thyroid enlargement(goiter). Circulating T3 exerts negative feedback in-hibition of TRH and TSH release.

PHYSIOLOGIC EFFECTS OF THYROID HORMONESThyroid hormones increase basal metabolic rate byincreasing oxygen consumption and heat production inseveral body tissues. Thyroid hormones also have spe-cific effects on several organ systems (Table 65–1).These effects are exaggerated in hyperthyroidism andlacking in hypothyroidism, accounting for the well-recognized signs and symptoms of these two disorders.

Thyroid EvaluationThyroid gland function and structure can be evaluatedby (1) serum thyroid hormone levels, (2) imaging ofthyroid gland size and architecture, (3) measurement ofthyroid autoantibodies, and (4) thyroid gland biopsy(by fine-needle aspiration [FNA]).

TESTS OF SERUM THYROID HORMONE LEVELSTotal serum T4 and T3 measure the total amount ofhormone bound to thyroid-binding proteins byradioimmunoassay. Total T4 and total T3 levels are ele-vated in hyperthyroidism and low in hypothyroidism.Increase in TBG (as with pregnancy or estrogen therapy)increases the total T4 and T3 measured in the absence ofhyperthyroidism. Similarly, total T4 and T3 are low

XI

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594 SECTION XI—Endocrine Disease

THYROID IMAGINGTechnetium-99m (99mTc) pertechnetate is concentratedin the thyroid gland and can be scanned with a gammacamera, yielding information about the size and shapeof the gland and the location of the functional activityin the gland (thyroid scan). The thyroid scan is oftenperformed in conjunction with a thyroid uptake assay, usually with iodine-123 (123I), which quantitatesthyroid uptake. Functioning thyroid nodules are called“warm” or “hot” nodules; “cold” nodules are non-functioning. Malignancy is usually associated with acold nodule; 16% of surgically removed cold nodulesare malignant.

Thyroid ultrasound evaluation is useful in the differ-entiation of solid from cystic nodules. It can also guidethe operator during FNA of a nodule that is difficult topalpate.

THYROID ANTIBODIESAutoantibodies to several different antigenic compo-nents in the thyroid gland, including thyroglobulin(TgAb), thyroid peroxidase (TPO Ab, formerly calledantimicrosomal antibodies), and the TSH receptor, can

HYPOTHALAMUS

TRH

TSH

+

–

–

PITUITARY BLOOD STREAM

T3

T3

T4

T4

THYROID

+

TISSUES

FIGURE 65–1 Hypothalamic-pituitary-thyroid axis. T3 = triiodothyro-nine; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.

TABLE 65–1 Physiologic Effects of Thyroid Hormone

Cardiovascular EffectsIncreased heart rate and cardiac output

Gastrointestinal EffectsIncreased gut motility

Skeletal EffectsIncreased bone turnover and resorption

Pulmonary EffectsMaintenance of normal hypoxic and hypercapnic drive in the

respiratory center

Neuromuscular EffectsIncreased muscle protein turnover and increased speed of

muscle contraction and relaxation

Lipids and Carbohydrate Metabolism EffectsIncreased hepatic gluconeogenesis and glycogenolysis as well

as intestinal glucose absorptionIncreased cholesterol synthesis and degradationIncreased lipolysis

Sympathetic Nervous System EffectsIncreased numbers of b-adrenergic receptors in the heart,

skeletal muscle, lymphocytes, and adipose cellsDecreased cardiac a-adrenergic receptorsIncreased catecholamine sensitivity

Hematopoietic EffectsIncreased red blood cell 2,3-diphosphoglycerate, facilitating

oxygen dissociation from hemoglobin with increased oxygenavailable to tissues

despite euthyroidism in conditions associated with lowthyroid-binding proteins (e.g., cirrhosis or nephroticsyndrome). Thus, further tests to assess the freehormone level that reflects biologic activity must be per-formed. Free T4 level can be estimated by calculating thefree T4 index or can be measured directly by dialysis.

The free T4 index is an indirect method of assessingfree T4. It is derived by multiplying the total T4 by theT3 resin uptake, which is inversely proportional to theavailable T4 binding sites on TBG. Free T4 can be measured directly by dialysis or ultrafiltration. This ismore accurate and is preferred to the free T4 index.

Serum TSH is measured by a third-generationimmunometric assay, which employs at least two dif-ferent monoclonal antibodies against different regionsof the TSH molecule, resulting in accurate discrimina-tion between normal TSH levels and levels below thenormal range. Thus, the TSH assay can diagnose clini-cal hyperthyroidism (elevated free T4 and suppressedTSH) and subclinical hyperthyroidism (normal free T4

and suppressed TSH). In primary (thyroidal) hypothy-roidism, serum TSH is supranormal because of dimin-ished feedback inhibition. In secondary (pituitary) ortertiary (hypothalamic) hypothyroidism, the TSH isusually low but may be normal.

