7 Thyroid Gland
Salil D. Sarkar
7.1 Thyroid Anatomy 209
7.2 Hormone Synthesis and Secretion 210 7.2.1 Iodide Transport 210
7.2.2 Hormone Synthesis 210
7.2.3 Release of Hormone and Thyroglobulin 210 7.2.4 T3and T4 210
7.2.5 Antithyroid Drugs 210 7.2.6 Summary 211
7.3 Thyroid Handling of Radiotracers 211 7.3.1 Technetium-99m-pertechnetate 211 7.3.2 Iodine-123 211
7.3.3 Iodine-131 211
7.3.4 Fluorine-18-fluorodeoxyglucose 212 7.3.5 Summary 212
7.4 TSH and Thyroid Function 212 7.4.1 TSH Secretion 212
7.4.2 Serum TSH in Thyroid Disorders 212 7.4.3 Manipulation of TSH Levels 213 7.4.3.1 Suppressing TSH Levels 213 7.4.3.2 Increasing TSH Levels 213 7.4.4 Summary 213
7.5 Iodine Intake and Thyroid Function 213 7.5.1 Iodine Deficiency 213
7.5.2 Iodine Excess 214
7.5.2.1 Thyroid Autoregulation 214 7.5.2.2 Thyroid Dysfunction 214
7.5.2.3 Iodine and Autoimmune Thyroid Disease 214 7.5.3 Summary 214
7.6 Endemic Goiter 215 7.6.1 Goitrogens 215 7.6.2 Pathophysiology 215 7.6.3 Radionuclide Procedures 215 7.6.4 Summary 215
7.7 Destructive (“Subacute”) Thyroiditis 216 7.7.1 Postpartum Thyroiditis 216
7.7.2 Viral Thyroiditis 217
7.7.3 Thyroiditis and Other Effects of Amiodarone 217 7.7.4 Radionuclide Procedures 217
7.7.5 Summary 217
7.8 Autoimmune Thyroid Disease 217 7.8.1 Etiological Factors 217
7.8.2 Pathophysiology 218 7.8.3 Radionuclide Procedures 218 7.8.4 Summary 218
7.9 Thyroid Dysfunction During Gestation 218 7.9.1 Hyperthyroidism 218
7.9.2 Hypothyroidism 219 7.9.3 Summary 219 References 219
7.1
Thyroid Anatomy
The thyroid gland develops from the foramen cecum of the tongue, to which it is connected by the thyroglossal duct. It descends during fetal life to reach the anterior neck by about the seventh week, and absent or aberrant descent results in ectopic locations, including the sub- lingual region and superior mediastinum (Fig. 7.1).
The thyroglossal duct undergoes atrophy, though rem- nant duct tissue frequently is visualized by scintigraphy as an upper midline neck structure following thyroid- ectomy and TSH stimulation. The duct remnant occa- sionally may form a cyst.
The normal adult thyroid gland in iodine-sufficient regions weighs about 14 – 18 g. It is generally smaller in women than in men, and is barely palpable [1, 2]. The thyroid is located in the mid to lower anterior neck, with the isthmus in front of the trachea, usually just be- low the cricoid cartilage, and the lobes on the sides of the trachea. In older individuals with shorter necks, the thyroid may lie at or just above the suprasternal notch, and it is often partly substernal. The thyroid gland moves cephalad during swallowing, a characteristic that aids in palpation and in distinction of thyroid from nonthyroid neck masses.
Fig. 7.1. Scintigraphic images in the anterior and left lateral projections show partly descended thyroid gland extending from the sublingual region to the upper neck
Chapter 7
7.2
Hormone Synthesis and Secretion
7.2.1
Iodide Transport
The thyroid follicle consists of a colloid center, which acts as a storage site for thyroid hormone, surrounded by epi- thelial cells. The thyroid epithelial cell has a transport mechanism, also referred to as “trapping” or “uptake”, that enables thyroid concentration of iodide far in excess of that in the plasma [3, 4]. A plasma membrane protein, the sodium/iodide symporter (NIS), is responsible for io- dide transport. Symporter activity is influenced primari- ly by pituitary thyrotropin, also called thyroid stimulat- ing hormone (TSH), which increases the transport of io- dide. The trapped iodide subsequently undergoes orga- nification and incorporation into thyroid hormones.
Iodide is accumulated, though not organified, in other organs including the salivary glands, stomach, mucous glands, skin, breast, and placenta, which may be associated with undesirable consequences for the clinical use of radioiodine. After therapeutic adminis- tration of131I for thyroid cancer, uptake in the salivary glands and gastric mucosa may cause sialitis and gas- tritis respectively, while activity in the skin and mucous secretions may increase environmental contamination and interfere with image interpretation [5 – 7]. Iodide uptake by the placenta and mammary glands exposes the fetus and the nursing child to unacceptable amounts of radiation from both the therapeutic and di- agnostic use of131I [8, 9].
Other anions, including pertechnetate, thiocyanate, and perchlorate, also are accumulated by the thyroid gland. The uptake of pertechnetate is the basis for
99mTc-pertechnetate scintigraphy. Thiocyanate, de- rived from certain foods, decreases thyroid accumula- tion of iodine and may exacerbate iodine deficiency.
Perchlorate has diagnostic and therapeutic applica- tions, which are discussed later.
7.2.2
Hormone Synthesis
Iodide transported via NIS at the basolateral cell mem- brane is converted to an oxidized form at the apical sur- face of the cell by thyroid peroxidase (TPO) in the pres- ence of hydrogen peroxide. Oxidation of iodide permits its binding to the amino acid tyrosine. Synthesis of hor- mone takes place in thyroglobulin, a glycoprotein, which is produced in the thyroid cell and extruded into the colloid. Iodine combines with tyrosine in thyro- globulin to form monoiodotyrosine (MIT) and diiodo- tyrosine (DIT). Subsequently, the iodotyrosines are coupled, with the formation of thyroxine (T4) and triio- dothyronine (T3). The coupling reaction also is medi- ated by peroxidase.
