Chapter 42. Disorders of the Thyroid Gland

The normal thyroid gland is located anterior to the trachea and midway between the apex of the thyroid cartilage and the suprasternal notch (Figure 42–1). Important neighboring posterior structures include the four parathyroid glands situated behind the upper and middle thyroid lobes, and the recurrent laryngeal nerves coursing along the trachea. The thyroid consists of two pear-shaped lobes connected by an isthmus. The typical dimensions of the lobes are 2.5–4.0 cm in length, 1.5–2.0 cm in width, and 1.0–1.5 cm in thickness. Also, in about 50% of patients, a small pyramidal lobe is present at the isthmus or adjacent part of the lobes. The functional unit of the thyroid is the follicle consisting of a central collection of colloidal material (thyroglobulin) surrounded by a single layer of polarized epithelial cells.

A normal thyroid gland weighs approximately 10–20 g, depending on dietary iodine intake, age, and weight. The thyroid gland usually grows posteriorly and inferiorly, since it is limited from upward extension by the sternothyroid muscle. In large multinodular goiters, substernal extension is not uncommon.

The thyroid gland has a rich blood supply, derived from the superior, inferior, and the small inferior ima artery (Figure 42–2). Venous flow returns via multiple surface veins draining into the superior, lateral, and inferior thyroid veins.

Thyroid Hormone Synthesis

The essential steps to thyroid hormone production are as follows (Figure 42–3).

Active Uptake of Iodide (I−) into the Thyroid Cell (Trapping)

Iodide is actively transported across the basal membrane of the thyroid cell by membrane-bound sodium-iodide symporters (NIS). The iodide concentration inside the cell is about 30 to 40 times greater than in the plasma. NIS action is stimulated by thyroid-stimulating hormone (TSH).

Oxidation of Iodide and Iodination of Tyrosyl Residues in Thyroglobulin (Organification)

Iodide entering the thyroid cell is oxidized by locally produced hydrogen peroxide to an active iodide intermediate which then covalently binds to the tyrosyl residues in thyroglobulin at the apical-colloid border. The thyroglobulin molecule is a dimer of two identical chains and about 1/3 of the tyrosyl residues of the molecule undergoes iodination. Thyroid peroxidase (TPO) catalyzes both iodide oxidation and iodination of tyrosyl residues.

Linking Pairs of Iodotyrosine Molecules Within Thyroglobulin to Form Thyroxine (T4). and Triiodothyronine (T3) (Coupling)

The coupling of iodotyrosyl residues in thyroglobulin is also catalyzed by TPO. Two molecules of diiodotyrosine (DIT) couple to form T4; and one molecule of monoiodotyrosine (MIT) and DIT couple to form T3. In thyroglobulin molecule containing 0.5% iodine by weight, there are approximately three molecules of T4 and one molecule of T3.

Proteolysis of Thyroglobulin and the Release of Free Iodothyronines and Iodotyrosines

After a variable period of storage in the thyroid follicles, thyroglobulin is taken up into the thyroid cell by pinocytosis. The colloid vesicles fuse with lysosomes containing proteolytic enzymes releasing T4, T3, inactive iodotyrosines, peptides, and aminoacids. The T4 and T3 enter the circulation, whereas MIT and DIT are deiodinated and their iodide conserved.

A small amount of intact thyroglobulin is normally released into the circulation. The amount is markedly increased in thyroiditis, nodular goiter, and Graves' disease. It is a very useful tumor marker in patients who have had total thyroidectomy and ablation for differentiated papillary or follicular thyroid cancer. Detectable thyroglobulin in these circumstances indicates the presence of thyroid cancer cells.

Thyroid hormone synthesis is mostly controlled by the hypothalamic-pituitary-thyroid axis, as illustrated in Figure 42–4.

Thyroid Hormone Transport

Thyroid hormones are mostly bound to carrier proteins; 99.96% of T4 and 99.60% of T3 are bound in the serum (Figure 42–5). The small fraction of unbound T4 and T3 hormones are responsible for biologic activity. Thyroid hormones are transported throughout the body bound to three carrier proteins in the serum: (1) thyroxine-binding globulin (TBG) which has a single binding site for T4 or T3. In patients who have TBG deficiency, the total T4 and T3 levels are low but the free hormone levels are normal and so the patients are clinically euthyroid. TBG levels are increased during pregnancy and with estrogen therapy. (2) Thyroxine-binding prealbumin (TBPA), also known as transthyretin which binds about 10% of circulating T4; and (3) albumin which binds about 15% of circulating thyroid hormones.

Metabolism of Thyroid Hormones

Biologic activity is dependent on the degree and location of iodination (see Figure 42–5). T3 is three to eight times more potent than T4. T4 is the predominant circulating thyroid hormone, whereas T3 is the main peripherally active hormone. The thyroid normally secretes about 100 nmol of T4 and 5 nmol of T3. Most of the peripheral T3, therefore, is derived from circulating T4 by the action of peripheral 5′-deiodinases. Certain drugs can inhibit the conversion of T4 to T3: propylthiouracil, amiodarone, ipodate, glucocorticoids, and propranolol. T4 has a half-life of approximately 7 days, whereas T3 has a half-life of 1 day.

Thyroid Function Tests

The most commonly used thyroid function tests in clinical practice are serum immunoassays for TSH (or thyrotropin) and free thyroxine (or free T4, also known as FT4). TSH can be used alone in screening for overt thyroid disease, but both TSH and FT4 are needed for the diagnosis, especially if pituitary or hypothalamic disease is suspected. With a normal hypothalamus and pituitary, TSH maintains an inverse relationship with FT4. Figure 42–6 provides an algorithm for the evaluation of thyroid function tests. The common profiles of thyroid function tests in different disease states are outlined in Table 42–1. TSH is an extremely sensitive pituitary indicator of thyroid disease, but it requires 4–6 weeks to reflect changes in thyroid hormone levels. FT4 is a less sensitive indicator of thyroid hormone production, but it may be helpful in monitoring more acute changes in thyroid activity. In evaluating hyperthyroidism, it may also be helpful to obtain a total T3 or FT3 to rule out T3 thyrotoxicosis.

Thyroid-Stimulating Hormone Immunoassay

The TSH assays currently used are immunoassays based on two monoclonal antibodies detecting different epitopes of the TSH. Most laboratories use either a second- or third-generation TSH assay, which detects levels as low as 0.10  and 0.01 mU/L, respectively. TSH is a sensitive measure of the response of the pituitary gland to circulating FT4 levels.

The reference range for most TSH assays is 0.4 to 4.0 mIU/L. It is likely, however, that some individuals with thyroid dysfunction, especially subclinical hypothyroidism, were included when this reference range was established. The TSH level for truly euthyroid subjects lies in the 1.0 to 1.5 mIU/L with a normal range of 0.4 to 2.5 mIU/L

TSH levels are elevated mostly in primary hypothyroidism and are accompanied by a low level of FT4. Table 42–2 lists situations in which the TSH is elevated (other than in hypothyroidism), including drugs, recovery from an acutely ill state, acute psychiatric admission, and the very rare TSH-secreting pituitary tumor.

A decreased TSH level should be interpreted in conjunction with the FT4 level. A decreased TSH level with an elevated FT4 level suggests primary hyperthyroidism. A low FT4 level with a normal to decreased TSH level may indicate secondary or central hypothyroidism (<5% of all cases of hypothyroidism), which are due to a pituitary or hypothalamic tumor. A number of situations, including drugs and nonthyroidal illness, can also cause both low TSH and FT4 levels (see Table 42–1).

Free Thyroxine Immunoassay (FT4)

Direct FT4 determination by an immunoassay has largely replaced indirect measurements of FT4 concentrations, such as the free T4 index (FT4I), which is the product of resin T3 (or T4) uptake and total T4. Most laboratories use a chemiluminescent immunoassay to measure FT4 levels. It is valid in most cases, except in patients with very high or low thyroid-binding proteins or severe illness. Under these circumstances, the measurement of FT4 levels by equilibrium dialysis is more reliable. FT4 is elevated in hyperthyroidism and decreased in hypothyroidism. Table 42–2 lists the conditions that affect FT4 levels. Of note, the antiepileptic drugs phenytoin, carbamazepine, and rifampin can cause a significantly increased hepatic metabolism of T4. Also, drugs and illness rarely suppress the TSH to undetectable levels. The measurement of FT4 levels by dialysis is spuriously elevated by heparin, which activates lipoprotein lipase, which in turn generates fatty acids that displace T4 from TBG.