Serum thyroglobulin measurements are useful in thefollow-up of patients with papillary or follicular carci-noma. After thyroidectomy and iodine-131 (131I) abla-tion therapy, thyroglobulin levels should be less than 2mg/L while the patient is on suppressive levothyroxinetreatment. Levels in excess of this value indicate thepresence of persistent or metastatic disease.

Calcitonin is produced by the medullary cells of the thyroid. Calcitonin measurements are invaluable inthe diagnosis of medullary carcinoma of the thyroid andfor following the effects of therapy for this entity.

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be measured in the serum. A strongly positive test forTPO Ab indicates autoimmune thyroid disease. Elevatedthyroid receptor-stimulating antibody occurs in Graves’disease (see later discussion).

THYROID BIOPSYFNA of a nodule to obtain thyroid cells for cytology isthe best way to differentiate benign from malignantdisease. FNA requires adequate tissue samples andinterpretation by an experienced cytologist.

HyperthyroidismThyrotoxicosis is the clinical syndrome that results fromelevated circulating thyroid hormones. Clinical mani-festations of thyrotoxicosis are due to the direct physi-ologic effects of the thyroid hormones, as well as to theincreased sensitivity to catecholamines. Tachycardia,tremor, stare, sweating, and lid lag are due to cate-cholamine hypersensitivity.

SIGNS AND SYMPTOMSTable 65–2 lists the signs and symptoms of hyperthy-roidism with their frequency of occurrence. Thyrotoxiccrisis, or “thyroid storm,” is a life-threatening

complication of hyperthyroidism that can be precipi-tated by surgery, radioactive iodine therapy, or severestress (e.g., uncontrolled diabetes mellitus, myocardialinfarction, acute infection). Patients develop fever, flush-ing, sweating, marked tachycardia, atrial fibrillation,and cardiac failure. Marked agitation, restlessness,delirium, and coma occur frequently. Gastrointestinalmanifestations may include nausea, vomiting, and diar-rhea. Hyperpyrexia out of proportion to other clinicalfindings is the hallmark of thyroid storm.

DIFFERENTIAL DIAGNOSISThyrotoxicosis usually reflects hyperactivity of thethyroid gland resulting from Graves’ disease, toxicadenoma, multinodular goiter, or thyroiditis (Table65–3 and Fig. 65–2). However, it may be due to exces-sive ingestion of thyroid hormone or, rarely, thyroidhormone production from an ectopic site, as seen instruma ovarii.

GRAVES’ DISEASEGraves’ disease, the most common cause of thyrotoxi-cosis, is an autoimmune disease that is more commonin women, with a peak age incidence of 20 to 40 years.One or more of the following features are present: (1)goiter; (2) thyrotoxicosis; (3) eye disease ranging fromtearing to proptosis, extraocular muscle paralysis, andloss of sight as a result of optic nerve involvement; and(4) thyroid dermopathy, usually presenting as markedskin thickening without pitting in a pretibial distribu-tion (pretibial myxedema).

PathogenesisThyrotoxicosis in Graves’ disease is due to overproduc-tion of an antibody that binds to the TSH receptor.These thyroid-stimulating immunoglobulins increase

CHAPTER 65—The Thyroid Gland 595

TABLE 65–2 Prevalence of Symptoms and Signs in PatientsWith Thyrotoxicosis

Symptom Prevalence (%)

Nervousness 99Increased sweating 91Hypersensitivity to heat 89Palpitation 89Fatigue 88Weight loss 85Tachycardia 82Dyspnea 75Weakness 70Increased appetite 65Eye complaint (diplopia, pain, swelling) 54Swelling of legs 35Diarrhea 23Anorexia 9Tachycardia 100Goiter 100Skin changes 97Tremor 97Eye signs (lid lag, proptosis) 71Atrial fibrillation 10Splenomegaly 10Gynecomastia 10Liver palms 8

From Williams RH: Thiouracil treatment of thyrotoxicosis. J Clin Endocrinol Metab 1946;6:1–22.

TABLE 65–3 Causes of Thyrotoxicosis

Common CausesGraves’ diseaseToxic adenoma (solitary)Toxic multinodular goiter

Less Common CausesSubacute thyroiditis (de Quervain’s or granulomatous)Hashimoto’s thyroiditis with transient hyperthyroid phaseThyrotoxicosis factitiaPostpartum (probably variant of silent thyroiditis)

Rare CausesStruma ovariiMetastatic thyroid carcinomaHydatidiform moleThyroid-stimulating hormone–secreting pituitary tumorPituitary resistance to triiodothyronine and thyroxine

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thyroid cell growth and thyroid hormone secretion.Ophthalmopathy is due to inflammatory infiltration of the extraocular eye muscles by lymphocytes, withmucopolysaccharide deposition. The inflammatoryreaction that contributes to the eye signs in Graves’disease may be caused by lymphocytes sensitized to anti-gens common to the orbital muscles and thyroid.