Decrease in peroxidase, associated with certain con- genital and acquired thyroid disorders, impairs organic iodination and increases the proportion of unbound intrathyroidal iodine. Potassium perchlorate in phar- macological doses discharges unbound iodine from the thyroid. This is the basis for its use in the “Perchlorate Discharge Test” to detect an organification defect [10 – 12], and in the treatment of thyroid dysfunction caused by amiodarone, an iodine-rich drug (see later).
7.2.3
Release of Hormone and Thyroglobulin
In response to TSH, a small amount of colloid is en- gulfed by the epithelial cell and proteolyzed, with re- lease of T3and T4, which diffuse into the circulation.
Thyroglobulin not undergoing proteolysis also enters the circulation in small quantities. The serum thyro- globulin has been used as a tumor marker in differenti- ated thyroid cancer. Thyroglobulin becomes undetect- able following thyroidectomy and131I ablation, and its subsequent rise indicates a recurrence. TSH stimula- tion, by promoting colloid endocytosis, increases the amount of thyroglobulin released. Consequently, the serum thyroglobulin is a more reliable tumor marker at high TSH levels [13, 14].
7.2.4 T3and T4
Most of the circulating thyroid hormones are bound to plasma proteins, the free fraction comprising about 0.05% of T4and 0.2% of T3. Only the free hormone has metabolic effects, and it is a more accurate measure of thyroid function than the total hormone, which varies with plasma proteins levels.
T3is considered the active hormone. About 20% – 30% of the circulating T3 is secreted by the thyroid gland and the remainder is produced by monodeiodin- ation of T4in extrathyroid tissues, notably the liver, kidney, brain, and pituitary [14]. Decrease in the pe- ripheral conversion of T4to T3is a basis for the use of some antithyroid drugs (see below).
Synthetic forms of thyroid hormones are commonly used for replacement and/or suppressive therapy. Thy- roxine is preferred for this purpose because it has a lon- ger biological half-life (6 – 7 days) compared with T3 (about 1 – 2 days). However, T3has a more rapid onset of action and may be useful in selected clinical situa- tions.
7.2.5
Antithyroid Drugs
Most antithyroid drugs generally block one or more steps in the synthesis and metabolism of thyroid hor-
mone. The thiourea derivatives (“thionamides”), in- cluding propylthiouracil (PTU) and methimazole, are the most common antithyroid agents in use [14, 15].
Both decrease hormone synthesis primarily by block- ing iodine organification, while PTU alone decreases the monodeiodination of T4to T3. These drugs also lower serum levels of thyrotropin receptor autoanti- bodies (TRAB), which are responsible for Graves’ hy- perthyroidism. Methimazole or PTU may be used to control hyperthyroidism in Graves’ disease and toxic nodular goiter before treatment with131I. In selected patients, these drugs also may be used as primary ther- apy for Graves’ disease. Remission occurs in a minority of patients after thionamide treatment for 1 – 2 years.
Other drugs used for their antithyroid actions in- clude glucocorticoids, iodides, lithium, and potassium perchlorate [14]. Glucocorticoids have a rapid inhibito- ry effect on the peripheral conversion of T4to T3, and are a useful adjunct in thyroid storm. Their anti-in- flammatory and cell membrane stabilizing actions have been utilized in Graves’ ophthalmopathy and protract- ed subacute thyroiditis. Iodide in pharmacological amounts decreases the synthesis of thyroid hormones, permitting rapid control of hyperthyroidism in thyroid storm (see “Thyroid Autoregulation”). It also blocks thyroid uptake of radioiodine, and is recommended as a prophylactic measure after a nuclear reactor accident [16]. Lithium blocks the release of thyroid hormone, and may be used as an adjunct for the control of severe hyperthyroidism. Lithium prolongs iodine retention in thyroid tissue, and increases the absorbed radiation dose from131I, an advantage in the treatment of differ- entiated thyroid cancer [17]. Potassium perchlorate de- creases thyroid iodine uptake and discharges unbound iodine. It may be used for the treatment of thyroid dys- function caused by amiodarone, a drug with a high io- dine content, and after accidental exposure to radioac- tive iodine.
7.2.6 Summary
Synthesis and secretion of thyroid hormone are regu- lated primarily by thyrotropin. Circulating iodide is trapped by the thyroid epithelial cell, oxidized, and bound to tyrosine. Coupling of iodotyrosines yields T3 and T4. Thyroid peroxidase promotes oxidation of io- dide, a necessary step for iodination of tyrosine, as well as coupling of iodotyrosines. Thyroid hormone action is mediated by T3. About 20% – 30% of the circulating T3is secreted by the thyroid, and the remainder is de- rived from the peripheral monodeiodination of T4. Among the drugs with antithyroid actions, PTU and methimazole are most commonly used. Both drugs de- crease hormone synthesis and TRAB levels, while PTU alone decreases the conversion of T4to T3.
7.3
Thyroid Handling of Radiotracers
7.3.1
Technetium-99m-pertechnetate
Technetium-99m-pertechnetate is widely used for im- aging the thyroid gland [18, 19]. The popularity of this radiotracer stems from its easy availability (from por- table molybdenum-99 generators) and low absorbed radiation dose (short half-life of 6 h and absence of beta emissions).
99mTc-pertechnetate is trapped by the thyroid, but unlike iodine, it does not undergo organification and remains in the gland for a relatively short period.
Therefore, imaging is done about 20 – 30 min after ad- ministration of the radiotracer. Approximately 5 – 10 mCi (185 – 370 MBq) is used. The thyroid-to- background activity ratio is not as high as that with ra- dioiodine, so that99mTc-pertechnetate is unsuitable for imaging of metastatic thyroid carcinoma, which usual- ly functions poorly compared with normal tissue. Im- aging of ectopic mediastinal thyroid tissue also may be suboptimal due to high blood and soft tissue back- ground activity.
