3. • 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
5. • Normal
• 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
6. 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-
7. 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:
8. 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:
9. • 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
10. 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: 
11. • 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
12. 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
13. 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.
14. 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
15. 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.
16. 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.
17. 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).
18. 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
19. • 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
20. 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
21. 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.
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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.
28. 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
29. 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)
31. 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
32. 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,
33. 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
35. 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,
36. 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
38. 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.
39. 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
40. family members of affected patients, and the concordance rate in monozygotic twins is as
high as 60%. A recurring theme, as with other autoimmune disorders, is a genetic
susceptibility to Graves disease associated with the presence of certain major
histocompatibility haplotypes, specifically HLA-B8 and -DR3. Polymorphisms in the
cytotoxic T-lymphocyte-associated-4 (CTLA-4) gene are also linked to Graves disease. 
Recall that the HLA proteins are a critical component of antigen presentation to T cells,
while CTLA-4 is an inhibitory receptor that prevents T-cell responses to self-antigens
( Chapter 6 ). Genomewide linkage analyses have revealed additional susceptibility loci
localized to chromosome 6p (also linked to Hashimoto thyroiditis) and to chromosome
20q, among others. 
Graves disease is an autoimmune disorder in which a variety of antibodies may be
present in the serum, including antibodies to the TSH receptor, thyroid peroxisomes, and
thyroglobulin. Of these, autoantibodies to the TSH receptor are central to disease
pathogenesis, although the specific effects of the antibodies vary depending on which
TSH receptor epitope they are directed against:
• Thyroid-stimulating immunoglobulin (TSI): Almost 50 years ago, serum from
patients with Graves disease was found to contain a long-acting thyroid stimulator
(LATS), so named because it stimulated thyroid function more slowly than TSH.
LATS proved to be an IgG antibody that binds to the TSH receptor and mimics
the action of TSH, stimulating adenyl cyclase, with resultant increased release of
thyroid hormones. Almost all patients with Graves disease have detectable levels
of this autoantibody to the TSH receptor. TSI is relatively specific for Graves
disease, in contrast to thyroglobulin and thyroid peroxidase antibodies.
• Thyroid growth-stimulating immunoglobulins (TGI): Also directed against the
TSH receptor, thyroid growth-stimulating immunoglobulins have been implicated
in the proliferation of thyroid follicular epithelium.
• TSH-binding inhibitor immunoglobulins (TBII): These anti-TSH receptor
antibodies prevent TSH from binding normally to its receptor on thyroid epithelial
cells. In so doing, some forms of TSH-binding inhibitor immunoglobulins mimic
the action of TSH, resulting in the stimulation of thyroid epithelial cell activity,
whereas other forms may actually inhibit thyroid cell function. It is not unusual to
find the coexistence of stimulating and inhibiting immunoglobulins in the serum
of the same patient, a finding that could explain why some patients with Graves
disease spontaneously develop episodes of hypothyroidism.
The key role of anti-TSH receptor antibodies in the pathogenesis of hyperthyroidism is
underscored by animal models that recapitulate human Graves disease. Immunization of
mice with the TSH receptor results in generation of antibodies that cause thyroid
stimulation, thyroid enlargement with lymphocytic infiltration, elevated thyroxine levels,
and, in a subset of mice, ocular signs reminiscent of Graves ophthalmopathy (see below).
Similar to the human disease, a gender predisposition as well as a genetic predisposition
are seen in these animal models—females are affected more frequently than males and
only certain inbred strains of mice demonstrate signs and symptoms of the disease. The
41. trigger for the initiation of the autoimmune reaction in Graves disease remains uncertain,
although the underlying mechanism is likely to be breakdown in helper T-cell tolerance,
resulting in the production of anti-TSH autoantibodies.
A T cell-mediated autoimmune phenomenon also plays a role in the development of the
infiltrative ophthalmopathy that is characteristic of Graves disease. In Graves
ophthalmopathy, the volume of the retro-orbital connective tissues and extraocular
muscles is increased owing to several causes, including (1) marked infiltration of the
retro-orbital space by mononuclear cells, predominantly T cells; (2) inflammatory edema
and swelling of extraocular muscles; (3) accumulation of extracellular matrix
components, specifically hydrophilic glycosaminoglycans (GAGs) such as hyaluronic
acid and chondroitin sulfate; and (4) increased numbers of adipocytes (fatty infiltration).
These changes displace the eyeball forward and can interfere with the function of the
extraocular muscles. Recent evidence suggests that orbital preadipocyte fibroblasts
express the TSH receptor and thus become targets of an autoimmune attack. T cells
reactive against these fibroblasts secrete cytokines, which stimulate fibroblast
proliferation and synthesis of extracellular matrix proteins (GAGs) and increase surface
TSH receptor expression, perpetuating the autoimmune response. The result is
progressive infiltration of the retro-orbital space and ophthalmopathy.
Autoimmune disorders of the thyroid thus span a continuum in which Graves disease,
characterized by hyperfunction of the thyroid, lies at one extreme and Hashimoto
disease, manifesting as hypothyroidism, occupies the other end. Sometimes
hyperthyroidism may supervene on pre-existing Hashimoto thyroiditis (hashitoxicosis); at
other times, patients with Graves disease may spontaneously develop thyroid
hypofunction; occasionally, there are families with coexistence of Hashimoto and Graves
disease within the affected kindred. Not surprisingly, there is also an element of
histologic overlap between the autoimmune thyroid disorders (most characteristically,
prominent intrathyroidal lymphoid cell infiltrates with germinal center formation; see
below). In both disorders, the frequency of other autoimmune diseases, such as systemic
lupus erythematosus, pernicious anemia, type I diabetes, and Addison disease, is
The thyroid gland is usually symmetrically enlarged because of diffuse hypertrophy
and hyperplasia of thyroid follicular epithelial cells. Increases in weight to over 80 gm
are not uncommon. The gland is usually smooth and soft, and its capsule is intact. On cut
section, the parenchyma has a soft, meaty appearance resembling normal muscle.
Histologically, the dominant feature is too many cells. The follicular epithelial cells in
untreated cases are tall and more crowded than usual. This crowding often results in the
formation of small papillae, which project into the follicular lumen and encroach on the
colloid, sometimes filling the follicles ( Fig. 24-12 ). Such papillae lack fibrovascular
42. cores, in contrast to those of papillary carcinoma (see below). The colloid within the
follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting
predominantly of T cells, with fewer B cells and mature plasma cells, are present
throughout the interstitium; germinal centers are common.
Preoperative therapy alters the morphology of the thyroid in Graves disease. Preoperative
administration of iodine causes involution of the epithelium and the accumulation of
colloid by blocking thyroglobulin secretion. Treatment with the antithyroid drug
propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia by stimulating
TSH secretion. Thus, in pre-treated patients it is impossible from histologic examination
of surgical specimens to evaluate the functional activity of the gland.
Changes in extrathyroidal tissue include generalized lymphoid hyperplasia. The heart
may be hypertrophied, and ischemic changes may be present, particularly in patients with
preexisting coronary artery disease. In patients with ophthalmopathy, the
Figure 24-12 Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall,
columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These
cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the
edges of the colloid.
tissues of the orbit are edematous because of the presence of hydrophilic
mucopolysaccharides. In addition, there is infiltration by lymphocytes and fibrosis.
Orbital muscles are edematous initially but may undergo fibrosis late in the course of the
disease. The dermopathy, if present, is characterized by thickening of the dermis due to
deposition of glycosaminoglycans and lymphocyte infiltration.
The clinical findings in Graves disease include changes referable to thyrotoxicosis as well
as those associated uniquely with Graves disease: diffuse hyperplasia of the thyroid,
ophthalmopathy, and dermopathy. The degree of thyrotoxicosis varies from case to case
and is sometimes less conspicuous than other manifestations of the disease. Diffuse
43. enlargement of the thyroid is present in all cases of Graves disease. The thyroid
enlargement may be accompanied by increased flow of blood through the hyperactive
gland, often producing an audible bruit. Sympathetic overactivity produces a
characteristic wide, staring gaze and lid lag. The ophthalmopathy of Graves disease
results in abnormal protrusion of the eyeball (exophthalmos). The extraocular muscles are
often weak. The exophthalmos may persist or progress despite successful treatment of the
thyrotoxicosis, sometimes resulting in corneal injury. The infiltrative dermopathy, or
pretibial myxedema, is most common in the skin overlying the shins, where it presents as
scaly thickening and induration of the skin. However, it is present only in a minority of
patients. The skin lesions may be slightly pigmented papules or nodules and often have
an orange peel texture.
Laboratory findings in Graves disease include elevated free T4 and T3 levels and
depressed TSH levels. Because of ongoing stimulation of the thyroid follicles by thyroid-
stimulating immunoglobulins, radioactive iodine uptake is increased, and radioiodine
scans show a diffuse uptake of iodine.
Treatment of Graves disease consists of decreasing the symptoms of hyperthyroidism that
are induced by increased β-adrenergic tone (e.g., tachycardia, palpitations, tremulousness,
and anxiety) and measures aimed at decreasing thyroid hormone synthesis, such as the
administration of thionamides (e.g., propylthiouracil), radioiodine ablation, and surgical
Diffuse and Multinodular Goiters
Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid
disease. Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone,
most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis
leads to a compensatory rise in the serum TSH level, which, in turn, causes hypertrophy
and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the
thyroid gland. The compensatory increase in functional mass of the gland is able to
overcome the hormone deficiency, ensuring an euthyroid metabolic state in the vast
majority of individuals. If the underlying disorder is sufficiently severe (e.g., a congenital
biosynthetic defect or endemic iodine deficiency, see below), the compensatory responses
may be inadequate to overcome the impairment in hormone synthesis, resulting in
goitrous hypothyroidism. The degree of thyroid
enlargement is proportional to the level and duration of thyroid hormone deficiency.
44. DIFFUSE NONTOXIC (SIMPLE) GOITER
Diffuse nontoxic (simple) goiter specifies a form of goiter that diffusely involves the
entire gland without producing nodularity. Because the enlarged follicles are filled with
colloid, the term colloid goiter has been applied to this condition. This disorder occurs in
both an endemic and a sporadic distribution.
Endemic goiter occurs in geographic areas where the soil, water, and food supply contain
only low levels of iodine. The term endemic is used when goiters are present in more than
10% of the population in a given region. Such conditions are particularly common in
mountainous areas of the world, including the Alps, Andes, and Himalayas, where iodine
deficiency is widespread. The lack of iodine leads to decreased synthesis of thyroid
hormone and a compensatory increase in TSH, leading to follicular cell hypertrophy and
hyperplasia and goitrous enlargement. With increasing dietary iodine supplementation,
the frequency and severity of endemic goiter have declined significantly.
Variations in the prevalence of endemic goiter in regions with similar levels of iodine
deficiency point to the existence of other causative influences, particularly dietary
substances, referred to as goitrogens. The ingestion of substances that interfere with
thyroid hormone synthesis at some level, such as excessive calcium and vegetables
belonging to the Brassica and Cruciferae families (e.g., cabbage, cauliflower, Brussels
sprouts, turnips, and cassava), has been documented to be goitrogenic. Native populations
subsisting on cassava root are particularly at risk. Cassava contains a thiocyanate that
inhibits iodide transport within the thyroid, worsening any possible concurrent iodine
Sporadic goiter occurs less frequently than does endemic goiter. There is a striking
female preponderance and a peak incidence at puberty or in young adult life. Sporadic
goiter can be caused by a number of conditions, including the ingestion of substances that
interfere with thyroid hormone synthesis. In other instances, goiter may result from
hereditary enzymatic defects that interfere with thyroid hormone synthesis, all
transmitted as autosomal-recessive conditions (dyshormonogenetic goiter; see above). In
most cases, however, the cause of sporadic goiter is not apparent.
Two phases can be identified in the evolution of diffuse nontoxic goiter: the hyperplastic
phase and the phase of colloid involution. In the hyperplastic phase, the thyroid gland is
diffusely and symmetrically enlarged, although the increase is usually modest, and the
gland rarely exceeds 100 to 150 gm. The follicles are lined by crowded columnar cells,
which may pile up and form projections similar to those seen in Graves disease. The
accumulation is not uniform throughout the gland, and some follicles are hugely
distended, whereas others remain small. If dietary iodine subsequently increases or if the
demand for thyroid hormone decreases, the stimulated follicular epithelium involutes to
form an enlarged, colloid-rich gland (colloid goiter). In these cases, the cut surface of the
thyroid is usually brown, somewhat glassy, and translucent. Histologically, the follicular
epithelium is flattened and cuboidal, and colloid is abundant during periods of involution.
45. Clinical Course.
The vast majority of patients with simple goiters are clinically euthyroid. Therefore, the
clinical manifestations are primarily related to mass effects from the enlarged thyroid
gland (discussed in detail with multinodular goiter; see below). Although serum T3 and T4
levels are normal, the serum TSH is usually elevated or at the upper range of normal, as
is expected in marginally euthyroid individuals. In children, dyshormonogenetic goiter,
caused by a congenital biosynthetic defect, may induce cretinism.
With time, recurrent episodes of hyperplasia and involution combine to produce a more
irregular enlargement of the thyroid, termed multinodular goiter. Virtually all long-
standing simple goiters convert into multinodular goiters. They may be nontoxic or may
induce thyrotoxicosis (toxic multinodular goiter). Multinodular goiters produce the most
extreme thyroid enlargements and are more frequently mistaken for neoplastic
involvement than any other form of thyroid disease. Because they derive from simple
goiter, they occur in both sporadic and endemic forms, having the same female-to-male
distribution and presumably the same origins but affecting older individuals because they
are late complications.
It is believed that multinodal goiters may arise because of variations among follicular
cells in responses to external stimuli, such as trophic hormones. If some cells in a follicle
have a growth advantage, perhaps because of intrinsic genetic abnormalities similar to
those that give rise to adenomas, those cells will develop into clones of proliferating cells.
This may result in the formation of a nodule whose continued growth could even be
autonomous, without the external stimulus. Consistent with this model, both polyclonal
and monoclonal nodules coexist within the same multinodular goiter, the latter
presumably having arisen owing to the acquisition of a genetic abnormality favoring
growth. Not surprisingly, mutations in proteins of the TSH-signaling pathway that lead
to constitutive activation of this pathway have been identified in a subset of autonomous
thyroid nodules. (TSH signaling pathway mutations and their implications are discussed
in the section on follicular adenomas.) With uneven follicular hyperplasia, generation of
new follicles, and uneven accumulation of colloid, tensions and stresses are produced that
lead to rupture of follicles and vessels followed by hemorrhages, scarring, and sometimes
calcifications. The scarring adds to the tensions, and in this cyclical manner, nodularity
appears. Moreover, the preexisting stromal framework of the gland may more or less
enclose areas of expanded parenchyma, contributing to the nodularity.
Multinodular goiters are multilobulated, asymmetrically enlarged glands that can achieve
a weight of more than 2000 gm ( Fig. 24-13 ). The pattern of enlargement is quite
46. Figure 24-13 Nodular goiter. The gland is coarsely nodular and contains areas of fibrosis and cystic
may involve one lobe far more than the other, producing lateral pressure on midline
structures, such as the trachea and esophagus. In other instances, the goiter grows behind
the sternum and clavicles to produce the so-called intrathoracic or plunging goiter.
