Download 7 Thyroid Gland

Chapter 7
Thyroid Gland
7
Salil D. Sarkar
7.1
Thyroid Anatomy 209
7.2
7.2.1
7.2.2
7.2.3
7.2.4
7.2.5
7.2.6
Hormone Synthesis and Secretion 210
Iodide Transport 210
Hormone Synthesis 210
Release of Hormone and Thyroglobulin 210
T3 and T4 210
Antithyroid Drugs 210
Summary 211
7.3
7.3.1
7.3.2
7.3.3
7.3.4
7.3.5
Thyroid Handling of Radiotracers 211
Technetium-99m-pertechnetate 211
Iodine-123 211
Iodine-131 211
Fluorine-18-fluorodeoxyglucose 212
Summary 212
7.4
7.4.1
7.4.2
7.4.3
7.4.3.1
7.4.3.2
7.4.4
TSH and Thyroid Function 212
TSH Secretion 212
Serum TSH in Thyroid Disorders 212
Manipulation of TSH Levels 213
Suppressing TSH Levels 213
Increasing TSH Levels 213
Summary 213
7.5
7.5.1
7.5.2
7.5.2.1
7.5.2.2
7.5.2.3
7.5.3
Iodine Intake and Thyroid Function 213
Iodine Deficiency 213
Iodine Excess 214
Thyroid Autoregulation 214
Thyroid Dysfunction 214
Iodine and Autoimmune Thyroid Disease 214
Summary 214
7.6
7.6.1
7.6.2
7.6.3
7.6.4
Endemic Goiter 215
Goitrogens 215
Pathophysiology 215
Radionuclide Procedures
Summary 215
7.7
7.7.1
7.7.2
7.7.3
7.7.4
7.7.5
Destructive (“Subacute”) Thyroiditis 216
Postpartum Thyroiditis 216
Viral Thyroiditis 217
Thyroiditis and Other Effects of Amiodarone 217
Radionuclide Procedures 217
Summary 217
7.8
7.8.1
7.8.2
7.8.3
7.8.4
Autoimmune Thyroid Disease 217
Etiological Factors 217
Pathophysiology 218
Radionuclide Procedures 218
Summary 218
7.9
7.9.1
7.9.2
7.9.3
Thyroid Dysfunction During Gestation
Hyperthyroidism 218
Hypothyroidism 219
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 sublingual region and superior mediastinum (Fig. 7.1).
The thyroglossal duct undergoes atrophy, though remnant duct tissue frequently is visualized by scintigraphy
as an upper midline neck structure following thyroidectomy and TSH stimulation. The duct remnant occasionally 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 below 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.
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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
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7 Thyroid Gland
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 epithelial 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 iodide transport. Symporter activity is influenced primarily by pituitary thyrotropin, also called thyroid stimulating hormone (TSH), which increases the transport of iodide. The trapped iodide subsequently undergoes organification 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 administration of 131I for thyroid cancer, uptake in the salivary
glands and gastric mucosa may cause sialitis and gastritis 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 diagnostic use of 131I [8, 9].
Other anions, including pertechnetate, thiocyanate,
and perchlorate, also are accumulated by the thyroid
gland. The uptake of pertechnetate is the basis for
99m
Tc-pertechnetate scintigraphy. Thiocyanate, derived from certain foods, decreases thyroid accumulation of iodine and may exacerbate iodine deficiency.
Perchlorate has diagnostic and therapeutic applications, which are discussed later.
7.2.2
Hormone Synthesis
Iodide transported via NIS at the basolateral cell membrane is converted to an oxidized form at the apical surface of the cell by thyroid peroxidase (TPO) in the presence of hydrogen peroxide. Oxidation of iodide permits
its binding to the amino acid tyrosine. Synthesis of hormone takes place in thyroglobulin, a glycoprotein,
which is produced in the thyroid cell and extruded into
the colloid. Iodine combines with tyrosine in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Subsequently, the iodotyrosines are
coupled, with the formation of thyroxine (T4) and triiodothyronine (T3). The coupling reaction also is mediated by peroxidase.