Clinical FeaturesThe common manifestations of thyrotoxicosis (seeTable 65–2) are characteristic features of youngerpatients with Graves’ disease. In addition, patients maypresent with a diffuse goiter or the eye signs character-istic of Graves’ disease. Older patients often do notmanifest the florid clinical features of thyrotoxicosis,and the condition termed apathetic hyperthyroidismpresents as flat affect, emotional lability, weight loss,muscle weakness, or congestive heart failure and atrialfibrillation resistant to standard therapy.

Eye signs of Graves’ disease may be either a nonspe-cific manifestation of hyperthyroidism from any cause(e.g., thyroid stare) or may result from Graves’ diseasedue to a specific inflammatory infiltrate of the orbitaltissues leading to periorbital edema, conjunctival con-gestion and swelling, proptosis, extraocular muscleweakness, and/or optic nerve damage with visualimpairment.

Pretibial myxedema (thyroid dermopathy) occurs in2 to 3% of patients with Graves’ disease and presentsas thickening of the skin over the lower tibia withoutpitting. Onycholysis, characterized by separation of thefingernails from their beds, often occurs in Graves’disease. Thyroid acropachy, or clubbing, may also occurin Graves’ disease.

Laboratory FindingsElevated T4 and/or T3 and a suppressed TSH confirmthe clinical diagnosis of thyrotoxicosis. Thyroid-stimu-lating immunoglobulin (TSH receptor antibody) isusually elevated and may be useful in patients with eyesigns who do not have other characteristic clinical fea-tures. Increased uptake of 123I differentiates Graves’disease from early subacute or Hashimoto’s thyroiditis,in which uptake is low in the presence of hyperthy-roidism. Magnetic resonance imaging or ultrasono-graphy of the orbit usually shows orbital muscleenlargement, whether or not there are clinical signs ofophthalmopathy.

TreatmentThree treatment modalities are employed to control thehyperthyroidism of Graves’ disease.

Antithyroid Drugs. The thiocarbamide drugs propylth-iouracil, methimazole, and carbimazole block thyroidhormone synthesis by inhibiting thyroid peroxidase.Propylthiouracil also partially inhibits peripheral con-version of T4 to T3. Medical therapy must be adminis-tered for a prolonged period (12 to 18 months), untilthe disease undergoes spontaneous remission. On ces-sation of medication, only a small percentage of patients(20 to 30%) remain in remission, and the patients whoexperience relapse must then undergo definitive surgeryor radioactive iodine treatment. Side effects of the thio-carbamides include pruritus and rash (about 5% ofpatients), cholestatic jaundice, acute arthralgias, and,rarely, agranulocytosis (0.5% of patients). Patients mustbe instructed to discontinue the medication and consulta physician if they develop fever or sore throat, becausethese may indicate agranulocytosis. At the onset oftreatment, during the acute phase of thyrotoxicosis, b-adrenergic blocking drugs help alleviate tachycardia,hypertension, and atrial fibrillation. As the thyroidhormone levels return to normal, treatment with b-blockers is tapered.

Radioactive Iodine. In terms of cost, efficacy, ease, andshort-term side effects, radioactive iodine has benefitsthat exceed both surgery and antithyroid drugs. Iodine-131 is the treatment of choice in adults with Graves’disease. Patients with severe thyrotoxicosis, very largeglands, or underlying heart disease should be renderedeuthyroid with antithyroid medication before receivingradioactive iodine because 131I treatment can causerelease into the circulation of preformed thyroidhormone from the thyroid gland; this can precipitatecardiac arrhythmias and exacerbate symptoms of

Clinical suspicion of hyperthyroidism

Ultrasensitive TSH

Low Normal

Low or normalElevated

ØUptake

Thyroiditis

Observe

≠Uptake

Possible normalvs. subclinical

hyperthyroidism

Hyperthyroidism

Radioactive iodineuptake and scan

Graves' diseaseToxic adenomaMNGOther cases of thyrotoxicosis

Hyperthyroidismruled out

Free T4

T3RIA

FIGURE 65–2 Algorithm for differential diagnosis of hyperthyroidism.MNG = multinodular goiter; T3RIA = triiodothyronine radioimmunoassay;T4 = thyroxine; TSH = thyroid-stimulating hormone.

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thyrotoxicosis. After administration of radioactive iodine, the thyroid gland shrinks and patients becomeeuthyroid over a period of 6 weeks to 3 months. Ten to 20% of patients become hypothyroid within the first year of treatment, and thereafter hypothyroidismoccurs at a rate of 3 to 5% per year. Ultimately 50 to 80% of patients become hypothyroid after radioac-tive iodine treatment. Serum TSH levels should be monitored and replacement with levothyroxine insti-tuted if the TSH level rises. Hypothyroidism may alsodevelop after surgery or antithyroid medication, man-dating lifelong follow-up in all patients with Graves’disease.

