Thyroid gland 1083

hormone has diverse cellular effects, including the

stimulation of carbohydrate and lipid catabolism and
protein synthesis in a wide range of cells. The net result is
an increase in the basal metabolic rate. In addition, thyroid
hormone has a critical role in brain development in the
fetus and neonate (see later).
The function of the thyroid gland can be inhibited by a
TRH variety of chemical agents, collectively referred to as goi-
trogens. Because they suppress T3 and T4 synthesis, the level
of TSH increases, and subsequent hyperplastic enlarge-
T3, T4 ment of the gland (goiter) follows. The antithyroid agent
propylthiouracil inhibits the oxidation of iodide and thus
TSH
Pituitary blocks the production of thyroid hormones; parentheti-
cally, propylthiouracil also inhibits the peripheral deiodin-
ation of circulating T4 into T3, thus ameliorating symptoms
TSH receptor of thyroid hormone excess (see later). Iodide, when given
Thyroid in large doses to individuals with thyroid hyperfunction,
hormone
G G protein also blocks the release of thyroid hormones by inhibiting
receptor
the proteolysis of thyroglobulin. Thus, thyroid hormone is
GTP GDP T3, T4 synthesized and incorporated into colloid, but it is not
released into the blood.
Thyroid Target The thyroid gland follicles also contain a population of
cAMP gene parafollicular cells, or C cells, which synthesize and secrete
the hormone calcitonin. This hormone promotes the absorp-
tion of calcium by the skeletal system and inhibits the
resorption of bone by osteoclasts.
Diseases of the thyroid include conditions associated
Gene expression on with excessive release of thyroid hormones (hyperthyroid-
Figure 24-8 Homeostasis in the hypothalamus-pituitary-thyroid axis and ism), thyroid hormone deficiency (hypothyroidism), and
mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 mass lesions of the thyroid. We will first consider the clini-
and T4) is controlled by trophic factors secreted by both the hypothalamus cal consequences of disturbed thyroid function, and then
and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release turn to the disorders that generate these problems.
of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-
stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels
to rise. Elevated T3 and T4 levels, in turn, feed back to suppress the secretion
of both TRH and TSH. TSH binds to the TSH receptor on the thyroid follicular Hyperthyroidism
epithelium, which causes activation of G proteins, and cAMP-mediated syn-
thesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and Thyrotoxicosis is a hypermetabolic state caused by ele-
T4 interact with the thyroid hormone receptor (TR) to form a hormone- vated circulating levels of free T3 and T4 . Because it is
receptor complex that translocates to the nucleus and binds to so-called caused most commonly by hyperfunction of the thyroid
thyroid response elements (TREs) on target genes to initiate transcription. gland, it is often referred to as hyperthyroidism. However,
in certain conditions the oversupply is related to either
excessive release of preformed thyroid hormone (e.g., in
events that result in an increase in intracellular cAMP thyroiditis) or to an extrathyroidal source, rather than
levels, which stimulates thyroid growth and thyroid hyperfunction of the gland (Table 24-3). Thus, strictly
hormone synthesis and release via cAMP-dependent speaking, hyperthyroidism is only one (albeit the most
protein kinases. common) cause of thyrotoxicosis. The terms primary and
Thyroid follicular epithelial cells convert thyroglobulin secondary hyperthyroidism are sometimes used to designate
into thyroxine (T4 ) and lesser amounts of triiodothyronine hyperthyroidism arising from an intrinsic thyroid abnor-
(T3 ). T4 and T3 are released into the systemic circulation, mality and that arising from processes outside of the
where most of these peptides are reversibly bound to cir- thyroid, such as a TSH-secreting pituitary tumor, respec-
culating plasma proteins, such as thyroxine-binding globu- tively. With this caveat, we follow the common practice of
lin and transthyretin. The binding proteins act as a buffer using the terms thyrotoxicosis and hyperthyroidism inter-
that maintains the serum unbound (“free”) T3 and T4 con- changeably. The three most common causes of thyrotoxi-
centrations within narrow limits, while ensuring that the cosis are associated with hyperfunction of the gland and
hormones are readily available to the tissues. In the periph- include the following:
ery, the majority of free T4 is deiodinated to T3; the latter
binds to thyroid hormone nuclear receptors in target cells • Diffuse hyperplasia of the thyroid associated with Graves
with tenfold greater affinity than does T4 and has propor- disease (approximately 85% of cases)
tionately greater activity. Binding of thyroid hormone to • Hyperfunctional multinodular goiter
its nuclear thyroid hormone receptor (TR) results in the • Hyperfunctional thyroid adenoma
assembly of a multiprotein hormone-receptor complex
on thyroid hormone response elements (TREs) in target Clinical Course. The clinical manifestations of hyperthy-
genes, up regulating their transcription (Fig. 24-8). Thyroid roidism are protean and include changes referable to the
1084 C H A P T E R 24 The Endocrine System

Table 24-3 Disorders Associated with Thyrotoxicosis ophthalmopathy associated with proptosis occurs only in
Associated with Hyperthyroidism Graves disease (see later).