7.3.2 Iodine-123
Iodine-123 has ideal characteristics for imaging the thyroid gland, with a short physical half-life of 13 h, ab- sence of beta emissions, and high uptake in thyroid tis- sue relative to background. However, it is less readily available and more expensive than99mTc-pertechneta- te.123I undergoes organic binding in the thyroid gland, and imaging is usually done 4 – 24 h after the adminis- tration of 200 – 400 µCi (7.4 – 14.8 MBq) of radiotracer [18, 19]. Because of its superior biodistribution charac- teristics,123I is preferred over99mTc-pertechnetate for imaging of poorly functioning and ectopic thyroid glands.123I also may be used for whole body imaging in differentiated thyroid cancer (see below). Approxi- mately 2 – 4 mCi (74 – 148 MBq) of the radiotracer are used for this purpose.
7.3.3 Iodine-131
Iodine-131 may be used for the measurement of thy- roid uptake, which requires only small amounts of ra- diotracer. It is no longer used for routine imaging of the thyroid gland because of a high absorbed radiation dose related to the long physical half-life of 8 days and beta emissions.131I, however, continues to be valuable for the detection of metastases and recurrences in dif- ferentiated thyroid cancer [13, 19, 20]. Following ap- propriate patient preparation to increase TSH levels
7.3 Thyroid Handling of Radiotracers 211
(see “Manipulation of Thyrotropin Levels”), 2 – 4 mCi (74 – 148 MBq) of 131I is administered and imaging is performed 48 – 96 h later. Radioiodine imaging has di- agnostic as well as prognostic value. Iodine-avid tu- mors tend to have well-differentiated histological fea- tures and a favorable prognosis, whereas tumors that do not accumulate iodine are likely to be less differenti- ated and more aggressive [13, 21, 22].
Iodine-131 delivers a high radiation absorbed dose to the thyroid, with relative sparing of non-thyroid tis- sues. It is therefore ideal for the treatment of thyroid disease, and used extensively in the management of Graves’ disease, toxic nodular goiter, and differentiated thyroid cancer.
7.3.4
Fluorine-18-fluorodeoxyglucose
Positron emission tomography (PET) with 18F-fluor- odeoxyglucose (FDG) is used in evaluating a variety of neoplasms including differentiated thyroid cancer. Im- aging is possible for two reasons. First, malignant tu- mors derive energy from a higher rate of glycolysis, so that the uptake of glucose (and FDG) is increased. Sec- ond, unlike glucose, FDG is not metabolized complete- ly and retained longer within the tumor. In differentiat- ed thyroid cancer, FDG may be used to identify metas- tases not visualized at radioiodine imaging, and to as- sess prognosis. Lesions that accumulate FDG tend to follow a more aggressive course than lesions that are not FDG-avid [23, 24]. Whole body FDG-PET, there- fore, is useful in evaluating high-risk thyroid cancer.
Patient preparation is similar to that for radioiodine scintigraphy, since the uptake and diagnostic sensitivi- ty of FDG are increased by TSH stimulation [25, 26].
Focal uptake of FDG within the thyroid gland, an occa- sional finding at evaluation of non-thyroid cancers, may be related to a benign or malignant pathology.
7.3.5 Summary
99mTc-pertechnetate is trapped but not organified by thyroid tissue. Imaging with this radiotracer is limited to the intact thyroid gland.123I and131I are trapped and organified, and provide higher thyroid-to-background uptake ratios. Both tracers are used to detect thyroid cancer metastases, while123I is also used for imaging the thyroid gland.131I delivers a high absorbed radia- tion dose to thyroid tissue, and is a mainstay in the management of Graves’ disease, toxic nodular goiter, and differentiated thyroid cancer. Imaging and treat- ment of thyroid cancer metastases with 131I require high TSH levels.18F-FDG, a glucose analogue, is accu- mulated in various malignant tumors including differ- entiated thyroid cancer. FDG-PET is particularly useful
in high risk thyroid cancer, where it may detect metas- tases not visualized at radioiodine imaging and provide prognostic information. Tumor uptake of FDG is in- creased by TSH stimulation.
7.4
TSH and Thyroid Function
7.4.1 TSH Secretion
Thyrotropin-releasing hormone (TRH), a tripeptide originating from the hypothalamic median eminence, stimulates the secretion and synthesis of thyroid stimu- lating hormone (TSH, thyrotropin), a glycoprotein, by the anterior pituitary. TSH comprises an alpha unit, also present in other anterior pituitary hormones (FSH, LH), and a beta unit responsible for its specific actions. It acts on specific membrane-bound receptors of the thyroid epithelial cell, activating the adenylate cyclase system and increasing sodium/iodide symporter expression. As a result, the transport of iodide, synthesis of hormone, and release of T3, T4, and thyroglobulin are increased.
The production and release of TSH are influenced by the concentration of T3within the pituitary. When the T3concentration falls below a “set point”, TSH secre- tion increases, and synthesis and release of thyroid hor- mones are accelerated. Conversely, when the T3level rises above the set point, TSH release is inhibited. In ad- dition to its pituitary effect, T3inhibits hypothalamic TRH release. Other mechanisms reported more recent- ly include the inhibitory actions of the released TSH on TRH secretion, and on TSH receptors in the pituitary itself. In sum, TSH secretion is influenced by thyroid- to-pituitary, thyroid-to-hypothalamus, pituitary-to- hypothalamus, and pituitary-to-pituitary feedback control mechanisms, which combine to reduce fluctua- tions in circulating T3and T4[14, 27 – 28]. In the rare condition of partial tissue resistance to thyroid hor- mone, the pituitary fails to respond to increasing T3 levels, so that TSH continues to be secreted and serum TSH and thyroid hormones are both elevated. Individ- uals with this condition may become hyperthyroid if tissue resistance is limited to the pituitary or remain euthyroid if resistance is generalized [29].
