• Symptomatic Primary Hyperparathyroidism.
» SECONDARY HYPERPARATHYROIDISM
• Clinical Course.
– The Endocrine Pancreas
– Diabetes Mellitus
» NORMAL INSULIN PHYSIOLOGY
• Regulation of Insulin Release
• Insulin Action and Insulin Signaling
» PATHOGENESIS OF TYPE 1 DIABETES
• Mechanisms of β Cell Destruction
• Genetic Susceptibility
• The MHC Locus.
• Non-MHC Genes.
• Environmental Factors
» PATHOGENESIS OF TYPE 2 DIABETES
• Insulin Resistance
• Genetic Defects of the Insulin Receptor and
Insulin Signaling Pathway.
• Obesity and Insulin Resistance.
• β-Cell Dysfunction
» MONOGENIC FORMS OF DIABETES
• Maturity-Onset Diabetes of the Young
• Mitochondrial Diabetes.
• Diabetes Associated with Insulin Gene or
Insulin Receptor Mutations.
» PATHOGENESIS OF THE COMPLICATIONS
• Formation of Advanced Glycation End
• Activation of Protein Kinase C.
• Intracellular Hyperglycemia with
Disturbances in Polyol Pathways.
» MORPHOLOGY OF DIABETES AND ITS LATE
• Clinical Course.
» TUMORS OF EXTRA-ADRENAL
– Multiple Endocrine Neoplasia Syndromes
» MULTIPLE ENDOCRINE NEOPLASIA, TYPE 1
» MULTIPLE ENDOCRINE NEOPLASIA, TYPE 2
– Pineal Gland
The endocrine system contains a highly integrated and widely distributed group of organs
that orchestrates a state of metabolic equilibrium, or homeostasis, among the various
organs of the body. Signaling by extracellular secreted molecules can be classified into
three types—autocrine, paracrine, or endocrine—on the basis of the distance over which
the signal acts. In endocrine signaling, the secreted molecules, which are frequently
called hormones, act on target cells that are distant from their site of synthesis. An
endocrine hormone is frequently carried by the blood from its site of release to its target.
Increased activity of the target tissue often down-regulates the activity of the gland that
secretes the stimulating hormone, a process known as feedback inhibition.
Hormones can be classified into several broad categories on the basis of the nature of
their receptors. Cellular receptors and signaling pathways were discussed in Chapter 3 ,
and only a few comments about signaling by hormone receptors follow:
• Hormones that trigger biochemical signals upon interacting with cell-surface
receptors: This large class of compounds is composed of two groups: (1) peptide
hormones, such as growth hormone and insulin, and (2) small molecules, such as
epinephrine. Binding of these hormones to cell-surface receptors leads to an
increase in intracellular signaling molecules, termed second messengers, such as
cyclic adenosine monophosphate (cAMP); production of mediators from
membrane phospholipids, such as inositol 1,4,5-trisphosphate or IP3 ; and shifts in
the intracellular levels of ionized calcium. The elevated levels of one or more of
these can control proliferation, differentiation, survival, and functional activity of
cells, mainly by regulating the expression of specific genes.
• Hormones that diffuse across the plasma membrane and interact with
intracellular receptors: Many lipid-soluble hormones diffuse across the plasma
membrane and interact with receptors in the cytosol or the nucleus. The resulting
hormone-receptor complexes bind specifically to recognition elements in DNA,
thereby affecting the expression of specific target genes. Hormones of this type
include the steroids (e.g., estrogen, progesterone, and glucocorticoids), and
A number of processes can disturb the normal activity of the endocrine system, including
impaired synthesis or release of hormones, abnormal interactions between hormones and
their target tissues, and abnormal responses of target organs. Endocrine diseases can be
generally classified as (1) diseases of underproduction or overproduction of hormones
and their resulting biochemical and clinical consequences and (2) diseases associated
with the development of mass lesions. Such lesions might be nonfunctional, or they
might be associated with overproduction or underproduction of hormones. The study of
endocrine diseases requires integration of morphologic findings with biochemical
measurements of the levels of hormones, their regulators, and other metabolites.
The pituitary is a small bean-shaped organ that measures about 1 cm in greatest diameter
and weighs about 0.5 gm, although it enlarges during pregnancy. Its small size belies its
great functional significance. It is located at the base of the brain, where it lies nestled
within the confines of the sella turcica in close proximity to the optic chiasm and the
cavernous sinuses. The pituitary is attached to the hypothalamus by the pituitary stalk,
which passes out of the sella through an opening in the dura mater surrounding the brain.
Along with the hypothalamus, the pituitary gland plays a critical role in
Figure 24-1 Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases
five hormones that are in turn under the control of various stimulatory and inhibitory hypothalamic
releasing factors. TSH, thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH,
adrenocorticotrophic hormone (corticotropin); GH, growth hormone (somatotropin); FSH, follicle-
stimulating hormone; LH, luteinizing hormone. The stimulatory releasing factors are TRH (thyrotropin-
releasing factor), CRH (corticotropin-releasing factor), GHRH (growth hormone-releasing factor), GnRH
(gonadotropin-releasing factor). The inhibitory hypothalamic influences are comprised of PIF (prolactin
inhibitory factor or dopamine) and growth hormone inhibitory factor (GIH or somatostatin).
the regulation of most of the other endocrine glands. The pituitary is composed of two
morphologically and functionally distinct components: The anterior lobe
(adenohypophysis) and the posterior lobe (neurohypophysis).
The anterior pituitary, or adenohypophysis, constitutes about 80% of the gland. It is
derived embryologically from Rathke pouch, which is an extension of the developing oral
cavity. It is eventually cut off from its origins by the growth of the sphenoid bone, which
creates a saddle-like depression, the sella turcica. The anterior pituitary has a portal
vascular system that is the conduit for the transport of hypothalamic releasing hormones
from the hypothalamus to the pituitary. Hypothalamic neurons have terminals in the
median eminence where the hormones are released into the portal system, from where
they traverse the pituitary stalk and enter the anterior pituitary gland. The production of
most pituitary hormones is controlled predominantly by positive-acting releasing factors
from the hypothalamus ( Fig. 24-1 ). Prolactin is the major exception, since its primary
hypothalamic control is inhibitory, through the action of dopamine, while pituitary
Figure 24-2 A, Photomicrograph of normal pituitary. The gland is populated by several distinct cell
populations containing a variety of stimulating (trophic) hormones. B, Each of the hormones has different
staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Immunostain
for human growth hormone.
growth hormone receives both stimulatory and inhibitory influences via the
hypothalamus. In routine histologic sections of the anterior pituitary, a colorful array of
cells is present that contain eosinophilic cytoplasm (acidophil), basophilic cytoplasm
(basophil), or poorly staining cytoplasm (chromophobe) cells ( Fig. 24-2 ). Specific
antibodies against the pituitary hormones identify five cell types:
1. Somatotrophs, producing growth hormone (GH): These acidophilic cells
constitute half of all the hormone-producing cells in the anterior pituitary.
2. Lactotrophs (mammotrophs), producing prolactin: These acidophilic cells secrete
prolactin, which is essential for lactation.
3. Corticotrophs: These basophilic cells produce adrenocorticotropic hormone
(ACTH), pro-opiomelanocortin (POMC), melanocyte-stimulating hormone
(MSH), endorphins, and lipotropin.
4. Thyrotrophs: These pale basophilic cells produce thyroid-stimulating hormone
5. Gonadotrophs: These basophilic cells produce both follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). FSH stimulates the formation of graafian
follicles in the ovary, and LH induces ovulation and the formation of corpora
lutea in the ovary.
The posterior pituitary, or neurohypophysis, consists of modified glial cells (termed
pituicytes) and axonal processes extending from nerve cell bodies in the supraoptic and
paraventricular nuclei of the hypothalamus, through the pituitary stalk to the posterior
lobe. These neurons produce two peptide hormones, anti-diuretic hormone (ADH, also
called vasopressin) and oxytocin. The hormones are stored in axon terminals in the
posterior pituitary and are released into the circulation in response to appropriate stimuli.
Oxytocin stimulates contraction of the smooth muscle cells in the gravid uterus and cells
surrounding the lactiferous ducts of the mammary glands. ADH is a nonapeptide
hormone synthesized predominantly in the supraoptic nucleus. In response to a number of
different stimuli, including increased plasma osmotic pressure, left atrial distention,
exercise, and certain emotional states, ADH is released from the axon terminals in the
neurohypophysis into the general circulation. The posterior pituitary is derived
embryologically from an outpouching of the floor of the third ventricle, which grows
downward alongside the anterior lobe. In contrast to the anterior lobe, the posterior lobe
of the pituitary is supplied by an artery and drains into a vein, where its hormones are
released directly into the systemic circulation. Thus, the pituitary has a dual circulation,
composed of arteries and veins and a portal venous system linking the hypothalamus and
the anterior lobe.