Occasionally, most of it is hidden behind the trachea and esophagus; in other instances,
one nodule may so stand out as to impart the clinical appearance of a solitary nodule. On
cut section, irregular nodules containing variable amounts of brown, gelatinous colloid
are present. Regressive changes occur frequently, particularly in older lesions, and
include areas of hemorrhage, fibrosis, calcification, and cystic change. The microscopic
appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas
of follicular epithelial hypertrophy and hyperplasia, accompanied by the degenerative
changes noted previously.
The dominant clinical features of goiter are those caused by the mass effects of the
enlarged gland. In addition to the obvious cosmetic effects of a large neck mass, goiters
may cause airway obstruction, dysphagia, and compression of large vessels in the neck
and upper thorax. Most patients are euthyroid, but in a substantial minority of patients, a
hyperfunctioning nodule may develop within a long-standing goiter, resulting in
hyperthyroidism (toxic multinodular goiter). This condition, known as Plummer
syndrome, is not accompanied by the infiltrative ophthalmopathy and dermopathy of
Graves disease. As was previously mentioned, goiter may be associated with clinical
evidence of hypothyroidism in specific clinical settings. Radioiodine uptake is uneven,
reflecting varied levels of activity in different regions. Hyperfunctioning nodules
concentrate radioiodine and appear "hot." Goiters are also of clinical significance because
of their ability to mask or to mimic neoplastic diseases arising in the thyroid.
47. Neoplasms of the Thyroid
The solitary thyroid nodule is a palpably discrete swelling within an otherwise apparently
normal thyroid gland. The estimated incidence of solitary palpable nodules in the adult
population of the United States varies between 1% and 10%, although it is significantly
higher in endemic goitrous regions. Single nodules are about four times more common in
women than in men. The incidence of thyroid nodules increases throughout life.
From a clinical standpoint, the possibility of neoplastic disease is of major concern in
patients who present with thyroid nodules. Fortunately, the overwhelming majority of
solitary nodules of the thyroid prove to be localized, non-neoplastic conditions (e.g.,
nodular hyperplasia, simple cysts, or foci of thyroiditis) or benign neoplasms such as
follicular adenomas. In fact, benign neoplasms outnumber thyroid carcinomas by a ratio
of nearly 10:1. Carcinomas of the thyroid are thus uncommon, accounting for well under
1% of solitary thyroid nodules and representing about 15,000 new cancer cases each year.
Moreover, as will be seen subsequently, most are indolent, permitting a 90% survival at
20 years. Several clinical criteria might provide a clue to the nature of a given thyroid
• Solitary nodules, in general, are more likely to be neoplastic than are multiple
• Nodules in younger patients are more likely to be neoplastic than are those in
• Nodules in males are more likely to be neoplastic than are those in females.
• A history of radiation treatment to the head and neck region is associated with
an increased incidence of thyroid malignancy.
• Nodules that take up radioactive iodine in imaging studies (hot nodules) are
more likely to be benign than malignant.
Such general trends and statistics, however, are of little significance in the evaluation of a
given patient, in whom the timely recognition of a malignancy, however uncommon, can
be life-saving. Ultimately, it is the morphologic evaluation of a given thyroid nodule, in
the form of fine-needle aspiration biopsy and histologic study of surgically resected
thyroid parenchyma, that provides the most definitive information about its nature. In the
following sections, we consider the major thyroid neoplasms, including adenoma and
carcinoma in its various forms.
Adenomas of the thyroid are typically discrete, solitary masses. With rare exception, they
are derived from follicular epithelium and so might all be called follicular adenomas. A
variety of terms have been proposed for classifying adenomas on the basis of degree of
follicle formation and the colloid content of the follicles. Simple colloid adenomas
(macrofollicular adenomas), a common form, resemble normal thyroid tissue; others
recapitulate stages in the embryogenesis of the normal thyroid (fetal or microfollicular,
48. embryonal or trabecular). There is limited utility in these classifications because mixed
patterns are common, and most of these benign tumors are nonfunctional. Clinically,
follicular adenomas can be difficult to distinguish from dominant nodules of follicular
hyperplasia or from the less common follicular carcinomas. Numerous studies have made
it clear that adenomas are not forerunners of cancer except in rare instances. Although the
vast majority of adenomas are nonfunctional, a small proportion
produce thyroid hormones and cause clinically apparent thyrotoxicosis. Hormone
production in functional adenomas ("toxic adenomas") occurs independent of TSH
stimulation and represents another example of thyroid autonomy, analogous to toxic
The TSH receptor signaling pathway plays an important role in the pathogenesis of toxic
adenomas. Activating ("gain of function") somatic mutations in one of two components of
this signaling system—most often the TSH receptor itself or the α-subunit of Gs —cause
chronic overproduction of cAMP, generating cells that acquire a growth advantage (see
Fig. 24-3 ). This results in clonal expansion of follicular epithelial cells that can
autonomously produce thyroid hormone and cause symptoms of thyroid excess. Overall,
mutations leading to constitutive activation of the cAMP pathway appear to be the cause
of a proportion (10% to 75%) of autonomously functioning thyroid adenomas. However,
the molecular pathogenesis of a significant proportion of thyroid tumors remains to be
defined, especially the pathogenesis of nonfunctioning adenomas.
The typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is well
demarcated from the surrounding thyroid parenchyma ( Fig. 24-14 ). Follicular adenomas
average about 3 cm in diameter, but some are smaller and others are much larger (up to
10 cm in diameter). In freshly resected specimens, the adenoma bulges from the cut
surface and compresses the adjacent thyroid. The color ranges from gray-white to red-
brown, depending on the cellularity of the adenoma and its colloid content. The
neoplastic cells are demarcated from the adjacent parenchyma by a well-defined, intact
capsule. These features are important in making the distinction from multinodular
goiters, which contain multiple nodules on their cut surface (even though the patient may
present clinically with a solitary dominant nodule), produce less compression of the
adjacent thyroid parenchyma, and lack a well-formed capsule. Areas of hemorrhage,
fibrosis, calcification, and cystic change, similar to those encountered in multinodular
goiters, are common in follicular adenomas, particularly within larger lesions.
Microscopically, the constituent cells often form uniform-appearing follicles that contain
colloid ( Fig. 24-15 ). The follicular growth pattern within the adenoma is usually quite
distinct from the adjacent non-neoplastic thyroid. This is another feature distinguishing
49. Figure 24-14 Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen.
Figure 24-15 Follicular adenoma. The photomicrograph shows well-differentiated follicles resembling
normal thyroid parenchyma.
adenomas from multinodular goiters, in which nodular and uninvolved thyroid
parenchyma may have similar growth patterns. The epithelial cells composing the
follicular adenoma reveal little variation in cell and nuclear morphology. Mitotic figures
are rare, and extensive mitotic activity warrants careful examination of the capsule to
exclude follicular carcinoma. Similarly, papillary change is not a typical feature of
adenomas and, if extensive, should raise the suspicion of an encapsulated papillary
carcinoma (see below). Occasionally, the neoplastic cells acquire brightly eosinophilic
granular cytoplasm (oxyphil or Hürthle cell change) ( Fig. 24-16 ); the clinical
presentation and behavior of a follicular adenoma with oxyphilia (Hürthle cell
adenoma) is no different from that of a conventional adenoma. Other variants of
follicular adenomas include extensive clear cell change of the cytoplasm (clear cell
follicular adenoma) and adenomas with "signet-ring" features (signet-ring cell follicular
adenoma). Similar to endocrine tumors at other anatomic sites, even benign follicular
50. adenomas may, on occasion, exhibit focal nuclear pleomorphism, atypia, and prominent
nucleoli (endocrine atypia); this by itself does not constitute
Figure 24-16 Hürthle cell tumor. A high-power view showing that the tumor is composed of cells with
abundant eosinophilic cytoplasm and small regular nuclei. (Courtesy of Dr. Mary Sunday, Brigham and
Women's Hospital, Boston, MA.)
a feature of malignancy. Infrequently, adenomas can demonstrate increased cellularity,
more extensive variation in cellular size and nuclear morphology, and even mitotic
activity. These adenomas have been called atypical follicular adenomas and warrant
careful examination of the tumor capsule to exclude capsular and/or vascular invasion. 
The hallmark of all follicular adenomas is the presence of an intact, well-formed capsule
encircling the tumor. Careful evaluation of the integrity of the capsule is therefore
critical in distinguishing follicular adenomas from follicular carcinomas, which
demonstrate capsular and/or vascular invasion (see below).
Many thyroid adenomas present as a unilateral painless mass, often discovered during a
routine physical examination. Larger masses may produce local symptoms, such as
difficulty in swallowing.
Most adenomas take up less radioactive iodine than does normal thyroid parenchyma. On
radionuclide scanning, therefore, adenomas usually appear as cold nodules relative to the
adjacent thyroid tissue. Up to 10% of cold nodules eventually prove to be malignant on
histologic analysis. By contrast, malignancy is rare in hot nodules. In a minority of cases,
adenomas may be hyperfunctional, producing signs and symptoms of hyperthyroidism
(toxic adenomas). On radionuclide imaging, hyperfunctioning adenomas appear hot
compared with the paranodular thyroid tissue, which is deprived of thyrotropin
stimulation. Hot adenomas occasionally have some dependence on TSH and may be
51. induced to regress by the administration of thyroid hormones, which suppress TSH
Other techniques used in the preoperative evaluation of suspected adenomas are
ultrasonography and fine-needle aspiration biopsy. Owing to the need for evaluating
capsular integrity, the definitive diagnosis of adenomas can be made only after careful
histologic examination of the resected specimen. Suspected adenomas of the thyroid are
therefore removed surgically to exclude malignancy. Thyroid adenomas, including
atypical adenomas, have an excellent prognosis and do not recur or metastasize. About
20% of follicular adenomas have point mutations in the RAS family of oncogenes, which
have also been identified in 30% to 40% of follicular carcinomas. This finding raises the
possibility that some adenomas may progress to carcinomas.
OTHER BENIGN TUMORS
Solitary nodules of the thyroid gland may also prove to be cysts. The great preponderance
of these lesions represent cystic degeneration of a follicular adenoma; the remainder
probably arise in multinodular goiters. They are often filled with a brown, turbid fluid
containing blood, hemosiderin pigment, and cell debris. Additional benign rarities
include dermoid cysts, lipomas, hemangiomas, and teratomas (see mainly in infants).
Carcinomas of the thyroid are relatively uncommon in the United States, accounting for
about 1.5% of all cancers. Most cases occur in adults, although some forms, particularly
papillary carcinomas, may present in childhood. A female predominance has been noted
among patients who develop thyroid carcinoma in the early and middle adult years,
perhaps related to the expression of estrogen receptors on neoplastic thyroid epithelium.
In contrast, cases presenting in childhood and late adult life are distributed equally among
males and females. Most thyroid carcinomas are well-differentiated lesions. The major
subtypes of thyroid carcinoma and their relative frequencies include the following:
• Papillary carcinoma (75% to 85% of cases)
• Follicular carcinoma (10% to 20% of cases)
• Medullary carcinoma (5% of cases)
• Anaplastic carcinoma (<5% of cases)
Most thyroid carcinomas are derived from the follicular epithelium, except for medullary
carcinomas; the latter are derived from the parafollicular or C cells. Because of the
unique clinical and biologic features associated with each variant of thyroid carcinoma,
these subtypes are described separately.
There are several factors, genetic and environmental, implicated in the pathogenesis of
52. Genetic factors are important in both familial and nonfamilial ("sporadic") forms of
thyroid cancer. Familial medullary cancers account for most inherited cases of thyroid
cancer. Familial nonmedullary thyroid cancers (papillary and follicular variants) are very
rare. Distinct genes are involved in the histologic variants of thyroid cancer.
Follicular Thyroid Carcinomas.
Approximately half of follicular thyroid carcinomas harbor mutations in the RAS family
of oncogenes (HRAS, NRAS, and KRAS) ( Chapter 7 ), NRAS mutations being the most
common. Recently, a unique translocation has been described between PAX8, a paired
homeobox gene that is important in thyroid development (see above), and the peroxisome
proliferator-activated receptor γ1 (PPARγ1), a nuclear hormone receptor implicated in
terminal differentiation of cells. The PAX8-PPARγ1 fusion is present in approximately
one-third of follicular thyroid carcinomas, specifically those cancers with a t(2;3)
(q13;p25) translocation, which permits juxtaposition of portions of both genes. Follicular
carcinomas appear to arise by at least two distinct and virtually nonoverlapping molecular
pathways: Tumors carry either a RAS mutation or a PAX8-PPARγ1 fusion, and rarely
are both genetic abnormalities present in the same case. Fewer than 10% of follicular
adenomas harbor a PAX8-PPARγ1 fusion transcript, and this translocation has not been
documented to date in other thyroid neoplasms. 
Papillary Thyroid Carcinomas.
Like follicular thyroid carcinomas, papillary carcinomas also appear to arise by multiple
distinct, nonoverlapping molecular pathways. One pathway involves rearrangements of
the tyrosine kinase receptors RET or NTRK1 (neurotrophic tyrosine kinase receptor 1)
and another involves activating mutations in the BRAF oncogene. A third pathway
involves RAS mutations (10% to 20% of papillary carcinomas), suggesting that some of
these cancers are related to follicular adenomas. RET, located on chromosome 10q11, and
NTRK1, located on chromosome 1q21, belong to the family of receptor tyrosine kinases
that transduce extracellular signals for cell growth and differentiation and exert many of
their downstream effects through the
ubiquitous MAP kinase signaling pathway ( Chapter 7 ). Neither receptor is normally
expressed on the surface of thyroid follicular cells. In papillary thyroid cancers, either a
paracentric inversion of chromosome 10 or a reciprocal translocation between
chromosomes 10 and 17 places the tyrosine kinase domain of RET under the
transcriptional control of constitutively active genes on these two chromosomes. The
novel fusion genes that are so formed are known as ret/PTC (ret/papillary thyroid
carcinoma) and are present in approximately one-fifth of papillary thyroid cancers. The
frequency of ret/PTC rearrangements is significantly higher in papillary cancers arising
in children and in the backdrop of radiation exposure. Similarly, paracentric inversions or
translocations of NTRK1 that constitutively activate its tyrosine kinase domain are
present in 5% to 10% of papillary thyroid cancers. One-third to one-half of papillary
53. thyroid carcinomas harbor an activating mutation in the BRAF gene, which encodes a
signaling intermediary in the MAP kinase pathway. Since chromosomal
rearrangements of the RET or NTRK1 genes and mutations of BRAF have redundant
effects on the thyroid epithelium (recall that both mechanisms result in activation of the
MAP kinase signaling pathway), papillary thyroid carcinomas demonstrate either one or
the other molecular abnormality, but not both. 
Medullary Thyroid Carcinomas.