Decrease in peroxidase, associated with certain congenital and acquired thyroid disorders, impairs organic
iodination and increases the proportion of unbound
intrathyroidal iodine. Potassium perchlorate in pharmacological 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 engulfed by the epithelial cell and proteolyzed, with release of T3 and T4, which diffuse into the circulation.
Thyroglobulin not undergoing proteolysis also enters
the circulation in small quantities. The serum thyroglobulin has been used as a tumor marker in differentiated thyroid cancer. Thyroglobulin becomes undetectable following thyroidectomy and 131I ablation, and its
subsequent rise indicates a recurrence. TSH stimulation, 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
T3 and T4
Most of the circulating thyroid hormones are bound to
plasma proteins, the free fraction comprising about
0.05% of T4 and 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.
T3 is considered the active hormone. About 20% –
30% of the circulating T3 is secreted by the thyroid
gland and the remainder is produced by monodeiodination of T4 in extrathyroid tissues, notably the liver,
kidney, brain, and pituitary [14]. Decrease in the peripheral conversion of T4 to T3 is 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. Thyroxine is preferred for this purpose because it has a longer biological half-life (6 – 7 days) compared with T3
(about 1 – 2 days). However, T3 has a more rapid onset
of action and may be useful in selected clinical situations.
7.2.5
Antithyroid Drugs
Most antithyroid drugs generally block one or more
steps in the synthesis and metabolism of thyroid hor-
7.3 Thyroid Handling of Radiotracers
mone. The thiourea derivatives (“thionamides”), including propylthiouracil (PTU) and methimazole, are
the most common antithyroid agents in use [14, 15].
Both decrease hormone synthesis primarily by blocking iodine organification, while PTU alone decreases
the monodeiodination of T4 to T3. These drugs also
lower serum levels of thyrotropin receptor autoantibodies (TRAB), which are responsible for Graves’ hyperthyroidism. Methimazole or PTU may be used to
control hyperthyroidism in Graves’ disease and toxic
nodular goiter before treatment with 131I. In selected
patients, these drugs also may be used as primary therapy for Graves’ disease. Remission occurs in a minority
of patients after thionamide treatment for 1 – 2 years.
Other drugs used for their antithyroid actions include glucocorticoids, iodides, lithium, and potassium
perchlorate [14]. Glucocorticoids have a rapid inhibitory effect on the peripheral conversion of T4 to T3, and
are a useful adjunct in thyroid storm. Their anti-inflammatory and cell membrane stabilizing actions have
been utilized in Graves’ ophthalmopathy and protracted 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 from 131I, an advantage in the treatment of differentiated thyroid cancer [17]. Potassium perchlorate decreases thyroid iodine uptake and discharges unbound
iodine. It may be used for the treatment of thyroid dysfunction caused by amiodarone, a drug with a high iodine content, and after accidental exposure to radioactive iodine.
7.2.6
Summary
Synthesis and secretion of thyroid hormone are regulated 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 iodide, 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
T3 is secreted by the thyroid, and the remainder is derived from the peripheral monodeiodination of T4.
Among the drugs with antithyroid actions, PTU and
methimazole are most commonly used. Both drugs decrease hormone synthesis and TRAB levels, while PTU
alone decreases the conversion of T4 to T3.
7.3
Thyroid Handling of Radiotracers
7.3.1
Technetium-99m-pertechnetate
Technetium-99m-pertechnetate is widely used for imaging the thyroid gland [18, 19]. The popularity of this
radiotracer stems from its easy availability (from portable molybdenum-99 generators) and low absorbed
radiation dose (short half-life of 6 h and absence of beta
emissions).