Clinical Manifestations of Pituitary Disease
The manifestations of pituitary disorders are as follows:
• Hyperpituitarism: Arising from excess secretion of trophic hormones. The
causes of hyperpituitarism include pituitary adenoma, hyperplasia and carcinomas
of the anterior pituitary, secretion of hormones by nonpituitary tumors, and
certain hypothalamic disorders. The symptoms of hyperpituitarism are discussed
in the context of individual tumors below.
• Hypopituitarism: Arising from deficiency of trophic hormones. This may be
caused by destructive processes, including ischemic injury, surgery or radiation,
and inflammatory reactions. In addition, nonfunctional pituitary adenomas may
encroach upon and destroy adjacent normal anterior pituitary parenchyma and
• Local mass effects: Among the earliest changes referable to mass effect are
radiographic abnormalities of the sella turcica, including sellar expansion, bony
erosion, and disruption of the diaphragma sella. Because of the close proximity of
the optic nerves and chiasm to the sella, expanding pituitary lesions often
compress decussating fibers in the optic chiasm. This gives rise to visual field
abnormalities, classically in the form of defects in the lateral (temporal) visual
fields, so-called bitemporal hemianopsia. In addition, a variety of other visual
field abnormalities may be caused by asymmetric growth of many tumors. Like
any expanding intracranial mass, pituitary adenomas can produce signs and
symptoms of elevated intracranial pressure, including headache, nausea, and
vomiting. On occasion, acute hemorrhage into an adenoma is associated with
clinical evidence of rapid enlargement of the lesion, a situation appropriately
termed pituitary apoplexy. Acute pituitary apoplexy is a neurosurgical emergency,
since it can cause sudden death (see below).
• Diseases of the posterior pituitary often come to clinical attention because of
increased or decreased secretion of one of its products, ADH.
Pituitary Adenomas and Hyperpituitarism
The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe.
Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary,
secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders.
Pituitary adenomas can be functional (i.e., associated with hormone excess and clinical
manifestations thereof) or silent (i.e., immunohistochemical and/or ultrastructural
demonstration of hormone production at the tissue level only, without clinical symptoms
of hormone excess). Both functional and silent pituitary adenomas are usually composed
of a single cell type and produce a single predominant hormone, although exceptions are
known to occur. Pituitary adenomas are classified on the basis of hormone(s) produced
by the neoplastic cells detected by immunohistochemical stains performed on tissue
sections ( Table 24-1 ). Some pituitary adenomas can secrete two hormones (GH and
prolactin being the most common combination), and rarely, pituitary adenomas are
plurihormonal. Finally, pituitary adenomas may be hormone-negative, based on absence
of immunohistochemical reactivity and ultrastructural
TABLE 24-1 -- Classification of Pituitary Adenomas
Prolactin cell (lactotroph) adenoma
Growth hormone cell (somatotroph) adenoma
Densely granulated GH cell adenoma
Sparsely granulated GH cell adenoma with fibrous bodies
Thyroid-stimulating hormone cell (thyrotroph) adenomas
ACTH cell (corticotroph) adenomas
Gonadotroph cell adenomas
Silent gonadotroph adenomas include most so-called null cell and oncocytic
Mixed growth hormone-prolactin cell (mammosomatotroph) adenomas
Other plurihormonal adenomas
ACTH, adrenocorticotropic hormone.
demonstration of lineage-specific differentiation. Both silent and hormone-negative
pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent
anterior pituitary parenchyma.
Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial
neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact,
using high-resolution computed tomography or magnetic resonance imaging suggest that
approximately 20% of "normal" adult pituitary glands harbor an incidental lesion
measuring 3 mm or more in diameter, usually a silent adenoma. Pituitary adenomas are
usually found in adults, with a peak incidence from the thirties to the fifties. Most
pituitary adenomas occur as isolated lesions. In about 3% of cases, however, adenomas
are associated with multiple endocrine neoplasia (MEN) type 1 (discussed later). Pituitary
adenomas are designated, somewhat arbitrarily, microadenomas if they are less than 1 cm
in diameter and macroadenomas if they exceed 1 cm in diameter. Silent and hormone-
negative adenomas are likely to come to clinical attention at a later stage than those
associated with endocrine abnormalities and are therefore more likely to be
With recent advances in molecular techniques, substantial insight has been gained into
the genetic abnormalities associated with pituitary adenomas: 
• The great majority of pituitary adenomas are monoclonal in origin, even those
that are plurihormonal, suggesting that most arise from a single somatic cell.
Some plurihormonal tumors may arise from clonal expansion of primitive stem
cells, which then differentiate in several directions simultaneously.
• G-protein mutations are possibly the best-characterized molecular abnormalities
in pituitary adenomas. G-proteins are described in Chapter 3 ; here we will review
their function in the context of endocrine neoplasms. G-proteins play a critical
role in signal transduction, transmitting signals from cell-surface receptors (e.g.,
GHRH receptor) to intracellular effectors (e.g., adenyl cyclase), which then
generate second messengers (e.g., cyclic AMP, cAMP). These are heterotrimeric
proteins, composed of a specific α-subunit that binds guanine nucleotide and
interacts with both cell surface receptors and intracellular effectors ( Fig. 24-3 );
the β- and γ-subunits are noncovalently bound to the specific α-subunit. Gs is a
stimulatory G-protein that has a pivotal role in signal transduction in several
endocrine organs, including the pituitary. The α-subunit of Gs (Gs α) is encoded by
the GNAS1 gene, located on chromosome 20q13. In the basal state, Gs exists as an
inactive protein, with GDP bound to the guanine nucleotide-binding site of the α-
subunit of Gs . On interaction with the ligand-bound cell-surface receptor, GDP
dissociates, and GTP binds to Gs α, activating the G-protein. The activation of Gs
α results in the generation of cAMP, which acts as a potent mitogenic stimulus for
a variety of endocrine cell types (such as pituitary somatotrophs and
corticotrophs, thyroid follicular cells, parathyroid cells), promoting cellular
proliferation and hormone synthesis and secretion. The activation of Gs α, and
resultant generation of cAMP, are transient because of an intrinsic GTPase
activity in the α-subunit, which hydrolyzes GTP into GDP. A mutation in the α-
subunit that interferes with its intrinsic GTPase activity will therefore result in
constitutive activation of Gs α, persistent generation of cAMP, and unchecked
cellular proliferation ( Fig. 24-3 ). Approximately 40% of somatotroph cell
adenomas bear GNAS1 mutations that abrogate the GTPase activity of Gs α. The
mutant form of GNAS1 is also known as the gsp oncogene because of its effects
on tumorigenesis. In addition, GNAS1 mutations have also been described in a
minority of corticotroph adenomas; in contrast, GNAS1 mutations are absent in
thyrotroph, lactotroph, and gonadotroph adenomas, since their respective
hypothalamic release hormones do not mediate their action via cAMP-dependent
• Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a
familial disorder associated with tumors and hyperplasias of multiple endocrine
organs, including the pituitary. A subtype of MEN syndrome, known as MEN-1,
is caused by germ line mutations of the gene MEN1, on chromosome 11q13.
While MEN1 mutations are, by definition, present in pituitary adenomas arising in
context of the MEN-1 syndrome, they are uncommon in sporadic pituitary
• Additional molecular abnormalities present in aggressive or advanced pituitary
adenomas include activating mutations of the RAS oncogene and overexpression
of the c-MYC oncogene, suggesting that these genetic events are linked to disease
Figure 24-3 The mechanism of G-protein mutations in endocrine neoplasia. Mutations in the G-protein-
signaling pathway are seen in a variety of endocrine neoplasms, including pituitary, thyroid, and
parathyroid adenomas. G-proteins play a critical role in signal transduction, transmitting signals from cell-
surface receptors (GHRH, TSH, or PTH receptor) to intracellular effectors (e.g., adenyl cyclase), which
then generate second messengers (cAMP).
The common pituitary adenoma is a soft, well-circumscribed lesion that may be confined
to the sella turcica. Larger lesions typically extend superiorly through the diaphragm sella
into the suprasellar region, where they often compress the optic chiasm and adjacent
structures, such as some of the cranial nerves ( Fig. 24-4 ). As these adenomas expand,
they frequently erode the sella turcica and anterior clinoid processes. They may also
extend locally into the cavernous and sphenoid sinuses. In up to 30% of cases, the
adenomas are not grossly encapsulated and infiltrate adjacent bone, dura, and (rarely)
brain, but they do not demonstrate the ability for distant metastasis. Such lesions are
termed invasive adenomas. Foci of hemorrhage and necrosis are common in larger
Histologically, pituitary adenomas are composed of relatively uniform, polygonal cells
arrayed in sheets or cords. Supporting connective tissue, or reticulin, is sparse, accounting
for the soft, gelatinous consistency of many of these lesions. The nuclei of the neoplastic
cells may be uniform or pleomorphic. Mitotic activity is usually modest. The cytoplasm
of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on
the type and amount of secretory product within the cells, but it is generally uniform
throughout the cytoplasm. This cellular monomorphism and the absence of a
significant reticulin network distinguish pituitary adenomas from nonneoplastic
anterior pituitary parenchyma ( Fig. 24-5 ). The functional status of the adenoma
cannot be reliably predicted from its histologic appearance.