In addition to regulation of thyroid function, TSH promotes thyroid growth. If thyroid hormone synthe- sis is chronically impaired, as in iodine deficiency and autoimmune thyroid disease, chronic TSH stimulation eventually may lead to the development of a goiter.
7.4.2
Serum TSH in Thyroid Disorders
The serum TSH is a sensitive marker of thyroid func- tion. Normal serum TSH is about 0.45 – 4.5 µunits/ml,
and levels up to 20 µunits/ml are considered normal in newborns because of the contribution of maternal TSH. During early gestation, TSH tends to be at low normal (at times below normal) levels, which coincide with a surge in human chorionic gonadotropin (hCG) release. Serum TSH is increased in primary hypothy- roidism and decreased in hyperthyroxinemia of all eti- ologies except for the uncommon entity of thyrotropin- induced hyperthyroidism.
The availability of high sensitivity assays, which can accurately measure very low TSH levels, has significant- ly improved the ability to diagnose mild hyperthyroid- ism. Third-generation assays can detect levels as low as 0.01 – 0.03 µunits/ml and are particularly helpful in es- tablishing subclinical hyperthyroidism in nodular goiter and athyrotic persons receiving replacement levothy- roxine therapy [27, 30]. Subclinical hyperthyroidism in older individuals has been associated with adverse ef- fects on the heart and bone mineral density [31 – 34].
The serum TSH is also a sensitive marker of hypo- thyroidism. As such it is commonly used to detect hy- pothyroidism in Hashimoto’s disease, newborns, and hyperthyroid patients treated with131I. The TRH Stim- ulation Test measures the TSH response to TRH. It was used in the past for the diagnosis of subtle thyroid dys- function including central hypothyroidism, but has been largely abandoned with the emergence of high- sensitivity TSH assays [35].
7.4.3
Manipulation of TSH Levels 7.4.3.1
Suppressing TSH Levels
The secretion of TSH is suppressed with exogenous thyroid hormone to avoid stimulation of tumor growth in patients with differentiated thyroid cancer, and to decrease thyroid size or arrest thyroid growth in the early stages of goiter development. While levothyroxine (T4) is the traditional thyroid hormone preparation for this purpose, regimens combining T4and T3are cur- rently under investigation. Not infrequently, patients receiving levothyroxine are referred for a nuclear up- take and scan, requiring hormone withdrawal to allow the recovery of the hypothalamus-pituitary-thyroid ax- is. It may take as long as 8 weeks for recovery and for re- turn of radioiodine uptakes to baseline values; howev- er, shorter periods of up to 3 weeks may suffice for eval- uating nodular function.
7.4.3.2
Increasing TSH Levels
Stimulation with TSH increases thyroid function and thyroid uptake of radioiodine. This principle is used in differentiated thyroid cancer for the detection and treat-
ment of thyroid remnants and thyroid cancer metastases with radioiodine [13, 19, 36]. Thyroid stimulating hor- mone levels are allowed to rise to 30 – 50 µunits/ml or higher after withholding thyroid hormone supplements, or after administering recombinant human TSH. The latter is gaining in popularity since it shortens the prepa- ration time and avoids a period of hypothyroidism [37 – 41]. Currently, recombinant TSH is approved pri- marily for diagnostic use, i.e., prior to scintigraphy and serum thyroglobulin measurement. It appears to be ef- fective in monitoring thyroid cancer, especially the low- risk papillary type, though the radioiodine uptake and serum thyroglobulin usually are lower than after hor- mone withdrawal. As noted earlier, PET with fluorode- oxyglucose is optimal at high TSH levels, and it may be combined with radioiodine imaging and thyroglobulin measurement in selected patients [23 – 26].
Recombinant human TSH may have the potential to facilitate the treatment of large nodular goiters with
131I. Radioiodine uptake in these goiters is usually low and heterogeneous. As a result, large and multiple ther- apeutic131I doses may be needed to reduce goiter vol- ume and cure the associated hyperthyroidism. In re- cent studies, a small dose of recombinant TSH resulted in a more uniform131I distribution, a higher 24-h up- take, and increased therapeutic efficacy [42, 43].
7.4.4 Summary
Thyroid stimulating hormone (thyrotropin) promotes iodide transport, and the synthesis and release of thy- roid hormone and thyroglobulin. The secretion of TSH is modulated by the hypothalamus-pituitary-thyroid axis. The serum TSH level is a sensitive and specific marker of primary hyperthyroidism and hypothyroid- ism, and is particularly valuable for diagnosing sub- clinical thyroid dysfunction. Suppression of TSH secre- tion with exogenous thyroid hormone may help reduce goiter size and limit the growth of thyroid cancer. In athyrotic patients with differentiated thyroid cancer, a high serum TSH is needed for radioiodine/FDG imag- ing, thyroglobulin measurement, and 131I treatment.
The serum TSH may be increased by withdrawing thy- roid hormone, or by administering recombinant hu- man TSH.
7.5
Iodine Intake and Thyroid Function
7.5.1
Iodine Deficiency
The daily requirement for iodine is about 150 µg, in- creasing to roughly 200 – 250 µg during pregnancy. Io- dine deficiency is most prevalent in the mountainous
7.5 Iodine Intake and Thyroid Function 213
regions of the Himalayas, Alps, and Andes, and in some low lands remote from the ocean. Iodine deficiency alone or in combination with goitrogens present in cer- tain foods results in decreased thyroid hormone syn- thesis [44, 45]. Selenium deficiency may be a contribut- ing factor. Reduced synthesis of thyroid hormone is compensated, at least in part, by increased TSH secre- tion, resulting eventually in goiter formation. Because an adequate supply of thyroid hormone is needed for fetal neurological development, maternal and fetal hy- pothyroidism resulting from iodine deficiency is asso- ciated with varying degrees of neuropsychological defi- cits including cretinism [46 – 50].