Medullary carcinomas arise from the parafollicular C cells in the thyroid. Familial
medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2, see
below) and are associated with germ-line RET protooncogene mutations that affect
residues in the cysteine-rich extracellular or the intracellular tyrosine kinase domains,
leading to constitutive activation of the receptor. RET mutations are detectable in
approximately 95% of families with MEN-2; in the remaining few cases, the mutations
may arise in hard-to-detect promoter sequences or intronic sites. RET mutations are also
seen in nonfamilial (sporadic) medullary thyroid cancers. Chromosomal rearrangements
involving RET, such as the ret/PTC translocations reported in papillary cancers, are not
seen in medullary carcinomas.
These highly aggressive and lethal tumors can arise de novo or by "dedifferentiation" of a
well-differentiated papillary or follicular carcinoma. Inactivating point mutations in the
p53 tumor suppressor gene are rare in well-differentiated thyroid carcinomas but
common in anaplastic tumors. 
The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation,
particularly during the first two decades of life. In the past, radiation therapy was liberally
employed in the treatment of a number of head and neck lesions in infants and children,
including reactive tonsillar enlargement, acne, and tinea capitis. Up to 9% of people
receiving such treatment during childhood have subsequently developed thyroid
malignancies, usually several decades after exposure. The importance of radiation as a
risk factor for thyroid carcinoma was highlighted by the increased incidence of papillary
thyroid carcinomas in children in the Marshall Islands after atomic bomb testing and,
more recently, by the dramatic rise in the incidence of pediatric thyroid carcinoma among
children exposed to ionizing radiation after the Chernobyl nuclear disaster in the Ukraine
in 1986. More than 400 cases of pediatric thyroid carcinoma have been observed in this
region of Belarus between the time of the incident and the present, a number far in excess
of the usual incidence for this area. More than half of the children lived in areas that had
the highest radiation exposure.
Long-standing multinodular goiter has been suggested as a predisposing factor in some
cases, since areas with iodine deficiency-related endemic goiter have a higher prevalence
of follicular carcinomas. While most, if not all, thyroid lymphomas arise from pre-
54. existing Hashimoto thyroiditis, there is no conclusive evidence to suggest that thyroiditis
is associated with an increased risk of thyroid epithelial carcinomas.
Papillary carcinomas are the most common form of thyroid cancer. They occur at any age
but most often in the twenties to forties, and account for the majority of thyroid
carcinomas associated with previous exposure to ionizing radiation.
Papillary carcinomas are solitary or multifocal lesions. Some tumors may be well-
circumscribed and even encapsulated; others may infiltrate the adjacent parenchyma with
ill-defined margins. The lesions may contain areas of fibrosis and calcification and are
often cystic. On the cut surface, they may appear granular and may sometimes contain
grossly discernible papillary foci. The definitive diagnosis of papillary carcinoma can be
made only after microscopic examination. The characteristic hallmarks of papillary
neoplasms include the following ( Fig. 24-17 ):
• Papillary carcinomas can contain branching papillae having a fibrovascular
stalk covered by a single to multiple layers of cuboidal epithelial cells. In most
neoplasms, the epithelium covering the papillae consists of well-differentiated,
uniform, orderly, cuboidal cells, but at the other extreme are those with fairly
anaplastic epithelium showing considerable variation in cell and nuclear
morphology. When present, the papillae of papillary carcinoma differ from those
seen in areas of hyperplasia. In contrast to hyperplastic papillary lesions, the
neoplastic papillae are more complex and have dense fibrovascular cores.
• The nuclei of papillary carcinoma cells contain finely dispersed chromatin,
which imparts an optically clear or empty appearance, giving rise to the
designation ground glass or Orphan Annie eye nuclei. In addition, invaginations
of the cytoplasm may in cross-sections give the appearance of intranuclear
inclusions ("pseudo-inclusions") or intranuclear grooves. As currently used, the
diagnosis of papillary carcinoma is based on these nuclear features even in the
absence of papillary architecture.
• Concentrically calcified structures termed psammoma bodies are often present
within the lesion, usually within the cores of papillae. These structures are almost
never found in follicular and medullary carcinomas, and so, when present, they
are a strong indication that the lesion is a papillary carcinoma. It is said that
whenever a psammoma body is found within a lymph node or perithyroidal
tissues, a hidden papillary carcinoma must be considered. 
• Foci of lymphatic invasion by tumor are often present, but involvement of blood
vessels is relatively uncommon, particularly in smaller lesions. Metastases to
adjacent cervical lymph nodes are estimated to occur in up to half the cases.
55. Figure 24-17 Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma
with grossly discernible papillary structures. This particular example contains well-formed papillae (B),
lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei
(C). D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear
inclusions are visible in some of the aspirated cells.
There are variant forms of papillary carcinoma that are important to recognize because
they can resemble other lesions and have unique clinical features. The encapsulated
variant constitutes about 10% of all papillary neoplasms. It is usually confined to the
thyroid gland, is well encapsulated, and rarely presents with vascular or lymph node
dissemination, and so it can easily be confused with a benign adenoma. In most cases,
this variant has an excellent prognosis.
The follicular variant has the characteristic nuclei of papillary carcinoma but has an
almost totally follicular architecture. Grossly, the tumor may be encapsulated, and
focally, psammoma bodies may be seen. These follicular variants still behave
biologically as usual papillary carcinomas as long as they meet the nuclear criteria for
diagnosis of papillary cancers (see above). The true follicular carcinoma, in contrast,
lacks these nuclear features, frequently demonstrates capsular and vascular invasion, and
has a less favorable prognosis. A differential diagnosis of thyroid lesions with a follicular
architecture is summarized in Table 24-4 .
A tall cell variant is marked by tall columnar cells with intensely eosinophilic cytoplasm
lining the papillary structures. Typically, the cells are at least twice as tall as they are
56. wide (hence the eponym "tall cell" variant). These tumors tend to occur in older
individuals and are usually large with prominent vascular invasion, extrathyroidal
extension, and cervical and distant metastases. It has been recently demonstrated that
more than half the tall cell variants harbor a ret/PTC translocation that confers greater
TABLE 24-4 -- Thyroid Lesions with a Follicular Architecture
Hyperplastic nodule in goiter
Follicular adenoma *
Follicular carcinoma *
Follicular variant of papillary carcinoma †
*Differentiating follicular carcinoma from follicular adenoma requires histologic evidence of capsular or
blood vessel invasion, or documented metastasis.
†The diagnosis of papillary carcinoma is rendered on the presence of characteristic nuclear features,
irrespective of the presence or absence of papillae.
potential than the ret/PTC observed in usual papillary thyroid cancers. The presence of
this genetic abnormality might result in more aggressive behavior.  
An unusual diffuse sclerosing variant of papillary carcinoma occurs in younger
individuals, including children. These tumors do not present with a mass, but rather with
a bilateral goiter. There is a characteristic "gritty" sensation to the cut surface of the
lesion due to the presence of abundant psammoma bodies. The tumor demonstrates a
prominent papillary growth pattern, intermixed with solid areas containing nests of
squamous cells (squamous morules). The neoplastic cells exhibit classic nuclear features
of a papillary neoplasm. As the name suggests, there is extensive, diffuse fibrosis
throughout the thyroid gland, often associated with a prominent lymphocytic infiltrate,
simulating Hashimoto thyroiditis. The neoplastic cells have a peculiar propensity to
invade intrathyroidal lymphatic channels; hence, nodal metastases are present in almost
Hyalinizing trabecular tumors, a group that includes both adenomas and carcinomas,
have recently been reconsidered as a variant of papillary carcinomas, based on the
presence of ret/PTC gene rearrangements in 30% to 60% of these tumors. They are 
characterized by an "organoid" growth pattern, with nests and trabeculae of elongated
57. tumor cells within a fibrovascular stroma; at first glance, the tumor may resemble an
extra-adrenal paraganglioma (see below). Both intracellular and extracellular
hyalinization are prominent and confer a pink hue on the tumor on low-power
microscopic examination. The nuclear features resemble those seen in classic papillary
carcinomas, and psammoma bodies may be present. Hyalinizing trabecular adenomas are
well encapsulated, while carcinomas demonstrate capsular and/or vascular invasion.
Most papillary carcinomas present as asymptomatic thyroid nodules, but the first
manifestation may be a mass in a cervical lymph node. Interestingly, the presence of
isolated cervical nodal metastases does not appear to have a significant influence on the
generally good prognosis of these lesions. The carcinoma, which is usually a single
nodule, moves freely during swallowing and is not distinguishable from a benign nodule.
Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease. In a minority of
patients, hematogenous metastases are present at the time of diagnosis, most commonly
in the lung.
A variety of diagnostic tests have been employed to help separate benign from malignant
thyroid nodules, including radionuclide scanning and fine-needle aspiration. Most
papillary lesions are cold masses on scintiscans. Improvements in cytologic analysis have
made fine-needle aspiration cytology a reliable test for distinguishing between benign
and malignant nodules. The nuclear features are often nicely demonstrable in aspirated
Papillary thyroid cancers have an excellent prognosis, with a 10-year survival rate in
excess of 95%. Five per cent to 20% of patients have local or regional recurrences, and
10% to 15% have distant metastases. The prognosis of a patient with papillary thyroid
cancers is dependent on several factors including age (in general, the prognosis is less
favorable among patients older than 40 years), the presence of extrathyroidal extension,
and presence of distant metastases (stage).
Follicular carcinomas are the second most common form of thyroid cancer, accounting
for 10% to 20% of all thyroid cancers. They tend to present in women, and at an older
age than do papillary carcinomas, with a peak incidence in the forties and fifties. The
incidence of follicular carcinoma is increased in areas of dietary iodine deficiency,
suggesting that in some cases, nodular goiter may predispose to the development of the
neoplasm. The high frequency of RAS mutations in follicular adenomas and carcinomas
suggests that the two may be related tumors.
Follicular carcinomas are single nodules that may be well circumscribed or widely
infiltrative ( Fig. 24-18 ). Sharply demarcated lesions may be exceedingly difficult to
distinguish from follicular adenomas by gross examination. Larger lesions may penetrate
58. the capsule and infiltrate well beyond the thyroid capsule into the adjacent neck. They are
gray to tan to pink on cut section and, on occasion, are somewhat translucent when large,
colloid-filled follicles are present. Degenerative changes, such as central fibrosis and foci
of calcification, are sometimes present.
Microscopically, most follicular carcinomas are composed of fairly uniform cells forming
small follicles containing colloid, quite reminiscent of normal thyroid ( Fig. 24-19 ). In
other cases, follicular differentiation may be less apparent, and there may be nests
Figure 24-18 Follicular carcinoma. Cut surface of a follicular carcinoma with substantial replacement of
the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage.
59. Figure 24-19 Follicular carcinoma of the thyroid. A few of the glandular lumens contain recognizable
or sheets of cells without colloid. Occasional tumors are dominated by cells with
abundant granular, eosinophilic cytoplasm (Hürthle cells). Whatever the pattern, the
nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not
present. It is important to note the absence of these details because some papillary
carcinomas may appear almost entirely follicular (see Table 24-4 ). Follicular lesions in
which the nuclear features are typical of papillary carcinomas should be treated as
papillary cancers. While nuclear features are helpful in distinguishing papillary from
follicular neoplasms, they are of little value in distinguishing follicular adenomas from
minimally invasive follicular carcinomas. This distinction requires extensive histologic
sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular
invasion ( Fig. 24-20 ). The criterion
Figure 24-20 Capsular integrity in follicular neoplasms. Evaluating the integrity of the capsule is critical in
distinguishing follicular adenomas from follicular carcinomas. In adenomas (A), a fibrous capsule, usually
thin but occasionally more prominent, circumferentially surrounds the neoplastic follicles and no capsular
invasion is seen (arrowheads); compressed normal thyroid parenchyma is usually present external to the
capsule (top of the panel). In contrast, follicular carcinomas demonstrate capsular invasion (B, arrow-
60. heads) that may be minimal, as in this case, or widespread with extension into local structures of the neck.
The presence of vascular invasion is another feature of follicular carcinomas.
for vascular invasion is applicable only to capsular vessels and vascular spaces beyond
the capsule; the presence of tumor plugs within intratumoral blood vessels has little
prognostic significance. Unlike in papillary cancers, lymphatic spread is distinctly
uncommon in follicular cancers.
In contrast to minimally invasive follicular cancers, extensive invasion of adjacent
thyroid parenchyma or extrathyroidal tissues makes the diagnosis of carcinoma obvious
in widely invasive follicular carcinomas. Histologically, these cancers tend to have a
greater proportion of solid or trabecular growth pattern, less evidence of follicular
differentiation, and increased mitotic activity.
Follicular carcinomas present as slowly enlarging painless nodules. Most frequently, they
are cold nodules on scintigrams, although in rare cases, the better-differentiated lesions
may be hyperfunctional, take up radioactive iodine, and appear warm on scintiscan.
Follicular carcinomas have little propensity for invading lymphatics; therefore, regional
lymph nodes are rarely involved, but vascular invasion is common, with spread to bone,
lungs, liver, and elsewhere. The prognosis is largely dependent on the extent of invasion
and stage at presentation. Widely invasive follicular carcinomas not infrequently develop
metastases, and up to half succumb to their disease within 10 years. This is in stark
contrast to minimally invasive follicular carcinoma, which has a 10-year survival rate
greater than 90%. Most follicular carcinomas are treated with total thyroidectomy
followed by the administration of radioactive iodine, the rationale being that metastases
are likely to take up the radioactive element, which can be used to identify and ablate
such lesions. In addition, because any residual follicular carcinoma may respond to TSH
stimulation, patients are usually treated with thyroid hormone after surgery to suppress
Medullary carcinomas of the thyroid are neuroendocrine neoplasms derived from the
parafollicular cells, or C cells, of the thyroid. The cells of medullary carcinomas, similar
to normal C cells, secrete calcitonin, the measurement of which plays an important role in
the diagnosis and postoperative follow-up of patients. In some instances, the tumor cells
elaborate other polypeptide hormones, such as somatostatin, serotonin, and vasoactive
intestinal peptide (VIP). The tumors arise sporadically in about 80% of cases. The
remainder occurs in the setting of MEN syndrome 2A or 2B or as familial tumors without
an associated MEN syndrome (familial medullary thyroid carcinoma, or FMTC;
discussed later). Recall that activating point mutations in the RET protooncogene play an
important role in the development of both familial and sporadic medullary carcinomas.
61. Cases associated with MEN-2 occur in younger patients and may even arise during
childhood. In contrast, sporadic medullary carcinomas as well as FMTC are lesions of
adulthood, with a peak incidence in the forties and fifties.
Medullary carcinomas can arise as a solitary nodule or may present as multiple lesions
involving both lobes of the thyroid. The sporadic neoplasms tend to originate in one lobe
( Fig. 24-21 ). In contrast, bilaterality and multicentricity are common in familial cases.
Larger lesions often contain areas of necrosis and hemorrhage and may extend through
the capsule of the thyroid. The tumor tissue is firm, pale gray to tan, and infiltrative.
There may be foci of hemorrhage and necrosis in the larger lesions.