Surgery. Subtotal thyroidectomy is the treatment of choice for patients with very large glands andobstructive symptoms or multinodular glands, or forpatients desiring pregnancy within the next year. It isessential that the surgeon be experienced in thyroidsurgery. Preoperatively, patients receive 6 weeks of treat-ment with antithyroid drugs so that they will be euthy-roid at the time of surgery. Two weeks before surgery,oral saturated solution of potassium iodide is adminis-tered daily to decrease the vascularity of the gland. Per-manent hypoparathyroidism and recurrent laryngealnerve palsy occur in less than 2% of patients postoper-atively. Ten percent of patients develop recurrent thyro-toxicosis, which should be treated with radioactiveiodine.

TOXIC ADENOMASolitary toxic nodules, which usually are benign, occurmore frequently in older patients. Clinical manifesta-tions are those of thyrotoxicosis. Physical examinationshows a distinct solitary nodule. Laboratory investiga-tion shows suppressed TSH and markedly elevated T3

levels, often with only moderately elevated T4. Thyroidscan shows a “hot nodule” of the affected lobe withcomplete suppression of the unaffected lobe. Solitarytoxic nodules are treated with radioactive iodine.However, unilateral lobectomy, after the administrationof antithyroid drugs to render the patient euthyroid,may be required for large nodules.

TOXIC MULTINODULAR GOITERToxic multinodular goiter occurs in older patients withlong-standing multinodular goiter, especially in patientsfrom iodine-deficient regions. The presenting clinicalfeatures are frequently tachycardia, heart failure, andarrhythmias.

Physical examination shows a multinodular goiter.The diagnosis is confirmed by laboratory features ofsuppressed TSH, elevated T3 and T4, and a thyroid scanwith multiple functioning nodules. The treatment ofchoice is often 131I ablation. It is especially effective inpatients with small glands and a high radioactiveuptake.

SUBCLINICAL HYPERTHYROIDISMIn subclinical hyperthyroidism, T4 and T3 levels arenormal with a suppressed TSH. The causes of this con-dition include early presentation of all forms of hyper-thyroidism, including Graves’ disease, toxic adenoma,and toxic multinodular goiter. Because these patients,especially the elderly, are at an increased for developingcardiac dysrhythmias, many patients with a persistentlysuppressed TSH should be treated with thiocarbamidedrugs or radioactive iodine.

ThyroiditisThyroiditis may be classified as acute, subacute, orchronic. Although thyroiditis may eventually result inclinical hypothyroidism, the initial presentation is oftenthat of hyperthyroidism as a result of acute release ofT4 and T3. Hyperthyroidism caused by thyroiditis canbe readily differentiated from other causes of hyperthy-roidism by suppressed uptake of radioactive iodine,reflecting decreased hormone production by damagedcells.

Acute suppurative thyroiditis, a rare complication of septicemia, presents as high fever, redness of the overlying skin, and thyroid gland tenderness; it may beconfused with subacute thyroiditis. If blood cultures are negative, needle aspiration should identify theorganism. Intensive antibiotic treatment and, occasion-ally, incision and drainage are required.

SUBACUTE THYROIDITISSubacute thyroiditis (de Quervain’s thyroiditis or granulomatous thyroiditis) is an acute inflammatory disorder of the thyroid gland, probably secondary toviral infection, which resolves completely in 90% ofcases. Subacute thyroiditis presents as fever and ante-rior neck pain. The patient may have symptoms andsigns of hyperthyroidism. The classic feature on physical examination is an exquisitely tender thyroidgland. Laboratory findings vary with the course of thedisease. Initially, the patient may be symptomaticallythyrotoxic, with elevated serum T4, depressed serumTSH, and very low radioactive iodine uptake on scan.Subsequently, the thyroid status will fluctuate througheuthyroid and hypothyroid phases and may return toeuthyroidism. Increase in radioactive iodine uptake onthe scan reflects recovery of the gland. Treatmentusually includes nonsteroidal anti-inflammatory drugs,but a short course of prednisone may be required if pain and fever are severe. During the hypothyroidphase, replacement therapy with levothyroxine may be indicated.

Postpartum thyroiditis resembles subacute thyroidi-tis in its clinical course. It usually presents within thefirst 6 months after delivery and goes through thetriphasic course of hyperthyroidism, hypothyroidism,and then euthyroidism, or it may present with onlyhypothyroidism. Some patients have an underlyingchronic thyroiditis.

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CHRONIC THYROIDITISChronic thyroiditis (Hashimoto’s thyroiditis or lym-phocytic thyroiditis) from destruction of normal thy-roidal architecture by lymphocytic infiltration results inhypothyroidism and goiter. Riedel’s struma is probablya variant of Hashimoto’s thyroiditis, characterized byextensive thyroid fibrosis resulting in a rock-hardthyroid mass. Hashimoto’s thyroiditis is more commonin women and is the most common cause of goiter andhypothyroidism in the United States. Occasionally,patients with Hashimoto’s thyroiditis may have tran-sient hyperthyroidism with low radioactive iodineuptake, owing to release of T4 and T3 into the circula-tion. This can be differentiated from subacute thyroidi-tis in that the gland is nontender to palpation andantithyroid antibodies are present in high titer. Early inthe disease, TgAb is markedly elevated, but it may dis-appear later. TPO Ab also is present early and generallyremains present for years. Radioactive iodine uptakemay be high, normal, or low. Serum T3 and T4 levels areeither normal or low; when low, the TSH is elevated.FNA of the thyroid shows lymphocytes and Hürthlecells (enlarged basophilic follicular cells). Hypothy-roidism and marked glandular enlargement (goiter) areindications for levothyroxine therapy. Adequate dosesof levothyroxine are administered to normalize TSHlevels and shrink the goiter.