The signs and symptoms of pituitary adenomas include endocrine abnormalities and mass
effects. The abnormalities associated with the secretion of excessive quantities of anterior
pituitary hormones are mentioned below, when we describe the specific types of pituitary
adenoma. Local mass effects may be encountered in any type of pituitary tumor and have
been discussed previously under clinical manifestations of pituitary disease. Briefly, these
include radiographic abnormalities of the sella turcica, visual
Figure 24-4 Pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines
of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the
time of diagnosis than those that secrete a hormone.
Figure 24-5 Pituitary adenoma. The monomorphism of these cells contrasts markedly with the mixture of
cells seen in the normal anterior pituitary. Note also the absence of reticulin network.
field abnormalities, signs and symptoms of elevated intracranial pressure, and
occasionally hypopituitarism. Acute hemorrhage into an adenoma is sometimes
associated with pituitary apoplexy, as was noted previously.
With this general introduction to pituitary adenomas, we proceed to a discussion of the
individual types of tumors.
Prolactinomas (lactotroph adenomas) are the most frequent type of hyperfunctioning
pituitary adenoma, accounting for about 30% of all clinically recognized pituitary
adenomas. These lesions range from small microadenomas to large, expansile tumors
associated with substantial mass effect. Microscopically, the overwhelming majority of
prolactinomas are composed of weakly acidophilic or chromophobic cells (sparsely
granulated prolactinoma); rare prolactinomas are strongly acidophilic (densely
granulated prolactinoma) ( Fig. 24-6 ). Prolactin can be demonstrated within the
secretory granules in the cytoplasm of the cells using immunohistochemical approaches.
Prolactinomas have a propensity to undergo dystrophic calcification, ranging from
isolated psammoma bodies to extensive calcification of virtually the entire tumor mass
("pituitary stone"). Prolactin secretion by functioning adenomas is characterized by its
efficiency—even microadenomas secrete sufficient prolactin to cause hyperprolactinemia
—and by its proportionality, in that serum prolactin concentrations tend to correlate with
the size of the adenoma.
Increased serum levels of prolactin, or prolactinemia, cause amenorrhea, galactorrhea,
loss of libido, and infertility. The diagnosis of an adenoma is made more readily in
women than in men, especially between the ages of 20 and 40 years, presumably because
of the sensitivity of menses to disruption by hyperprolactinemia. This tumor underlies
almost a quarter of cases of amenorrhea. In contrast, in men and older women, the
hormonal manifestations may be subtle, allowing the tumors to reach considerable size
(macroadenomas) before being detected clinically.
Hyperprolactinemia may result from causes other than prolactin-secreting pituitary
adenomas. Physiologic hyperprolactinemia occurs in pregnancy; serum prolactin levels
Figure 24-6 Ultrastructural features of prolactinomas. A, Electron micrograph of a sparsely granulated
prolactinoma. The tumor cells contain abundant granular endoplasmic reticulum (indicative of active
protein synthesis) and small numbers of secretory granules (6000X). B, Electron micrograph of densely
granulated growth hormone-secreting adenoma. The tumor cells are filled with large, membrane-bound
secretory granules (6000X). (Courtesy of Dr. Eva Horvath, St. Michael's Hospital, Toronto, Ontario,
increase throughout pregnancy, reaching a peak at delivery. Prolactin levels are also
elevated by nipple stimulation, as occurs during suckling in lactating women, and as a
response to many types of stress. Pathologic hyperprolactinemia can also result from
lactotroph hyperplasia, such as when there is interference with normal dopamine
inhibition of prolactin secretion. This may occur as a result of damage to the
dopaminergic neurons of the hypothalamus, pituitary stalk section (e.g., owing to head
trauma), or drugs that block dopamine receptors on lactotroph cells. Any mass in the
suprasellar compartment may disturb the normal inhibitory influence of the hypothalamus
on prolactin secretion, resulting in hyperprolactinemia, a phenomenon called the stalk
effect. Therefore, a mild elevation in serum prolactin in a patient with a pituitary
adenoma does not necessarily indicate a prolactin-secreting tumor. Several classes of
drugs can cause hyperprolactinemia, including dopamine receptor antagonists such as the
neuroleptic drugs (phenothiazines, haloperidol) and older antihypertensive drugs, such as
reserpine, which inhibit dopamine storage. Other causes of hyperprolactinemia include
estrogens, renal failure, and hypothyroidism. Prolactinomas are treated by surgery or,
more commonly, with bromocriptine, a dopamine receptor agonist, which causes the
lesions to diminish in size.
GROWTH HORMONE (SOMATOTROPH CELL) ADENOMAS
GH-secreting tumors are the second most common type of functioning pituitary adenoma.
As we have mentioned, 40% of somatotroph cell adenomas express a mutant GTPase-
deficient α-subunit of the G-protein, Gs . Somatotroph cell adenomas may be quite large
by the time they come to clinical attention because the manifestations of excessive GH
may be subtle. Histologically, GH-containing adenomas are also classified into two
subtypes: densely granulated and sparsely granulated. The densely granulated adenomas
are composed of cells that are monomorphic and acidophilic in routine sections, retain
strong cytoplasmic GH reactivity on immunohistochemistry, and demonstrate cytokeratin
staining in a perinuclear distribution. In contrast, the sparsely granulated variants are
composed of chromophobe cells with considerable nuclear and cytologic pleomorphism,
and retain focal and weak GH reactivity. Bihormonal mammosomatotroph adenomas
that are reactive for both GH and prolactin are being increasingly recognized with the
availability of better reagents for immunohistochemical analysis; morphologically, most
bihormonal adenomas resemble the densely granulated pure somatotroph adenomas.
Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth
factor I (IGF-I or somatomedin C), which causes many of the clinical manifestations. If a
somatotrophic adenoma appears in children before the epiphyses have closed, the
elevated levels of GH (and IGF-1) result in gigantism. This is characterized by a
generalized increase in body size with disproportionately long arms and legs. If the
increased levels of GH are present after closure of the epiphyses, patients develop
acromegaly. In this condition, growth is most conspicuous in skin and soft tissues;
viscera (thyroid, heart, liver, and adrenals); and bones of the face, hands, and feet. Bone
density may be increased (hyperostosis) in both the spine and the hips. Enlargement of
the jaw results in protrusion (prognathism) with broadening of the lower face. The hands
and feet are enlarged with broad, sausage-like fingers. In most instances, gigantism is
also accompanied by evidence of acromegaly. These changes develop for decades before
being recognized, hence the opportunity for the adenomas to reach substantial size. GH
excess is also correlated with a variety of other disturbances, including gonadal
dysfunction, diabetes mellitus, generalized muscle weakness, hypertension, arthritis,
congestive heart failure, and an increased risk of gastrointestinal cancers.
The diagnosis of pituitary GH excess relies on documentation of elevated serum GH and
IGF-1 levels. In addition, failure to suppress GH production in response to an oral load
of glucose is one of the most sensitive tests for acromegaly. The goals of treatment are to
restore GH levels to normal and to decrease symptoms referable to a pituitary mass lesion
while not causing hypopituitarism. To achieve these goals, the tumor can be removed
surgically or destroyed by radiation therapy,
or GH secretion can be reduced by drug therapy. When effective control of GH
hypersecretion is achieved, the characteristic tissue overgrowth and related symptoms
gradually recede, and the metabolic abnormalities improve.
CORTICOTROPH CELL ADENOMAS
Corticotroph adenomas are usually small microadenomas at the time of diagnosis. These
tumors are most often basophilic (densely granulated) and occasionally chromophobic
(sparsely granulated). Both variants stain positively with periodic acid-Schiff (PAS)
because of the presence of carbohydrate in pre-opiomelanocorticotropin (POMC), the
ACTH precursor molecule; in addition, they demonstrate variable immunoreactivity for
POMC and its derivatives, including ACTH and β-endorphin.
Excess production of ACTH by the corticotroph adenoma leads to adrenal hypersecretion
of cortisol and the development of hypercortisolism (also known as Cushing syndrome).
This syndrome is discussed in more detail later with the diseases of the adrenal gland. It
can be caused by a wide variety of conditions in addition to ACTH-producing pituitary
tumors. When the hypercortisolism is due to excessive production of ACTH by the
pituitary, the process is designated Cushing disease. Large destructive adenomas can
develop in patients after surgical removal of the adrenal glands for treatment of Cushing
syndrome. This condition, known as Nelson syndrome, occurs most often because of a
loss of the inhibitory effect of adrenal corticosteroids on a pre-existing corticotroph
microadenoma. Because the adrenals are absent in patients with this disorder,
hypercortisolism does not develop. In contrast, patients present with mass effects of the
pituitary tumor. In addition, there can be hyperpigmentation because of the stimulatory
effect of other products of the ACTH precursor molecule on melanocytes.