Microscopically, medullary carcinomas are composed of polygonal to spindle-shaped
cells, which may form nests, trabeculae, and even follicles. Small, more anaplastic cells
are present in some tumors and may be the predominant cell type. Acellular amyloid
deposits, derived from altered calcitonin molecules, are present in the adjacent stroma in
many cases ( Fig. 24-22 ). Calcitonin
Figure 24-21 Medullary carcinoma of thyroid. These tumors typically show a solid pattern of growth and
do not have connective tissue capsules. (Courtesy of Dr. Joseph Corson, Brigham and Women's Hospital,
62. Figure 24-22 Medullary carcinoma of the thyroid. These tumors typically contain amyloid, visible here as
homogeneous extracellular material, derived from calcitonin molecules secreted by the neoplastic cells.
is readily demonstrable within the cytoplasm of the tumor cells as well as in the stromal
amyloid by immunohistochemical methods. Electron microscopy reveals variable
numbers of membrane-bound electron-dense granules within the cytoplasm of the
neoplastic cells ( Fig. 24-23 ). One of the peculiar features of familial medullary cancers
is the presence of multicentric C-cell hyperplasia in the surrounding thyroid
parenchyma, a feature that is usually absent in sporadic lesions. While the precise
criteria for defining C-cell hyperplasia are not establisted, the presence of multiple
prominent clusters of C cells scattered throughout the parenchyma should raise the
specter of a familial tumor, even if that history is not explicitly present. Foci of C-cell
hyperplasia are believed to represent the precursor lesions from which medullary
Sporadic cases of medullary carcinoma come to medical attention most often as a mass in
the neck, sometimes associated with local effects such as dysphagia or
63. Figure 24-23 Electron micrograph of medullary thyroid carcinoma. These cells contain membrane-bound
secretory granules that are the sites of storage of calcitonin and other peptides (30,000X).
hoarseness. In some instances, the initial manifestations are those of a paraneoplastic
syndrome, caused by the secretion of a peptide hormone (e.g., diarrhea owing to the
secretion of VIP). Notably, hypocalcemia is not a prominent feature, despite the presence
of raised calcitonin levels. Screening of relatives for elevated calcitonin levels or RET
mutations permits early detection of tumors in familial cases. As will be discussed later,
all MEN-2 kindred carrying RET mutations are offered prophylactic thyroidectomy to
preclude the development of medullary carcinomas, the major risk factor for poor
outcome in these families. Sometimes, the only histologic finding in the resected thyroid
of asymptomatic carriers is the presence of C-cell hyperplasia or small (<1 cm)
"micromedullary" carcinomas. Recent studies have shown that specific RET mutations
correlate with the aggressiveness of medullary carcinomas and the propensity of MEN-2
patients to develop other coincident endocrine tumors.  
Anaplastic carcinomas of the thyroid are undifferentiated tumors of the thyroid follicular
epithelium. In striking contrast to the differentiated thyroid carcinomas, anaplastic
carcinomas are aggressive tumors, with a mortality rate approaching 100%. These tumors
account for fewer than 5% of all thyroid cancers. Patients with anaplastic carcinoma are
older than those with other types of thyroid cancer, with a mean age of 65 years. About
half of the patients have a history of multinodular goiter, whereas 20% of the patients
with these tumors have a history of differentiated carcinoma, and another 20% to 30%
have a concurrent differentiated thyroid tumor, frequently a papillary carcinoma. These
findings have led to the proposal that anaplastic carcinoma develops by so-called
dedifferentiation from more differentiated tumors as a result of one or more genetic
changes, including the loss of the p53 tumor suppressor gene.
Microscopically, these neoplasms are composed of highly anaplastic cells, which may
take one of several histologic patterns: (1) large, pleomorphic giant cells, including
occasional osteoclast-like multinucleate giant cells; (2) spindle cells with a sarcomatous
appearance; (3) mixed spindle and giant cells; and (4) small cells resembling those seen
in small cell carcinomas arising at other sites. It is unlikely that a true small cell
carcinoma exists in the thyroid, and a significant number of such "small cell" tumors have
ultimately proven to be medullary carcinomas (discussed previously) or malignant
lymphomas, which may also occur in the thyroid but have a much better prognosis. Foci
of papillary or follicular differentiation may be present in some tumors, suggesting origin
from a better differentiated carcinoma.
64. Anaplastic carcinomas usually present as a rapidly enlarging bulky neck mass. In most
cases, the disease has already spread beyond the thyroid capsule into adjacent neck
structures or has metastasized to the lungs at the time of presentation. Compression and
invasion symptoms, such as dyspnea, dysphagia, hoarseness, and cough, are common.
There is no effective therapy for anaplastic thyroid carcinoma, and the disease is almost
uniformly fatal. Although metastases to distant sites are common, in most cases death
occurs in less than 1 year as a result of aggressive growth and compromise of vital
structures in the neck.
Thyroglossal duct or cyst is the most common clinically significant congenital anomaly
of the thyroid. A persistent sinus tract may remain as a vestigial remnant of the tubular
development of the thyroid gland. Parts of this tube may be obliterated, leaving small
segments to form cysts. These occur at any age and might not become evident until adult
life. Mucinous, clear secretions may collect within these cysts to form either spherical
masses or fusiform swellings, rarely over 2 to 3 cm in diameter. These are present in the
midline of the neck anterior to the trachea. Segments of the duct and cysts that occur high
in the neck are lined by stratified squamous epithelium, which is essentially identical with
that covering the posterior portion of the tongue in the region of the foramen cecum. The
anomalies that occur in the lower neck more proximal to the thyroid gland are lined by
epithelium resembling the thyroidal acinar epithelium. Characteristically, subjacent to the
lining epithelium, there is an intense lymphocytic infiltrate. Superimposed infection may
convert these lesions into abscess cavities, and rarely, they give rise to cancers.
The parathyroid glands are derived from the developing pharyngeal pouches that also
give rise to the thymus. The four glands normally lie in close proximity to the upper and
lower poles of each thyroid lobe but may also be found anywhere along the pathway of
descent of the pharyngeal pouches, including the carotid sheath, the thymus, and
elsewhere in the anterior mediastinum. Of note, 10% of individuals have only two or
In the adult, the parathyroid is a yellow-brown, ovoid encapsulated nodule weighing
approximately 35 to 40 mg.
65. Most of the gland is composed of chief cells. The chief cells vary from light to dark pink
with hematoxylin and eosin stains, depending on their glycogen content. They are
polygonal; are 12 to 20 mm in diameter; and have central, round, uniform nuclei. In
addition, they contain secretory granules of parathyroid hormone (PTH). Sometimes,
these cells have a water-clear appearance owing to lakes of glycogen. Oxyphil cells and
transitional oxyphils are found throughout the normal parathyroid, either singly or in
small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm,
and are tightly packed with mitochondria. Glycogen granules are also present in these
cells, but secretory granules are sparse or absent. In early infancy and childhood, the
parathyroid glands are composed almost entirely of solid sheets of chief cells. The
amount of stromal fat increases up to age 25, reaching a maximum of approximately 30%
of the gland, and then plateaus. The precise proportion of fat is determined largely by
constitutional factors; for instance, obese individuals have more adipose tissue in their
The activity of the parathyroid glands is controlled by the level of free (ionized) calcium
in the bloodstream rather than by trophic hormones secreted by the hypothalamus and
pituitary. Normally, decreased levels of free calcium stimulate the synthesis and secretion
of PTH. Circulating PTH is an 84-amino-acid linear polypeptide derived by sequential
cleavage in the chief cell of a larger pre-pro form. Its biologic activity resides within the
34 residues at the amino terminus. Smaller nonfunctional fragments of the hormone,
apparently lacking the critical amino-terminal domain, also circulate. These assume
importance because, although they are biologically inert, they contain epitopes that react
in certain radioimmunoassays for PTH.
The PTH receptor is a seven-transmembrane G-protein-coupled receptor. Binding of the
hormone leads to activation of the stimulatory G-protein, Gs , causing adenylate cyclase-
mediated generation of cAMP. This pathway assumes clinical significance when
abnormalities of the Gs protein result in either hyperactivity or hypoactivity of the
parathyroid gland (see below). The metabolic functions of PTH in supporting serum
calcium levels can be summarized as follows:
• PTH activates osteoclasts, thereby mobilizing calcium from bone.
• It increases the renal tubular reabsorption of calcium, thereby conserving free
• It increases the conversion of vitamin D to its active dihydroxy form in the
• It increases urinary phosphate excretion, thereby lowering serum phosphate
• It augments gastrointestinal calcium absorption.
The net result of these activities is an increase in the level of free calcium, which, in turn,
inhibits further PTH secretion in a classic feedback loop.
Hypercalcemia is one of a number of changes induced by elevated levels of PTH. As was
discussed in Chapter 7 , hypercalcemia is a relatively common complication of
66. malignancy, occurring both with solid tumors, such as lung, breast, head and neck, and
renal cancers, and with hematologic malignancies, notably multiple myeloma. In fact,
malignancy is the most common cause of clinically apparent hypercalcemia, while
primary hyperparathyroidism (see below) is a more common cause of asymptomatic
elevated blood calcium. The prognosis of patients with malignancy-associated
hypercalcemia is generally poor, in that it more frequently occurs in individuals with
advanced cancers. Hypercalcemia of malignancy is due to increased bone resorption and
subsequent release of calcium. There are two major mechanisms by which this can occur:
(1) osteolytic metastases and local release of cytokines and (2) release of PTH-related
• Osteolytic metastases: Metastatic tumor cells, as well as stromal cells in the
vicinity of the metastases, release a variety of soluble mediators that induce local
osteolysis by promoting differentiation of committed osteoclast precursors into
mature cells. Recently, a critical osteoclastogenic pathway has been discovered
that involves the osteoblast cell-surface receptor RANK (receptor activator of
nuclear factor κB), its ligand, RANKL, and a decoy receptor for RANKL,
osteoprotegerin. (A decoy receptor is a soluble receptor that competes with the
true receptor, in this case RANK, for binding the ligand of interest, in this case
RANKL; see Chapter 26 .) RANKL is also known as "osteoclast differentiation
factor," and by binding with the RANK receptor, it promotes all aspects of
osteoclast function, including proliferation, differentiation, fusion, and activation.
RANKL is secreted by tumor cells and peritumoral stromal cells in metastatic foci
and causes osteolysis. Osteoprotegerin inhibits this pathway of osteoclastogenesis
and has emerged as a possible therapeutic agent in cancer patients with
hypercalcemia of malignancy.
• PTH-related protein: The most frequent cause of hypercalcemia in
nonmetastatic solid tumors—particularly squamous cell cancers—is the release of
PTHrP. This protein is immunologically distinct from PTH yet it is similar
enough in structure to permit binding to identical receptors and simulation of
second messengers, notably cAMP. This accounts for the ability of PTHrP to
induce most of the actions of PTH, including increases in bone resorption and
inhibition of proximal tubule phosphate transport. Classically, PTHrP-induced
hypercalcemia was known as "humoral hypercalcemia of malignancy" to
distinguish it from hypercalcemia arising from osteolytic metastases. It is now
recognized that a significant proportion of cancer patients with osteolytic
metastases also have circulating PTHrP; therefore, PTHrP contributes to
hypercalcemia of malignancy irrespective of the presence or absence of
Similar to the other endocrine organs, abnormalities of the parathyroid glands include
both hyperfunction and hypofunction. Tumors of the parathyroid glands, in contrast to
67. thyroid tumors, usually come to attention because of excessive secretion of PTH rather
than because of mass effects.
Hyperparathyroidism occurs in two major forms—primary and secondary—and, less
commonly, tertiary. The first condition represents an autonomous, spontaneous
of PTH; the latter two conditions typically occur as secondary phenomena in patients
with chronic renal insufficiency.
Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an
important cause of hypercalcemia. The frequency of the various parathyroid lesions
underlying the hyperfunction is as follows:
• Adenoma: 75% to 80%
• Primary hyperplasia (diffuse or nodular): 10% to 15%
• Parathyroid carcinoma: less than 5%
Primary hyperparathyroidism is usually a disease of adults and is more common in
women than in men by a ratio of nearly 3:1. The annual incidence is now estimated to be
about 25 cases per 100,000 in the United States and Europe; more cases are being
detected due to the greater availability and use of advanced analyzers for measuring
serum electrolytes. Most cases occur in the fifties or later in life.
Studies have begun to provide a molecular understanding of the pathogenesis of primary
hyperparathyroidism. In more than 95% of cases, the disorder is caused by sporadic
parathyroid adenomas or sporadic hyperplasia ( Fig. 24-24 ). Although familial
syndromes are a distant second, they have provided a unique insight into the pathogenesis
of primary hyperparathyroidism. The genetic syndromes associated with familial primary
hyperparathyroidism include the following:
• Multiple endocrine neoplasia-1 (MEN-1): The MEN1 gene on chromosome
11q13 is a tumor suppressor gene inactivated in a variety of MEN-1-related
parathyroid lesions, including parathyroid adenomas and hyperplasia. In addition
to familial cases, MEN1 mutations have also been described in sporadic
parathyroid tumors. The MEN-1 syndrome is discussed in further detail below.
• Multiple endocrine neoplasia-2 (MEN-2): The MEN-2 syndrome is caused by
activating mutations in the tyrosine kinase receptor, RET, on chromosome 10q.
Primary hyperparathyroidism occurs as a component of MEN-2A, which is
68. discussed in further detail below. RET mutations have not been described in
sporadic parathyroid lesions outside the context of MEN-2.
• Familial hypocalciuric hypercalcemia (FHH) is an autosomal-dominant disorder
characterized by enhanced parathyroid function due to decreased sensitivity to
extracellular calcium. Mutations in the parathyroid calciumsensing receptor gene
(CASR) on chromosome 3q are a primary cause for this disorder. Patients with 
homozygous CASR mutations present in the neonatal period with severe
hyperparathyroidism. CASR mutations have not been described in sporadic
Figure 24-24 Parathyroid adenomas are almost always solitary lesions. Technetium-99m-sestamibi
radionuclide scan demonstrates an area of increased uptake corresponding to the left inferior parathyroid
gland (arrow). This patient had a parathyroid adenoma. Preoperative scintigraphy is useful in localizing
and distinguishing adenomas from parathyroid hyperplasia, where more than one gland would demonstrate
Most, if not all, sporadic parathyroid adenomas are monoclonal, suggesting that they are
true neoplastic outgrowths from a single abnormal progenitor cell. Sporadic parathyroid
hyperplasia is also monoclonal in many instances, particularly when associated with a
persistent stimulus for parathyroid growth (refractory secondary or tertiary
parathyroidism; see below). Among the sporadic adenomas, there are two molecular
defects that have an established role in pathogenesis: 
• Parathyroid adenoma 1 (PRAD1): PRAD1 encodes cyclin D1, a major regulator
of the cell cycle. A pericentromeric inversion on chromosome 11 results in
relocation of the PRAD1 protooncogene (normally on 11q) so that it is positioned
adjacent to the 5' flanking region of the PTH gene (on 11p). As a consequence of
these changes, a regulatory element from the PTH gene 5' flanking sequence
directs overexpression of cyclin D1 protein, forcing the cells to proliferate. Ten
per cent to 20% of adenomas have this clonal genetic defect. In addition, cyclin
D1 is overexpressed in approximately 40% of parathyroid adenomas, suggesting
that mechanisms other than PRAD1 inversion can lead to its activation.