Total Triiodothyronine (T3)

Total T3 measures both the free and bound T3 in circulation. Total T3 is helpful in diagnosing hyperthyroidism with elevated T3 levels but normal T4 levels (ie, T3 toxicosis). The preferential secretion of T3 can be seen in early Graves' disease or toxic multinodular goiter.

Free T3

Free T3 (FT3) is a newer test that allows for the direct measurement of FT3 levels via a chemiluminescent assay or a radioassay.

Antithyroid Peroxidase Antibody

TPO is the key enzyme that catalyzes the iodination of thyroglobulin and the coupling of iodinated tyrosyl residues to form T3 and T4. TPO is located on the microvilli at the thyroid-colloid interface. Almost all patients with Hashimoto's thyroiditis have antithyroid peroxidase (anti-TPO) antibodies present—these antibodies are usually measured to diagnose Hashimoto's thyroiditis. A large number of patients with Graves' disease also have anti-TPO antibodies.

The prevalence of TPO antibody positivity in the population is in the range of 5% to 12%. Its prevalence is increased in patients with other autoimmune diseases such as type 1 diabetes and pernicious anemia. A detectable TPO antibody in the absence of an overt thyroid disease is a risk factor for future development of hypothyroidism. TPO antibody positivity is also a risk factor for development of thyroid dysfunction in patients taking amiodarone, interferon-alpha, interleukin-2, and lithium therapies.

Thyroglobulin Antibody

Autoantibodies against thyroglobulin are present in patients with autoimmune thyroid disease. Most of these patients are also positive for TPO antibodies. Thyroglobulin antibody is primarily measured in conjunction with estimation of thyroglobulin level where its presence can lead to spurious results (vide infra).

TSH Receptor Antibodies (TRab)

Two classes of TSH receptor antibodies are associated with autoimmune diseases of the thyroid: (a) antibodies that activate the TSH receptor (thyroid-stimulating antibodies (TSAb)) resulting in Graves' hyperthyroidism; and (b) antibodies that block binding of TSH to its receptor (thyroid stimulation blocking antibody (TBAb)). Both TSAb and TBAb can be detected alone or in combination with Graves' disease and Hashimoto's thyroiditis. The relative contributions of the two classes of the antibodies may modulate the severity of Graves' hyperthyroidism and may change in response to treatment. TSAb, also referred to as thyroid-stimulating immunoglobulin (TSI), is an indirect test that confirms the diagnosis of Graves' disease. TSI is positive in approximately 90% of patients with Graves' disease, and negative both in normal patients and patients with Hashimoto's thyroiditis. Patient serum is incubated with either human thyroid cell culture or hamster ovary cells that express recombinant human TSH receptor; cyclic adenosine monophosphate (AMP) activity is measured. TSI is also of diagnostic value in patients with normal thyroid function who have exophthalmos. The measurement of TSI is helpful during pregnancy—high titers increase the risk of neonatal thyrotoxicosis.

Serum Thyroglobulin

Serum thyroglobulin is the precursor protein required for the synthesis of T4 and T3. The normal measure is <40 ng/mL in individuals with normal thyroid function, and <5 ng/mL in patients after a thyroidectomy. Thyroglobulin is raised when the thyroid is overactive, such as with Graves' disease or multinodular goiter. In very large goiters, the elevated levels of thyroglobulin reflect the gland size. In subacute or chronic thyroiditis, thyroglobulin is released as a consequence of tissue damage.

Thyroglobulin is a very useful marker for thyroid cancer, both to assess treatment efficacy and to monitor for recurrence after total thyroidectomy and radioiodine 131I therapy. Because thyroglobulin is made only by the thyroid gland, its level serves as an indicator of the presence of thyroid tissue, as in well-differentiated thyroid cancer. It is necessary to measure for endogenous thyroglobulin antibodies as part of interpreting the measurement of the thyroglobulin level. These antibodies can interfere with the assay and give spuriously high or low levels, depending on the measurement method used.

Radioactive Iodine Uptake & Scan

Radionuclide imaging of the thyroid with 123I or 99mTc is useful in evaluating the functional activity of the thyroid. The two tests that use radioactivity to assess the thyroid are the radioactive uptake and scan. Radioactive uptake evaluates thyroid function by reporting the percentage uptake of iodine, whereas the scan produces an image of the distribution of iodine in the thyroid. The radioactive scan gives information regarding the size and shape of the thyroid, as well as information about nodules that are either functioning (“hot” nodules) or nonfunctioning (“cold” nodules). 123I can be used to assess both radioactive uptake and scan, but 99mTc can only be used for scanning. A 99mTc study gives results within 30 minutes, whereas 123I images are obtained at 4–6 and at 24 hours. 123I delivers less radiation than 131I because of its short half-life of 13 hours and the absence of beta radiation. Its gamma photo energy of 159 keV is ideally suited for thyroid scanning. Both 123I and 99mTc are contraindicated in pregnancy.

123I allows assessment of the turnover of iodine by the thyroid gland. After 100–200 μCi of 123I, radioactivity over the thyroid area is measured by scintigraphy at 4 or 6 and at 24 hours. The normal ranges of uptake vary with iodine intake. In areas of low iodine intake and endemic goiter, uptake may be as high as 60–90%. In the United States, with a relatively high intake, the normal uptake is 5–15% at 6 hours, and 8–30% at 24 hours.

Both 123I uptake and scan are useful in delineating the cause of hyperthyroidism. Uptake is elevated in thyrotoxicosis due to Graves' disease and toxic multinodular goiter. Uptake is low in subacute thyroiditis, the active phase of Hashimoto's thyroiditis with the release of preformed hormone, exogenous thyroid hormone ingestion, excess iodine intake (from amiodarone, iodinate contrast dyes, or kelp pills), and hypopituitarism. More rare causes include ectopic thyroid hormone production from HCG (human chorionic gonadotropin), struma ovarii, and metastatic follicular thyroid carcinoma. 131I uptake and scans are very useful in monitoring the recurrence of well-differentiated thyroid cancer. Typically, 2–3 mCi of 131I is given to the patient, and images of the thyroid and the whole body are taken to look for recurrence or metastases. If the patient is treated with high-dose 131I to ablate remnant thyroid cancer, a post-treatment thyroid and whole-body scan is often helpful to look for tumor tissue that weakly uptakes iodine.

Nonthyroidal Illness & Thyroid Function Tests

Severely ill patients exhibit altered thyroid function tests. Most hospitalized patients have lower serum T3 concentrations due to inhibition of the peripheral conversion of T4 to T3 by 5′-deiodinase. Severely ill patients (50% of patients in the ICU and 15–20% of hospitalized patients) can have a low serum T4 level. This low level is mostly due to very low levels of thyroid-binding proteins, but the exact mechanism remains to be elucidated. The degree of T4 depression has been directly correlated with the overall patient outcome. Most hospitalized patients also have slightly depressed but detectable levels of TSH. It has been suggested that hospitalized patients may have a subtle form of central hypothyroidism as a protective mechanism against their ill health and an increased catabolism. Studies have shown that administering thyroxine to patients who are ill has no benefit and may, in fact, be harmful. In the recovery phase of nonthyroidal illness, the TSH level tends to transiently rise before it returns to normal levels.

The assessment of thyroid function in the setting of nonthyroidal illness is difficult and should be undertaken only when there is a strong suspicion of thyroid disease. A straightforward approach to thyroid function tests in a patient who is hospitalized is to measure both TSH and FT4. An elevated TSH, especially >20 μU/mL, is suggestive of primary hypothyroidism. In 75% of cases, patients with an undetectable TSH using a third-generation TSH assay are likely to have primary hyperthyroidism. A depressed but detectable TSH usually accompanied by a low T4 level could indicate nonthyroidal illness, drug effect, subclinical hyperthyroidism, or central hypothyroidism. In these situations, other aspects of the patient history and examination may be helpful in making the diagnosis. The presence of a goiter, known pituitary disease, and thyroid test results obtained before the illness can direct the diagnosis and treatment. If nonthyroidal illness or a drug effect is highly suspected, the intermittent monitoring of thyroid function tests may be warranted.