Thyrotoxicosis FactitiaThyrotoxicosis factitia presents as typical features ofthyrotoxicosis from ingestion of excessive amounts ofthyroxine, often in an attempt to lose weight. Serum T3

and T4 levels are elevated, and TSH is suppressed, as is the serum thyroglobulin concentration. Radioactiveiodine uptake is absent. Patients may require psychotherapy.

Rare Causes of ThyrotoxicosisStruma ovarii occurs when an ovarian teratoma con-tains thyroid tissue, which secretes thyroid hormone.Diagnosis is confirmed by demonstrating uptake ofradioiodine in the pelvis on body scan.

Hydatidiform mole is due to proliferation andswelling of the trophoblast during pregnancy, withexcess production of chorionic gonadotropin, which has intrinsic TSH-like activity. The hyperthyroidismremits with surgical and medical treatment of the molarpregnancy.

HypothyroidismHypothyroidism is a clinical syndrome caused by defi-ciency of thyroid hormones. In infants and children,hypothyroidism causes retardation of growth and devel-opment and may result in permanent motor and mental

retardation. Congenital causes of hypothyroidisminclude agenesis (complete absence of thyroid tissue),dysgenesis (ectopic or lingual thyroid gland), hypoplas-tic thyroid, thyroid dyshormogenesis, and congenitalpituitary diseases. Adult-onset hypothyroidism results ina slowing of metabolic processes and is reversible withtreatment. Hypothyroidism (Table 65–4) is usuallyprimary (thyroid failure), but it may be secondary(hypothalamic or pituitary deficiency) or due to resist-ance at the thyroid hormone receptor. In adults, auto-immune thyroiditis (Hashimoto’s thyroiditis) is the most common cause of hypothyroidism. This may beisolated or part of the polyglandular failure syndrometype II (Schmidt’s syndrome), which also includesinsulin-dependent diabetes mellitus, pernicious anemia,vitiligo, gonadal failure, hypophysitis, celiac disease,myasthenia gravis, and primary biliary cirrhosis. Iatrogenic causes of hypothyroidism include 131Itherapy, thyroidectomy, and treatment with lithium or

TABLE 65–4 Causes of Hypothyroidism

Primary HypothyroidismAutoimmuneHashimoto’s thyroiditisPart of polyglandular failure syndrome, type II

Iatrogenic 131I therapy Thyroidectomy

Drug-induced Iodine deficiency Iodine excess Lithium AmiodaroneAntithyroid drugs

Congenital Thyroid agenesisThyroid dysgenesisHypoplastic thyroidBiosynthetic defect

Secondary HypothyroidismHypothalamic dysfunction Neoplasms Tuberculosis SarcoidosisLangerhans cell histiocytosis Hemochromatosis Radiation treatment

Pituitary dysfunction Neoplasms Pituitary surgery Postpartum pituitary necrosis Idiopathic hypopituitarism Glucocorticoid excess (Cushing’s syndrome) Radiation treatment

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amiodarone. Iodine deficiency or excess can also causehypothyroidism.

CLINICAL MANIFESTATIONSThe clinical presentation of hypothyroidism (Table65–5) depends on the age of onset and severity ofthyroid deficiency. Infants with congenital hypothy-roidism (also called cretinism) may present with feedingproblems, hypotonia, inactivity, an open posteriorfontanelle, and/or edematous face and hands. Mentalretardation, short stature, and delayed puberty occur if treatment is delayed.

Hypothyroidism in adults usually develops insidi-ously. Patients often have fatigue, lethargy, and gradualweight gain for years before the diagnosis is established.A delayed relaxation phase of deep tendon reflexes(“hung-up” reflexes) is a valuable clinical sign charac-teristic of severe hypothyroidism. Subcutaneous infiltra-tion by mucopolysaccharides, which bind water, causesthe edema (termed myxedema) and is responsible for thethickened features and puffy appearance of patientswith severe hypothyroidism.

Severe untreated hypothyroidism can result inmyxedema coma, characterized by hypothermia,extreme weakness, stupor, hypoventilation, hypo-

glycemia, and hyponatremia and is often precipitated bycold exposure, infection, or psychoactive drugs.

LABORATORY TESTSLaboratory abnormalities in patients with primaryhypothyroidism include elevated serum TSH and lowtotal and free T4. Secondary hypothyroidism is charac-terized by a low or low-normal morning serum TSH inthe setting of hypothalamic or pituitary dysfunction.Often, the serum total and free T4 levels are at the lowerlimit of normal.