69. • MEN1: Approximately 20% to 30% of parathyroid tumors not associated with
the MEN-1 syndrome demonstrate mutations in both copies of the MEN1 gene.
The spectrum of MEN1 mutations in the sporadic tumors is virtually identical to
that in familial parathyroid adenomas.
The morphologic changes seen in primary hyperparathyroidism include those in the
parathyroid glands as well as those in other organs affected by elevated levels of calcium.
Parathyroid adenomas are almost always solitary and, similar to the normal parathyroid
glands, may lie in close proximity to the thyroid gland or in an ectopic site (e.g., the
mediastinum). The typical parathyroid adenoma averages 0.5 to 5.0 gm; is a well-
circumscribed, soft, tan to reddish-brown nodule; and is invested by a delicate capsule
( Fig. 24-25 ). In contrast to primary hyperplasia, the glands outside the adenoma are
usually normal in size or somewhat shrunken because of feedback inhibition by
elevations in serum calcium. Microscopically, parathyroid adenomas are often composed
predominantly of fairly uniform, polygonal chief cells with small, centrally placed nuclei
(see Fig. 24-25 ). In most cases, at least a few nests of larger cells containing oxyphil
cells are present as well; uncommonly, entire adenomas may be composed of this cell
type (oxyphil adenomas). The chief cells are
Figure 24-25 Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma (low-power
photomicrograph) revealing clear delineation from the residual gland below. B, High-power detail of a
chief cell parathyroid adenoma. There is some slight variation in nuclear size but no anaplasia and some
slight tendency to follicular formation.
arranged in a variety of patterns; follicles reminiscent of those seen in the thyroid are
present in some cases. Mitotic figures are rare. A rim of compressed, non-neoplastic
parathyroid tissue, generally separated by a fibrous capsule, is often visible at the edge of
the adenoma. It is not uncommon to find bizarre and pleomorphic nuclei even within
adenomas (so-called endocrine atypia), and this should not be used as a criterion for
70. defining malignancy. In contrast to the normal parathyroid parenchyma, adipose tissue is
inconspicuous within the adenoma.
Primary hyperplasia may occur sporadically or as a component of MEN syndrome.
Although classically all four glands are involved, there is frequently asymmetry with
apparent sparing of one or two glands, making the distinction between hyperplasia and
adenoma difficult. The combined weight of all glands rarely exceeds 1.0 gm and is often
less. Microscopically, the most common pattern seen is that of chief cell hyperplasia,
which may involve the glands in a diffuse or multinodular pattern. Less commonly, the
constituent cells contain abundant water-clear cells ("water-clear cell hyperplasia"). In
many instances, there are islands of oxyphils, and poorly developed, delicate fibrous
strands may envelop the nodules. As in the case of adenomas, stromal fat is
inconspicuous within the foci of hyperplasia.
Parathyroid carcinomas may be fairly circumscribed lesions that are difficult to
distinguish from adenomas, or they may be clearly invasive neoplasms. These tumors
enlarge one parathyroid gland and consist of gray-white, irregular masses that sometimes
exceed 10 gm in weight. The cells of parathyroid carcinomas are usually uniform and
resemble normal parathyroid cells. They are arrayed in nodular or trabecular patterns
with a dense, fibrous capsule enclosing the mass. There is general agreement that a
diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of
surrounding tissues and metastasis are the only reliable criteria of malignancy.
Local recurrence occurs in one third of cases, and more distant dissemination occurs in
Morphologic changes in other organs deserving special mention include skeletal and
renal lesions. Skeletal changes include prominence of osteoclasts, which, in turn, erode
bone matrix and mobilize calcium salts, particularly in the metaphyses of long tubular
bones ( Chapter 26 ). Bone resorption is accompanied by increased osteoblastic activity
and the formation of new bone trabeculae. In many cases, the resultant bone contains
widely spaced, delicate trabeculae reminiscent of those seen in osteoporosis. In more
severe cases, the cortex is grossly thinned, and the marrow contains increased amounts of
fibrous tissue accompanied by foci of hemorrhage and cyst formation (osteitis fibrosa
cystica). Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris
occasionally form masses that may be mistaken for neoplasms (brown tumors of
hyperparathyroidism). PTH-induced hypercalcemia favors formation of urinary tract
stones (nephrolithiasis) as well as calcification of the renal interstitium and tubules
(nephrocalcinosis). Metastatic calcification secondary to hypercalcemia may also be seen
in other sites, including the stomach, lungs, myocardium, and blood vessels.
Primary hyperparathyroidism presents in one of two general ways: (1) It may be
asymptomatic and be identified after a routine chemistry profile, or (2) patients may have
the classic clinical manifestations of primary hyperparathyroidism.
71. Because serum calcium levels are routinely assessed in the work-up of most patients who
need blood tests for unrelated conditions, clinically silent hyperparathyroidism is often
detected early. Hence, many of the classic clinical manifestations, particularly those
referable to bone and renal disease, are now seen infrequently in clinical practice. The
most common manifestation of primary hyperparathyroidism is an increase in the level of
serum ionized calcium; in fact, primary hyperparathyroidism is the most common cause
of asymptomatic hypercalcemia. It should be recalled that other conditions also produce
hypercalcemia ( Table 24-5 ). Malignancy, in particular, is the most common cause of
clinically apparent hypercalcemia in adults and must be excluded by appropriate clinical
and laboratory investigations in patients with suspected hyperparathyroidism.
TABLE 24-5 -- Causes of Hypercalcemia
Raised PTH Decreased PTH
Hyperparathyroidism Hypercalcemia of malignancy
Primary (adenoma   > hyperplasia) *
Osteolytic metastases   (RANKL-mediated)
Tertiary   † Vitamin D toxicity
Familial hypocalciuric hypercalcemia Immobilization
Granulomatous disease (sarcoidosis)
PTH-rP, Parathyroid hormone-related protein. RANKL, Receptor activator of nuclear
factor κB ligand.
*Primary hyperparathyroidism is the most common cause of hypercalcemia overall. Malignancy is the most
common cause of symptomatic hypercalcemia. Primary hyperparathyroidism and malignancy account for
nearly 90% of cases of hypercalcemia.
†Secondary and tertiary hyperparathyroidism are most commonly associated with progressive renal failure.
In patients with primary hyperparathyroidism, serum PTH levels are inappropriately
elevated for the level of serum calcium, whereas PTH levels are low to undetectable in
hypercalcemia because of nonparathyroid disease (see Table 24-5 ). In patients with
hypercalcemia caused by secretion of PTHrP by certain nonparathyroid tumors,
radioimmunoassays specific for PTH and PTHrP can distinguish between the two
molecules. Other laboratory alterations referable to PTH excess include
hypophosphatemia and increased urinary excretion of both calcium and phosphate.
72. Secondary renal disease may lead to phosphate retention with normalization of serum
Symptomatic Primary Hyperparathyroidism.
The signs and symptoms of hyperparathyroidism reflect the combined effects of
increased PTH secretion and hypercalcemia. Primary hyperparathyroidism has been
Figure 24-26 Cardinal features of hyperparathyroidism. With routine evaluation of calcium levels in most
patients, primary hyperparathyroidism is often detected at a clinically silent stage. Hypercalcemia from any
other cause can also give rise to the same symptoms.
with a constellation of symptoms that included "painful bones, renal stones, abdominal
groans, and psychic moans" ( Fig. 24-26 ). The symptomatic presentation involves a
diversity of clinical manifestations:
• Bone disease includes bone pain secondary to fractures of bones weakened by
osteoporosis or osteitis fibrosa cystica.
• Nephrolithiasis (renal stones) occurs in 20% of newly diagnosed patients, with
attendant pain and obstructive uropathy. Chronic renal insufficiency and a variety
of abnormalities in renal function are found, including polyuria and secondary
• Gastrointestinal disturbances include constipation, nausea, peptic ulcers,
pancreatitis, and gallstones.
• Central nervous system alterations include depression, lethargy, and eventually
• Neuromuscular abnormalities include complaints of weakness and fatigue.
• Cardiac manifestations include aortic or mitral valve calcifications (or both).
73. The abnormalities most directly related to hyperparathyroidism are nephrolithiasis and
bone disease, whereas those attributable to hypercalcemia include fatigue, weakness, and
constipation. The pathogenesis of many of the other manifestations of the disorder
remains poorly understood.
Secondary hyperparathyroidism is caused by any condition associated with a chronic
depression in the serum calcium level because low serum calcium leads to compensatory
overactivity of the parathyroid glands. Renal failure is by far the most common cause of
secondary hyperparathyroidism, although a number of other diseases, including
inadequate dietary intake of calcium, steatorrhea, and vitamin D deficiency, may also
cause this disorder. The mechanisms by which
chronic renal failure induces secondary hyperparathyroidism are complex and not fully
understood. Chronic renal insufficiency is associated with decreased phosphate excretion,
which in turn results in hyperphosphatemia. The elevated serum phosphate levels directly
depress serum calcium levels and thereby stimulate parathyroid gland activity. In
addition, loss of renal substance reduces the availability of α-1-hydroxylase necessary for
the synthesis of the active form of vitamin D, which in turn reduces intestinal absorption
of calcium ( Chapter 9 ).
The parathyroid glands in secondary hyperparathyroidism are hyperplastic. As in
the case of primary hyperplasia, the degree of glandular enlargement is not necessarily
symmetric. Microscopically, the hyperplastic glands contain an increased number of chief
cells, or cells with more abundant, clear cytoplasm (so-called water-clear cells) in a
diffuse or multinodular distribution. Fat cells are decreased in number. Bone changes
similar to those seen in primary hyperparathyroidism may also be present. Metastatic
calcification may be seen in many tissues, including lungs, heart, stomach, and blood
The clinical features of secondary hyperparathyroidism are usually dominated by those
associated with chronic renal failure. Bone abnormalities (renal osteodystrophy) and
other changes associated with PTH excess are, in general, less severe than are those seen
in primary hyperparathyroidism. The vascular calcification associated with secondary
hyperparathyroidism may occasionally result in significant ischemic damage to skin and
other organs, a process sometimes referred to as calciphylaxis. In a minority of patients,
parathyroid activity may become autonomous and excessive, with resultant
hypercalcemia, a process that is sometimes termed tertiary hyperparathyroidism.
Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients.
Hypoparathyroidism is far less common than is hyperparathyroidism. There are many
possible causes of deficient PTH secretion resulting in hypoparathyroidism:
• Surgically induced hypoparathyroidism occurs with inadvertent removal of all
the parathyroid glands during thyroidectomy, excision of the parathyroid glands
in the mistaken belief that they are lymph nodes during radical neck dissection for
some form of malignant disease, or removal of too large a proportion of
parathyroid tissue in the treatment of primary hyperparathyroidism.
• Congenital absence of all glands, as in certain developmental abnormalities,
such as thymic aplasia and cardiac defects (22q11.2 syndrome) (see Chapter 5 ).
• Familial hypoparathyroidism is often associated with chronic mucocutaneous
candidiasis and primary adrenal insufficiency; this syndrome is known as
autoimmune polyendocrine syndrome type 1 (APS1) and is caused by mutations
in the autoimmune regulator (AIRE) gene. The syndrome typically presents in
childhood with the onset of candidiasis, followed several years later by
hypoparathyroidism and then adrenal insufficiency during adolescence. APS1 is
discussed further in the section on adrenal glands.
• Idiopathic hypoparathyroidism most likely represents an autoimmune disease
with isolated atrophy of the glands. Sixty per cent of the patients with this
disorder have autoantibodies directed against the calcium-sensing receptor
(CASR) in the parathyroid gland. Antibody binding to the receptor may prevent
the release of PTH.
The major clinical manifestations of hypoparathyroidism are referable to hypocalcemia
and are related to the severity and chronicity of the hypocalcemia.
• The hallmark of hypocalcemia is tetany, which is characterized by
neuromuscular irritability, resulting from decreased serum ionized calcium
concentration. These findings can range from circumoral numbness or
paresthesias (tingling) of the distal extremities and carpopedal spasm, to life-
threatening laryngospasm and generalized seizures. The classic findings on
physical examination of patients with neuromuscular irritability are Chvostek sign
and Trousseau sign. Chvostek sign is elicited in subclinical disease by tapping
along the course of the facial nerve, which induces contractions of the muscles of
the eye, mouth, or nose. Occluding the circulation to the forearm and hand by
inflating a blood pressure cuff about the arm for several minutes induces carpal
spasm, which disappears as soon as the cuff is deflated (Trousseau sign).
• Mental status changes can include emotional instability, anxiety and depression,
confusional states, hallucinations, and frank psychosis.
75. • Intracranial manifestations include calcifications of the basal ganglia,
parkinsonian-like movement disorders, and increased intracranial pressure with
• Ocular disease results in calcification of the lens leading to cataract formation.
• Cardiovascular manifestations include a conduction defect, which produces a
characteristic prolongation of the QT interval in the electrocardiogram.
• Dental abnormalities occur when hypocalcemia is present during early
development. These findings are highly characteristic of hypoparathyroidism and
include dental hypoplasia, failure of eruption, defective enamel and root
formation, and abraded carious teeth.
In this condition, hypoparathyroidism occurs because of end-organ resistance to the
actions of PTH. Indeed, serum PTH levels are normal or elevated. Central to the
understanding of PTH resistance are two key concepts: (1) G-proteins, principally Gs ,
mediate the cellular actions of PTH on bone and kidney, and (2) GNAS1 is a selectively
imprinted gene, with tissue-specific patterns of imprinting. In most tissues, Gs α, the
product of GNAS1, is expressed from both alleles. In the pituitary (see above) and the
kidneys, GNAS1 is expressed only from the maternally inherited chromosome, owing to
paternal imprinting (silencing) of the gene. As a result, a mutation that affects the
maternal allele results in
complete loss of Gs α expression in the kidney, while a mutation in the normally
unexpressed paternal allele has no effect on Gs α levels; in contrast, a mutation of either
allele will produce a 50% decrease in Gs α in tissues other than the kidneys and pituitary,
since GNAS1 is expressed from both copies of the gene. Two types of
pseudohypoparathyroidism have been identified depending on the parent of origin of the
1. Pseudohypoparathyroidism type 1A is associated with multihormone resistance
and Albright hereditary osteodystrophy (AHO), a syndrome characterized by
skeletal and developmental defects. Patients with AHO often have short stature,
obesity, short metacarpal and metatarsal bones, and variable mental deficits. The
multihormone resistance involves three hormones (PTH, TSH, and LH/FSH), all
of which activate Gs α-mediated pathways in target tissues. The PTH resistance is
the most obvious clinical manifestation, presenting as hypocalcemia,
hyperphosphatemia, and elevated circulating PTH. TSH resistance is generally
mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in
females. The mutation in this disorder is inherited on the maternal allele, severely
impeding the actions of PTH on the kidney in maintaining calcium homeostasis.