OTHER ANTERIOR PITUITARY ADENOMAS
Pituitary adenomas may elaborate more than one hormone. For example, prolactin may
be demonstrable by immunolabeling of somatotroph adenomas. In other cases, unusual
plurihormonal adenomas are capable of secreting multiple hormones; these tumors are
usually aggressive. A few comments are made about several of the less frequent
Gonadotroph (LH-producing and FSH-producing) adenomas can be difficult to
recognize because they secrete hormones inefficiently and variably, and the secretory
products usually do not cause a recognizable clinical syndrome. Gonadotroph adenomas
are most frequently found in middle-aged men and women when they become large
enough to cause neurologic symptoms, such as impaired vision, headaches, diplopia, or
pituitary apoplexy. Pituitary hormone deficiencies can also be found, most commonly
impaired secretion of LH. This causes decreased energy and libido in men (due to
reduced testosterone) and amenorrhea in premenopausal women. Thus, gonadotroph
adenomas are paradoxically associated with secondary gonadal hypofunction. Most
gonadotroph adenomas are large and composed of chromophobic cells. The neoplastic
cells usually demonstrate immunoreactivity for the common gonadotropin α-subunit and
the specific β-FSH and β-LH subunits; FSH is usually the predominant secreted hormone.
The availability of reliable immunoassays for the gonadotropin β-subunit and the
recognition of gonadotroph-specific transcription factors has led to the reclassification of
many previously hormone-negative adenomas ("null cell adenomas") as silent
gonadotroph adenomas (see below).
Thyrotroph (TSH-producing) adenomas are rare, accounting for approximately 1% of all
pituitary adenomas. Thyrotroph adenomas are chromophobic or basophilic and are a rare
cause of hyperthyroidism.
Nonfunctioning pituitary adenomas comprise both clinically silent counterparts of the
functioning adenomas described above (for example, a silent somatotroph adenoma) and
true hormone-negative adenomas. Nonfunctioning adenomas constitute approximately
25% of all pituitary tumors. In the past, the majority of nonfunctioning adenomas were
classified as "null cell adenomas" because of the inability to demonstrate markers of
differentiation. It is now known that most null cell adenomas have biochemical and
ultrastructural features that allow their characterization as silent tumors of
gonadotrophic lineage. True hormone-negative adenomas are therefore unusual. Not
surprisingly, the typical presentation of nonfunctioning adenomas is mass effects. These
lesions may also compromise the residual anterior pituitary sufficiently to cause
hypopituitarism. This may occur as a result of gradual enlargement of the adenoma or
after abrupt enlargement of the tumor because of acute hemorrhage (pituitary apoplexy).
Pituitary carcinomas are quite rare, and most are not functional. These malignant tumors
range from well differentiated, resembling somewhat atypical adenomas, to poorly
differentiated, with variable degrees of pleomorphism and the features that are
characteristic of carcinomas in other locations. The diagnosis of carcinoma requires the
demonstration of metastases, usually to lymph nodes, bone, liver, and sometimes
Hypopituitarism refers to decreased secretion of pituitary hormones, which can result
from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior
pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may
be congenital or the result of a variety of acquired abnormalities that are intrinsic to the
pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in
the form of diabetes insipidus (see below) is almost always of hypothalamic origin. Most
cases of hypofunction arise from destructive processes directly involving the anterior
pituitary, although other mechanisms have been identified:
• Tumors and other mass lesions: Pituitary adenomas, other benign tumors arising
within the sella, primary and metastatic malignancies, and cysts can cause
hypopituitarism. Any mass lesion in the sella can cause damage by exerting
pressure on adjacent pituitary cells.
• Pituitary surgery or radiation: Surgical excision of a pituitary adenoma may
inadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary,
used to prevent
regrowth of residual tumor after surgery, can damage the nonadenomatous
• Pituitary apoplexy: As has been mentioned, this is a sudden hemorrhage into the
pituitary gland, often occurring into a pituitary adenoma. In its most dramatic
presentation, apoplexy causes the sudden onset of excruciating headache, diplopia
owing to pressure on the oculomotor nerves, and hypopituitarism. In severe cases,
it can cause cardiovascular collapse, loss of consciousness, and even sudden
death. Thus, pituitary apoplexy is a true neurosurgical emergency.
• Ischemic necrosis of the pituitary and Sheehan syndrome: Ischemic necrosis of
the anterior pituitary is an important cause of pituitary insufficiency. Sheehan
syndrome, or postpartum necrosis of the anterior pituitary, is the most common
form of clinically significant ischemic necrosis of the anterior pituitary. During
pregnancy, the anterior pituitary enlarges to almost twice its normal size. This
physiologic expansion of the gland is not accompanied by an increase in blood
supply from the low-pressure venous system; hence, there is relative anoxia of the
pituitary. Further reduction in blood supply caused by obstetric hemorrhage or
shock may precipitate infarction of the anterior lobe. The posterior pituitary,
because it receives its blood directly from arterial branches, is much less
susceptible to ischemic injury in this setting and is therefore usually not affected.
Pituitary necrosis may also be encountered in other conditions, such as
disseminated intravascular coagulation and (more rarely) sickle cell anemia,
elevated intracranial pressure, traumatic injury, and shock of any origin. Whatever
the pathogenesis, the ischemic area is resorbed and replaced by a nubbin of
fibrous tissue attached to the wall of an empty sella.
• Rathke cleft cyst: These cysts, lined by ciliated cuboidal epithelium with
occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous
fluid and expand, compromising the normal gland.
• Empty sella syndrome: Any condition that destroys part or all of the pituitary
gland, such as ablation of the pituitary by surgery or radiation, can result in an
empty sella. The empty sella syndrome refers to the presence of an enlarged,
empty sella turcica that is not filled with pituitary tissue. There are two types: (1)
In a primary empty sella, there is a defect in the diaphragma sella that allows the
arachnoid mater and cerebrospinal fluid to herniate into the sella, resulting in
expansion of the sella and compression of the pituitary. Classically, affected
patients are obese women with a history of multiple pregnancies. The empty sella
syndrome may be associated with visual field defects and occasionally with
endocrine anomalies, such as hyperprolactinemia, owing to interruption of
inhibitory hypothalamic effects. Loss of functioning parenchyma can be severe
enough to result in hypopituitarism. (2) In a secondary empty sella, a mass, such
as a pituitary adenoma, enlarges the sella, but then it is either surgically removed
or undergoes spontaneous necrosis, leading to loss of pituitary function.
Hypopituitarism can result from the treatment or spontaneous infarction.
• Genetic defects: Rare congenital deficiencies of one or more pituitary hormones
have been recognized in children. For example, mutations in pit-1, a pituitary
transcription factor, result in combined deficiency of GH, prolactin, and TSH. 
Less frequently, disorders that interfere with the delivery of pituitary hormone-releasing
factors from the hypothalamus, such as hypothalamic tumors, may also cause
hypofunction of the anterior pituitary. Any disease involving the hypothalamus can alter
secretion of one or more of the hypothalamic hormones that influence secretion of the
corresponding pituitary hormones. In contrast to diseases that involve the pituitary
directly, any of these conditions can also diminish the secretion of ADH, resulting in
diabetes insipidus (discussed later). Hypothalamic lesions that cause hypopituitarism
• Tumors, including benign lesions that arise in the hypothalamus, such as
craniopharyngiomas, and malignant tumors that metastasize to that site, such as
breast and lung carcinomas. Hypothalamic hormone deficiency can ensue when
brain or nasopharyngeal tumors are treated with radiation.
• Inflammatory disorders and infections, such as sarcoidosis or tuberculous
meningitis, can cause deficiencies of anterior pituitary hormones and diabetes
The clinical manifestations of anterior pituitary hypofunction depend on the specific
hormone(s) that are lacking. Children can develop growth failure (pituitary dwarfism)
due to growth hormone deficiency. Gonadotropin (GnRH) deficiency leads to
amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic
and axillary hair in men. TSH and ACTH deficiencies result in symptoms of
hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter.
Prolactin deficiency results in failure of postpartum lactation. The anterior pituitary is
also a rich source of melanocyte-stimulating hormone (MSH), synthesized from the same
precursor molecule that produces ACTH; therefore, one of the manifestations of
hypopituitarism includes pallor due to a loss of stimulatory effects of MSH on
Posterior Pituitary Syndromes
The clinically relevant posterior pituitary syndromes involve ADH and include diabetes
insipidus and secretion of inappropriately high levels of ADH.