Physical Examination

There are three basic maneuvers in examining the thyroid. The patient should be seated with only a slightly flexed neck to relax the sternocleidomastoid muscles. The thyroid should first be observed while the patient swallows a sip of water. An enlarged gland or nodules can be observed as the gland moves up and down. The thyroid gland should then be palpated from behind the patient, with the middle three fingers on each lobe of the gland. While the patient swallows, thyroid nodules or an enlargement can be noted as the gland passes beneath the examiner's fingers. A normal thyroid is usually found to be 2 cm in length and 1 cm in width. A generalized enlargement of the thyroid is called a diffuse goiter (from gutta, Latin for “throat”), whereas an irregular enlargement is termed a nodular goiter.

Thyroid Nodules

General Considerations

The prevalence of palpable thyroid nodules is approximately 5% in women and 1% in women. High resolution ultrasonography can detect thyroid nodules in 19% to 67 % of randomly selected individuals. The nonpalpable nodules discovered on ultrasound or other imaging studies are referred to as incidentally discovered nodules or “incidentalomas.” The clinical importance of having a thyroid nodule rests on the need to exclude thyroid cancer. About 5% to 15% of nodules are malignant depending on age, sex, radiation exposure, and family history.

Clinical Findings

The initial evaluation of a thyroid nodule involves a careful history taking and physical examination (Table 42–3). Generally, incidental nodules over 1 cm in size discovered on imaging studies should undergo further evaluation since they have a greater potential to have clinical significant malignancies. Nonpalpable nodules have the same risk of malignancy as palpable nodules of the same size. Smaller than 1 cm incidental nodules, however, should be evaluated if there are suspicious sonographic findings or have additional risk factors for thyroid cancer. Risk factors include age, with adults younger than 30 or older than 60 years of age carrying a high risk for thyroid cancer; history of childhood head or neck irradiation or total body irradiation for bone marrow transplantation; and family history of thyroid cancer or thyroid cancer syndrome such as Cowden's syndrome, familial polyposis, Carney complex, multiple endocrine neoplasia [MEN] 2 syndrome in a first-degree relative. Recent growth, or evidence of hoarseness, dysphagia, or obstruction, should also raise suspicion. Incidental thyroid nodules are found in approximately 1–2% of people undergoing 2-deoxy-2[18F]fluoro-d-glucose positron emission tomography (18FDG-PET) imaging. The risk of malignancy in these 18FDG-positive nodules is about 33% and the cancers may be more aggressive and therefore undergo prompt evaluation.

An ultrasound study is particularly helpful in distinguishing a cyst from a solid nodule and also in identifying other nonpalpable nodules. Ultrasound can also identify nodules that are more concerning for malignancy, that is, those that have microcalcifications, irregular borders, and increased blood flow.

After primary thyroid disease is ruled out with normal thyroid function tests, the diagnostic procedure of choice is a fine-needle aspiration (FNA) biopsy of the thyroid nodule. Indications for a biopsy include solitary thyroid nodules, multiple nodules, or dominant or growing nodules that exist within a multinodular goiter. Although in the past, multinodular goiters and multiple nodules were thought to have a decreased incidence of thyroid cancer, recent data have suggested that the incidence of thyroid cancer may be higher. When more than two thyroid nodules are >1 cm, those with suspicious sonographic appearance should be biopsied. If none of the nodules have suspicious characteristics then it is reasonable to aspirate the dominant nodule(s).

Patients with subclinical or overt hyperthyroidism (low or suppressed TSH) and thyroid nodules (single or multiple) should undergo a radionuclide scan using either technetium 99mTc pertechnetate or 123I prior to the FNA. If the nodule in question is hyperfunctioning (“hot”) then an FNA is not necessary since such nodules are rarely malignant. If, however, the nodule is nonfunctioning (“cold”) or isofunctioning (“warm”) then an FNA is indicated. A FNA biopsy is performed using a 23- to 25-gauge needle with or without local anesthesia, and usually with ultrasound guidance. Several passes are made into the thyroid nodule, and the aspirated material is used in thin smear slides that are both air dried and alcohol preserved.

Cytopathologic examinations are typically reported as benign, suspicious or indeterminate (eg, follicular neoplasms), malignant, or nondiagnostic. One review of a thyroid biopsy reported that 70% of FNAs were benign, 10% were suspicious or were follicular neoplasms, 5% were malignant, and 15% were nondiagnostic. Cystic lesions yield serous fluid with immediate involution of the nodule. Although a malignant growth is less likely to occur in a purely cystic lesion, the fluid should still be sent for cytologic examination. If the cyst has tissue in the wall, then FNA of this region should be performed under ultrasound guidance. FNA is considered nondiagnostic if the specimens show a lack of follicular epithelium or the presence of excessive bloody dilution. A recent review of more than 5000 FNA procedures revealed an accuracy of over 95%, with a false-negative rate of 2.3% and a false-positive rate of 1.1%. Genetic markers (BRAF, RAS, RET/PTC, Pax8-PPARγ) or protein markers (galectin-3 expression) may be helpful in directing the treatment of indeterminate thyroid nodules.

Treatment

An algorithm of thyroid nodule management can be found in Figure 42–7. The management of a malignant growth, as indicated by FNA, requires total thyroidectomy, with careful attention paid to local, palpable lymph nodes that may require neck dissection at the time of surgery. Follicular adenomas are often deemed “indeterminate” because they are difficult to distinguish from follicular carcinomas on FNA. Evidence of vascular or capsular invasion is required for the diagnosis of follicular carcinoma. Roughly 10–20% of all suspicious lesions actually prove to be follicular carcinoma on excision.

Benign thyroid nodules are usually followed up clinically; these growths may enlarge, stay the same size, or involute. Serial ultrasounds are particularly helpful in follow-up measurements. Suppressive therapy of benign thyroid nodules is controversial. Most studies have not shown regression of solitary nodules with exogenous thyroxine, whereas some studies have shown a 20–30% reduction. Currently, most authorities do not recommend l-thyroxine therapy in the treatment of solitary nodules. Nodules that increase in size raise concern for a malignant growth and require reexamination with repeat FNA or surgical removal. Cystic lesions quickly involute on aspiration but are more prone to recur. In addition, FNA of cystic lesions can yield nondiagnostic cytology because of the difficulty of performing a biopsy of the thin cystic wall. Repeat FNAs are often required, and ultimately surgical removal may be needed. One small randomized trial showed that suppressive therapy for cystic nodules was not helpful.

The evaluation of a thyroid nodule discovered in a pregnant woman is the same as for a nonpregnant woman except that radionucleotide scans are contraindicated. For many pregnant patients found to have differentiated thyroid cancer on FNA, surgery can be deferred until after delivery. Retrospective studies indicate that there is no difference in recurrence or survival rates in women undergoing surgery during or after pregnancy. Surgery in the second trimester may be considered if there is ultrasound evidence for growth of the lesion or if the disease is advanced.

Multinodular Goiter

General Considerations

With multinodular goiter, the thyroid gland is usually large, weighing from 60 to 1000 g. On pathologic examination, it contains nodules that vary in size, number, and appearance. Some nodules contain colloid and others are cystic, containing brown fluid that indicates previous hemorrhage. Some of the nodules have autonomous function. The spectrum of function of these goiters ranges from the euthyroid state, with some degree of autonomous function, to thyrotoxicosis (eg, toxic multinodular goiter).

Clinical Findings

The principal clinical features of a nontoxic goiter are the same as those of a thyroid enlargement. Large goiters can cause dysphagia, a choking sensation, and inspiratory stridor. Hemorrhage into a nodule can present with acute painful enlargement and may induce or enhance obstructive symptoms.

Treatment

Thyroid hormone suppressive therapy may be effective in suppressing the growth of the multinodular goiter and preventing the development of new nodules. Up to 60% of these goiters respond to such treatment. Long-term treatment is required because stopping the suppression results in regrowth of the gland. It is important to start with a low dose of l-thyroxine and carefully monitor the FT4 and TSH levels, aiming for a level of FT4 in the normal range and a level of TSH in the low-normal range. Careful follow-up is necessary to monitor both for the development of autonomous function within the gland and for thyrotoxicosis. Radioactive iodine treatment is increasingly used and can result in a reduction of the thyroid volume and is safe in the treatment of a nontoxic multinodular goiter. Hypothyroidism can occur in 22–40% of subjects within 5 years after 131I treatment. Surgery should be considered in patients when either the gland grows on suppressive treatment or there are obstructive symptoms. Surgical complications, such as recurrent laryngeal nerve damage and hypoparathyroidism, can be as high as 7–10%.