2. Pseudopseudohypoparathyroidism: In this disorder, the mutation is inherited on
the paternal allele, and it is characterized by AHO without accompanying
76. multihormonal resistance. As a result, serum calcium, phosphate and PTH levels
The Endocrine Pancreas
The endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets
of Langerhans. The first evidence of islet formation in the human fetus is seen at 9 to 11
weeks. Embryologically, both endocrine and exocrine components of the pancreas are
endodermal derivatives. Several transcription factors have now been identified that
determine lineage specification (i.e., endocrine versus exocrine) in the developing
pancreas. For example, expression of the transcription factor neurogenin 3 (Ngn3)
delineates endocrine progenitors that eventually give rise to mature islet cells.
In aggregate, the islets in the adult human weigh only 1 to 1.5 gm; individually, most
islets measure 100 to 200 µm and consist of four major and two minor cell types. The
four main types are β, α, δ, and PP (pancreatic polypeptide) cells. These make up about
68%, 20%, 10%, and 2%, respectively, of the adult islet cell population. They can be
differentiated morphologically by their staining properties, by the ultrastructural
characteristics of their granules, and by their hormone content (see Fig. 24-27 ).
The β cell produces insulin, as will be detailed in the discussion of diabetes. The insulin-
containing intracellular granules contain a crystalline matrix with a rectangular profile,
surrounded by a halo. The α cell secretes glucagon, inducing hyperglycemia by its
glycogenolytic activity in the liver. α-cell granules are round, with closely applied
membranes and a dense center. δ cells contain somatostatin, which suppresses both
insulin and glucagon release; they have large, pale granules with closely applied
membranes. PP cells contain a unique pancreatic polypeptide that exerts a number of
gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes
and inhibition of intestinal motility. These cells have small, dark granules and not only
are present in islets, but also are scattered in the exocrine pancreas.
The two rare cell types are D1 cells and enterochromaffin cells. D1 cells elaborate
vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and
hyperglycemia; it also stimulates gastrointestinal fluid secretion and causes secretory
diarrhea. Enterochromaffin cells synthesize serotonin and are the source of pancreatic
tumors that cause the carcinoid syndrome ( Chapter 17 ).
We now turn to the two main disorders of islet cells: diabetes mellitus and pancreatic
Diabetes mellitus (DM) is not a single disease entity, but rather a group of metabolic
disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in
diabetes results from defects in insulin secretion, insulin action, or, most commonly,
both. The chronic hyperglycemia and attendant metabolic dysregulation may be
associated with secondary damage in multiple organ systems, especially the kidneys,
eyes, nerves, and blood vessels. Diabetes affects an estimated 16 million people in the
United States, as many as half of whom are undiagnosed. Each year, an additional
800,000 individuals develop diabetes in this country, and 54,000 die from diabetes-
related causes. Diabetes is a leading cause of end-stage renal disease, adult-onset
blindness, and nontraumatic lower extremity amputations in the United States. For
born in the United States in 2000, the estimated lifetime risk of being diagnosed with
diabetes mellitus is 1 in 3 for males and 2 in 5 for females. The risk is 2 to 5 times
higher in the African-American, Hispanic, and Native American communities, compared
to non-Hispanic whites. Worldwide, more than 140 million people suffer from diabetes,
making this one of the most common noncommunicable diseases. The number of
affected individuals with diabetes is expected to double by 2025. The countries with the
largest number of diabetics are India, China, and the United States.
Blood glucose values are normally maintained in a very narrow range, usually 70 to 120
mg/dL. The diagnosis of diabetes is established by noting elevation of blood glucose by
any one of three criteria:
1. A random glucose > 200 mg/dL, with classical signs and symptoms (discussed
2. A fasting glucose > 126 mg/dL on more than one occasion
3. An abnormal oral glucose tolerance test (OGTT), in which the glucose is > 200
mg/dL 2 hours after a standard carbohydrate load
Levels of blood glucose proceed along a continuum. Individuals with fasting glucoses
less than 110 mg/dL, or less than 140 mg/dL following an OGTT, are considered to be
euglycemic. However, those with fasting glucoses greater than 110 but less than 126, or
OGTT values greater than 140 but less than 200, are considered to have impaired glucose
tolerance (IGT). Individuals with IGT have a significant risk of progressing to overt
78. diabetes over time, with up to 5% to 10% advancing to DM per year. In addition, those
with IGT are at risk for cardiovascular disease, due to the abnormal carbohydrate
metabolism as well as the co-existence of other risk factors such as low HDL,
hypertriglyceridemia, and increased plasminogen activator inhibitor-1 (PAI-1) (see
Chapter 11 ).
Although all forms of diabetes mellitus share hyperglycemia as a common feature, the
pathogenic processes involved in the development of hyperglycemia vary widely. The
previous classification schemes of diabetes mellitus were based on the age at onset of the
disease or on the mode of therapy; in contrast, the recently revised classification reflects
our greater understanding of the pathogenesis of each variant ( Table 24-6 ). The vast
majority of cases of diabetes fall into one of two broad classes:
Type 1 diabetes is characterized by an absolute deficiency of insulin caused by
pancreatic β-cell destruction. It accounts for approximately 10% of all cases.
Type 2 diabetes is caused by a combination of peripheral resistance to insulin
action and an inadequate secretory response by the pancreatic β-cells ("relative
insulin deficiency"). Approximately 80% to 90% of patients have type 2 diabetes.
A variety of monogenic and secondary causes are responsible for the remaining cases,
and these will be discussed later. It should be stressed that while the major types of
diabetes have different pathogenic mechanisms, the long-term complications
TABLE 24-6 -- Classification of Diabetes Mellitus
1. Type 1 diabetes (β-cell destruction, leads to absolute insulin deficiency)
2. Type 2 diabetes (insulin resistance with relative insulin deficiency)
3. Genetic defects of β-cell function
Maturity-onset diabetes of the       young (MODY), caused by mutations in:
Hepatocyte nuclear factor 4α        [HNF-4α] (MODY1)
Hepatocyte nuclear factor 1α        [HNF-1α] (MODY3)
Insulin promoter factor [IPF-1]        (MODY4)
Hepatocyte nuclear factor 1β        [HNF-1β] (MODY5)
80. β-adrenergic agonists
9. Genetic syndromes associated with diabetes
10. Gestational diabetes mellitus
Data from the Report of the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus. Diabetic Care 25 (suppl. 1):S5–S20, 2002.
in kidneys, eyes, nerves, and blood vessels are the same, as are the principal causes of
morbidity and death. The pathogenesis of the two major types is discussed separately, but
first we briefly review normal insulin secretion and the mechanism of insulin signaling,
since these aspects are critical to understanding the pathogenesis of diabetes.
NORMAL INSULIN PHYSIOLOGY
Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose
production in the liver; glucose uptake and utilization by peripheral tissues, chiefly
muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on
Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During
fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and
glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby
preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily
by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall
in response to the large glucose load. Insulin promotes glucose uptake and utilization in
tissues (discussed later). The skeletal muscle is the major insulin-responsive site for
postprandial glucose utilization, and is critical for preventing hyperglycemia and
maintaining glucose homeostasis.
81. Regulation of Insulin Release
The insulin gene is expressed in the β cells of the pancreatic islets ( Fig. 24-27 ).
Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and
delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate the
mature insulin and a cleavage peptide, C-peptide. Both insulin and C-peptide are then
stored in secretory granules and secreted in equimolar quantities after physiologic
stimulation; increasingly, C-peptide
Figure 24-27 Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark
reaction product for insulin in β cells (A), glucagon in α cells (B), and somatostatin in δ cells (C). D,
Electron micrograph of a β cell shows the characteristic membrane-bound granules, each containing a
dense, often rectangular core and distinct halo. E, Portions of an α cell (left) and a δ cell (right) also exhibit
granules, but with closely apportioned membranes. The α-cell granule exhibits a dense, round center.
(Electron micrographs courtesy of Dr. A. Like, University of Massachusetts Medical School, Worcester,
levels are being used as a clinical assay to measure endogenous insulin secretion.
The most important stimulus that triggers insulin synthesis and release is glucose itself. A
rise in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by
an insulin-independent, glucose-transporting protein, GLUT-2 ( Fig. 24-28 ). 
Metabolism of glucose via glycolysis generates ATP, resulting in increase in cytoplasmic
ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ -channel on the β-cell
82. membrane, leading to membrane depolarization and the influx of extracellular Ca2+
through voltage-dependent Ca2+ -channels. The resultant increase in intracellular Ca2+
stimulates secretion of insulin, presumably from stored hormone within the β-cell
granules. This is the phase of immediate release of insulin. If the secretory stimulus
persists, a delayed and protracted response follows that involves active synthesis of
insulin. Other agents, including intestinal hormones and certain amino acids (leucine and
arginine), stimulate insulin release but not synthesis.
Insulin Action and Insulin Signaling Pathways
Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-
promoting effects ( Fig. 24-29 ). Its principal metabolic function is to increase the rate of
glucose transport into certain cells in the body. These are the striated
Figure 24-28 Insulin synthesis and secretion. Intracellular transport of glucose is mediated by GLUT-2, an
insulin-independent glucose transporter in β cells. Glucose undergoes oxidative metabolism in the β cell to
yield ATP. ATP inhibits an inward rectifying potassium channel receptor on the β-cell surface; the receptor
itself is a dimeric complex of the sulfonylurea receptor and a K+ -channel protein. Inhibition of this receptor
leads to membrane depolarization, influx of Ca2+ ions, and release of stored insulin from β cells.
muscle cells (including myocardial cells) and to a lesser extent, adipocytes, representing
collectively about two thirds of the entire body weight. Glucose uptake in other
83. peripheral tissues, most notably the brain, is insulin-independent. In muscle cells, glucose
is then either stored as glycogen or oxidized to
Figure 24-29 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.
generate ATP. In adipose tissue, glucose is primarily stored as lipid. Besides promoting
lipid synthesis, insulin also inhibits lipid degradation in adipocytes. Similarly, insulin
promotes amino acid uptake and protein synthesis, while inhibiting protein degradation.
Thus, the anabolic effects of insulin are attributable to increased synthesis and reduced
degradation of glycogen, lipids, and proteins. In addition, insulin has several mitogenic
functions, including initiation of DNA synthesis in certain cells and stimulation of their
growth and differentiation.
The binding of insulin to its receptor triggers a complex signaling cascade of protein
phosphorylation and dephosphorylation culminating in the metabolic and mitogenic
effects of insulin described above. Elucidation of the insulin signaling pathway has been
central to our understanding of the mechanisms underlying insulin resistance in diabetes
(see below). The complete description of this intricate network is beyond the scope of
this book, and we will only summarize some of the more pertinent mediators ( Fig.
24-30 ). The insulin receptor is a tetrameric protein composed of two α- and two β-
84. subunits. The β-subunit cytosolic domain possesses tyrosine kinase activity. Insulin
binding to the α-subunit extracellular domain activates the β-subunit tyrosine kinase,
resulting in both autophosphorylation of the receptor and phosphorylation of downstream
signal transduction elements. For the sake of simplicity, we can separate the signaling
pathways into two broad functional categories, mitogenic and metabolic, with the
understanding that there may be considerable cross-talk between the protein
intermediaries. The mitogen-activated protein kinase (MAPK) pathway is responsible
for the mitogenic effects of insulin (and insulin-like growth factors), promoting cellular
proliferation and growth. The metabolic effects of insulin are principally mediated by
phosphatidylinositol-3-kinase (PI-3K). PI-3K-dependent signaling mediates several of the
cellular effects of insulin described above and summarized in Figure 24-30 .  
PATHOGENESIS OF TYPE 1 DIABETES MELLITUS
This form of diabetes results from a severe lack of insulin caused by an immunologically
mediated destruction of β cells. Type 1 diabetes most commonly develops in childhood,
becomes manifest at puberty, and progresses with age. Since the disease can develop at
any age, including late adulthood, the appellation "juvenile diabetes" is now considered
obsolete. Similarly, the older moniker "insulin-dependent diabetes mellitus" (IDDM) has
been excluded from the recent classification of diabetes to reflect the emphasis on
pathogenic mechanisms rather than mode of therapy. Nevertheless, most patients
depend on insulin for survival; without insulin, they develop serious metabolic
complications such as acute ketoacidosis and coma. A rare form of "idiopathic" type 1
diabetes has been described in which the evidence for autoimmunity is not definitive.
Here we will focus on the typical immune-mediated type 1 diabetes.
Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily
by T lymphocytes reacting against as yet poorly defined β-cell antigens. As in all
autoimmune diseases, genetic susceptibility and environmental factors play important
roles in the pathogenesis ( Chapter 6 ). We first describe the mechanisms of β-cell
85. Figure 24-30 Insulin action on a target cell. Insulin binds to the α subunit of insulin receptor, leading to
activation of the kinase activity in the β-subunit, and sets in motion a phosphorylation (i.e., activation)
cascade of multiple downstream target proteins. The mitogenic functions of insulin (and the related insulin-
like growth factors) are mediated via the mitogen-activated protein kinase (MAP kinase) pathway. The
metabolic actions of insulin are mediated primarily by activation of the phosphatidylinositol-3-kinase
(PI-3K) pathway. The PI-3K-signaling pathway is responsible for a variety of effects on target cells,
including translocation of GLUT-4 containing vesicles to the surface; increasing GLUT-4 density on the
membrane and rate of glucose influx; promoting glycogen synthesis via activation of glycogen synthase;
and promoting protein synthesis and lipogenesis, while inhibiting lipolysis. The PI-3K pathway also
promotes cell survival and proliferation.
then discuss the current ideas about the factors that trigger autoimmune attack against
Mechanisms of β Cell Destruction
Although the clinical onset of type 1 diabetes is abrupt, this disease in fact results from a
chronic autoimmune attack on β cells that usually starts many years before the disease
becomes evident ( Fig. 24-31 ). The classic manifestations of the disease (hyperglycemia
and ketosis) occur late in its course, after more than 90% of the β cells have been
Several mechanisms contribute to β cell destruction: 
• T lymphocytes react against β-cell antigens and cause cell damage. These T cells
include (1) CD4+ T cells of the TH 1 subset, which cause tissue injury by
activating macrophages, and (2) CD8+ cytotoxic T lymphocytes, which directly
kill β cells and also secrete cytokines that activate macrophages. In the rare cases
86. in which the pancreatic lesions have been examined at the early active stages of
the disease, the islets show cellular necrosis and lymphocytic infiltration. This
lesion is called insulitis. The infiltrates consist of both CD4+ and CD8+ T cells.
Surviving β cells often express class II MHC molecules, probably an effect of
local production of the cytokine IFN-γ by the T cells. The specificity of these T
cells is largely unknown. Various studies have implicated a β-cell enzyme,
glutamic acid decarboxylase (GAD), and insulin itself as autoantigens, but the
evidence supporting their importance is mainly circumstantial or based on mouse
models of the disease. Also, the key question of why tolerance to these self-
antigens breaks down has not been answered. 
• Locally produced cytokines damage β cells. Among the cytokines implicated in
the cell injury are IFN-γ, produced by T cells, and TNF and IL-1, produced by
macrophages that are activated during the immune reaction. All these cytokines
have been shown to induce β-cell apoptosis in culture; in mouse models of the
disease, β-cell destruction can be reduced by treatment with antagonists against
• Autoantibodies against islet cells and insulin are also detected in the blood of
70% to 80% of patients. The autoantibodies are reactive with a variety of β-cell
antigens, including GAD. These antibodies may participate in causing the disease
or may be a result of T cell-mediated cell injury and release of normally
87. Figure 24-31 Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right,
and hypothetical β-cell mass is plotted against age. (From Eisenbarth GE: Type 1 diabetes: a chronic
autoimmune disease. N Engl J Med 314:1360, 1986. Copyright © 1986, Massachusetts Medical Society.