99m
Tc-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 administration of the radiotracer. Approximately
5 – 10 mCi (185 – 370 MBq) is used. The thyroid-tobackground activity ratio is not as high as that with radioiodine, so that 99mTc-pertechnetate is unsuitable for
imaging of metastatic thyroid carcinoma, which usually functions poorly compared with normal tissue. Imaging of ectopic mediastinal thyroid tissue also may be
suboptimal due to high blood and soft tissue background 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, absence of beta emissions, and high uptake in thyroid tissue relative to background. However, it is less readily
available and more expensive than 99mTc-pertechnetate. 123I undergoes organic binding in the thyroid gland,
and imaging is usually done 4 – 24 h after the administration of 200 – 400 µCi (7.4 – 14.8 MBq) of radiotracer
[18, 19]. Because of its superior biodistribution characteristics, 123I is preferred over 99mTc-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). Approximately 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 thyroid uptake, which requires only small amounts of radiotracer. 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 differentiated thyroid cancer [13, 19, 20]. Following appropriate patient preparation to increase TSH levels
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7 Thyroid Gland
(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 diagnostic as well as prognostic value. Iodine-avid tumors tend to have well-differentiated histological features and a favorable prognosis, whereas tumors that
do not accumulate iodine are likely to be less differentiated and more aggressive [13, 21, 22].
Iodine-131 delivers a high radiation absorbed dose
to the thyroid, with relative sparing of non-thyroid tissues. 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-fluorodeoxyglucose (FDG) is used in evaluating a variety of
neoplasms including differentiated thyroid cancer. Imaging is possible for two reasons. First, malignant tumors derive energy from a higher rate of glycolysis, so
that the uptake of glucose (and FDG) is increased. Second, unlike glucose, FDG is not metabolized completely and retained longer within the tumor. In differentiated thyroid cancer, FDG may be used to identify metastases not visualized at radioiodine imaging, and to assess 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, therefore, is useful in evaluating high-risk thyroid cancer.
Patient preparation is similar to that for radioiodine
scintigraphy, since the uptake and diagnostic sensitivity of FDG are increased by TSH stimulation [25, 26].
Focal uptake of FDG within the thyroid gland, an occasional 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 and 131I are trapped and
organified, and provide higher thyroid-to-background
uptake ratios. Both tracers are used to detect thyroid
cancer metastases, while 123I is also used for imaging
the thyroid gland. 131I delivers a high absorbed radiation dose to thyroid tissue, and is a mainstay in the
management of Graves’ disease, toxic nodular goiter,
and differentiated thyroid cancer. Imaging and treatment of thyroid cancer metastases with 131I require
high TSH levels. 18F-FDG, a glucose analogue, is accumulated in various malignant tumors including differentiated thyroid cancer. FDG-PET is particularly useful
in high risk thyroid cancer, where it may detect metastases not visualized at radioiodine imaging and provide
prognostic information. Tumor uptake of FDG is increased 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 stimulating 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 T3 within the pituitary. When the
T3 concentration falls below a “set point”, TSH secretion increases, and synthesis and release of thyroid hormones are accelerated. Conversely, when the T3 level
rises above the set point, TSH release is inhibited. In addition to its pituitary effect, T3 inhibits hypothalamic
TRH release. Other mechanisms reported more recently 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 thyroidto-pituitary, thyroid-to-hypothalamus, pituitary-tohypothalamus, and pituitary-to-pituitary feedback
control mechanisms, which combine to reduce fluctuations in circulating T3 and T4 [14, 27 – 28]. In the rare
condition of partial tissue resistance to thyroid hormone, 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. Individuals 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 synthesis 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 function. Normal serum TSH is about 0.45 – 4.5 µunits/ml,
7.5 Iodine Intake and Thyroid Function
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 hypothyroidism and decreased in hyperthyroxinemia of all etiologies except for the uncommon entity of thyrotropininduced hyperthyroidism.
The availability of high sensitivity assays, which can
accurately measure very low TSH levels, has significantly improved the ability to diagnose mild hyperthyroidism. Third-generation assays can detect levels as low as
0.01 – 0.03 µunits/ml and are particularly helpful in establishing subclinical hyperthyroidism in nodular goiter
and athyrotic persons receiving replacement levothyroxine therapy [27, 30]. Subclinical hyperthyroidism in
older individuals has been associated with adverse effects on the heart and bone mineral density [31 – 34].