For a toxic multinodular goiter, control of the hyperthyroid state with antithyroid drugs followed by 131I treatment is treatment of choice. Subtotal thyroidectomy is an alternate option. Patients who have some degree of autonomous function in their multinodular goiter can develop overt thyrotoxicosis when exposed to an iodine load (eg, amiodarone treatment or IV contrast). This iodide-induced thyrotoxicosis can be treated with methimazole and betaadrenergic blockade. 131I treatment may not be possible because of the large iodine pool. Total thyroidectomy is curative but is feasible only if the patient can withstand the stress of surgery.

Thyroid cancer represents about 3% of all cancers in women and 1% of cancers in men, with an estimated incidence of 37,000 new cases in 2008. In the past three decades, the incidence of thyroid cancer has increased by almost 50%; however, mortality rates have declined by 20%. This may be due to earlier detection by FNA and subsequent treatment. There are four main pathologies encountered in thyroid cancer: papillary, follicular, medullary, and anaplastic carcinomas (Table 42–4).

Papillary Carcinoma

General Considerations

Papillary carcinoma is the most common thyroid cancer, representing 75% of all thyroid cancers. It has the best prognosis, with a 5% mortality rate at 20 years for patients with no evidence of local invasion at diagnosis. In addition to a history of childhood exposure to radiation, risk factors for papillary carcinoma include familial papillary carcinoma, Cowden syndrome (eg, multiple hamartomas of the skin and mucous membranes), and familial adenomatous polyposis coli.

Clinical Findings

Microscopically, papillary carcinoma consists of single layers of thyroid cells arranged in avascular projections or papillae, which manifest as large pale nuclei, intranuclear inclusion bodies, and anaplastic features. “Psammoma bodies” are laminated calcified spheres and are usually diagnostic of papillary carcinoma. Papillary carcinoma can be either purely papillary or mixed with follicular carcinoma; both are treated with similar therapies. Certain histopathologic variants, such as tall cell, columnar cell, and diffuse sclerosing types, are associated with a higher risk of recurrence.

Papillary carcinoma typically has an indolent natural history. Usually unencapsulated, these lesions grow slowly, with intraglandular metastasis and local lymph node extension. Approximately 25% to 50% of patients have involvement of cervical lymph nodes at presentation. In the late stages, it can spread to the lung. In older patients, chronic low-grade papillary carcinoma may rarely convert to an aggressive anaplastic carcinoma.

Treatment

Because papillary carcinoma retains the ability to synthesize thyroglobulin and to concentrate iodine in the early stages, radiation therapy is often effective. The initial treatment involves either partial thyroidectomy or total thyroidectomy with possible modified neck dissection (Figure 42–8).

Surgical Measures

Preoperative ultrasound can identify lesions in the contralateral lobe and in the cervical lymph nodes assisting in the accurate staging of the disease. Prognosis depends on age, the size of the lesion, and evidence of extrathyroidal spread. Patients younger than 45 years of age who have lesions <1 cm with no evidence of intra- and extrathyroidal involvement are considered to have a low risk for future recurrence. All other patients should be considered at high risk. For both low-risk and high-risk patients, total thyroidectomy is generally recommended although a partial thyroidectomy may be adequate for the former group. If lymph node involvement is present on the initial evaluation, the patient should undergo a modified neck dissection as well; however, neck dissection is not indicated in the absence of lymph node involvement. Completion thyroidectomy is indicated if diagnosis of malignancy is made after lobectomy of an indeterminate lesion.

In the hands of a skilled surgeon, thyroid surgery portends less than a 1% complication rate; the primary complications are hypoparathyroidism and recurrent laryngeal nerve damage. Immediately after surgery, the patient should be placed on suppressive T4 therapy.

Postsurgical Measures

After undergoing a total thyroidectomy, patients should receive radioiodine to ablate the normal thyroid remnant or residual microscopic disease. The radioablation decreases the likelihood of recurrent disease and also allows the physician to subsequently follow thyroglobulin levels as a marker for thyroid cancer activity.

Remnant ablation can be performed either following thyroxine withdrawal or recombinant TSH stimulation. The thyroxine withdrawal protocol requires thyroxine therapy to be stopped for 6 weeks and l-triiodothyronine (25 to 50 mcg) to be initiated for 4 weeks. The patient is then taken off all thyroid hormone therapy and goes on a low iodine diet for 2 weeks. This protocol allows for a rise in the patient's TSH level, which stimulates iodide uptake by the residual tumor. At maximal TSH stimulation (usually a TSH of > 50 μU/mL), thyroglobulin is drawn and 1–3 mCi of 131I is administered to the patient. The patient is scanned for residual radioactive iodine uptake 24–72 hours later. A treatment dose of 131I is then given. The previous dose of thyroxine and regular diet can be restarted 2 days after the 131I treatment dose. Patients can also be given 1 week of l-triiodothyronine to rapidly reverse the hypothyroid state. A whole body scan is performed 1 week after the therapy dose. This posttreatment scan allows for identification of metastatic disease not visualized on the diagnostic scan. Additional metastatic foci are noted in 10% to 26% of patients on the posttherapy scan compared to the diagnostic scan. Approximately 30–50 mCi of 131I is used to ablate the thyroid remnant in a postsurgical patient who does not have metastatic disease; uptake is limited to the thyroid bed. For metastatic or recurrent disease, patients are generally treated with a 100–200 mCi dose of 131I. Side effects from doses larger than 100 mCi include sialadenitis, xerostomia, and temporary oligospermia. The recombinant TSH protocol allows the patient to avoid the discomfort of severe hypothyroidism and disrupting suppressive T4 therapy. The patient is on a low iodine diet for at least 2  weeks prior to the study but the l-thyroxine is only stopped 2 days before the procedures. Patients get intramuscular injections of recombinant TSH on days 1 and 2. Thyroglobulin and TSH levels are drawn and therapeutic dose of 131I is given on day 3. The l-thyroxine dose and regular diet are restarted 3 days later and a whole body scan is performed a week after therapy dose. After 131I ablative therapy, the patient is placed on suppressive l-thyroxine therapy. Suppression to below 0.1 mU/L is recommended for high-risk patients and below normal (0.1 to 0.5 mU/L) in the low-risk patient.

Long-term management is directed at early detection and treatment of recurrent disease. Patients can be considered low risk if the tumor did not have aggressive histology and was localized within the thyroid without evidences of local or distant metastasis and the diagnostic and/or posttreatment 131I uptake was restricted to the thyroid bed. Intermediate risk patients have microscopic disease into the perithyroidal soft tissues or have aggressive histology or vascular invasion. High-risk patients have macroscopic tumor invasion, incomplete tumor resection or distant metastasis or 131I uptake outside thyroid bed on a posttreatment scan.

Patients should be monitored at regular intervals with neck ultrasounds and clinical examination for new masses or lymphadenopathy and measurements of serum thyroglobulin, FT4, and TSH. The frequency of ultrasound examination depends on patient's risk for recurrent disease and thyroglobulin status. It is helpful to get a baseline study at 2 to 3 months after surgery and then at 6 and 12 months and then yearly for at least 3 to 5 years. Suspicious lymph nodes and/or suspicious soft tissue in the neck should undergo FNA under ultrasound guidance and if disease is confirmed then additional surgery may be indicated.

Serum thyroglobulin levels have a high degree of sensitivity and specificity to detect persistent or recurrent thyroid cancer after total thyroidectomy and remnant ablation. Serum thyroglobulin levels should be measured by using the same immunometric assay every 6 to 12 months. Thyroglobulin antibodies in patient's serum can interfere with the assay making the result unreliable, and so they should be quantified with every measurement of serum thyroglobulin. A rise in thyroglobulin above 2 ng/ml (using a thyroglobulin assay with a functional sensitivity of <1.0 ng/ml) after thyroxine withdrawal or recombinant TSH treatment indicates persistent disease. This testing should be performed at approximately 12 months after ablation. Newer immunometric assays have functional sensitivities as low as 0.1 ng/mL and may detect persistent disease even while on suppressive therapy. Thus, in the low-risk patient where the 12 month assessment is negative, thyroglobulin of <0.1 ng/mL while on suppressive therapy combined with a normal neck ultrasound is reassuring and may obviate the need for repeat-stimulated thyroglobulin measurement.