• Diabetes insipidus. ADH deficiency causes diabetes insipidus, a condition
characterized by excessive urination (polyuria) owing to an inability of the kidney
to resorb water properly from the urine. It can result from a variety of processes,
including head trauma, tumors, and inflammatory disorders of the hypothalamus
and pituitary as well as surgical procedures involving these organs. The condition
can also arise spontaneously, in the absence of an underlying disorder. Diabetes
insipidus from ADH deficiency is designated as central to differentiate it from
nephrogenic diabetes insipidus, which is a result of renal tubular
unresponsiveness to circulating ADH. The clinical manifestations of the two
diseases are similar and include the excretion of large volumes of dilute urine
with an inappropriately low specific gravity. Serum sodium and osmolality are
increased owing to excessive renal loss of free
water, resulting in thirst and polydipsia. Patients who can drink water can
generally compensate for urinary losses; patients who are obtunded, bedridden, or
otherwise limited in their ability to obtain water may develop life-threatening
• Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes
resorption of excessive amounts of free water, resulting in hyponatremia. The
most frequent causes of SIADH include the secretion of ectopic ADH by
malignant neoplasms (particularly small cell carcinomas of the lung), non-
neoplastic diseases of the lung, and local injury to the hypothalamus or posterior
pituitary (or both). The clinical manifestations of SIADH are dominated by
hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although
total body water is increased, blood volume remains normal, and peripheral
edema does not develop.
Hypothalamic Suprasellar Tumors
Neoplasms in this location may induce hypofunction or hyperfunction of the anterior
pituitary, diabetes insipidus, or combinations of these manifestations. The most
commonly implicated lesions are gliomas (sometimes arising in the chiasm; see Chapter
28 ) and craniopharyngiomas. The craniopharyngioma is thought to be derived from
vestigial remnants of Rathke pouch. These slow-growing tumors account for 1% to 5% of
intracranial tumors; a small minority of these lesions arise within the sella, but most are
suprasellar, with or without an intrasellar extension. A bimodal age distribution is
observed, with one peak in childhood (5 to 15 years) and a second peak in adults in the
sixth decade or older. Children usually come to clinical attention because of endocrine
deficiencies such as growth retardation, whereas adults usually present with visual
disturbances. Pituitary hormonal deficiencies, including diabetes insipidus, are common.
Craniopharyngiomas average 3 to 4 cm in diameter; they may be encapsulated and solid,
but more commonly, they are cystic and sometimes multiloculated. In their strategic
location, they often encroach on the optic chiasm or cranial nerves, and not infrequently,
they bulge into the floor of the third ventricle and base of the brain. Two distinct
pathologic variants are recognized: adamantinomatous craniopharyngioma and
papillary craniopharyngioma. The adamantinomatous type frequently contains
radiologically demonstrable calcifications; the papillary variant is calcified only rarely.
Adamantinomatous craniopharyngioma consists of nests or cords of stratified squamous
epithelium embedded in a spongy "reticulum" that becomes more prominent in the
internal layers. Peripherally, the nests of squamous cells gradually merge into a layer of
columnar cells, forming a palisade resting on a basement membrane. Compact, lamellar
keratin formation ("wet keratin") is a diagnostic feature of this tumor. As was previously
mentioned, dystrophic calcification is a frequent finding. Additional features include cyst
formation, fibrosis, and chronic inflammatory reaction. The cysts of adamantinomatous
craniopharyngiomas often contain a cholesterol-rich, thick brownish yellow fluid that has
been compared to "machinery oil." These tumors extend fingerlets of epithelium into
adjacent brain, where they elicit a brisk glial reaction.
Papillary craniopahryngiomas contain both solid sheets and papillae lined by well-
differentiated squamous epithelium. These tumors usually lack keratin, calcification, and
cysts. The squamous cells of the solid sections of the tumor do not have the peripheral
palisading and do not typically generate a spongy reticulum in the internal layers.
Patients with craniopharyngiomas have an excellent recurrence-free and overall survival.
Tumors greater than 5 cm in diameter are associated with a significantly higher
recurrence rate. Adamantinomatous tumors are associated with a higher frequency of
brain invasion, but this does not necessarily correlate with an adverse prognosis.
Malignant transformation of craniopharyngiomas into squamous carcinomas is
exceptionally rare and usually occurs postradiation.
The thyroid gland consists of two bulky lateral lobes connected by a relatively thin
isthmus, usually located below and anterior to the larynx. Normal variations in the
structure of the thyroid gland include the presence of a pyramidal lobe, a remnant of the
thyroglossal duct above the isthmus.
The thyroid gland develops from an evagination of the developing pharyngeal epithelium
that descends as part of the thyroglossal duct from the foramen cecum at the base of the
tongue to its normal position in the anterior neck. This pattern of descent explains the
occasional presence of ectopic thyroid tissue, most commonly located at the base of the
tongue (lingual thyroid) or at other sites abnormally high in the neck. Excessive descent
leads to substernal thyroid glands. The clinical significance of these lesions lies in
them from metastatic thyroid carcinomas and the extremely rare occasions on which
these ectopic sites can develop a primary thyroid malignancy. Patients with lingual
thyroids present an additional problem in that the ectopic thyroid tissue is sometimes the
only thyroid tissue (total migration failure), and removal of the lingual thyroid results in
symptomatic hypothyroidism. Malformations of branchial pouch differentiation may
result in intrathyroidal sites of the thymus or parathyroid glands. The implication of these
deviations becomes evident in the patient who has a total thyroidectomy and
subsequently develops hypoparathyroidism.
The weight of the normal adult thyroid is approximately 15 to 25 gm. The thyroid has a
rich intraglandular capillary network that is supplied by the superior and inferior
thyroidal arteries. Nerve fibers from the cervical sympathetic ganglia indirectly influence
thyroid secretion by acting on the blood vessels. The thyroid is divided by thin fibrous
septae into lobules composed of about 20 to 40 evenly dispersed follicles. Normal
follicles range from 50 to 500 µm in size, are lined by cuboidal to low columnar
epithelium, and are filled with periodic acid Schiff (PAS)-positive thyroglobulin.
In response to trophic factors from the hypothalamus, TSH (thyrotropin) is released by
thyrotrophs in the anterior pituitary into the circulation. The binding of TSH to its
receptor on the thyroid follicular epithelium results in activation and conformational
change in the receptor, allowing it to associate with a stimulatory G-protein ( Fig. 24-7 ).
Activation of the G-protein eventually results in an increase in intracellular cAMP levels,
which stimulates thyroid growth, and hormone synthesis and release via cAMP-
dependent protein kinases. The dissociation of thyroid hormone synthesis and release
from the controlled influence of TSH-signaling pathways results in so-called thyroid
autonomy and hyperfunction (see below).
Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4 ) and lesser
amounts of triiodothyronine (T3 ). T4 and T3 are released into the systemic circulation,
where most of these peptides are reversibly bound to circulating plasma proteins, such as
thyroxine-binding globulin (TBG) and transthyretin, for transport to peripheral tissues.
The binding proteins serve to maintain the serum unbound ("free") T3 and T4
concentrations within narrow limits yet ensure that the hormones are readily available to
the tissues. In the periphery, the majority of free T4 is deiodinated to T3 ; the latter binds
to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does
T4 and has proportionately greater activity. The interaction of thyroid hormone with its
nuclear thyroid hormone receptor (TR) results in the formation of a multi-protein
hormone-receptor complex that binds to thyroid hormone response elements (TREs) in
target genes, regulating their transcription (see Fig. 24-7 ). Thyroid hormone has
diverse cellular effects, including up-regulation of carbohydrate and lipid catabolism and
stimulation of protein synthesis in a wide range of cells. The net result of these processes
is an increase in the basal metabolic rate. One of the most important functions of thyroid
hormone is its critical role in brain development, since absence of thyroid hormone
during the fetal and neonatal periods may profoundly interfere with intellectual growth
The thyroid gland is one of the most responsive organs in the body and contains the
largest store of hormones of any endocrine gland. The gland responds to many stimuli
Figure 24-7 Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid
hormones. Secretion of thyroid hormones (T3 and T4 ) is controlled by trophic factors secreted by both the
hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release 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, suppress the secretion of both
TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the
thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (cAMP)-mediated
synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the thyroid
hormone receptor (TR) to form a hormone-receptor complex that translocates to the nucleus and binds to
so-called thyroid response elements (TREs) on target genes initiating transcription.
in a constant state of adaptation. During puberty, pregnancy, and physiologic stress from
any source, the gland increases in size and becomes more active. This functional lability
is reflected in transient hyperplasia of the thyroidal epithelium. At this time,
thyroglobulin is resorbed, and the follicular cells become tall and more columnar,
sometimes forming small, infolded buds or papillae. When the stress abates, involution
occurs; that is, the height of the epithelium falls, colloid accumulates, and the follicular
cells resume their normal size and architecture. Failure of this normal balance between
hyperplasia and involution can produce major or minor deviations from the usual
The function of the thyroid gland can be inhibited by a variety of chemical agents,
collectively referred to as goitrogens. Because they suppress T3 and T4 synthesis, the level
of TSH increases, and subsequent hyperplastic enlargement of the gland (goiter) follows.