7.5.2 Iodine Excess 7.5.2.1
Thyroid Autoregulation
Thyroid hormone homeostasis is maintained by an in- trathyroid autoregulatory mechanism in addition to the hypothalamus-pituitary-thyroid axis. When intra- thyroid iodine concentrations are significantly in- creased, the rate of thyroid hormone synthesis is de- creased, with a reduction in iodothyronine synthesis and decrease in the DIT/MIT ratio. This response is re- ferred to as the Wolff-Chaikoff effect [51].
The amount of intrathyroid iodine needed to trigger the Wolff-Chaikoff effect varies, depending on prior long-term iodine intake and thyroid function. Barring other mechanisms, continued exposure to large amounts of iodine would eventually lead to hypothy- roidism, with compensatory increase in TSH and devel- opment of goiter. While this does occur occasionally (see below), adaptation or “escape” from the effects of chronic iodide excess is more likely. Adaptation ap- pears to be the result of an absolute decrease in iodide transport, so that intrathyroid iodine is reduced to lev- els that allow resumption of hormone synthesis.
The inhibitory effect of iodides on thyroid function is utilized clinically for prompt control of severe hyper- thyroidism and thyroid storm. In Graves’ disease, large doses of iodide decrease not only hormone synthesis but also hormone release [52]. Since escape from the inhibitory effect is likely, iodide therapy is only a short- term measure for lowering thyroid hormone levels rap- idly.
7.5.2.2
Thyroid Dysfunction
Iodine excess may lead to hyperthyroidism or hypothy- roidism [51 – 54]. Iodine-induced hyperthyroidism, re- ferred to as jodbasedow, characteristically occurs in persons with nodular thyroid glands. Hyperthyroidism occurring after iodine supplementation in endemic
goiter areas is a classical example. Iodine-containing medical products, including amiodarone, radiographic dyes, and kelp, also have the potential to cause jodbase- dow [51, 55 – 58]. Amiodarone, a cardiac antiarrhyth- mic drug, is perhaps the commonest source of iodine today. Each 200 mg tablet yields about 7 mg free iodine, while the daily requirement is only 0.15 mg [55, 56].
Amiodarone-related hyperthyroidism may be related to another mechanism. The drug may cause thyroiditis, which is discussed later (see “Destructive (Subacute) Thyroiditis”].
Hypothyroidism related to increased iodine intake results from the inability to escape from the Wolff- Chaikoff effect. It is more frequent in iodine-sufficient areas, where autoimmune disease is more common than nodular disease [53, 54]. In the past, “iodide goi- ter” with or without hypothyroidism was related to the use of iodine solutions as mucolytic agents in bronchial asthma, often with reversal of clinical manifestations after stopping the drug. A similar condition has been reported from ingestion of large quantities of (iodine- rich) seaweed in the coastal regions of Japan [59].
7.5.2.3
Iodine and Autoimmune Thyroid Disease
Iodine appears to have another, more insidious effect on the thyroid. In regions that were previously iodine- deficient, a rise in autoimmune thyroid disease has been observed after the institution of iodine supple- mentation in foods [60]. Experimental work in animals confirms an association between iodine and autoim- munity, probably related in part to the greater antigenic potential of highly iodinated thyroglobulin [61]. Auto- immune thyroid disease and associated disorders are discussed under “Hashimoto’s Disease”.
7.5.3 Summary
Excessive amounts of iodine may cause hypothyroid- ism or hyperthyroidism. A significant increase in thy- roid concentration of iodine may initiate an autoregu- latory response, the Wolff-Chaikoff effect, which de- creases hormone synthesis. Although this effect is usu- ally temporary, occasionally it may be sustained and lead to hypothyroidism. Iodine-induced hypothyroid- ism is more frequent in iodine-replete regions with a high prevalence of autoimmune thyroid disease. Exces- sive iodine also may lead to hyperthyroidism. This may occur in individuals with nodular thyroid glands, and it is more common in iodine-deficient areas. In addition to its effects on thyroid function, iodine is believed to promote the development of autoimmune thyroid dis- ease, a view supported by epidemiological and experi- mental evidence.
7.6
Endemic Goiter
Endemic goiter is attributed primarily to iodine defi- ciency, possibly in association with selenium deficien- cy or goitrogens. Goitrogens are present in certain foods and chemicals and cause either decreased syn- thesis or increased metabolism of thyroid hormone.
7.6.1 Goitrogens
Certain foods including cassava and bamboo shoots contain cyanogenic compounds, which may interfere with thyroid accumulation of iodine and exacerbate io- dine deficiency [62]. Other foods with goitrogenic po- tential include pearl millet and plants from the brassica family [63].
Various chemicals may alter thyroid hormone metab- olism and lead to the development of goiter. Contamina- tion of drinking water with ammonium perchlorate from discarded rocket fuel is a concern. However, the suggested regulatory limit for perchlorate concentration in water is well below the amount needed to block iodine uptake [64]. Cigarette smoking has been linked to thy- roid disease and aggravation of Graves’ ophthalmopa- thy. The effects presumably are mediated in part by thio- cyanate [65]. Other industrial chemicals and drugs may induce hepatic enzymes that accelerate the metabolic elimination of thyroid hormone [66, 67].