Follow-up 131I uptake scans are not routinely required in the low-risk patient with negative TSH-stimulated thyroglobulin level and neck ultrasound. Diagnostic uptake scans should be performed in moderate- or high-risk patients at 12 month intervals with concomitant radioactive treatments as necessary (Figure 42-8). Once a negative scan and negative thyroglobulin are achieved, the patient is likely to be disease free and may be subsequently followed with neck ultrasound and stimulated thyroglobulin measurements.

The amount of 131I given for the treatment of thyroid cancer depends on the degree of disease, the response to previous treatments, and the amounts of 131I administered in the past. With cumulative doses of up to 300 mCi, no permanent sterility has been reported in women and <10% of men have permanent sterility. Cumulative doses larger than 500 mCi have been associated with infertility, pancytopenia (in <4.0% of cases), and leukemia (in 0.3% of cases). However, cumulative doses over 800 mCi have been associated with permanent sterility in up to 60% of women and 90% of men. In patients with significant pulmonary metastasis, repeated 131I treatment can rarely result in pulmonary pneumonitis and pulmonary fibrosis. Salivary gland damage, nasolacrimal duct obstruction, and secondary malignancies are risk factors of 131I therapy. Surgical correction should be considered for lacrimal outflow obstruction. Long-term followup studies suggest a slightly increased 131I dose-related risk for secondary malignancies such as bone, colorectal, salivary gland, and leukemia. There is no evidence, however, that these patients need more intensive screening for these malignancies than the general population. Radioiodine therapy is contraindicated in pregnancy and in breast-feeding women. Women receiving 131I therapy should avoid pregnancy for 6 to 12 months.

131I treatment is given either after l-thyroxine withdrawal or following recombinant TSH therapy. It should noted, however, that long-term outcome studies on the use of recombinant TSH for 131I treatment for metastatic disease are not yet available.

Thyroid cancer with a negative scan but a positive thyroglobulin positive thyroid level poses a diagnostic dilemma. As thyroid cancer dedifferentiates, it can potentially lose the ability to concentrate iodine and thus lose responsiveness to radioactive iodine treatment. Once excessive iodine intake is ruled out, patients generally undergo further imaging such as ultrasound, MRI, CT scanning, 18 FDG-PET/CT scanning, or thallium or technetium-MIBI scanning to locate metastatic disease. Complete surgical removal of isolated symptomatic metastases has been associated with improved survival especially in patients under 45 years old. External beam radiation can be used to manage unresectable gross residual cervical disease, painful bone metastasis and CNS lesions not amenable to resection. Chemotherapy has modest benefit in patients with advanced radioiodine thyroid disease. Patients should be considered for clinical trials such as those using tyrosine kinase inhibitors targeting activated RET/PTC oncogene. If the patient does not qualify or does not wish to participate in clinical trials then treatment with doxorubicin alone or in combination with other agents may be considered.

Prognosis

The overall prognosis of well-differentiated thyroid cancer is assessed by the initial staging and the adequacy of treatment. Table 42–5 describes the TNM staging system as well as 5- and 10-year survival rates. In this system, the staging is related to the age of the patient, recognizing that for patients who are younger than 45 years of age at the time of diagnosis, papillary tumors are relatively indolent. Stage 1 patients have an excellent 5-year survival rate of 99% and a 10-year survival rate of 98%.

The treatment modality, including the type of surgery, the radioactive treatment, and adequate l-thyroxine suppressive therapy, also affects the prognosis. Patients with tumors > 1 cm who receive partial thyroidectomies have a mortality rate that is 2.2 times greater than that of patients who undergo total thyroidectomies. Patients who have never undergone radioablation carry a twofold increased mortality rate at 10 years compared with patients who receive radioablation. Adequate suppressive therapy decreases the mortality rate but must be weighed against the possible side effects of tachycardia, arrhythmias, angina, and osteoporosis.

Follicular Carcinoma

General Considerations

Follicular carcinoma is the second most common thyroid cancer, accounting for 16% of all thyroid cancers.

Clinical Findings

Microscopically, follicular cancer forms small follicles that contain small, cuboidal cells with poor colloid formation. The distinction between carcinoma and adenoma requires the presence of capsular or vascular invasion. It is often difficult to distinguish a follicular carcinoma from a follicular adenoma on an FNA biopsy; therefore, a frozen section at the time of surgery is necessary. Like papillary carcinoma, follicular carcinoma retains the ability to synthesize thyroglobulin and concentrate iodine and is therefore responsive to radioactive iodine treatment. Rarely, follicular carcinoma synthesizes T3 and T4 and presents with hyperthyroidism and distant metastases. Follicular carcinoma tends to be slightly more aggressive than papillary carcinoma; it may spread to local lymph nodes or by the blood to bone or lung. Histologic variants, such as Hürthle cell and poorly differentiated carcinoma, rarely take up radioiodine and have a higher risk of metastases and recurrence.

Treatment & Prognosis

The treatment and prognosis of follicular carcinoma are the same as for papillary carcinoma (see the previous section).

Medullary Thyroid Cancer

General Considerations

Medullary thyroid cancer (MTC) represents only 5% of thyroid cancers. Papillary and follicular carcinomas involve thyroid epithelial cells; medullary carcinoma is a disorder of the parafollicular or C cells.

Clinical Findings

The neuroendocrine cells of MTC appear as sheets of cells with abundant, interspersed amyloid that stains Congo red. In addition to secreting calcitonin, medullary carcinoma can secrete histaminase, prostaglandins, serotonin, and other peptides. Local extension often occurs into the lymph nodes, surrounding muscle, and the trachea. In addition, medullary carcinoma can spread via the blood to the lungs and viscera. Treatment involves surgical resection, since radiation therapy has no effect.

MTC has a natural history that is more aggressive than papillary or follicular thyroid carcinoma. Patients with multiple endocrine neoplasia (MEN) type 2b have the most aggressive form, whereas the cancers found in patients with MEN 2a and familial medullary thyroid carcinoma (FMTC) are the least aggressive. This cancer also has a strong familial association; one third of cases are sporadic, a second third are associated with MEN 2, and the other third of cases are familial without other associated endocrinopathies. MEN 2a is composed of medullary carcinoma, pheochromocytoma, and hyperparathyroidism, whereas MEN 2b consists of medullary carcinoma, pheochromocytoma, and multiple mucosal neuromas. All patients with a MTC should be screened for other endocrinopathies found in MEN 2. Familial MTC is a clinical variant of MEN 2A in which MTC is the only manifestation. To prove that kindred has FMTC, it is necessary to demonstrate that pheochromocytoma or primary hyperparathyroidism is not present in two or more generations.

Germline RET mutations are present in MEN 2 and FMTC. Somatic RET mutations that occur later in life and are limited to C cells are present in 40% to 50% of sporadic MTC. All patients with MTC, MEN 2 or primary C-cell hyperplasia should be offered germline RET screening. All people with family history of MEN 2 or FMTC should be offered RET testing. For MEN 2b this should be done shortly after birth. For MEN 2a and FMTC this should be done before 5 years of age.

Treatment

Preoperative evaluation of patients presumed to have MTC should have serum measurements of calcitonin, antigen (CEA), serum calcium and albumin. Consideration should also be given to screening for pheochromocytoma using plasma or 24 hour urine metanephrines or normetanephrines. If the catecholamine measurements are consistent with a pheochromocytoma diagnosis then an adrenal MRI or CT scan is indicated. The pheochromocytoma should be surgically resected prior to surgery for MTC. Patients who have ultrasound evidence for LN involvement should also undergo a chest, neck and liver CT, or contrast-enhanced MRI.

Patients with MTC with no evidence of LN involvement or distant metastasis should undergo total thyroidectomy with prophylactic central compartment (level VI) neck dissection. Patients with local metastatic disease in the regional lymph nodes should also have lateral neck dissection. Since C-cell tumors are not TSH dependent, l-thyroxine replacement targets TSH levels between 0.5 and 2.5 mIU/L. There is no role of 131I or chemotherapy in the treatment of medullary carcinoma. Patients should be monitored for the recurrence of disease with serum calcitonin or CEA measurements (Figure 42–9). Imaging modalities include MRI of the neck and chest, PET scanning, indium-labeled somatostatin scanning, or sestamibi scanning. In addition, family members should be screened for familial medullary carcinoma and the RET proto-oncogene associated with MEN 2a and 2b.