Primary • The skeletal system is also affected. Thyroid hormone
stimulates bone resorption, increasing porosity of corti-
Diffuse hyperplasia (Graves disease) cal bone and reducing the volume of trabecular bone.
Hyperfunctioning (“toxic”) multinodular goiter
Hyperfunctioning (“toxic”) adenoma
The net effect is osteoporosis and an increased risk of
Iodine-induced hyperthyroidism fractures in patients with chronic hyperthyroidism.
Neonatal thyrotoxicosis associated with maternal Graves disease Other findings include atrophy of skeletal muscle, with
fatty infiltration and focal interstitial lymphocytic infil-
Secondary
trates; minimal liver enlargement due to fatty changes
TSH-secreting pituitary adenoma (rare)* in the hepatocytes; and generalized lymphoid hyperpla-
Not Associated with Hyperthyroidism sia and lymphadenopathy in patients with Graves
Granulomatous (de Quervain) thyroiditis (painful) disease.
Subacute lymphocytic thyroiditis (painless) • Thyroid storm refers to the abrupt onset of severe hyper-
Struma ovarii (ovarian teratoma with ectopic thyroid) thyroidism. This condition occurs most commonly in
Factitious thyrotoxicosis (exogenous thyroxine intake) patients with underlying Graves disease and probably
*Associated with increased thyroid-stimulating hormone (TSH); all other causes of thyrotoxicosis results from an acute elevation in catecholamine levels,
associated with decreased TSH. as might be encountered during infection, surgery, ces-
sation of antithyroid medication, or any form of stress.
Patients are often febrile and present with tachycardia
out of proportion to the fever. Thyroid storm is a medical
emergency. A significant number of untreated patients
hypermetabolic state induced by excess thyroid hormone and die of cardiac arrhythmias.
to overactivity of the sympathetic nervous system (i.e., an • Apathetic hyperthyroidism refers to thyrotoxicosis occur-
increase in the β-adrenergic “tone”). ring in older adults, in whom advanced age and various
co-morbidities may blunt the features of thyroid
• Excessive levels of thyroid hormone result in an increase
hormone excess that typically bring younger patients to
in the basal metabolic rate. The skin of thyrotoxic patients
tends to be soft, warm, and flushed because of increased attention. The diagnosis of thyrotoxicosis in these indi-
blood flow and peripheral vasodilation, adaptations viduals is often made during laboratory work-up for
that serve to increase heat loss. Heat intolerance is unexplained weight loss or worsening cardiovascular
common. Sweating is increased because of higher disease.