The serum TSH is also a sensitive marker of hypothyroidism. As such it is commonly used to detect hypothyroidism in Hashimoto’s disease, newborns, and
hyperthyroid patients treated with 131I. The TRH Stimulation Test measures the TSH response to TRH. It was
used in the past for the diagnosis of subtle thyroid dysfunction including central hypothyroidism, but has
been largely abandoned with the emergence of highsensitivity 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 T4 and T3 are currently under investigation. Not infrequently, patients
receiving levothyroxine are referred for a nuclear uptake and scan, requiring hormone withdrawal to allow
the recovery of the hypothalamus-pituitary-thyroid axis. It may take as long as 8 weeks for recovery and for return of radioiodine uptakes to baseline values; however, shorter periods of up to 3 weeks may suffice for evaluating nodular function.
ment of thyroid remnants and thyroid cancer metastases
with radioiodine [13, 19, 36]. Thyroid stimulating hormone 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 preparation time and avoids a period of hypothyroidism
[37 – 41]. Currently, recombinant TSH is approved primarily for diagnostic use, i.e., prior to scintigraphy and
serum thyroglobulin measurement. It appears to be effective in monitoring thyroid cancer, especially the lowrisk papillary type, though the radioiodine uptake and
serum thyroglobulin usually are lower than after hormone withdrawal. As noted earlier, PET with fluorodeoxyglucose 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
131
I. Radioiodine uptake in these goiters is usually low
and heterogeneous. As a result, large and multiple therapeutic 131I doses may be needed to reduce goiter volume and cure the associated hyperthyroidism. In recent studies, a small dose of recombinant TSH resulted
in a more uniform 131I distribution, a higher 24-h uptake, and increased therapeutic efficacy [42, 43].
7.4.4
Summary
Thyroid stimulating hormone (thyrotropin) promotes
iodide transport, and the synthesis and release of thyroid 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 hypothyroidism, and is particularly valuable for diagnosing subclinical thyroid dysfunction. Suppression of TSH secretion 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 imaging, thyroglobulin measurement, and 131I treatment.
The serum TSH may be increased by withdrawing thyroid hormone, or by administering recombinant human TSH.
7.5
Iodine Intake and Thyroid Function
7.4.3.2
Increasing TSH Levels
7.5.1
Iodine Deficiency
Stimulation with TSH increases thyroid function and
thyroid uptake of radioiodine. This principle is used in
differentiated thyroid cancer for the detection and treat-
The daily requirement for iodine is about 150 µg, increasing to roughly 200 – 250 µg during pregnancy. Iodine deficiency is most prevalent in the mountainous
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7 Thyroid Gland
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 certain foods results in decreased thyroid hormone synthesis [44, 45]. Selenium deficiency may be a contributing factor. Reduced synthesis of thyroid hormone is
compensated, at least in part, by increased TSH secretion, resulting eventually in goiter formation. Because
an adequate supply of thyroid hormone is needed for
fetal neurological development, maternal and fetal hypothyroidism resulting from iodine deficiency is associated with varying degrees of neuropsychological deficits including cretinism [46 – 50].
7.5.2
Iodine Excess
7.5.2.1
Thyroid Autoregulation
Thyroid hormone homeostasis is maintained by an intrathyroid autoregulatory mechanism in addition to
the hypothalamus-pituitary-thyroid axis. When intrathyroid iodine concentrations are significantly increased, the rate of thyroid hormone synthesis is decreased, with a reduction in iodothyronine synthesis
and decrease in the DIT/MIT ratio. This response is referred 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 hypothyroidism, with compensatory increase in TSH and development of goiter. While this does occur occasionally
(see below), adaptation or “escape” from the effects of
chronic iodide excess is more likely. Adaptation appears to be the result of an absolute decrease in iodide
transport, so that intrathyroid iodine is reduced to levels that allow resumption of hormone synthesis.
The inhibitory effect of iodides on thyroid function
is utilized clinically for prompt control of severe hyperthyroidism 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 shortterm measure for lowering thyroid hormone levels rapidly.