MEN 2 patients who present with palpable MTC have a low rate of surgical cure. Prophylactic thyroidectomy is therefore indicated in family members with germline RET mutations. The codon mutated is used to guide the timing of the surgery. Mutations at RET codons 883 and 918 are associated with the youngest age of onset and highest risk of metastasis and disease-specific mortality. Patients with these mutations should therefore undergo prophylactic thyroid surgery soon as possible in the first year of life. Patients with mutation at RET codon 634 should have thyroid surgery before the age of 5 years. For patients with mutation at RET codons 609, 611, 618, 620, and 630, surgery before the age of 5 is preferable but can be deferred if normal annual basal or stimulated calcitonin; normal annual neck ultrasound; less aggressive family history of MTC; and family preference. Patients with mutation at RET codons 768,790, 791, 804790, 791, 804, and 891 are at the least high risk and surgery can be deferred beyond 5 years of age provided normal annual basal or stimulated calcitonin; normal annual neck ultrasound; and less aggressive family history of MTC and family preference. Preimplantation and prenatal testing should be made available to carriers of RET mutations.

Anaplastic Carcinoma

General Considerations

Undifferentiated (anaplastic) carcinoma represents 1% of all thyroid cancers. Histopathologic types include small cell, giant cell, and spindle cell carcinomas. Anaplastic carcinoma is the most aggressive form of thyroid cancer and rapidly expands by local extension into surrounding structures. It results in death in 6–36 months.

Clinical Findings

The typical presentation of anaplastic thyroid carcinoma is an older patient with a long history of goiter with sudden rapid expansion of the gland followed by compressive symptoms or vocal cord paralysis.

Treatment & Prognosis

Anaplastic thyroid carcinoma is resistant to all treatment modalities. Treatment is palliative and includes isthmectomy to prevent tracheal compression, and external-beam therapy plus suppressive l-thyroxine therapy. Although chemotherapy is generally not effective with anaplastic carcinoma, doxorubicin may be useful in patients who cannot undergo other forms of therapy. Anaplastic carcinoma carries a very poor prognosis because of the aggressiveness of the disease and a lack of responsiveness to treatment.

Other Thyroid Cancers

Other types of malignant thyroid disorders represent approximately 3% of all thyroid cancers. These include lymphomas, metastatic carcinomas, fibrosarcomas, squamous cell carcinomas, malignant hemangioendotheliomas, and teratomas. Lymphoma can present rapidly in patients with long-standing Hashimoto's thyroiditis, or it may develop in association with generalized lymphoma. The thyroid lymphoma associated with Hashimoto's thyroiditis can sometimes be difficult to distinguish from chronic thyroiditis. In the absence of systemic spread, thyroid lymphoma is responsive to radiation therapy. Common meta-static cancers of the thyroid include breast, renal cell, and bronchogenic cancers, as well as melanoma.

Hyperthyroidism & Thyrotoxicosis

Thyrotoxicosis is a clinical syndrome that results from excessive levels of circulating thyroid hormone. The most common causes of thyrotoxicosis are due to overproduction of thyroid hormone by the thyroid gland, but other sources of thyroid hormone may exist, including exogenous ingestion of thyroid hormone or ectopic secretion (Table 42–6).

Patients with thyrotoxicosis classically present with a large number of symptoms related to hypermetabolism; these symptoms, listed in Table 42–7, include anxiety, insomnia, a racing heartbeat, palpitations, hand tremors, increased stool frequency, weight loss, heat intolerance, and increased perspiration. Older patients may exhibit “apathetic hyperthyroidism,” which is characterized by weight loss, severe depression, and the potential for slow atrial fibrillation.

On physical examination, patients may be hyperkinetic with an inability to sit still; they may also present with fine tremor and hyperreflexia. Lid retraction is responsible for the characteristic “stare” and lid lag may be evident whereby the sclera can be seen above the iris when the patient is asked to gaze downward slowly. Lid retraction and lid lag are due to the hyperadrenergic state and should not be confused with exophthalmos, which is unique to Graves' disease. The patient's skin may have a velvety, moist texture, and the hair is thin and fine. Cardiovascular signs include tachycardia, widening of the pulse pressure with an increase in systolic pressure and a decrease in diastolic pressure, and a hyperdynamic precordium. Atrial fibrillation occurs in approximately 10% of patients with thyrotoxicosis. Examination of the neck may reveal a diffusely enlarged or multinodular goiter, a single nodule, or a painful and tender thyroid. A bruit may be present and is most often heard over the gland in Graves' disease.

The diagnosis is confirmed by laboratory analysis. Overt thyrotoxicosis typically has a suppressed TSH and elevated FT4 and FT3 concentrations. A normal T4 but an elevated T3 is consistent with T3 toxicosis, usually seen in the early phase of toxic multinodular goiter and Graves' disease. The diagnosis of the etiology of thyrotoxicosis can be aided by the physical examination—the presence of ophthalmopathy, diffuse goiter, and pretibial myxedema is suggestive of Graves' disease. Additional laboratory tests, such as TSI (thyroid-stimulating immunoglobulin), anti-TPO, and ESR (erythrocyte sedimentation rate) can be helpful in diagnosing Graves' disease, the hyperthyroid phase of Hashimoto's disease, and viral thyroiditis. Radioactive thyroid uptake and scan are occasionally needed to confirm the cause of thyrotoxicosis.

Graves' Disease

General Considerations

Graves' disease is an autoimmune disorder characterized by the production of immunoglobulins that bind and activate the TSH receptor, which stimulates thyroid growth and hormone secretion. It tends to occur in women between the ages of 20 and 40, with an incidence of 1.9% in women. Females are five times more likely to be affected than males. There is a strong family predisposition in that 15% of patients have a close relative with the disorder.

Clinical Findings

In addition to the signs and symptoms of hyperthyroidism, several signs and symptoms are unique to Graves' disease, including ophthalmopathy, dermopathy, and osteopathy. Infiltrative ophthalmopathy is by far the most common sign. For unclear reasons, the increased inflammation and the accumulation of glycosaminoglycans cause swelling of extraocular and retroorbital muscles, as well as displacement of the eye forward (also known as proptosis or exophthalmos). Patients can experience eye irritation; excessive tearing worsened by cold air, bright lights, or wind; diplopia; blurred vision; and, rarely, loss of vision.

Other physical findings in Graves' disease include dermopathy and osteopathy. Glycosaminoglycans can accumulate in the dermis layer, causing thickening of the skin, especially over the anterior tibia (pretibial myxedema). Osteopathy may occur with subperiosteal bone formation and swelling. The extrathyroidal manifestations often have a course independent of the thyroid disease itself and can persist despite restoration of the euthyroid state.

Laboratory Tests

The diagnosis of Graves' disease can be made from evidence of ophthalmopathy on the physical exam, as well as a decreased TSH and an increased FT4 or FT3. If ophthalmopathy is absent, obtaining a measure of TSI can be helpful. TSI is specific for Graves' disease but the lack of a TSI elevation does not exclude the diagnosis. The presence of autoantibodies provides supportive evidence for Graves' disease. More than 95% of patients have anti-TPO antibodies and about 50% have antithyroglobulin antibodies. In the absence of eye signs or an elevated TSI, a radioactive scan and uptake can be performed to confirm the diagnosis of Graves' disease.

Treatment

There are three aspects in the treatment of Graves' disease: (1) the control of hyperadrenergic symptoms, (2) the short-term restoration of the euthyroid state, and (3) the long-term control of excess thyroid hormone production.

Control of Adrenergic Excess

To control the symptoms of adrenergic excess, beta-blockers—either propranolol or atenolol—are used. These agents should be instituted even before determining the cause of hyperthyroidism. Propranolol has the advantage of inhibiting peripheral T4 to T3 conversion, whereas atenolol is more convenient with once-daily dosing. A typical starting dose is 10–20 mg of propranolol—three to four times a day, or 25 mg of atenolol once daily. These drugs are then titrated up over a few days while the patient's pulse and blood pressure are monitored. The beta blockade is discontinued once the serum FT4 and T3 levels return to normal.

Restoration of Euthyroid State

Thionamides (methimazole or propylthiouracil) act by inhibiting TPO-mediated iodination of thyroglobulin to form T4 and T3 within the thyroid gland and are generally used to restore the patient to the euthyroid state before deciding on long-term management. Methimazole is the preferred drug in most circumstances because propylthiouracil has been associated with the increased risk of fulminant hepatitis resulting in death or need for liver transplantation. Also, in patients for whom 131I treatment is planned, methimazole is preferable to propylthiouracil because propylthiouracil may inhibit radioactive iodine uptake for weeks or months after discontinuation. Typically, a patient is started on a daily 20–40 mg dose of methimazole for 1–2 months, and then titrated down to a maintenance dose of 5–10 mg. Titration of the drug dose is based on the measurement of TSH and FT4, as well as on the signs and symptoms of hyper- or hypothyroidism.