The antithyroid agent propylthiouracil inhibits the oxidation of iodide and blocks
of the thyroid hormones; parenthetically, propylthiouracil also inhibits the peripheral
deiodination of circulating T4 into T3 , thus ameliorating symptoms of thyroid hormone
excess (see below). Iodide, when given to patients with thyroid hyperfunction, also
blocks the release of thyroid hormones but through different mechanisms. Iodides in
large doses inhibit proteolysis of thyroglobulin. Thus, thyroid hormone is synthesized and
incorporated within increasing amounts of colloid, but it is not released into the blood.
The thyroid gland follicles also contain a population of parafollicular cells, or C cells,
which synthesize and secrete the hormone calcitonin. This hormone promotes the
absorption of calcium by the skeletal system and inhibits the resorption of bone by
Diseases of the thyroid are of great importance because most are amenable to medical or
surgical management. They include conditions associated with excessive release of
thyroid hormones (hyperthyroidism), those associated with thyroid hormone deficiency
(hypothyroidism), and mass lesions of the thyroid. We first consider the clinical
consequences of disturbed thyroid function, then focus on the disorders that generate
Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3
and T4 . Because it is caused most commonly by hyperfunction of the thyroid 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 thyroiditis) or to
an extrathyroidal source, rather than hyperfunction of the gland ( Table 24-2 ). Thus,
strictly speaking, hyperthyroidism is only
TABLE 24-2 -- Disorders Associated with Thyrotoxicosis
Associated with Hyperthyroidism
Diffuse toxic hyperplasia (Graves disease)
Hyperfunctioning ("toxic") multinodular goiter
Hyperfunctioning ("toxic") adenoma
Hyperfunctioning thyroid carcinoma
Neonatal thyrotoxicosis associated with maternal Graves disease
TSH-secreting pituitary adenoma (rare) *
Not Associated with Hyperthyroidism
Subacute granulomatous thyroiditis (painful)
Subacute lymphocytic thyroiditis (painless)
Struma ovarii (ovarian teratoma with ectopic thyroid)
Factitious thyrotoxicosis (exogenous thyroxine intake)
*Associated with increased TSH; all other causes of thyrotoxicosis associated with decreased TSH.
one (albeit the most common) cause of thyrotoxicosis. The terms primary and secondary
hyperthyroidism are sometimes used to designate hyperthyroidism arising from an
intrinsic thyroid abnormality and that arising from processes outside of the thyroid, such
as a TSH-secreting pituitary tumor. With this disclaimer, we will follow the common
practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three
most common causes of thyrotoxicosis are also associated with hyperfunction of the
gland and include the following:
• Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for
85% of cases)
• Hyperfunctional multinodular goiter
• Hyperfunctional adenoma of the thyroid
The clinical manifestations of hyperthyroidism are protean and include changes referable
to the hypermetabolic state induced by excess thyroid hormone as well as those related to
overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic
Excessive levels of thyroid hormone result in an increase in the basal metabolic rate.
The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased
blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common.
Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic
rate also results in characteristic weight loss despite increased appetite.
Cardiac manifestations are among the earliest and most consistent features of
hyperthyroidism. Patients with hyperthyroidism can have an increase in cardiac output,
owing to both increased cardiac contractility and increased peripheral oxygen
requirements. Tachycardia, palpitations, and cardiomegaly are common. Arrhythmias,
particularly atrial fibrillation, occur frequently and are more common in older patients.
Congestive heart failure may develop, particularly in elderly patients with pre-existing
cardiac disease. Myocardial changes, such as foci of lymphocytic and eosinophilic
infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase
in size and number of mitochondria, have been described. Some patients with
thyrotoxicosis develop a reversible diastolic dysfunction and a "low-output" failure, so-
called thyrotoxic dilated cardiomyopathy.
In the neuromuscular system, overactivity of the sympathetic nervous system produces
tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia.
Proximal muscle weakness is common with decreased muscle mass (thyroid myopathy).
Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag
are present because of sympathetic overstimulation of the levator palpebrae superioris
( Fig. 24-8 ). However, true thyroid ophthalmopathy associated with proptosis is a feature
seen only in Graves disease (see below).
In the gastrointestinal system, sympathetic hyperstimulation of the gut results in
hypermotility, malabsorption, and diarrhea.
The skeletal system is also affected in hyperthyroidism. Thyroid hormone stimulates bone
resorption, resulting in increased porosity of cortical bone and reduced volume of
trabecular bone. The net effect is osteoporosis and an increased risk of fractures in
patients with chronic hyperthyroidism.
Figure 24-8 A patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the
sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most
important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds
to the protuberant appearance of the eyes.
Other findings throughout the body include atrophy of skeletal muscle, with fatty
infiltration and focal interstitial lymphocytic infiltrates; minimal liver enlargement due to
fatty changes in the hepatocytes; and generalized lymphoid hyperplasia with
lymphadenopathy in patients with Graves disease.
Thyroid storm is used to designate the abrupt onset of severe hyperthyroidism. This
condition occurs most commonly in patients with underlying Graves disease and
probably results from an acute elevation in catecholamine levels, as might be encountered
during infection, surgery, cessation 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 die of
Apathetic hyperthyroidism refers to thyrotoxicosis occurring in the elderly, in whom old
age and various comorbidities may blunt the typical features of thyroid hormone excess
seen in younger patients. The diagnosis of thyrotoxicosis in these patients is often made
during laboratory work-up for unexplained weight loss or worsening cardiovascular
A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The
measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides
the most useful single screening test for hyperthyroidism, as its levels are decreased even
at the earliest stages, when the disease may still be subclinical. A low TSH value is
usually confirmed with measurement of free T4 , which is expectedly increased. In an
occasional patient, hyperthyroidism results predominantly from increased circulating
levels of T3 ("T3 toxicosis"). In these cases, free T4 levels may be decreased, and direct
measurement of serum T3 may be useful. In rare cases of pituitary-associated (secondary)
hyperthyroidism, TSH levels are either normal or raised. Determining TSH levels after
the injection of TRH (TRH stimulation test) is used in the evaluation of cases of
suspected hyperthyroidism with equivocal changes in the baseline serum TSH level. A
normal rise in TSH after administration of TRH excludes secondary hyperthyroidism.
Once the diagnosis of thyrotoxicosis has been confirmed by a combination of sTSH
assays and free thyroid hormone levels, measurement of radioactive iodine uptake by the
thyroid gland may be valuable in determining the etiology. For example, there may be
diffusely increased uptake in the whole gland (Graves disease), increased uptake in a
solitary nodule (toxic adenoma), or decreased uptake (thyroiditis). The therapeutic
options for hyperthyroidism include multiple medications, each of which has a different
mechanism of action. Typically, these include a β-blocker to control symptoms induced
by increased adrenergic tone, a thionamide to block new hormone synthesis, an iodine
solution to block the release of thyroid hormone, and agents that inhibit peripheral
conversion of T4 to T3 . Radioiodine, which is incorporated into thyroid tissues, resulting
in ablation of thyroid function over a period of 6 to 18 weeks, may also be used.
Hypothyroidism is caused by any structural or functional derangement that interferes with
the production of adequate levels of thyroid hormone. It can result from a defect
anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism,
this disorder is divided into primary and secondary categories, depending on whether the
hypothyroidism arises from an intrinsic abnormality in the thyroid or occurs as a result of
pituitary disease; rarely, hypothalamic failure is a cause of tertiary hypothyroidism
( Table 24-3 ). Primary hypothyroidism accounts for the vast majority of cases of
hypothyroidism. Primary hypothyroidism can be thyroprivic (due to absence or loss of
thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the
influence of TSH). The causes of primary hypothyroidism include the following.
Surgical or radiation-induced ablation of thyroid parenchyma can cause hypothyroidism.
A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism
of a primary neoplasm can lead to hypothyroidism. The gland may also be ablated by
radiation, whether in the form of radioiodine administered for the treatment of
TABLE 24-3 -- Causes of Hypothyroidism
Developmental (thyroid dysgenesis: PAX-8, TTF-2, TSH-receptor mutations)
Thyroid hormone resistance syndrome (TRβ mutations)
Surgery, radioiodine therapy, or external radiation
Hashimoto thyroiditis *
Iodine deficiency *
Drugs (lithium, iodides, p-aminosalicylic acid) *
Congenital biosynthetic defect (dyshormonogenetic goiter) *
Hypothalamic failure (rare)
*Associated with enlargement of thyroid ("goitrous hypothyroidism"). Hashimoto thyroiditis and
postablative hypothroidism account for the majority of cases.
exogenous irradiation, such as external radiation therapy to the neck.
Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in
iodine-sufficient areas of the world. The vast majority of cases of autoimmune
hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including
anti-TSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis. Some
patients with hypothyroidism have circulating anti-TSH antibodies, but they usually do
not have the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto
thyroiditis. In the past, many of these patients were classified as having primary
"idiopathic" hypothyroidism, but the disease is now recognized as a type of autoimmune
disorder of the thyroid, occurring either in isolation or in conjunction with other
autoimmune endocrine manifestations.
Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and
propylthiouracil) can cause hypothyroidism, as can agents used to treat nonthyroid
conditions (e.g., lithium, p-aminosalicylic acid).