7.5.2.2
Thyroid Dysfunction
Iodine excess may lead to hyperthyroidism or hypothyroidism [51 – 54]. Iodine-induced hyperthyroidism, referred 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 jodbasedow [51, 55 – 58]. Amiodarone, a cardiac antiarrhythmic 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 WolffChaikoff effect. It is more frequent in iodine-sufficient
areas, where autoimmune disease is more common
than nodular disease [53, 54]. In the past, “iodide goiter” 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 (iodinerich) 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 iodinedeficient, a rise in autoimmune thyroid disease has
been observed after the institution of iodine supplementation in foods [60]. Experimental work in animals
confirms an association between iodine and autoimmunity, probably related in part to the greater antigenic
potential of highly iodinated thyroglobulin [61]. Autoimmune thyroid disease and associated disorders are
discussed under “Hashimoto’s Disease”.
7.5.3
Summary
Excessive amounts of iodine may cause hypothyroidism or hyperthyroidism. A significant increase in thyroid concentration of iodine may initiate an autoregulatory response, the Wolff-Chaikoff effect, which decreases hormone synthesis. Although this effect is usually temporary, occasionally it may be sustained and
lead to hypothyroidism. Iodine-induced hypothyroidism is more frequent in iodine-replete regions with a
high prevalence of autoimmune thyroid disease. Excessive 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 disease, a view supported by epidemiological and experimental evidence.
7.6 Endemic Goiter
7.6
Endemic Goiter
Endemic goiter is attributed primarily to iodine deficiency, possibly in association with selenium deficiency or goitrogens. Goitrogens are present in certain
foods and chemicals and cause either decreased synthesis 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 iodine deficiency [62]. Other foods with goitrogenic potential include pearl millet and plants from the brassica
family [63].
Various chemicals may alter thyroid hormone metabolism and lead to the development of goiter. Contamination 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 thyroid disease and aggravation of Graves’ ophthalmopathy. The effects presumably are mediated in part by thiocyanate [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 synthesis. There is natural heterogeneity in cellular growth
and response to TSH, and rapid proliferation of thyrocytes with a growth advantage leads eventually to the
development of nodules. An additional mechanism for
nodule formation involves the activation of the adenylate 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 multinodular 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 typically seen in older individuals.
Hyperthyroidism associated with nodular goiter is
often subclinical, with a suppressed TSH and a normal
free T4. Nonetheless, treatment with 131I or surgery is
generally recommended in the elderly because of increased risk of osteopenia, and of adverse cardiovascu-
lar sequelae including atrial fibrillation [31 – 34]. Suppressive levothyroxine therapy is often attempted to arrest 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 distribution of radioiodine or technetium pertechnetate,
and a normal or mildly elevated 24-h radioiodine uptake. 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 associated with poor uptake in the extranodular thyroid tissue. The latter consists of “suppressed” normal tissue,
and/or small autonomous nodules with relatively less
tracer accumulation. Following 131I 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 diagnostic work-up to exclude malignancy.
Nodular disease may be treated with 131I or surgery.
For large multinodular goiters, the goal of 131I treatment is to reduce thyroid volume and cure hyperthyroidism. But the treatment may fail because radioiodine distribution is heterogeneous and the 24-h uptake
is not significantly elevated. Stimulation with recombinant human TSH causes a global increase in thyroid
uptake of 131I, and appears to improve the therapeutic
outcome [42, 43].
7.6.4
Summary
Endemic goiter is the result of iodine deficiency, occasionally 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-function mutations of the TSH receptor. Nodular thyroid
disease is a common cause of subclinical hyperthyroidism in the elderly, and it may be associated with atrial
fibrillation and osteopenia. Radionuclide studies typically show heterogeneous tracer distribution in the thyroid gland, with a normal or mildly elevated 24-h radioiodine uptake. Recombinant human TSH increases
the thyroid uptake globally, and may facilitate the treatment of nodular goiters with 131I.