Propylthiouracil should only be used if the patient is allergic to methimazole. The typical starting dose of propylthiouracil is 100–150 mg three times a day; after 1–2 months it is titrated down to 50–100 mg twice daily. It also is more protein bound and is therefore the preferred drug at time of conception and in the first trimester of pregnancy. Because of hepatotoxicity concerns, consider switching back to methimazole in the second and third trimesters. Although less propylthiouracil is excreted in breast milk than methimazole, both drugs are considered safe for use during breast feeding provided the doses are kept low. In pregnancy, if the initial dose of propylthiouracil is 300 mg or less and the maintenance dose is 50–150 mg daily, the risk of fetal hypothyroidism is extremely low. The thionamide doses are titrated to maintain total T4 at the upper limit of normal.

Both methimazole and propylthiouracil cause a rash in approximately 5.0% of patients. Agranulocytosis, which occurs in about 0.5% of patients, is usually heralded by a severe sore throat and fever. Patients should be counseled to stop the drug if they get a sore throat or fever and to see their physician. If the white blood cell count is normal, then the antithyroid drug can be resumed. Other serious side effects requiring discontinuation of drug include arthritis with both drugs; cholestatic jaundice with methimazole; angioneurotic edema, hepatocellular toxicity, and vasculitis with propylthiouracil.

Long-Term Therapy

The choice of long-term therapy is based on the age of the patient, the severity and duration of the hyperthyroidism, the size of the gland, and the potential for a future pregnancy. In the one randomized trial that assessed the efficacy of drug treatment, radioablation, and surgery, all three modalities were found to be equally effective. However, there are several guidelines for choosing a treatment modality.

Methimazole

Methimazole treatment is chosen for long-term therapy, particularly in adolescents and young patients with small glands and less severe disease. The drug is usually given for up to 18 months to allow the disease to remit spontaneously. This remission occurs in 30–40% of patients treated for 18 months. If the patient relapses after stopping the methimazole, then the patient has the option of going back on methimazole or consider radioactive iodine therapy or surgery.

Radioactive Iodine

Radioactive iodine ablation is the treatment of choice in patients 21 years and older. From a survey performed by the American Thyroid Association, 69% of American thyroid specialists recommended radioablation as the therapy of choice. In contrast, only 22% and 11% of European and Japanese thyroid doctors recommended radioablation as a first-line therapy.

With this treatment modality, patients are dosed with radioactive iodine based on their uptake scan. Patients with severe hyperthyroidism, serious thyroid enlargement, or a history of heart disease should be adequately returned to the euthyroid state with methimazole prior to radioablation, with methimazole discontinued about 5 days prior to radioablation. Most patients subsequently become hypothyroid and require thyroid hormone replacement. Approximately 10% of patients have unsuccessful radioablation and may require a second dose. Radioactive iodine treatment is contraindicated in pregnancy, and it is important to advise women who may become pregnant in the near future that they should wait at least 6 months after 131I treatment to allow for the resolution of any transient effects of the radiation on the ovaries. Alternative options should be offered to a female patient who cannot wait that long. Radioiodine therapy can exacerbate Graves' ophthalmopathy especially if the disease is severe or if the patient is a smoker. Concomitant glucocorticoid therapy can prevent exacerbation. Surgery may be a better option for such patients.

Thyroidectomy

Total or subtotal thyroidectomy should be considered in patients with a very large gland (ie, >150 g), those with severe Graves' ophthalmopathy, those who are allergic to antithyroid drugs, and the patient who wants to get pregnant soon. Patients should be given thionamides until a euthyroid state is achieved (approximately 6 weeks), and a saturated solution of potassium iodide—5 drops twice daily for the 2 weeks before surgery. The preoperative iodine treatment decreases the vascularity of the gland and reduces intraoperative blood loss. The degree of the thyroidectomy is variable among surgeons but generally 2–3 g of thyroid tissue is left intact. If an experienced surgeon is available then total thyroidectomy is preferable because leaving behind too much tissue may result in disease recurrence. Total thyroidectomy is also preferred in patients with progressive exophthalmos.

Surgical complications include neck hematoma, recurrent laryngeal nerve injury, and hypoparathyroidism. A neck hematoma can cause airway compromise and must be evacuated immediately. In experienced surgeons the rate of hypoparathyroidism is less than 1%. Approximately 10% of patients develop transient post-operative hypocalcemia. Oral and intravenous calcium supplementation is sufficient to control the symptoms. The rate of recurrent laryngeal nerve injury leading to ipsilateral vocal cord paralysis is also about 1%. Bilateral recurrent laryngeal nerve injury can cause severe respiratory impairment and may require tracheostomy. It is now extremely rare after subtotal thyroidectomy.

Most patients require thyroid hormone replacement therapy postoperatively.

Complications

Thyroid Crisis (Thyroid Storm)

Thyroid crisis is an acute exacerbation of all symptoms of thyrotoxicosis. It occurs in patients with inadequately controlled thyrotoxicosis who undergo surgery, radioactive iodine treatment, parturition, and severe stressful illnesses such as infections, uncontrolled diabetes, and myocardial infarction. This disorder results from hypermetabolism and excessive adrenergic response. It is typically associated with Graves' disease but can also occur in patients with toxic nodular goiter.

Systemic symptoms include fever (38–41°C), flushing, and sweating. Cardiac symptoms and signs include tachycardia, atrial fibrillation, and congestive cardiac failure. Neurologic symptoms and signs include agitation, restlessness, delirium, and coma. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, diarrhea, and jaundice.

Thyroid crisis is a medical emergency and should be treated promptly. Propranolol, either in a dose of 1–2 mg given as a slow IV injection, or in a dose of 40–80 mg administered orally, is given to control tachyarrhythmias. Methimazole is given at a dose of 20 mg every 6 to 8 hours. Propylthiouracil (250 mg every 6 hours) was traditionally favored because it partially blocked the peripheral conversion of T4 to T3. It is however no longer considered first line therapy because of its association with hepatocellular injury. If the patient cannot take oral medications, then 60 mg of methimazole every 24 hours or 400 mg of propylthiouracil can be administered rectally. An hour after a dose of methimazole or propylthiouracil has been given, hormone release can be retarded by giving an oral, saturated solution of potassium iodide (10 drops twice daily). The oral cholecystographic agents (sodium ipodate or iopanoic acid) similarly retard hormone release and also potently block T4 to T3 conversion, but they are not currently available in the United States. Sodium iodide (1 g) can be given intravenously over 24 hours. In addition, 50 g of hydrocortisone is administered intravenously every 6 hours, then tapered as clinical improvement occurs. Supportive measures include intravenous fluids and the management of electrolytes and nutrition. Aspirin should be avoided because it can displace T3 from TBG.

Graves Ophthalmopathy

The American Thyroid Association has classified Graves ophthalmopathy into six classes: (1) Class 1, spasm of the upper eyelids; (2) Class 2, soft tissue involvement with periorbital edema and conjunctival chemosis; (3) Class 3, proptosis; (4) Class 4, muscle involvement that limits gaze; (5) Class 5, corneal involvement (eg, keratitis); and (6) Class 6, visual loss due to optic nerve involvement.

The treatment of Graves' ophthalmopathy involves (1) reversal of the hyperthyroid state; (2) symptomatic treatment with eye lubrication, glucocorticoids, or both; and (3) with severe symptoms, the surgical decompression of the orbit. Most patients have mild disease; one study found that approximately 65% of patients treated with thionamide therapy alone had no progression of eye disease, and only 8% demonstrated deterioration.

Restoration of the euthyroid state can be achieved by thionamide therapy, radioablation, and surgery. Radioablation can aggravate the ophthalmopathy, especially in smokers. Treatment with a short course of prednisone (40–60 mg/d) tapered over 4–6 weeks at the same time as 131I treatment can prevent this exacerbation.