Hypothyroidism is often associated with hypercho-lesterolemia and elevated creatine phosphokinase MBfraction (the fraction representative of cardiac muscle).Anemia is usually normocytic, normochromic but maybe macrocytic (vitamin B12 deficiency resulting fromassociated pernicious anemia) or microcytic (caused by nutritional deficiencies or menstrual blood loss in women).

DIFFERENTIAL DIAGNOSISBecause the initial manifestations of hypothyroidism aresubtle, the early diagnosis of hypothyroidism demandsa high index of suspicion in patients presenting with oneor more of the signs or symptoms listed in Table 65–5.Early symptoms that are often overlooked include men-strual irregularities (usually menorrhagia), arthralgias,and myalgias.

Laboratory diagnosis may be complicated by thefinding of a low total T4 in euthyroid states associatedwith low TBG, such as nephrotic syndrome, cirrhosis,or TBG deficiency; in these situations TSH and free T4

levels are normal. A low total T4 may also be found inthe “euthyroid sick syndrome,” a condition occurringin acutely ill patients. In such patients, total and, occa-sionally, free T4 levels are low and the serum TSH levelis usually normal but may be mildly elevated. Most ofthese patients should not be treated with levothyroxinereplacement, although select patients may benefit fromT3 treatment. This condition may be differentiated fromprimary hypothyroidism by absence of a goiter, negativeantithyroid antibodies, and elevated serum reverse T3

levels, as well as by clinical presentation.

TREATMENTPatients with hypothyroidism initially should be treatedwith synthetic levothyroxine. Although T3 is the morebioactive thyroid hormone, peripheral tissues convert T4

to T3 to maintain physiologic levels of the latter. Thusadministration of levothyroxine results in bioavailableT3 and T4. A recent study, however, suggested that brainT4-to-T3 conversion may be impaired in some patientsand that a select group of patients should be treatedwith both levothyroxine and T3 (liothyronine). BecauseT3 treatment results in fluctuating blood levels, we recommend that patients be initially treated withlevothyroxine, and, if they remain symptomatic despitea normal TSH, then low doses of T3 given two or three

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TABLE 65–5 Clinical Features of Hypothyroidism

ChildrenLearning disabilities

Mental retardationShort stature

Delayed bone age Delayed puberty

AdultsFatigueCold intoleranceWeaknessLethargyWeight gainConstipationMyalgiasArthralgiasMenstrual irregularitiesHair lossDry, coarse, cold skinCoarse, thin hairHoarse voiceBrittle nailsPeriorbital, peripheral edemaDelayed reflexesSlow reaction timeOrange skin hueBradycardiaPleural, pericardial effusions

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times a day can be added to levothyroxine cautiously.Levothyroxine has a half-life of 8 days, so it needs tobe given only once a day. The average replacement dosefor adults is 100 to 150mg/day. In healthy adults, 100mg/day is an appropriate starting dose. In elderlypatients or those with cardiac disease, levothyroxineshould be increased gradually, starting at 25mg dailyand increasing this dose by 25mg every 2 weeks. Thetherapeutic response to levothyroxine therapy should bemonitored clinically and with serum TSH levels, whichshould be measured 6 weeks after a dose adjustment.TSH levels between 0.5 and 2.0mU/L are optimal.Patients with secondary hypothyroidism should betreated with levothyroxine until their free T4 is in the mid-normal range. Appropriate treatment of thesepatients will result in suppressed serum TSH levels.

In patients with myxedema coma, 300 to 400mg oflevothyroxine is administered intravenously as a loadingdose followed by 50mg daily as well as hydrocortisone(100mg intravenously three times a day) and intra-venous fluids. The underlying precipitating event shouldbe corrected. Respiratory assistance and treatment ofhypothermia with warming blankets may be required.Although myxedema coma carries a high mortalitydespite appropriate treatment, many patients improvein 1 to 3 days.

Subclinical HypothyroidismIn subclinical hypothyroidism, T4 and/or T3 levels arenormal or low normal, with a mildly elevated TSH. Itis thought that some, but not all, of these patients willdevelop overt hypothyroidism. The decision about whento treat patients with a mildly elevated TSH is contro-versial; we recommend that patients should be treatedwith levothyroxine if they have a TSH greater than 6mU/L on two occasions and either positive anti-TPOAb test results or a goiter. If the patient does not havean appreciable goiter and has negative anti-TPO Abresults, then we would recommend treatment withlevothyroxine only if he or she has a TSH greater than10mU/L on two occasions.

GoiterEnlargement of the thyroid gland is called goiter.Patients with goiter may be euthyroid (simple goiter),hyperthyroid (toxic nodular goiter, or Graves’ disease),or hypothyroid (nontoxic goiter, or Hashimoto’s thy-roiditis). Thyroid enlargement (often focal) also may bedue to a thyroid adenoma or carcinoma. In nontoxicgoiter, inadequate thyroid hormone synthesis leads toTSH stimulation with resultant enlargement of thethyroid gland. Iodine deficiency (endemic goiter) wasonce the most common cause of nontoxic goiter; withthe use of iodized salt, it is now almost nonexistent in North America.