7.6.2
Pathophysiology
The thyroid enlarges primarily in response to TSH stimulation resulting from inefficient hormone synthe- sis. There is natural heterogeneity in cellular growth and response to TSH, and rapid proliferation of thyro- cytes with a growth advantage leads eventually to the development of nodules. An additional mechanism for nodule formation involves the activation of the adeny- late cyclase system, usually by somatic mutations of the TSH receptor, with increase in cell replication rates [68 – 71]. Evidence of such mutations has been found in both solitary nodules and nodules associated with mul- tinodular goiters. The development of toxic nodular goiter occurs over a period of years, if not decades, with gradual transition of cell clones to micronodules, and subsequently to macronodules of sufficient size to cause hyperthyroidism. The disorder, therefore, is typi- cally seen in older individuals.
Hyperthyroidism associated with nodular goiter is often subclinical, with a suppressed TSH and a normal free T4. Nonetheless, treatment with131I or surgery is generally recommended in the elderly because of in- creased risk of osteopenia, and of adverse cardiovascu-
lar sequelae including atrial fibrillation [31 – 34]. Sup- pressive levothyroxine therapy is often attempted to ar- rest nodular growth in euthyroid patients, but is rarely successful since the nodules are largely independent of TSH control [72].
Hyperfunctioning nodules may become “cold” or non-functional due to hemorrhage and necrosis. Cold nodules also may be caused by the failure of iodide transport with aging, rapid proliferation of cells with decreased function, and malignant transformation.
7.6.3
Radionuclide Procedures
Toxic multinodular goiters typically show irregular dis- tribution of radioiodine or technetium pertechnetate, and a normal or mildly elevated 24-h radioiodine up- take. The irregular tracer distribution is consistent with heterogeneity in cell function and growth, and the presence of micro- and macronodules (Fig. 7.2). Large and discrete hyperfunctioning nodules may be associ- ated with poor uptake in the extranodular thyroid tis- sue. The latter consists of “suppressed” normal tissue, and/or small autonomous nodules with relatively less tracer accumulation. Following131I treatment, the areas that were previously “cold” may appear more active. A dominant nonfunctioning nodule may be related to a number of causes, but may require additional diagnos- tic work-up to exclude malignancy.
Nodular disease may be treated with131I or surgery.
For large multinodular goiters, the goal of 131I treat- ment is to reduce thyroid volume and cure hyperthy- roidism. But the treatment may fail because radioio- dine distribution is heterogeneous and the 24-h uptake is not significantly elevated. Stimulation with recombi- nant human TSH causes a global increase in thyroid uptake of131I, and appears to improve the therapeutic outcome [42, 43].
7.6.4 Summary
Endemic goiter is the result of iodine deficiency, occa- sionally in association with goitrogens, with decrease in hormone production and compensatory increase in TSH secretion. Hyperfunctioning nodules may result from a growth advantage of some cells or gain-of-func- tion mutations of the TSH receptor. Nodular thyroid disease is a common cause of subclinical hyperthyroid- ism in the elderly, and it may be associated with atrial fibrillation and osteopenia. Radionuclide studies typi- cally show heterogeneous tracer distribution in the thy- roid gland, with a normal or mildly elevated 24-h ra- dioiodine uptake. Recombinant human TSH increases the thyroid uptake globally, and may facilitate the treat- ment of nodular goiters with131I.
7.6 Endemic Goiter 215
Fig. 7.2a–d. Scintigraphic im- ages in four types of hyper- thyroidism show: a multino- dular goiter, b solitary hy- perfunctioning thyroid nod- ule, c thyroiditis, d Graves’
disease
7.7
Destructive (“Subacute”) Thyroiditis
Destructive thyroiditis, also referred to as “subacute thyroiditis” or simply “thyroiditis”, is characterized by cell membrane breakdown and release of excessive amounts of thyroid hormone into the circulation. Se- rum thyroglobulin levels also are increased. The usual causes are autoimmune thyroid disease, viral infection, and amiodarone treatment. These are discussed below.
Less commonly, thyroiditis may be related to treatment with interferon alpha, interleukin-2, lymphokine-acti- vated killer (LAK) cells, and lithium. These therapeutic agents probably exacerbate existing autoimmune thy- roid disease [73 – 77]. Bacterial thyroiditis is rarely en- countered today.
Thyroiditis tends to resolve spontaneously. Hyper- thyroidism in the active phase is followed by transient hypothyroidism before restoration of the euthyroid state, usually in 6 – 12 months. Treatment usually con- sists of q -adrenergic blockers in the hyperthyroid phase, with analgesics for pain. Protracted thyroiditis may require glucocorticoids.
7.7.1
Postpartum Thyroiditis
Postpartum thyroiditis, also known as “painless” or
“subacute lymphocytic” thyroiditis, is the principal thyroid disorder in postpartum women. It may be con- sidered an accelerated form of autoimmune thyroid disease, attributed to suppression of immune-related disorders during pregnancy with a rebound after child- birth [78 – 82]. For the same reason, Graves’ disease al- so may occur in the postpartum period, though less frequently, and a strong association with insulin-de- pendent diabetes mellitus, an autoimmune condition, has been noted.
Postpartum thyroiditis, like other forms of destruc- tive thyroiditis, is a self-limited disease, but tends to re- occur in subsequent pregnancies. Permanent hypothy- roidism occurs in 20% – 25% of patients over a period of 5 years. The incidence is greater in iodine-replete re- gions with a higher prevalence of autoimmune thyroid disease. Elevated thyroid peroxidase (“anti-microsom- al”) antibodies during pregnancy are associated with a sharp increase in postpartum thyroiditis.
7.7.2
Viral Thyroiditis
Viral subacute thyroiditis, also known as “de Quer- vain’s” thyroiditis, usually occurs after an upper respi- ratory tract infection. The disorder tends to be seasonal and may occur in clusters, occasionally causing mini epidemics [83]. It usually presents as a painful and ten- der goiter, associated with general malaise and possibly fever. Inflammation frequently begins in one lobe of the thyroid and gradually spreads to involve the entire gland. Permanent hypothyroidism is uncommon.