All rights reserved.)
It is likely that many of these immune mechanisms work together to produce progressive
destruction of β cells, resulting in clinical diabetes. The factors that predispose to
autoimmunity are discussed next.
Type 1 diabetes has a complex pattern of genetic associations, and putative susceptibility
genes have been mapped to at least 20 loci. Many of these associations are with
chromosomal regions, and the particular genes involved are not known yet. Of the
multiple loci that are associated with the disease, by far the most important is the class II
MHC (HLA) locus; according to some estimates, the MHC contributes about half the
genetic susceptibility, and all the other genes combined make up the other half.
The MHC Locus.
88. The principal susceptibility locus for type 1 diabetes resides in the region that encodes the
class II molecules of the MHC on chromosome 6p21 (HLA-D). You will recall that
linkage to the HLA locus has also been demonstrated in other autoimmune diseases
( Chapter 6 ). Ninety per cent to 95% of Caucasians with type 1 diabetes have HLA-DR3,
DR4, or both, in contrast to about 40% of normal subjects; and 40% to 50% of patients
are DR3/DR4 heterozygotes, in contrast to 5% of normal subjects. Interestingly,
susceptibility to type 1 diabetes is actually associated with a linked DQ allele called
DQB1 0302 that is often in linkage disequilibrium with DR4. Thus, the DQB1 0302
allele is considered the primary determinant of susceptibility for the HLA-DR4
haplotype; in contrast, the HLA-DQB1 0602 allele is considered "protective" against
diabetes. Sequencing of DQ molecules associated with diabetes, both in humans and in
the nonobese diabetic (NOD) mouse strain, suggests that an asparagine at position 57 in
the DQβ chain protects against type 1 diabetes and that its absence increases
susceptibility. Although there are many exceptions to this finding, a general hypothesis is
that development of type 1 diabetes is influenced by the structure of the entire DQ
peptide-binding cleft, with residue 57 playing a significant but not exclusive role. Despite
the high relative risk of type 1 diabetes in individuals with particular class II alleles, most
individuals who inherit these alleles do not develop the disease. We still do not know
precisely how the MHC contributes to autoimmunity in this or in any other autoimmune
disease ( Chapter 6 ). Since MHC molecules normally function to display peptides to T
cells, these associations clearly point to an important role of T cells in the disease.
The first disease-associated non-MHC gene to be identified was insulin, with tandem
repeats in the promoter region being associated with disease susceptibility. The
mechanism of this association is unknown. It may be that the disease-associated
polymorphism makes the protein less functional or stable and thus compromises the
functional reserve. Alternatively, these polymorphisms may influence the level of
expression of insulin in the thymus, thus altering the negative selection of insulin-reactive
T cells ( Chapter 6 ). Recently, another gene has been shown to be associated with the
disease, encoding the T-cell inhibitory receptor CTLA-4. Patients with type 1 diabetes
show increased frequency of a splice variant that may abrogate the normal ability of this
receptor to keep self-reactive T lymphocytes under control. 
There is evidence that environmental factors, especially infections, are involved in
triggering autoimmunity in type 1 diabetes and other autoimmune diseases ( Chapter 6 ).
Epidemiologic studies suggest a role of viruses. Seasonal trends that often correspond to
the prevalence of common viral infections have long been noted in the diagnosis of new
cases, as has the association between coxsackieviruses of group B and pancreatic
diseases, including diabetes. Other implicated viral infections include mumps, measles,
cytomegalovirus, rubella, and infectious mononucleosis. In all these cases, the viruses are
not thought to cause diabetes by directly damaging β cells. Rather, as was discussed in
Chapter 6 , two mechanisms, which are not mutually exclusive, have been proposed to
explain how infections can trigger autoimmunity. One is that the infections induce
89. tissue damage and inflammation, leading to the release of β-cell antigens and the
recruitment and activation of lymphocytes and other inflammatory leukocytes in the
tissue. The other possibility is that the viruses produce proteins that mimic self-antigens
and the immune response to the viral protein cross-reacts with the self tissue. Although
there is experimental evidence in support of both possibilities, neither has been
established as being actually involved. It should also be pointed out that recent
epidemiologic studies have shown that in the United States, the incidence of type 1
diabetes in children under 15 years of age has tripled since the 1960s. Similar trends are
seen in Western Europe. These findings are often interpreted as suggesting that infections
may actually be protective in this disease and the increased incidence reflects the
reduction in common infections. Consistent with this possibility, infections also prevent
disease development in the nonobese diabetic mouse model.
PATHOGENESIS OF TYPE 2 DIABETES MELLITUS
While much has been learned in recent years, the pathogenesis of type 2 diabetes remains
enigmatic. Environmental factors, such as a sedentary life style and dietary habits, clearly
play a role, as will become evident when obesity is considered. Nevertheless, genetic
factors are even more important than in type 1 diabetes. Among identical twins, the
concordance rate is 50% to 90%, while among first-degree relatives with type 2 diabetes
(and in fraternal twins), the risk of developing the disease is 20% to 40%, compared to
5% to 7% in the population
at large. Unlike type 1 diabetes, however, the disease is not linked to genes involved in
immune tolerance and regulation, and there is no evidence to suggest an autoimmune
basis for type 2 diabetes.
The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of
peripheral tissues to respond to insulin (insulin resistance) and (2) β-cell dysfunction
that is manifested as inadequate insulin secretion in the face of insulin resistance and
hyperglycemia. In most cases, insulin resistance is the primary event, and is followed by
increasing degrees of β-cell dysfunction (Fig. 24-32 (Figure Not Available) ).
Insulin resistance is defined as resistance to the effects of insulin on glucose uptake,
metabolism, or storage. Insulin resistance is a characteristic feature of most patients
with type 2 diabetes and is an almost universal finding in diabetic individuals who are
obese. The role of insulin resistance in the pathogenesis of type 2 diabetes can be gauged
from the findings that (1) insulin resistance is often detected 10 to 20 years before the
onset of diabetes in predisposed individuals (e.g., offspring of type 2 diabetics) and (2) in
prospective studies, insulin resistance is the best predictor for subsequent progression to
diabetes. Insulin resistance leads to decreased uptake of glucose in muscle and adipose
tissues and an inability of the hormone to suppress hepatic gluconeogenesis. Functional
90. studies in individuals with insulin resistance have demonstrated numerous quantitative
and qualitative abnormalities
Figure 24-32 (Figure Not Available) Metabolic staging of type 2 diabetes mellitus. Genetic predisposition
and environmental influences converge to cause insulin resistance. Compensatory β-cell hyperplasia can
maintain normoglycemia, but eventually, β-cell secretory dysfunction sets in, leading to impaired glucose
tolerance and eventually frank diabetes. Rare instances of primary β-cell failure can directly lead to type 2
diabetes without a state of insulin resistance.
of the insulin signaling pathway, including down-regulation of the insulin receptor;
decreased insulin receptor phosphorylation and tyrosine kinase activity; reduced levels of
active intermediates in the insulin signaling pathway; and impairment of translocation,
docking, and fusion of GLUT-4-containing vesicles with the plasma membrane. 
It is recognized that insulin resistance is a complex phenomenon. Here we discuss some
of the likely culprits responside for decreased sensitivity to insulin in diabetic individuals.
Genetic Defects of the Insulin Receptor and Insulin Signaling Pathway.
Loss-of-function abnormalities of either the insulin receptor or its downstream
intermediates are obvious candidates for mediating insulin resistance in type 2 diabetes.
In mice, tissue-specific knockout of genes encoding various insulin signaling proteins has
resulted in insulin resistance, hyperinsulinemia and hyperglycemia, recapitulating human
type 2 diabetes. Unfortunately, the extrapolation of these single-gene knockout models
to human disease has been less than gratifying. Point mutations of the insulin receptor are
relatively rare, accounting for no more than 1% to 5% of patients with insulin resistance
(see the section entitled "Monogenic Forms of Diabetes"). Analysis of candidate genes
involved in insulin secretion or insulin action, as well as whole genome linkage studies of
affected families, have yielded many polymorphisms that associate with the type 2
diabetic phenotype, but in most cases, the associations have been weak, or the studies
were not reproducible. From these analyses, it appears that while the population risk
associated with any particular genetic variant (polymorphism) may be significant, the
increased risk for developing diabetes for a given individual harboring that variant is
small at best. Suffice it to say that while no one questions a genetic component to insulin
resistance, the high "noise" to signal ratio has hampered identification of the genes
involved. The genetic basis of insulin resistance, and by extension type 2 diabetes,
therefore, remains an enigma.
Obesity and Insulin Resistance.
The association of obesity with type 2 diabetes has been recognized for decades, visceral
obesity being a common phenomenon in the majority of type 2 diabetics. The link
between obesity and diabetes is mediated via effects on insulin resistance. Insulin 
resistance is present even in simple obesity unaccompanied by hyperglycemia, indicating
a fundamental abnormality of insulin signaling in states of fatty excess. The risk for
91. diabetes increases as the body mass index (a measure of body fat content) increases. It is
not only the absolute amount but also the distribution of body fat that has an effect on
insulin sensitivity: Central obesity (abdominal fat) is more likely to be linked with insulin
resistance than are peripheral (gluteal/subcutaneous) fat depots. Although many details of
the so-called adipo-insulin axis remain to be elucidated, following are some of the
putative pathways leading to insulin resistance:
• Role of free fatty acids (FFAs): Cross-sectional studies have demonstrated an
inverse correlation between fasting plasma FFAs and insulin sensitivity.
Furthermore, the level of intracellular triglycerides is often markedly increased in
muscle and liver tissues in obese individuals, presumably because excess
circulating FFAs are deposited in these organs. Intracellular triglycerides and
products of fatty acid metabolism are potent inhibitors of insulin signaling and
result in an acquired insulin resistance state. These "lipotoxic"
effects of FFAs are most likely mediated through a decrease in activity of key
• Role of adipokines in insulin resistance: It is increasingly recognized that
adipose tissue is not merely a passive storage depot for fat, but can also operate as
a functional endocrine organ, releasing hormones in response to changes in the
metabolic status. A variety of proteins released into the systemic circulation by
adipose tissue have been identified, and these are collectively termed adipokines
(or adipose cytokines). Dysregulation of adipokine secretion (either abnormally
increased or decreased levels) may be one of the mechanisms by which insulin
resistance is tied to obesity. Several adipokines have been implicated in insulin
resistance, including leptin, adiponectin and resistin. For brevity, only the
  
first will be discussed. Leptin acts on central nervous system receptors and other
sites to reduce food intake and induce satiety ( Chapter 9 ). Leptin-deficient
animals demonstrate severe insulin resistance that is reversed by administration of
leptin. Whereas many of leptin's insulin-sensitizing actions are mediated by
central nervous system receptors, some effects may be exerted directly at the level
of insulin target tissues. The role of leptin in states of insulin resistance in humans
is an area of active investigation.
• Role of the peroxisome proliferator-activated receptor gamma (PPARγ) and
thiazolidinediones (TZDs): TZDs are a class of antidiabetic compounds that were
developed in the early 1980s as antioxidants. The target receptor for TZDs has
been identified as peroxisome proliferator-activated receptor gamma (PPARγ), a
nuclear receptor and transcription factor. PPARγ is most highly expressed in
adipose tissue, and activation of the receptor by TZDs results in modulation of
gene expression in adipocytes, eventually leading to reduction of insulin
resistance. The targets of PPARγ activation include several of the adipokines
discussed above. PPARγ activation also decreases levels of free fatty acids,
which, as mentioned earlier, contributes to insulin resistance in obesity.
92. To summarize, insulin resistance in type 2 diabetes is a complex and multifactorial
phenomenon. Genetic defects in the insulin signaling pathway are not common and, when
present, are more likely polymorphisms with subtle effects rather than inactivating
mutations. Insulin resistance is acquired in the overwhelming majority of individuals, and
obesity is central to this phenomenon. Figure 24-33 illustrates the links between obesity
and insulin resistance.
β-cell dysfunction in type 2 diabetes reflects the inability of these cells to adapt
themselves to the long-term demands of peripheral insulin resistance and increased
insulin secretion. In states of insulin resistance, insulin secretion is initially higher for
each level of glucose than in controls. This hyperinsulinemic state is a compensation for
peripheral resistance and can often maintain normal plasma glucose for years. Eventually,
however, β-cell compensation becomes inadequate, and there is progression to overt
diabetes. The underlying basis for failure of β-cell adaptation is not known, although it is
postulated that several mechanisms, including
Figure 24-33 Obesity and insulin resistance: the missing links? Adipocytes release a variety of factors (free
fatty acids and adipokines) that may play a role in modulating insulin resistance in peripheral tissues
(illustrated here is striated muscle). Excess free fatty acids (FFAs) and resistin are associated with insulin
93. resistance; in contrast, adiponectin, whose levels are decreased in obesity, is an insulin-sensitizing
adipokine. Leptin is also an insulin-sensitizing agent, but it acts via central receptors (in the hypothalamus).
The peroxisome proliferator-activated receptor gamma (PPARγ) is an adipocyte nuclear receptor that is
activated by a class of insulin-sensitizing drugs called thiazolidinediones (TZDs). The mechanism of action
of TZDs may eventually be mediated through modulation of adipokine and FFA levels that favor a state of
adverse effects of high circulating free fatty acids ("lipotoxicity") or chronic
hyperglycemia ("glucotoxicity"), may play a role. β-cell dysfunction in type 2 diabetes
manifests itself as both qualitative and quantitative defects:
• Qualitative β-cell dysfunction is initially subtle, and seen as loss of the normal
pulsatile, oscillating pattern of insulin secretion and attenuation of the rapid first
phase of insulin secretion triggered by an elevation in plasma glucose. Over time,
the secretory defect affects all phases of insulin secretion, and even though some
basal insulin secretion persists in type 2 diabetes, it is grossly inadequate to
overcome the insulin resistance.
• Quantitative β-cell dysfunction is reflected by a decrease in β-cell mass, islet
degeneration, and deposition of islet amyloid. Islet amyloid protein (amylin) is a
characteristic finding in patients with type 2 diabetes and is present in more than
90% of diabetic islets examined. Islet amyloidosis is associated with a decrease in
β-cell mass, although it is uncertain whether the amyloid is involved in or merely
a consequence of the β-cell decrease. Although there are scant data in humans,
studies from animal models of diabetes support the aforementioned sequence of
events wherein β-cell
hyperplasia in the prediabetic state is followed by a decrease in β-cell mass that
coincides with clinical progression to diabetes. In this context, it is important to
note that even a "normal" β-cell mass in diabetic individuals may in fact indicate a
relative reduction for the degree of insulin resistance.
MONOGENIC FORMS OF DIABETES
Although genetically defined causes of diabetes are uncommon, they have been
intensively studied in the hope of gaining insights into the disease. As Table 24-6
illustrates, monogenic forms of diabetes are classified separately from types 1 and 2.