Dietary goitrogens can cause goiter, and iodine is themost common goitrogen. Other goitrogens includelithium and vegetable products such as thioglucosides

found in cabbage. Thyroid hormone biosyntheticdefects can cause goiter associated with hypothyroidismor, with adequate compensation, euthyroidism.

A careful thyroid examination coupled with thyroidhormone tests can delineate the cause of the goiter. Asmooth, symmetrical gland, often with a bruit, andhyperthyroidism are suggestive of Graves’ disease. Anodular thyroid gland with hypothyroidism and positive antithyroid antibodies is consistent withHashimoto’s thyroiditis. A diffuse, smooth goiter withhypothyroidism and negative antithyroid antibodiesmay be indicative of iodine deficiency or a biosyntheticdefect. Goiters may become very large, extend subster-nally, and cause dysphagia, respiratory distress, orhoarseness. An ultrasound evaluation or radioiodinescan delineates the thyroid gland, and a thyroid uptakescan can determine the functional activity of the goiter.

Hypothyroid goiters are treated with thyroidhormone at a dose that normalizes TSH. Euthyroidgoiters may be treated with levothyroxine therapy;however, in most cases, especially with long-standinggoiters, regression is unlikely. Surgery is indicated for nontoxic goiter only if obstructive symptomsdevelop or substantial substernal extension is present.

Solitary Thyroid NodulesThyroid nodules are common. They can be detectedclinically in about 4% of the population and are foundin about 50% of the population at autopsy. Benignthyroid nodules are usually follicular adenomas, colloidnodules, benign cysts, or nodular thyroiditis. Patientswith Hashimoto’s thyroiditis may have one prominentnodule on clinical examination, but thyroid ultrasoundevaluation may reveal multiple nodules. Although themajority of nodules are benign, a small percentage ismalignant. In addition, most thyroid cancers are of low-grade malignancy. History, physical examination, andlaboratory tests can be helpful in differentiating benignfrom malignant lesions (Table 65–6). For example,lymph node involvement or hoarseness is strongly suggestive of a malignant tumor.

The major etiologic factor for thyroid cancer is child-hood or adolescent exposure to head and neck radia-tion. Previously, radiation was used to treat an enlargedthymus, tonsillar disease, hemangioma, or acne.Recently, exposure to radiation from nuclear plants(e.g., Chernobyl, Ukraine) has contributed to anincreased incidence of thyroid cancer. The incidence ofthyroid cancer is linearly related to the radiation doseup to 1500rads. TSH is possibly a co-carcinogen; thuspatients exposed to high-risk radiation may benefit fromTSH suppression by thyroid hormone. Patients with ahistory of irradiation should have their thyroid carefullypalpated every 2 years. In the absence of palpabledisease, imaging procedures are not warranted.

The thyroid status of a patient with a thyroid nodulemay dictate further evaluation. A hyperthyroid patientis most likely to have a toxic nodule or thyroiditis,whereas a hypothyroid patient probably has a promi-nent nodule in a gland with Hashimoto’s thyroiditis.

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These patients are unlikely to have malignant lesions.Euthyroid patients with a solitary nodule shouldundergo an FNA biopsy. This is a safe procedure thathas reduced the need for surgical excision. An expertcytologist can identify most benign lesions (75% of all biopsies). In addition, malignant lesions (5% ofbiopsies), such as papillary, anaplastic, and medullarycarcinoma, can be specifically identified. Follicular neoplasms, however, cannot be diagnosed as benign or malignant by FNA; a cytology report of follicularneoplasia, along with “suspicious” cytology, requiressurgical excision.

In the past, thyroid scans were used to evaluate singlethyroid nodules. “Hot” thyroid nodules are almostalways benign. Most cancers are “cold,” but, becausemost benign lesions are also “cold,” these patients stillrequire FNA. Thus thyroid scans have largely been sup-planted by aspiration for evaluation of thyroid nodules.

Benign thyroid nodules may be treated with levothy-roxine suppression therapy with a follow-up thyroidexamination in 6 months. A significant decrease in thesize of the nodule occurs in a few cases and may be mon-itored by ultrasound. Most benign lesions and somecancers remain unchanged in size. An increase in size ofthe nodule while the patient is on suppression therapywarrants a reevaluation.

Thyroid CarcinomaThe most common type of thyroid carcinoma is papil-lary carcinoma (65 to 70%). Follicular carcinoma(20%), anaplastic carcinoma (5 to 10%), medullary

carcinoma (5%), and lymphoma (1%) occur less fre-quently. Papillary carcinoma is associated with localinvasion and lymph node spread. Poor prognosis isassociated with thyroid capsule invasion, size greaterthan 2.5cm, age at onset older than 45 years, tall-cellvariant, and lymph node involvement. Follicular carci-noma is slightly more aggressive than papillary carci-noma and can spread by local invasion of lymph nodesor hematogenously to bone, brain, or lung. Patients maypresent with metastases before diagnosis of the primarythyroid lesion. Anaplastic carcinoma tends to occur inolder individuals (>50 years), is very aggressive, andrapidly causes pain, dysphagia, and hoarseness. Deathusually occurs in the first year.