7.7.3
Thyroiditis and Other Effects of Amiodarone
Amiodarone is an iodine-rich benzofuran derivative used to treat and prevent cardiac arrhythmias. It may precipitate a number of thyroid conditions including thyroiditis, which appears to be related to a cytotoxic effect [55, 56]. Since amiodarone and its metabolite de- sethylamiodarone have long half-lives of up to 100 days, the thyroid-related effects can be protracted and occasionally may begin after stopping the drug.
Amiodarone-induced thyroiditis generally requires treatment with a glucocorticoid. Permanent hypothy- roidism is uncommon.
Other side effects of amiodarone stem from its high iodine content (see Sect. 7.5, “Iodine Intake and Thy- roid Function”). Thyroid hormone synthesis may in- crease or decrease. Increased hormone synthesis (jod- basedow) typically occurs in nodular thyroid glands, which are common in iodine-deficient areas. De- creased hormone synthesis, resulting from a persistent Wolff-Chaikoff effect, is more frequent in iodine-suffi- cient regions with a higher incidence of autoimmune thyroid disease.
Treatment of amiodarone-induced hyperthyroidism depends on the cause, although this may be difficult to determine. Thyroiditis, as noted earlier, responds to glucocorticoid therapy. Jodbasedow is treated with a thionamide, and if needed with potassium perchlorate to deplete thyroid iodine content. A clear distinction between thyroiditis and jodbasedow is frequently not possible, and treatment should be initiated with both a glucocorticoid and a thionamide. In resistant cases,131I treatment may be feasible if the radioiodine uptake is adequate. Thyroidectomy may be an alternative in re- fractory cases, or when continued amiodarone treat- ment and prompt relief of hyperthyroidism are re- quired.
Other actions of amiodarone are worth noting. It blocks peripheral conversion of T4 to T3, binding of T3 to its receptors, and thyroid release of T3 and T4. These effects may permit the use of amiodarone in very se- lected cases of hyperthyroidism [84].
7.7.4
Radionuclide Procedures
Poor radioiodine/99mTc-pertechnetate uptake in the thyroid gland is the hallmark of subacute thyroiditis of any etiology (Fig. 7.2). Decreased tracer uptake is relat- ed to TSH suppression by excessive thyroid hormone released from damaged follicles, and to decreased hor- mone synthesis in the damaged gland. The thyroid up- take and scan normalize with resolution of thyroiditis.
The nuclear study is frequently used in hyperthyroid individuals to differentiate thyroiditis, with low uptake, from Graves’ disease, with high uptake. A thyroid up- take/scan also may be worthwhile in amiodarone-relat- ed hyperthyroidism, which may be due to jodbasedow or thyroiditis. A suppressed thyroid uptake is non-di- agnostic, while a normal or high uptake suggests that jodbasedow is likely. The thyroid uptake measurement also helps determine the feasibility of131I treatment in refractory cases.
7.7.5 Summary
Subacute thyroiditis is usually caused by exacerbation of autoimmune disease, viral infection, and amiodaro- ne therapy. It is characterized by an initial thyroid-de- structive phase, with release of stored hormone into the circulation. Nuclear studies in this phase show poor ra- diotracer uptake, and help differentiate thyroiditis from other causes of hyperthyroidism. The disorder is self-limited and treated symptomatically, though ami- odarone-related thyroiditis tends to last longer and generally requires a glucocorticoid. Amiodarone may be associated with other thyroid disorders related to its high iodine content, including jodbasedow (iodine-in- duced hyperthyroidism) and hypothyroidism.
7.8
Autoimmune Thyroid Disease
7.8.1
Etiological Factors
Autoimmune thyroid disease comprises two major en- tities, Hashimoto’s disease (also known as chronic au- toimmune thyroiditis) and Graves’ disease. Variants of Hashimoto’s disease include “subacute” thyroiditis, which occurs typically in the postpartum period, and atrophic thyroiditis. There is a genetic predisposition to the disease, with contribution from environmental factors [65, 85 – 89]. As discussed earlier, iodine excess has been associated with autoimmune thyroid disease.
Cigarette smoking has been linked to exacerbation of autoimmune thyroid conditions including Graves’ oph- thalmopathy, and increased occurrence in women im-
7.8 Autoimmune Thyroid Disease 217
plies a role of sex steroids. The relationship between psychological stress and Graves’ disease presumably is related to immune suppression and rebound. A similar mechanism is believed to apply to postpartum thyroid dysfunction. The occasional occurrence of Graves’ dis- ease in couples suggests that infection may be a precipi- tating factor. In support of this hypothesis, antibodies to certain microbial proteins have been found to cross- react with the human TSH receptor. Rarely, Graves’ dis- ease may be precipitated by131I treatment of nodular goiter in patients with underlying autoimmune thyroid disease [90]. Follicular disruption and release of thy- roid antigens is believed to be the initiating event in these instances. Onset of Graves’ disease after subacute thyroiditis probably represents an analogous situation [91, 92].
7.8.2
Pathophysiology
Elevation of thyroid peroxidase antibodies is character- istic of Hashimoto’s disease. Antithyroglobulin anti- bodies also may be elevated. Hormone synthesis is im- paired with compensatory increase in TSH secretion, which stimulates thyroid function and growth. Eventu- ally, many patients become hypothyroid. Both overt and subclinical hypothyroidism related to autoimmune disease are widely prevalent in iodine-sufficient re- gions [93 – 95]. Exacerbation of Hashimoto’s disease, frequently occurring in the postpartum period, is a cause of subacute thyroiditis (see “Postpartum Thy- roiditis”). Graves’ disease is associated with high levels of thyrotropin receptor autoantibodies (TRAB) that stimulate thyroid growth, and thyroid hormone syn- thesis and release [86 – 89]. Most organ systems are af- fected by Graves’ disease, the cardiovascular manifesta- tions being the most apparent [31 – 33]. Increased heart rate and contractility increases the cardiac output.