Inborn errors of thyroid metabolism are an uncommon cause of goitrous hypothyroidism
(dyshormonogenetic goiter). Any one of the multiple steps leading to thyroid hormone
synthesis may be deficient: (1) iodide transport defect, (2) organification defect, (3)
dehalogenase defect, and (4) iodotyrosine coupling defect. Organification of iodine
involves binding of oxidized iodide with tyrosyl residues in thyroglobulin, and this
process is deficient in patients with Pendred syndrome, wherein goitrous hypothyroidism
is accompanied by sensorineural deafness.
Thyroid hormone resistance syndrome is a rare autosomal-dominant disorder caused by
inherited mutations in the thyroid hormone receptor (TR), which abolish the ability of the
receptor to bind thyroid hormones. Patients demonstrate a generalized resistance to
thyroid hormone, despite high circulating levels of T3 and T4 . Since the pituitary is also
resistant to feedback from thyroid hormones, TSH levels tend to be high as well. In rare
instances, there may be complete absence of thyroid parenchyma (thyroid agenesis), or
the gland may be greatly reduced in size (thyroid hypoplasia). Mutations in the TSH
receptor are a newly recognized cause of congenital hypothyroidism associated with a
hypoplastic thyroid gland. Recently, mutations in two transcription factors that are
expressed in the developing thyroid and regulate follicular differentiation—thyroid
transcription factor-2 (TTF-2) and Paired Homeobox-8 (PAX-8) —have been
reported in patients with thyroid agenesis. Thyroid agenesis caused by TTF-2 mutations
is usually associated with a cleft palate.
Secondary hypothyroidism is caused by TSH deficiency, and tertiary (central)
hypothyroidism is caused by TRH deficiency. Secondary hypothyroidism can result from
any of the causes of hypopituitarism. Frequently, the cause is a pituitary tumor; other
causes include postpartum pituitary necrosis, trauma, and nonpituitary tumors, as was
previously discussed. Tertiary (central) hypothyroidism can be caused by any disorder
that damages the hypothalamus or interferes with hypothalamic-pituitary portal blood
flow, thereby preventing delivery of TRH to the pituitary. This can result from
hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases.
Classic clinical manifestations of hypothyroidism include cretinism and myxedema.
Cretinism refers to hypothyroidism that develops in infancy or early childhood. The term
cretin was derived from the French chrétien, meaning Christian or Christlike, and was
applied to these unfortunates because they were considered to be so mentally retarded as
to be incapable of sinning. In the past, this disorder occurred fairly commonly in areas of
the world where dietary iodine deficiency is endemic, such as the Himalayas, inland
China, Africa, and other mountainous areas. It has become much less frequent in recent
years, owing to the widespread supplementation of foods with iodine. On rare occasions,
cretinism may also result from inborn errors in metabolism (e.g., enzyme deficiencies)
that interfere with the biosynthesis of normal levels of thyroid hormone (sporadic
Clinical features of cretinism include impaired development of the skeletal system and
central nervous system, manifested by severe mental retardation, short stature, coarse
facial features, a protruding tongue, and umbilical hernia. The severity of the mental
impairment in cretinism appears to be related to the time at which thyroid deficiency
occurs in utero. Normally, maternal hormones, including T3 and T4 , cross the placenta
and are critical to fetal brain development. If there is maternal thyroid deficiency before
the development of the fetal thyroid gland, mental retardation is severe. In contrast,
reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has
developed, allows normal brain development.
The term myxedema is applied to hypothyroidism developing in the older child or adult.
Myxedema, or Gull disease, was first linked with thyroid dysfunction in 1873 by Sir
William Gull in a paper addressing the development of a "cretinoid state" in adults. The
clinical manifestations vary with the age of onset of the deficiency. The older child shows
signs and symptoms intermediate between those of the cretin and those of the adult with
hypothyroidism. In the adult, the condition appears insidiously and may take years to
reach the level of clinical suspicion.
Clinical features of myxedema are characterized by a slowing of physical and mental
activity. The initial symptoms include generalized fatigue, apathy, and mental
sluggishness, which may mimic depression in the early stages of the disease. Speech and
intellectual functions become slowed. Patients with myxedema are listless, cold-
intolerant, and frequently overweight. Reduced cardiac output probably contributes to
shortness of breath and decreased exercise capacity, two frequent complaints in patients
with hypothyroidism. Decreased sympathetic activity results in constipation and
decreased sweating. The skin in these patients is cool and pale because of decreased
blood flow. Histologically, there is an accumulation of matrix substances, such as
glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and a number of
visceral sites. This results in edema, a broadening and coarsening of facial features,
enlargement of the tongue, and deepening of the voice.
Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism
because of the nonspecific nature
of symptoms. Measurement of the serum TSH level is the most sensitive screening test
for this disorder. The TSH level is increased in primary hypothyroidism due to a loss of
feedback inhibition of TRH and TSH production by the hypothalamus and pituitary,
respectively. The TSH level is not increased in patients with hypothyroidism due to
primary hypothalamic or pituitary disease. T4 levels are decreased in patients with
hypothyroidism of any origin.
Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of
disorders characterized by some form of thyroid inflammation. These diseases include
conditions that result in acute illness with severe thyroid pain (e.g., infectious thyroiditis,
subacute granulomatous thyroiditis) and disorders in which there is relatively little
inflammation and the illness is manifested primarily by thyroid dysfunction (subacute
lymphocytic thyroiditis and fibrous [Reidel] thyroiditis).
Infectious thyroiditis may be either acute or chronic. Acute infections can reach the
thyroid via hematogenous spread or through direct seeding of the gland, such as via a
fistula from the piriform sinus adjacent to the larynx. Other infections of the thyroid,
including mycobacterial, fungal, and Pneumocystis infections, are more chronic and
frequently occur in immunocompromised patients. Whatever the cause, the inflammatory
involvement may cause sudden onset of neck pain and tenderness in the area of the gland
and is accompanied by fever, chills, and other signs of infection. Infectious thyroiditis
can be self-limited or can be controlled with appropriate therapy. Thyroid function is
usually not significantly affected, and there are few residual effects except for possible
small foci of scarring. This section focuses on the more common and clinically
significant types of thyroiditis: (1) Hashimoto thyroiditis (or chronic lymphocytic
thyroiditis), (2) subacute granulomatous thyroiditis, and (3) subacute lymphocytic
Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of
hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized
by gradual thyroid failure because of autoimmune destruction of the thyroid gland. The
name Hashimoto thyroiditis is derived from the 1912 report by Hashimoto describing
patients with goiter and intense lymphocytic infiltration of the thyroid (struma
lymphomatosa). This disorder is most prevalent between 45 and 65 years of age and is
more common in women than in men, with a female predominance of 10:1 to 20:1.
Although it is primarily a disease of older women, it can occur in children and is a major
cause of nonendemic goiter in children.
Epidemiologic studies have demonstrated a significant genetic component to Hashimoto
thyroiditis, although, as in most other autoimmune disorders, the pattern of inheritance is
non-Mendelian and likely to be influenced by subtle variations in the functions of
multiple genes. The concordance rate in monozygotic twins is 30% to 60%, and up to
50% of asymptomatic first-degree relatives of Hashimoto patients demonstrate
circulating antithyroid antibodies. Several chromosomal abnormalities have been
associated with thyroid autoimmunity. For example, adults with Turner syndrome (see
Chapter 5 ) have a high prevalence of circulating antithyroid antibodies, and a substantial
minority (∼20%) develops subclinical or clinical hypothyroidism that is indistinguishable
from Hashimoto thyroiditis. Similarly, adults with trisomy 21 (Down syndrome, see
Chapter 5 ) are also at an increased risk for developing Hashimoto thyroiditis and
hypothyroidism. There are reports that polymorphisms in the HLA locus, specifically the
HLA-DR3 and HLA-DR5 alleles, are linked to Hashimoto thyroiditis, but the association
is weak. Finally, genomewide linkage analyses in families with Hashimoto thyroiditis
have provided evidence for several susceptibility loci, such as on chromosomes 6p and
12q, that may harbor genes predisposing to this disorder. 
Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts
against a variety of thyroid antigens. The overriding feature of Hashimoto thyroiditis is
progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually
replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms
may contribute to the death of thyrocytes ( Fig. 24-9 ). Sensitization of autoreactive
CD4+ T-helper cells to thyroid antigens appears to be the initiating event. The effector
mechanisms for thyrocyte death include the following:
• CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may cause
thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme
granules or engagement of death receptors, specifically CD95 (also known as Fas)
on the target cell ( Chapter 6 ).
• Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines
such as IFN-γ in the immediate thyrocyte milieu, with resultant recruitment and
activation of macrophages and damage to follicles.
• Binding of antithyroid antibodies (anti-TSH receptor antibodies,
antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-
dependent cell-mediated cytotoxicity (ADCC) ( Chapter 6 ).