Medullary thyroid carcinoma is derived from calci-tonin-producing parafollicular cells and is more malig-nant than papillary or follicular carcinoma. It ismultifocal and spreads both locally and distally. It maybe either sporadic or familial. When familial, it is inher-ited in an autosomal dominant pattern and is part ofmultiple endocrine neoplasia type IIA (medullary carci-noma of the thyroid, pheochromocytoma, and hyper-parathyroidism) or multiple endocrine neoplasia typeIIB (medullary carcinoma of the thyroid, mucosal neu-romas, intestinal ganglioneuromas, marfanoid habitus,and pheochromocytoma). Elevated basal serum calci-tonin levels confirm the diagnosis. Evaluation for RETproto-oncogene mutations should be performed inpatients with medullary carcinoma, and, if present, allfirst-degree relatives of the patients should be examined.

TREATMENTLobectomy can be performed for papillary carcinomasless than 1.5cm. These patients require lifelong levothy-roxine suppressive therapy and yearly thyroid examina-tions. Larger papillary or follicular tumors requirenear-total thyroidectomy, with modified neck dissectionif there is evidence of lymph node metastases. Post-operatively, T3 is administered for 2 months. The medication is stopped for 2 weeks, and the patient isscanned with 3mCi of 131I. If uptake occurs, the patientis treated with 131I until no further uptake is observed.Sufficient levothyroxine is then administered to suppressserum TSH to subnormal levels. Frequent neck exami-nations for masses should be accompanied by measure-ment of serum thyroglobulin levels. Recurrence/metastases are also evaluated by 131I total-body scanscarried out under conditions of TSH stimulation, whichincrease 131I uptake by the thyroid tissue. Elevated TSHlevels can be achieved by withdrawal of thyroxine sup-plementation for 6 weeks. As an alternative, in order toavoid the resultant symptomatic hypothyroidism,recombinant human TSH can be administered while thepatient remains on thyroid hormone. A rise in serumthyroglobulin levels suggests recurrence of thyroidcancer. Local or metastatic lesions that take up 131I(whole-body scan) can be treated with radioactiveiodine after the patient has stopped thyroid hormonereplacement, whereas those that do not take up 131I canbe treated with local x-ray therapy. Medullary carci-noma of the thyroid requires total thyroidectomy with

CHAPTER 65—The Thyroid Gland 601

TABLE 65–6 High-Risk Factors for Malignancy in a ThyroidNodule

HistoryHead/neck irradiationExposure to nuclear radiationRapid growthRecent onsetYoung ageMale sexFamilial incidence (medullary)

Physical ExaminationHard consistency of noduleFixation of noduleLymphadenopathyVocal cord paralysisDistant metastasis

Laboratory/ImagingElevated serum calcitonin“Cold” nodule on technetium scanSolid lesion on ultrasonography

Levothyroxine TherapyNo regression

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602 SECTION XI—Endocrine Disease

removal of the central lymph nodes in the neck. Com-pleteness of the procedure is determined by measure-ment of serum calcitonin, which is also used inmonitoring for recurrence.

Anaplastic carcinoma is treated with isthmusectomyto confirm the diagnosis and to prevent tracheal com-pression, followed by palliative x-ray treatment.Thyroid lymphomas are also treated with x-ray therapy.

The prognosis for well-differentiated thyroid carci-nomas is good. Age at the time of diagnosis and sex arethe most important prognostic factors. Men older than40 and women older than 50 have higher recurrence anddeath rates than do younger patients. The 5-year sur-vival rate for invasive medullary carcinoma is 50%,whereas the mean survival for anaplastic carcinoma is6 months.

REFERENCESCooper DS: Clinical practice. Subclinical hypothyroidism. N Engl J

Med 2001;345:260–265.Dabon-Almirante CL, Surks MI: Clinical and laboratory diagnosis of

thyrotoxicosis. Endocrinol Metab Clin North Am 1998;27:25.Dillman WH: The thyroid. In Goldman L, Bennett JC (eds): Cecil

Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000,pp 1231–1250.

Hermus AR, Huysmans DA: Treatment of benign nodular thyroiddisease. N Engl J Med 1998;338:1438.

Weetman AP, McGregor AM: Autoimmune thyroid disease: Furtherdevelopments in our understanding. Endocr Rev 1994;15:788.

PROSPECTUS FOR THE FUTURE• Development of short-acting preparations of triiodothyronine,

allowing for the treatment of hypothyroidism with a combina-tion of triiodothyronine and levothyroxine

• Use of recombinant thyroid-stimulating hormone (TSH) in combination with radioactive iodine to treat euthyroid goitersand thyroid cancer recurrences and metastases

• Acceptance of a TSH screening regimen to detect asympto-matic thyroid disease

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