In most patients, symptomatic treatment involves alleviating corneal irritation and wearing dark glasses. Glucocorticoid therapy is indicated for worsening chemosis, diplopia, or proptosis. Surgical decompression is warranted for progressive eye disease despite glucocorticoids, optic nerve changes, corneal ulceration or infection, and cosmetic reconstruction. A loss of vision, which is heralded by a loss of color vision, is considered a medical emergency; the patient should be treated with high-dose glucocorticoids and surgical decompression. Orbital radiotherapy can also be used if glucocorticoid therapy is ineffective or if there is recurrence after the dose is tapered.

Other Forms of Thyrotoxicosis

Amiodarone-Induced Hyperthyroidism

General Considerations

The antiarrhythmic drug amiodarone contains 37.3% iodine and has a half-life of about 50 days. Although amiodarone-induced hypothyroidism is far more common than hyperthyroidism, 2% of patients on amiodarone will develop hyperthyroidism. The symptoms of amiodaroneinduced hyperthyroidism may be blunted by the antiadrenergic effects of amiodarone itself, and hyperthyroidism often develops years after starting this medication.

Etiology & Clinical Findings

There are two etiologies responsible for hyperthyroidism that manifests in the setting of amiodarone: (1) excess iodine in an underlying abnormal gland causes excessive hormone production and (2) thyroiditis caused by amiodarone itself. Thyroid ultrasound may be useful in differentiating between the two causes, with an increased Doppler flow in excess hormone production and a decreased Doppler flow in thyroiditis. However, many patients may have a mixed etiology, and it is often difficult to differentiate between the two forms.

Treatment

Patients may be treated with higher-dose thionamides, such as 40–60 mg of methimazole, and beta-adrenergic blockade. If there is inadequate control, a 40-mg daily dose of prednisone is often helpful, especially in cases of amiodarone-induced thyroiditis. Total thyroidectomy should be considered since it is curative, but patients often have a poor operative status.

Subacute Thyroiditis

General Considerations

Subacute granulomatous thyroiditis is an acute inflammatory disorder of the thyroid gland presumed to be due to viral infection. Subacute granulomatous thyroiditis may also be referred to as de Quervain thyroiditis, subacute thyroiditis, and subacute nonsuppurative thyroiditis.

Clinical Findings

The classic signs and symptoms are fever, malaise, and soreness of the neck; the thyroid gland is extremely tender on examination. Patients need a changing pattern of thyroid function tests throughout the course of the disease. Initially, with thyroid follicle damage and the release of preformed thyroid hormones, TSH is decreased, with an increase in T4 and T3 and a low radioactive iodine uptake. After 2–6 weeks, patients enter a euthyroid phase as T4, T3, and TSH levels return to normal. A transient hypothyroid phase of 2–8 weeks ensues while thyroid hormone stores are exhausted and the thyroid follicles regenerate. Most patients return to the euthyroid state once the thyroiditis has resolved; however, a hypothyroid state may be permanent in 10% of patients.

Diagnosis

The diagnosis of subacute thyroiditis is made clinically. A markedly elevated ESR as high as 100 mm/h is strongly suggestive of the diagnosis. Additional helpful laboratory findings include negative thyroid autoantibodies.

Treatment

Patients are usually treated symptomatically with beta-blockers and nonsteroidal anti-inflammatories (NSAIDs); prednisone is usually reserved for more severe cases. Patients who become hypothyroid should be administered l-thyroxine.

Rare Forms of Thyrotoxicosis

Thyrotoxicosis Factitia

Thyrotoxicosis factitia is a psychoneurotic disorder in which patients purposely take thyroid hormones, usually for weight control. In addition, patients may be given thyroid hormones by psychiatrists to facilitate the treatment of depression. Clinical findings include the absence of a goiter, a suppressed TSH level, mild elevation of T4 and T3, a negative radioactive iodine uptake level, and a low thyroglobulin level.

Struma Ovarii

Teratoma of the ovaries may contain functioning thyroid tissue, which results in hyperthyroidism. Radioactive iodine uptake in the neck is absent, but a whole body scan shows an increased uptake in the pelvis. Curative treatment involves resection of the teratoma.

Metastatic Follicular Carcinoma

Follicular thyroid carcinoma usually does not retain the ability to produce active hormone, but in rare instances, as in the presence of metastatic disease, follicular carcinoma can produce a hyperthyroid state. A radioactive body scan usually shows an increased uptake in the lungs or bones.

Hydatidiform Mole

Hydatidiform moles do not produce thyroid hormone; rather, they produce chorionic gonadotropin, which displays TSH-like activity. Clinical evidence of hyperthyroidism is usually not present, but a laboratory workup can reveal a suppressed TSH and a mild elevation of serum T4 and T3. Resection of the mole is curative.

Hypothyroidism

General Considerations

The failure of thyroid hormone production results in a generalized hypometabolic state and seriously impairs normal growth and development if it occurs early in life. Hypothyroidism may be due to a primary disease of the thyroid gland, or it may be secondary to a pituitary deficiency. Hypothalamic dysfunction, resulting in a TSH deficiency or peripheral resistance to the action of thyroid hormone, is a rare cause (Table 42–8).

Clinical Findings

In adults, the onset of symptoms of hypothyroidism is often insidious. These symptoms include fatigue, weight gain, intolerance to cold, and a delayed relaxation phase to deep tendon reflexes (Table 42–9).

Hashimoto's thyroiditis is the most common cause of hypothyroidism. It is an autoimmune disease characterized by lymphocytic infiltration, destruction of thyroid follicles, and fibrosis. Several autoantibodies are present, including anti-TPO, antithyroglobulin antibody, and TSH-receptor-blocking antibody. Thyroperoxidase antibodies remain positive for many years and are useful for diagnosis. There may or may not be a goiter. The goiter in Hashimoto's thyroiditis is usually moderate in size and firm in consistency. In older patients, the thyroid may be totally destroyed by the immune process, and the gland is found to be small on examination.

Diagnosis

The diagnosis of suspected hypothyroidism is outlined in an algorithm listed in Figure 42–6. In primary hypothyroidism, the TSH is elevated with a low FT4 level. In secondary hypothyroidism, the TSH level is low or inappropriately normal with a low FT4 level. Secondary hypothyroidism may also present with other signs of pituitary deficiency, including hypogonadism and adrenal insufficiency.

Treatment

Treatment involves hormone replacement with l-thyroxine; the average replacement dosage in adults is 1.6 mcg/kg/d. In young, healthy adults, a starting dosage of 75–100 mcg can be used, followed by a dosing adjustment every 4–6 weeks. Elderly patients or patients with coronary artery disease should be started on much smaller doses of 12.5–25.0 mcg/d, and then increased by 12.5–25.0 mcg every 4–6 weeks until the TSH level normalizes between 0.5 and 2 mU/L. Once stabilized, patients should be monitored once or twice a year with TSH and FT4. T4 has a half-life of about 7 days and therefore needs to be given only once daily.

Desiccated thyroid is unsatisfactory because of its variable hormone content and should not be used. The use of T3 is controversial. The current preparation is rapidly absorbed, has a short half-life, and a rapid biological effect. Patients who experience malabsorption or who ingest drugs such as calcium and iron, which impair T4 absorption, may require an increase in T4 dosing. Since the half-life of T4 is long, it is not a problem omitting the drug for a few days if the patient is unable to take oral medications. Alternately, the patient can be given parenteral l-thyroxine at 75% of the usual oral dose.

Myxedema Coma

General Considerations

Severe, untreated hypothyroidism can result in a hypothermic coma. It tends to occur in elderly patients and is frequently fatal (>20% incidence).

Clinical Findings

Myxedema coma is characterized by hypothermia, bradycardia, alveolar hypoventilation with CO2 retention, hyponatremia, hypoglycemia, and either stupor or coma. The diagnosis is often difficult because the coma and hypothermia may be due to other causes, such as stroke. Heart failure, pneumonia, excessive fluid administration, and sedatives or narcotic use can precipitate myxedema coma.

Treatment

Treatment consists of l-thyroxine administered intravenously, at an initial loading dose of 300–400 mcg, followed by 80% of the calculated full replacement dose intravenously daily. Ventilatory support may be required for hypoventilation and hypercarbia. Hyponatremia is treated with fluid restriction. Active rewarming is contra-indicated, because it may induce vasodilation and vascular collapse. The patient should be screened for concomitant adrenal insufficiency by a cosyntropin stimulation test. Until the cortisol results are available, the patient should be treated with hydrocortisone (100-mg IV bolus followed by 50 mg intravenously every 6 hours).