The thyroid is often diffusely enlarged, although more localized enlargement may be seen
in some cases. The capsule is intact, and the gland is well demarcated from adjacent
structures. The cut surface is pale, yellow-tan, firm, and somewhat nodular. Microscopic
examination reveals extensive infiltration of the parenchyma by a mononuclear
inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed
germinal centers ( Fig. 24-10 ). The thyroid follicles are atrophic and are lined in many
areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular
cytoplasm, termed Hürthle cells. This is a metaplastic response of the normally low
cuboidal follicular epithelium to ongoing injury. In fine-needle aspiration biopsies, the
presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes
is characteristic of Hashimoto thyroiditis. In "classic" Hashimoto thyroiditis, interstitial
connective tissue is increased and may be abundant. A fibrous variant is
Figure 24-9 Pathogenesis of Hashimoto thyroiditis. Three proposed models for mechanism of thyrocyte
destruction in Hashimoto disease. Sensitization of autoreactive CD4+ T cells to thyroid antigens appears to
be the initiating event for all three mechanisms of thyroid cell death. See the text for details.
characterized by severe thyroid follicular atrophy and dense "keloid-like" fibrosis, with
broad bands of acellular collagen encompassing residual thyroid tissue. Unlike Reidel
thyroiditis (see below), the fibrosis does not extend beyond the capsule of the gland. The
remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis.
Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid,
usually associated with some degree of hypothyroidism, in a middle-aged woman. The
enlargement of the gland is usually symmetric and diffuse, but in some cases, it may be
sufficiently localized to raise a suspicion of neoplasm. In the usual clinical course,
Figure 24-10 Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with
germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells are also seen.
hypothyroidism develops gradually. In some cases, however, it may be preceded by
transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release
of thyroid hormones ("hashitoxicosis"). During this phase, free T4 and T3 levels are
elevated, TSH is diminished, and radioactive iodine uptake is decreased. As
hypothyroidism supervenes, T4 and T3 levels progressively fall, accompanied by a
compensatory increase in TSH. Patients with Hashimoto thyroiditis are at increased risk
for developing other concomitant autoimmune diseases, both endocrine (type 1 diabetes,
autoimmune adrenalitis), and nonendocrine (systemic lupus erythematosus, myasthenia
gravis, and Sjögren syndrome; see Chapter 6 ), and also at increased risk for the
development of B-cell non-Hodgkin lymphomas. However, there is no established risk
for developing thyroid epithelial neoplasms.
SUBACUTE (GRANULOMATOUS) THYROIDITIS
Subacute thyroiditis, which is also referred to as granulomatous thyroiditis or De
Quervain thyroiditis, occurs much less frequently than does Hashimoto disease. The
disorder is most common between the ages of 30 and 50 and, like other forms of
thyroiditis, affects women considerably more often than men (3:1 to 5:1).
Subacute thyroiditis is believed to be caused by a viral infection or a postviral
inflammatory process. The majority of patients have a history of an upper respiratory
infection just before the onset of thyroiditis. The disease has a seasonal incidence, with
occurrences peaking in the summer, and clusters of cases have been reported in
association with coxsackievirus, mumps, measles, adenovirus, and other viral illnesses.
Although the pathogenesis of the disease is unclear, one model suggests that it results
from a viral infection that provides an antigen, either viral or a thyroid antigen that is
released secondary to virus-induced host tissue damage. This antigen stimulates cytotoxic
T lymphocytes, which then damage thyroid follicular cells. In contrast to autoimmune
thyroid disease, the immune response is virus-initiated and not self-perpetuating, so the
process is limited.
The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule. It
may be slightly adherent to surrounding structures. On cut section, the involved areas are
firm and yellow-white and stand out from the more rubbery, normal brown thyroid
substance. Histologically, the changes are patchy and depend on the stage of the disease.
Early in the active inflammatory phase, scattered follicles may be entirely disrupted and
replaced by neutrophils forming microabscesses. Later, the more characteristic features
appear in the form of aggregations of lymphocytes, histiocytes, and plasma cells about
collapsed and damaged thyroid follicles. Multinucleate giant cells enclose naked pools
or fragments of colloid ( Fig. 24-11 ), hence the designation granulomatous thyroiditis.
In later stages of the disease, a chronic inflammatory infiltrate and fibrosis may replace
the foci of injury. Different histologic stages are sometimes found in the same gland,
suggesting waves of destruction over a period of time.
The presentation of subacute thyroiditis may be sudden or gradual. It is characterized by
pain in the neck, which may radiate to the upper neck, jaw, throat, or ears, particularly
when swallowing. Fever, fatigue, malaise, anorexia, and myalgia accompany a variable
enlargement of the thyroid. The resultant thyroid inflammation and hyperthyroidism are
transient, usually diminishing in 2 to 6 weeks, even if the patient is not treated. It may be
followed by a period of transient, usually asymptomatic hypothyroidism lasting from 2 to
8 weeks, but recovery is virtually always complete.
The transient hyperthyroidism, as in other cases of thyroiditis, is due to disruption of
thyroid follicles and release of excessive thyroid hormone. Nearly all patients have high
serum T4 and T3 levels and low serum TSH levels. Radioactive
Figure 24-11 Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with
a multinucleate giant cell (above left) and a colloid follicle (bottom right).
iodine uptake is low because of suppression of TSH. The serum T4 and T3 levels are only
modestly elevated. However, unlike in hyperthyroid states such as Graves disease,
radioactive iodine uptake is diminished. After recovery, generally in 6 to 8 weeks, normal
thyroid function returns.
SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS
Subacute lymphocytic thyroiditis, which is also referred to as painless thyroiditis or silent
thyroiditis, is an uncommon cause of hyperthyroidism. It usually comes to clinical
attention because of mild hyperthyroidism, goitrous enlargement of the gland, or both.
Although it can occur at any age, it is most often seen in middle-aged adults and is more
common in women, especially during the postpartum period (postpartum thyroiditis),
than in men. Depending on the study, the frequency of this form of thyroiditis varies
considerably, from 1% to about 10% of cases of hyperthyroid patients. The pathogenesis
of this disorder is unknown. An autoimmune basis has been suggested because some
patients have elevated levels of antibodies to thyroglobulin and thyroid peroxidase or a
family history of thyroid autoimmune disease, and occasionally the disease evolves into
overt chronic autoimmune thyroiditis several years later. There is no evidence that points
toward a particular viral or other agent.
Except for possible mild symmetric enlargement, the thyroid appears normal on gross
inspection. The most specific histologic features consist of lymphocytic infiltration with
hyperplastic germinal centers within the thyroid parenchyma and patch disruption and
collapse of thyroid follicles. Unlike in Hashimoto thyroiditis, fibrosis and Hürthle cell
metaplasia are not commonly seen.
The principal clinical manifestation of painless thyroiditis is hyperthyroidism. Symptoms
usually develop over 1 to 2 weeks and last from 2 to 8 weeks before subsiding. The
patient may have any of the common findings of hyperthyroidism (e.g., palpitations,
tachycardia, tremor, weakness, and fatigue). The thyroid gland is not usually tender but is
minimally and diffusely enlarged. Infiltrative ophthalmopathy and other manifestations of
Graves disease (see below) are not present. Patients with one episode of postpartum
thyroiditis are at an increased risk of recurrence following subsequent pregnancies. A
minority of affected individuals eventually progress to hypothyroidism. Some patients
have no signs or symptoms, and the disorder is detected incidentally during routine
Laboratory findings during periods of thyrotoxicosis include elevated levels of T4 and T3
and depressed levels of TSH.
Other, less common forms of thyroiditis include Riedel thyroiditis, a rare disorder of
unknown etiology characterized by extensive fibrosis involving the thyroid and
contiguous neck structures. The presence of a hard and fixed thyroid mass clinically
simulates a thyroid carcinoma. It may be associated with idiopathic fibrosis in other sites
in the body, such as the retroperitoneum. The presence of circulating antithyroid
antibodies in most patients suggests an autoimmune etiology. Palpation
thyroiditis, caused by vigorous clinical palpation of the thyroid gland, results in
multifocal follicular disruption associated with chronic inflammatory cells and occasional
giant cell formation. Unlike De Quervain thyroiditis, abnormalities of thyroid function
are not present, and this is usually an incidental finding in specimens resected for other
Graves reported in 1835 his observations of a disease characterized by "violent and long
continued palpitations in females" associated with enlargement of the thyroid gland.
Graves disease is the most common cause of endogenous hyperthyroidism. It is
characterized by a triad of clinical findings:
1. Hyperthyroidism owing to hyperfunctional, diffuse enlargement of the thyroid
2. Infiltrative ophthalmopathy with resultant exophthalmos
3. Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which
is present in a minority of patients
Graves disease has a peak incidence between the ages of 20 and 40, women being
affected up to seven times more frequently than men. This disorder is said to be present in
1.5% to 2.0% of women in the United States. Genetic factors are important in the
etiology of Graves disease. An increased incidence of Graves disease occurs among