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Fig. 7.2a–d. Scintigraphic images in four types of hyperthyroidism show: a multinodular goiter, b solitary hyperfunctioning thyroid nodule, c thyroiditis, d Graves’
disease
7.7
Destructive (“Subacute”) Thyroiditis
7.7.1
Postpartum 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. Serum 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-activated killer (LAK) cells, and lithium. These therapeutic
agents probably exacerbate existing autoimmune thyroid disease [73 – 77]. Bacterial thyroiditis is rarely encountered today.
Thyroiditis tends to resolve spontaneously. Hyperthyroidism in the active phase is followed by transient
hypothyroidism before restoration of the euthyroid
state, usually in 6 – 12 months. Treatment usually consists of q -adrenergic blockers in the hyperthyroid
phase, with analgesics for pain. Protracted thyroiditis
may require glucocorticoids.
Postpartum thyroiditis, also known as “painless” or
“subacute lymphocytic” thyroiditis, is the principal
thyroid disorder in postpartum women. It may be considered an accelerated form of autoimmune thyroid
disease, attributed to suppression of immune-related
disorders during pregnancy with a rebound after childbirth [78 – 82]. For the same reason, Graves’ disease also may occur in the postpartum period, though less
frequently, and a strong association with insulin-dependent diabetes mellitus, an autoimmune condition,
has been noted.
Postpartum thyroiditis, like other forms of destructive thyroiditis, is a self-limited disease, but tends to reoccur in subsequent pregnancies. Permanent hypothyroidism occurs in 20% – 25% of patients over a period
of 5 years. The incidence is greater in iodine-replete regions with a higher prevalence of autoimmune thyroid
disease. Elevated thyroid peroxidase (“anti-microsomal”) antibodies during pregnancy are associated with a
sharp increase in postpartum thyroiditis.
7.8 Autoimmune Thyroid Disease
7.7.2
Viral Thyroiditis
7.7.4
Radionuclide Procedures
Viral subacute thyroiditis, also known as “de Quervain’s” thyroiditis, usually occurs after an upper respiratory 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 tender 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.
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 related to TSH suppression by excessive thyroid hormone
released from damaged follicles, and to decreased hormone synthesis in the damaged gland. The thyroid uptake 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 uptake/scan also may be worthwhile in amiodarone-related hyperthyroidism, which may be due to jodbasedow
or thyroiditis. A suppressed thyroid uptake is non-diagnostic, while a normal or high uptake suggests that
jodbasedow is likely. The thyroid uptake measurement
also helps determine the feasibility of 131I treatment in
refractory cases.
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 desethylamiodarone 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 hypothyroidism is uncommon.
Other side effects of amiodarone stem from its high
iodine content (see Sect. 7.5, “Iodine Intake and Thyroid Function”). Thyroid hormone synthesis may increase or decrease. Increased hormone synthesis (jodbasedow) typically occurs in nodular thyroid glands,
which are common in iodine-deficient areas. Decreased hormone synthesis, resulting from a persistent
Wolff-Chaikoff effect, is more frequent in iodine-sufficient 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 refractory cases, or when continued amiodarone treatment and prompt relief of hyperthyroidism are required.
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 selected cases of hyperthyroidism [84].
7.7.5
Summary
Subacute thyroiditis is usually caused by exacerbation
of autoimmune disease, viral infection, and amiodarone therapy. It is characterized by an initial thyroid-destructive phase, with release of stored hormone into the
circulation. Nuclear studies in this phase show poor radiotracer uptake, and help differentiate thyroiditis
from other causes of hyperthyroidism. The disorder is
self-limited and treated symptomatically, though amiodarone-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-induced hyperthyroidism) and hypothyroidism.