levels of calorigenesis. Heightened catabolic metabo- A diagnosis of hyperthyroidism is made using both
lism results in weight loss despite increased appetite. clinical and laboratory findings. The measurement of
• Cardiac manifestations are among the earliest and most con- serum TSH concentration is the most useful single
sistent features. Individuals with hyperthyroidism can screening test for hyperthyroidism, because its levels are
have elevated cardiac contractility and cardiac output, decreased even at the earliest stages, when the disease
in response to increased peripheral oxygen require- may still be subclinical. A low TSH value is usually con-
ments. Tachycardia, palpitations, and cardiomegaly are firmed with measurement of free T4, which is predictably
common. Arrhythmias, particularly atrial fibrillation, increased. In occasional patients, hyperthyroidism results
occur frequently and are more common in older
patients. Congestive heart failure may develop, espe-
cially in older patients with preexisting cardiac disease.
Myocardial changes, such as focal lymphocytic and
eosinophilic infiltrates, mild fibrosis, myofibril fatty
change, and an increase in size and number of mito-
chondria, have been described. Some individuals with
thyrotoxicosis develop reversible left ventricular dysfunc-
tion and “low-output” heart failure, so-called thyrotoxic
or hyperthyroid cardiomyopathy.
• Overactivity of the sympathetic nervous system produces
tremor, hyperactivity, emotional lability, anxiety, inabil-
ity to concentrate, and insomnia. Proximal muscle
weakness and decreased muscle mass are common
(thyroid myopathy). In the gastrointestinal system, sympa-
thetic hyperstimulation of the gut results in hypermotil-
ity, diarrhea, and malabsorption.
• Ocular changes often call attention to hyperthyroidism.
A wide, staring gaze and lid lag are present because of
Figure 24-9 A person with hyperthyroidism. A wide-eyed, staring gaze,
sympathetic overstimulation of the superior tarsal caused by overactivity of the sympathetic nervous system, is one of the
muscle (also known as Müller’s muscle), which functions features of this disorder. In Graves disease, one of the most important causes
alongside the levator palpebrae superioris muscle to of hyperthyroidism, accumulation of loose connective tissue behind the eye-
raise the upper eyelid (Fig. 24-9). However, true thyroid balls, also adds to the protuberant appearance of the eyes.
 Thyroid gland 1085

predominantly from increased circulating levels of T3 (“T3 Table 24-4 Causes of Hypothyroidism
toxicosis”). In these cases, free T4 levels may be decreased, Primary
and direct measurement of serum T3 may be useful. In rare
Genetic defects in thyroid development (PAX8, FOXE1, TSH receptor
cases of pituitary-associated (secondary) hyperthyroidism, mutations) (rare)
TSH levels are either normal or raised. Determining TSH Thyroid hormone resistance syndrome (THRB mutations) (rare)
levels after the injection of thyrotropin-releasing hormone Postablative
(TRH stimulation test) is used in the evaluation of cases of Surgery, radioiodine therapy, or external irradiation
suspected hyperthyroidism with equivocal changes in the Autoimmune hypothyroidism
baseline serum TSH level. A normal rise in TSH after Hashimoto thyroiditis*
administration of TRH excludes secondary hyperthyroid- Iodine deficiency*
Drugs (lithium, iodides, p-aminosalicylic acid)*
ism. Once the diagnosis of thyrotoxicosis has been con-
Congenital biosynthetic defect (dyshormonogenetic goiter) (rare) *
firmed by a combination of TSH assays and free thyroid
hormone levels, measurement of radioactive iodine uptake Secondary (Central)
by the thyroid gland can help to determine the etiology. Pituitary failure (rare)
For example, there may be diffusely increased uptake in Hypothalamic failure (rare)
the whole gland (Graves disease), increased uptake in a *Associated with enlargement of thyroid (“goitrous hypothyroidism”). Hashimoto thyroiditis and
solitary nodule (toxic adenoma), or decreased uptake postablative hypothyroidism account for the majority of cases of hypothyroidism in developed
countries. FOXE1, forkhead box E1; PAX8, paired box 8; THRB, thyroid hormone receptor β.
(thyroiditis).