These effects are related to a direct inotropic effect of T3, decreased systemic vascular resistance, increased preload related to a higher blood volume, and height- ened sensitivity to sympathetic stimulation. Blood vol- ume is increased by activation of the renin-angioten- sin-aldosterone system caused by the reduction in sys- temic vascular resistance, and by increased erythropoi- etin activity. Overt cardiac failure may result from se- vere and prolonged hyperthyroidism, but is rarely seen today. Atrial fibrillation is not an uncommon complica- tion, occurring in up to 15% of patients with hyperthy- roidism.
7.8.3
Radionuclide Procedures
Nuclear studies are non-specific in Hashimoto’s dis- ease. The thyroid gland is usually symmetrically en-
larged with uniform tracer distribution, and the 24-h uptake is normal. In subacute thyroiditis resulting from exacerbation of Hashimoto’s disease, tracer up- take is typically absent or very low.
Graves’ disease typically shows uniformly increased tracer uptake in a diffusely enlarged thyroid gland, frequently with visualization of a pyramidal lobe (Fig. 7.2). However, atypical appearances, particularly in Graves’ disease superimposed on nodular goiter, are occasionally encountered. If needed, TRAB measure- ment may assist in confirming the diagnosis. The 24-h uptake is elevated and, on average, much higher than in toxic nodular goiter. 131I treatment and antithyroid drugs remain the primary means of management of Graves’ disease.
7.8.4 Summary
Autoimmune thyroid disorders, including Hashimoto’s disease and Graves’ disease, are related primarily to ge- netic susceptibility, with contributions from environ- mental factors including chronic iodine excess. Elevat- ed serum anti-TPO antibodies are characteristic of Hashimoto’s disease. Exacerbation of Hashimoto’s dis- ease, usually observed in postpartum women, may cause subacute thyroiditis with hyperthyroidism. Scin- tigraphy in such cases shows poor tracer uptake in the thyroid gland. Graves’ disease is characterized by ele- vated TSH receptor antibodies (TRAB). It affects most organ systems, but the cardiovascular manifestations generally are the most pronounced, and cardiac com- plications are not uncommon. The thyroid uptake and scan may be used to confirm the diagnosis of Graves’
disease and differentiate it from a destructive thyroid- itis.
7.9
Thyroid Dysfunction During Gestation
7.9.1
Hyperthyroidism
Hyperthyroidism during pregnancy is usually caused by gestational transient thyrotoxicosis (GTT) or Graves’ disease [48, 49]. Gestational transient thyrotox- icosis appears to be related to the TSH-like effects of human chorionic gonadotropin (hCG), which increases in early gestation. The condition resolves spontaneous- ly in the second half of pregnancy. The incidence and severity of GTT are variable. It is occasionally associat- ed with hyperemesis gravidarum. As in other hyper- thyroid conditions, the serum TSH is low and free T4 may be elevated, but thyroid autoantibodies including TSH receptor antibodies (TRAB) are absent, since GTT is not an autoimmune condition.
Graves’ disease in pregnancy is a more serious con- dition associated with significant maternal and fetal risks, including pre-eclampsia, premature delivery, low infant birth weight, neonatal Graves’ disease, and cen- tral congenital hypothyroidism [48, 49, 96]. Character- istically, TRAB levels are elevated. Management of ges- tational Graves’ disease poses several challenges. Io- dine-131 therapy is contraindicated, and thyroidecto- my is inherently risky for both the mother and the fe- tus. Left untreated or inadequately treated, Graves’ dis- ease in pregnancy increases the risk of fetal hyperthy- roidism because of the transplacental passage of mater- nal TRAB. Of the available treatment options, thiona- mides – either PTU or methimazole – appear to be the safest. These drugs help control hyperthyroidism and reduce TRAB levels, but should be used only in small doses since they cross the placenta and may decrease fetal thyroid function [15, 49]. Graves’ disease tends to improve in the later stages of pregnancy, probably due to immune suppression, allowing thionamides to be ta- pered or discontinued. But therapy should be resumed after childbirth because of the risk of recurrence relat- ed to postpartum immune rebound.
7.9.2
Hypothyroidism
Normal neurological development is dependent on ad- equate maternal and fetal thyroid function, and on thy- roid hormone sufficiency in the early neonatal period [45 – 50, 97]. Iodine deficiency, present in regions of en- demic goiter, may be associated with hypothyroidism in both the mother and the fetus, and may cause vary- ing severities of neurological and growth retardation including cretinism. Fortunately, the incidence of these disorders has declined due to iodine supplementation programs.
Maternal thyroid hormone is increasingly recog- nized as an important factor in fetal development in the second and third trimesters. Maternal hypothyroidism alone, i.e., without fetal hypothyroidism, has been linked to neuropsychological deficits in the offspring, and to increased risk of fetal loss and preterm delivery.
Autoimmune thyroid disease is the most frequent cause of hypothyroidism in the mother. While overt iodine deficiency is relatively uncommon today, iodine intake has gradually declined in many “iodine-sufficient” ar- eas and may actually fall short of requirement during pregnancy. This may have the potential to aggravate au- toimmune hypothyroidism.
7.9.3 Summary
Hyperthyroidism in pregnancy is generally caused by GTT or Graves’ disease. Management of Graves’ disease
remains a challenge, with thionamide treatment as the best option. Patients should be monitored closely be- cause undertreatment, with persistently high maternal TRAB, increases the risk of fetal hyperthyroidism, while overtreatment may cause fetal hypothyroidism.
Gestational hypothyroidism is usually related to auto- immune thyroid disease, and less frequently to iodine deficiency. The latter may be associated with fetal hy- pothyroidism as well. Neurological development is in- fluenced by maternal thyroid function, fetal thyroid function, and thyroid hormone levels in the newborn.
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