7.8
Autoimmune Thyroid Disease
7.8.1
Etiological Factors
Autoimmune thyroid disease comprises two major entities, Hashimoto’s disease (also known as chronic autoimmune 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’ ophthalmopathy, and increased occurrence in women im-
217
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7 Thyroid Gland
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’ disease in couples suggests that infection may be a precipitating factor. In support of this hypothesis, antibodies
to certain microbial proteins have been found to crossreact with the human TSH receptor. Rarely, Graves’ disease may be precipitated by 131I treatment of nodular
goiter in patients with underlying autoimmune thyroid
disease [90]. Follicular disruption and release of thyroid 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 characteristic of Hashimoto’s disease. Antithyroglobulin antibodies also may be elevated. Hormone synthesis is impaired with compensatory increase in TSH secretion,
which stimulates thyroid function and growth. Eventually, many patients become hypothyroid. Both overt
and subclinical hypothyroidism related to autoimmune
disease are widely prevalent in iodine-sufficient regions [93 – 95]. Exacerbation of Hashimoto’s disease,
frequently occurring in the postpartum period, is a
cause of subacute thyroiditis (see “Postpartum Thyroiditis”). Graves’ disease is associated with high levels
of thyrotropin receptor autoantibodies (TRAB) that
stimulate thyroid growth, and thyroid hormone synthesis and release [86 – 89]. Most organ systems are affected by Graves’ disease, the cardiovascular manifestations 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 heightened sensitivity to sympathetic stimulation. Blood volume is increased by activation of the renin-angiotensin-aldosterone system caused by the reduction in systemic vascular resistance, and by increased erythropoietin activity. Overt cardiac failure may result from severe and prolonged hyperthyroidism, but is rarely seen
today. Atrial fibrillation is not an uncommon complication, occurring in up to 15% of patients with hyperthyroidism.
7.8.3
Radionuclide Procedures
Nuclear studies are non-specific in Hashimoto’s disease. 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 uptake 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 measurement 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 genetic susceptibility, with contributions from environmental factors including chronic iodine excess. Elevated serum anti-TPO antibodies are characteristic of
Hashimoto’s disease. Exacerbation of Hashimoto’s disease, usually observed in postpartum women, may
cause subacute thyroiditis with hyperthyroidism. Scintigraphy in such cases shows poor tracer uptake in the
thyroid gland. Graves’ disease is characterized by elevated TSH receptor antibodies (TRAB). It affects most
organ systems, but the cardiovascular manifestations
generally are the most pronounced, and cardiac complications are not uncommon. The thyroid uptake and
scan may be used to confirm the diagnosis of Graves’
disease and differentiate it from a destructive thyroiditis.
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 thyrotoxicosis appears to be related to the TSH-like effects of
human chorionic gonadotropin (hCG), which increases
in early gestation. The condition resolves spontaneously in the second half of pregnancy. The incidence and
severity of GTT are variable. It is occasionally associated with hyperemesis gravidarum. As in other hyperthyroid 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.
References
Graves’ disease in pregnancy is a more serious condition associated with significant maternal and fetal
risks, including pre-eclampsia, premature delivery, low
infant birth weight, neonatal Graves’ disease, and central congenital hypothyroidism [48, 49, 96]. Characteristically, TRAB levels are elevated. Management of gestational Graves’ disease poses several challenges. Iodine-131 therapy is contraindicated, and thyroidectomy is inherently risky for both the mother and the fetus. Left untreated or inadequately treated, Graves’ disease in pregnancy increases the risk of fetal hyperthyroidism because of the transplacental passage of maternal TRAB. Of the available treatment options, thionamides – 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 tapered or discontinued. But therapy should be resumed
after childbirth because of the risk of recurrence related to postpartum immune rebound.
7.9.2
Hypothyroidism
Normal neurological development is dependent on adequate maternal and fetal thyroid function, and on thyroid hormone sufficiency in the early neonatal period
[45 – 50, 97]. Iodine deficiency, present in regions of endemic goiter, may be associated with hypothyroidism
in both the mother and the fetus, and may cause varying 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 recognized 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” areas and may actually fall short of requirement during
pregnancy. This may have the potential to aggravate autoimmune 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 because undertreatment, with persistently high maternal
TRAB, increases the risk of fetal hyperthyroidism,
while overtreatment may cause fetal hypothyroidism.
Gestational hypothyroidism is usually related to autoimmune thyroid disease, and less frequently to iodine
deficiency. The latter may be associated with fetal hypothyroidism as well. Neurological development is influenced by maternal thyroid function, fetal thyroid
function, and thyroid hormone levels in the newborn.
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