The therapeutic options for hyperthyroidism include
several medications, each with a different mechanism of
action. Typically, these include a β-blocker to control
symptoms induced by increased adrenergic tone, a thion- parenchyma (thyroid agenesis), or the gland may be greatly
amide to block new hormone synthesis, an iodine solution reduced in size (thyroid hypoplasia) due to germline muta-
to block the release of thyroid hormone, and agents that tions in genes responsible for thyroid development
inhibit peripheral conversion of T4 to T3. Radioiodine, (Table 24-4).
which is incorporated into thyroid tissues, resulting in
ablation of thyroid function over a period of 6 to 18 weeks, Autoimmune hypothyroidism. Autoimmune hypothy-
may also be used. roidism is the most common cause of hypothyroidism in
iodine-sufficient areas of the world. The vast majority of
cases of autoimmune hypothyroidism are due to Hashimoto
Hypothyroidism thyroiditis. Circulating autoantibodies, including anti-
microsomal, antithyroid peroxidase, and antithyroglobulin anti-
Hypothyroidism is a condition caused by a structural or bodies, are found in this disorder, and the thyroid is
functional derangement that interferes with the produc- typically enlarged (goitrous). Autoimmune hypothyroid-
tion of thyroid hormone. Hypothyroidism is a fairly ism can occur in isolation or in conjunction with autoim-
common disorder. By some estimates the population prev- mune polyendocrine syndrome (APS), types 1 and 2 (see
alence of overt hypothyroidism is 0.3%, while subclinical discussion in “Adrenal Glands”).
hypothyroidism can be found in greater than 4%. The prev-
alence increases with age, and it is nearly tenfold more Iatrogenic hypothyroidism. This can be caused by either
common in women than in men. It can result from a defect surgical or radiation-induced ablation. A large resection of the
anywhere in the hypothalamic-pituitary-thyroid axis. As gland (total thyroidectomy) for the treatment of hyperthy-
in the case of hyperthyroidism, this disorder is divided into roidism or a primary neoplasm can lead to hypothyroid-
primary and secondary forms, depending on whether the ism. The gland may also be ablated by radiation, whether
hypothyroidism arises from an intrinsic abnormality in the in the form of radioiodine administered for the treatment
thyroid itself, or occurs as a result of pituitary and hypo- of hyperthyroidism, or exogenous irradiation, such as
thalamic disease (Table 24-4). Primary hypothyroidism external radiation therapy to the neck. Drugs given inten-
accounts for the vast majority of cases, and may be accom- tionally to decrease thyroid secretion (e.g., methimazole
panied by an enlargement in the size of the thyroid gland and propylthiouracil) can also cause acquired hypothy-
(goiter). roidism, as can agents used to treat nonthyroid conditions
Primary hypothyroidism can be congenital, autoim- (e.g., lithium, p-aminosalicylic acid).
mune, or iatrogenic. Secondary (or central) hypothyroidism is caused by
deficiencies of TSH or, far more uncommonly, TRH. Any
Congenital hypothyroidism. Worldwide, congenital hy- of the causes of hypopituitarism (for example, pituitary
pothyroidism is most often the result of endemic iodine tumor, postpartum pituitary necrosis, trauma, and nonpi-
deficiency in the diet (see later). Other rare forms of con- tuitary tumors), or of hypothalamic damage from tumors,
genital hypothyroidism include inborn errors of thyroid me- trauma, radiation therapy, or infiltrative diseases can cause
tabolism (dyshormonogenetic goiter), wherein any one of the central hypothyroidism.
multiple steps leading to thyroid hormone synthesis may
be defective, such as (1) iodide transport into thyrocytes, Cretinism
(2) “organification” of iodine (binding of iodine to tyrosine
residues of the storage protein, thyroglobulin), and (3) io- Cretinism refers to hypothyroidism that develops in
dotyrosine coupling to form hormonally active T3 and T4. infancy or early childhood. The term cretin was de-
In rare instances there may be complete absence of thyroid rived from the French chrétien, meaning “Christian” or