Monogenic causes of diabetes result from either a primary defect in β-cell function or a
defect in insulin/insulin receptor signaling, as described below.
Maturity-Onset Diabetes of the Young (MODY).
Two per cent to 5% of diabetic patients do not fall clearly into either the type 1 or type 2
diabetes phenotype and are said to have "maturity-onset diabetes of the young." In these
patients, there is a primary defect in β-cell function that occurs without β-cell loss,
affecting either β-cell mass and/or insulin production. It now appears that MODY is the
outcome of a heterogeneous group of genetic defects characterized by (1) autosomal-
94. dominant inheritance as a monogenic defect, with high penetrance; (2) early onset,
usually before age 25, as opposed to after age 40 for most patients with type 2 diabetes;
(3) absence of obesity; and (4) lack of islet cell autoantibodies and insulin resistance
Six distinct genetic defects have been identified thus far (see Table 24-6 ). Glucokinase,
implicated in MODY2, catalyzes the transfer of phosphate from ATP to glucose, which is
the first and rate-limiting step in glucose metabolism. Glucokinase expressed in the
pancreatic β-cell controls the influx of glucose by controlling its entry into the glycolytic
cycle, which in turn is coupled to insulin secretion. Inactivating mutations of this enzyme
increase the threshold for insulin release, such that insulin secretion is low for the degree
of hyperglycemia present, causing modest increases in blood glucose. Activating
mutations have been described that shift the enzyme activity in the opposite direction,
with increased insulin secretion at a lower glucose level, resulting in states of chronic
hypoglycemia with hyperinsulinism. The remaining five genes associated with MODY
are transcription factors controlling insulin expression in β-cells and β-cell mass; IPF-1
also plays a central role in the development of the pancreas. In addition to genetic
heterogeneity, MODY is characterized by clinical heterogeneity. Some forms (MODY1,
MODY3, and MODY5) are associated with severe β-cell insulin secretory defects with
the full range of diabetic complications, while others (MODY2) feature mild chronic
hyperglycemia that typically does not worsen over time.
Up to 50% of carriers of glucokinase mutations develop gestational diabetes mellitus,
defined as any degree of glucose intolerance with onset or first recognition during
pregnancy; conversely, approximately 5% of women with gestational diabetes mellitus
and a first-degree relative with diabetes carry a mutation in the glucokinase gene. It is
important to emphasize that mutations or polymorphisms in the six known MODY genes
do not appear to contribute to the development of late-onset (classic) type 2 diabetes in
the vast majority of patients.
Mitochondrial DNA is inherited maternally and encodes several genes in the oxidative
phosphorylation pathway, ribosomal RNAs, and 22 transfer RNAs (tRNAs). In rare
cases, (<1%), diabetes is associated with point mutations in a mitochondrial tRNA gene,
tRNALeu(UUR) . Mitochondrial diabetes is caused by a primary defect in β-cell function.
Recall that ATP is required for insulin secretion in β cells ( Fig. 24-29 ), and impairment
of mitochondrial ATP synthesis results in decreased insulin secretion.
Diabetes Associated with Insulin Gene or Insulin Receptor Mutations.
Mutations that affect insulin processing from its precursor (proinsulin) or those that affect
insulin structure and binding to its receptor are a rare cause of diabetes. The metabolic
impairment in most cases is mild, since these patients are heterozygous for their
mutations. Insulin receptor mutations that affect either receptor synthesis, insulin
binding, or receptor tyrosine kinase activity can, in rare cases, result in mild to severe
95. insulin resistance and type 2 diabetes. Neither insulin gene nor insulin receptor mutations
contribute significantly to the incidence of type 2 diabetes.
PATHOGENESIS OF THE COMPLICATIONS OF DIABETES
The morbidity associated with long-standing diabetes of either type results from a
number of serious complications, involving both large- and medium-sized muscular
arteries (macrovascular disease), as well as capillary dysfunction in target organs
(microvascular disease). Macrovascular disease causes accelerated atherosclerosis
among diabetics, resulting in increased risk of myocardial infarction, stroke, and lower-
extremity gangrene. The effects of microvascular disease are most profound in the retina,
kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and
neuropathy, respectively. Diabetes is the leading cause of blindness and end-stage renal
disease in the Western hemisphere, besides contributing substantially to the incidence of
cardiovascular events each year. Hence, the basis of long-term complications of diabetes
is the subject of a great deal of research. Most of the available experimental and clinical
evidence suggests that the complications of diabetes are a consequence of the metabolic
derangements, mainly hyperglycemia. For example, when kidneys are transplanted into
diabetics from nondiabetic donors, the lesions of diabetic nephropathy may develop
within 3 to 5 years after transplantation. Conversely, kidneys with lesions of diabetic
nephropathy demonstrate a reversal of the lesion when transplanted into normal
recipients. Two large multicenter trials to evaluate the effects of plasma glucose
concentrations on long-term complications of diabetes—the Diabetes Control and
Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study
(UKPDS) —have convincingly demonstrated delayed progression of microvascular
complications by strict control of the hyperglycemia. It is important to stress, however,
that not all diabetics have long-term complications, irrespective of the level of blood
glucose control over time, indicating that there are additional factors that modulate an
individual's risk for microvascular disease. It is likely that such disease-modifying
elements are genetic, and there is an ongoing search to identify these additional genes.
At least three distinct metabolic pathways appear to be involved in the pathogenesis of
long-term diabetic complications,
although the primacy of any one has not been established. These pathways include the
Formation of Advanced Glycation End Products.
Advanced glycation end products (AGEs) are formed as a result of nonenzymatic
reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal,
methylglyoxal, and 3-deoxyglucosone) with the amino group of both intracellular and
extracellular proteins. AGEs have a number of chemical and biologic properties that are
96. detrimental to extracellular matrix components and the target cells of diabetic
complications (e.g., endothelial cells) ( Table 24-7 ):
• On extracellular matrix components, such as collagen or laminin, the formation
of AGEs causes cross-linking between polypeptides, resulting in abnormal
matrix-matrix and matrix-cell interactions. For example, cross-linking between
collagen type I molecules in large vessels decreases their elasticity, which may
predispose these vessels to shear stress and endothelial injury ( Chapter 11 ).
Similarly, AGE-induced cross-linking of type IV collagen in basement membrane
decreases endothelial cell adhesion and increases fluid filtration. AGE cross-
linked proteins are resistant to proteolytic digestion. Thus, cross-linking
decreases protein removal while enhancing protein deposition. AGE-modified
matrix components also trap nonglycated plasma or interstitial proteins. In large
vessels, trapping low-density lipoprotein (LDL), for example, retards its efflux
from the vessel wall and enhances the deposition of cholesterol in the intima, thus
accelerating atherogenesis ( Chapter 11 ). In capillaries, including those of renal
glomeruli, plasma proteins such as albumin may bind to the glycated basement
membrane, accounting in part for the increased basement membrane thickening
characteristic of diabetic microangiopathy.
• Circulating plasma proteins are modified by addition of AGE residues; these
proteins, in turn, bind to AGE receptors on several cell types (endothelial cells,
mesangial cells, macrophages). The AGE-receptor ligation results in activation
and nuclear translocation of the pleotropic transcription factor NF-κB, generating
a variety of cytokines, growth factors and other pro-inflammatory molecules. 
The biologic effects of AGE-receptor signaling include (1) release of cytokines
and growth factors from macrophages and mesangial cells (insulin-like growth
factor-1, TGF-β, platelet-derived growth factor, VEGF); (2) increased endothelial
permeability; (3) increased procoagulant activity on endothelial cells and
macrophages (induction of thrombomodulin and tissue factor); and (4) enhanced
proliferation of and synthesis of extracellular matrix by fibroblasts and smooth
TABLE 24-7 -- Effects of Advanced Glycation End Products (AGEs)
Extracellular Matrix Components
Abnormal matrix-matrix and matrix-cell interactions
Corss-linking of polypeptides of same protein (e.g., collagen)
Trapping of nonglycated proteins (e.g., LDL, albumin)
Resistance to proteolytic digestion
Intracellular and Plasma Proteins
AGE receptor ligation leads to generation of reactive oxygen species and NF-κB
Target cells (endothelium, mesangial cells, macrophages) respond by:
97. Cytokines and growth factor   secretion
Induction of procoagulant   activity
Increased vascular permeability
Enhanced ECM production
ECM, extracellular matrix; LDL, low-density lipoprotein.
You will recall from the discussion of atherosclerosis ( Chapter 11 ) that endothelial
dysfunction, particularly endothelial activation, is a critical process in vascular injury and
atherogenesis. AGEs, by virtue of their ability to modify extracellular matrix
components, as well as to activate NF-κB and its downstream targets in the vascular
endothelium, are postulated to play a central role in the accelerated atherogenesis
characteristic of diabetes. In addition to large vessel disease, AGEs also contribute to
microvascular injury in diabetes. The AGE inhibitor aminoguanidine has recently been
shown to retard the progression of nephropathy in type 1 diabetics.
Activation of Protein Kinase C.
Activation of intracellular protein kinase C (PKC) by calcium ions and the second
messenger diacylglycerol (DAG) is an important signal transduction pathway in many
cellular systems. Intracellular hyperglycemia can stimulate the de novo synthesis of DAG
from glycolytic intermediates and hence cause activation of PKC. The downstream
effects of PKC activation are numerous and include the following: 
• Production of the proangiogenic molecule vascular endothelial growth factor
(VEGF), implicated in the neovascularization characterizing diabetic retinopathy (
Chapter 29 )
• Increased activity of the vasoconstrictor endothelin-1 and decreased activity of
the vasodilator endothelial nitric oxide synthase (eNOS)
• Production of profibrogenic molecules like transforming growth factor-β (TGF-
β), leading to increased deposition of extracellular matrix and basement
• Production of the procoagulant molecule plasminogen activator inhibitor-1
(PAI-1), leading to reduced fibrinolysis and possible vascular occlusive episodes
• Production of pro-inflammatory cytokines by the vascular endothelium.
It should be evident that some effects of AGEs and activated PKCs (e.g., activation of
NF-κB) are overlapping. Not surprisingly, therefore, therapeutic inhibition of PKC can
retard the progression of diabetic retinopathy. 
Intracellular Hyperglycemia with Disturbances in Polyol Pathways.
In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses,
kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is
98. then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to
fructose. In this process, intracellular NADPH is used as a cofactor. NADPH is also
required as a cofactor by the enzyme glutathione reductase for regenerating reduced
glutathione (GSH). You will recall that GSH is one of the important antioxidant
mechanisms in the cell ( Chapter 1 ), and a reduction in GSH levels increases cellular
susceptibility to oxidative stress. In the face of sustained hyperglycemia, progressive
depletion of intracellular NADPH by aldol reductase leads to a compromise of
GSH regeneration. Thus, the deleterious consequences of the aldose reductase pathway
arise primarily by increasing cellular susceptibility to oxidative stress. The importance of
this pathway in human diabetes was best exemplified in clinical trials using an aldose
reductase inhibitor, which significantly ameliorated the development of diabetic
neuropathy. Unfortunately, the effects of these inhibitors on other long-term
complications have been less promising.
MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS
Pathologic findings in the pancreas are variable and not necessarily dramatic. The
important morphologic changes are related to the many late systemic complications of
diabetes. There is extreme variability among patients in the time of onset of these
complications, their severity, and the particular organ or organs involved. In individuals
with tight control of diabetes, the onset might be delayed. In most patients, however,
morphologic changes are likely to be found in arteries (macrovascular disease), basement
membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina
(retinopathy), nerves (neuropathy), and other tissues. These
99. Figure 24-34 Long-term complications of diabetes.
change are seen in both type 1 and type 2 diabetes. A schematic overview is provided in
Figure 24-34 .
Lesions in the pancreas are inconstant and rarely of diagnostic value. Distinctive changes
are more commonly associated with type 1 than with type 2 diabetes. One or more of the
following alterations may be present:
100. • Reduction in the number and size of islets. This is most often seen in type 1
diabetes, particularly with rapidly advancing disease. Most of the islets are small
and inconspicuous, and not easily detected.
• Leukocytic infiltration of the islets (insulitis) principally composed of T
lymphocytes similar to that in animal models of autoimmune diabetes ( Fig.
24-35A ). This may be seen in type 1 diabetics at the time of clinical presentation.
The distribution of insulitis may be strikingly uneven. Eosinophilic infiltrates may
also be found, particularly in diabetic infants who fail to survive the immediate
• By electron microscopy, β-cell degranulation may be observed, reflecting
depletion of stored insulin in already damaged β cells. This is more commonly
seen in patients with newly diagnosed type 1 disease, when some β cells are still
• In type 2 diabetes, there may be a subtle reduction in islet cell mass,
demonstrated only by special morphometric studies.
• Amyloid replacement of islets in type 2 diabetes appears as deposition of
pink, amorphous material beginning in and around capillaries and between cells.
At advanced stages, the islets may be virtually obliterated ( Fig. 24-35B ); fibrosis
may also be observed. This change is often seen in long-standing cases of type 2
diabetes. Similar lesions may be found in elderly nondiabetics, apparently as part
of normal aging.
• An increase in the number and size of islets is especially characteristic of
nondiabetic newborns of diabetic mothers. Presumably, fetal islets undergo
hyperplasia in response to the maternal hyperglycemia.
Figure 24-35 A, Insulitis, shown here from a rat (BB) model of autoimmune diabetes, also seen in type 1
human diabetes. (Courtesy of Dr. Arthur Like, University of Massachusetts, Worchester, MA.) B,
Amyloidosis of a pancreatic islet in type 2 diabetes.
Diabetic Macrovascular Disease.
101. Diabetes exacts a heavy toll on the vascular system. The hallmark of diabetic
macrovascular disease is accelerated atherosclerosis involving the aorta and large- and
medium-sized arteries. Except for its greater severity and earlier age at onset,
atherosclerosis in diabetics is indistinguishable from that in nondiabetics ( Chapter 11 ).
Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the
most common cause of death in diabetics. Significantly, it is almost as common in
diabetic women as in diabetic men. In contrast, myocardial infarction is uncommon in
nondiabetic women of reproductive age. Gangrene of the lower extremities, as a result
of advanced vascular disease, is about 100 times more common in diabetics than in the
general population. The larger renal arteries are also subject to severe atherosclerosis, but
the most damaging effect of diabetes on the kidneys is exerted at the level of the
glomeruli and the microcirculation. This will be discussed later.
Hyaline arteriolosclerosis, the vascular lesion associated with hypertension ( Chapter 11
and Chapter 20 ), is both more prevalent and more severe in diabetics than in
nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics
without hypertension. It takes the form of an amorphous, hyaline thickening of the wall
of the arterioles, which causes narrowing of the lumen ( Fig. 24-36 ). Not surprisingly, in
diabetics, it is related not only to the duration of the disease, but also to the level of blood
One of the most consistent morphologic features of diabetes is diffuse thickening of
basement membranes. The thickening is most evident in the capillaries of the skin,
skeletal muscle, retina, renal glomeruli, and renal medulla. However, it may also be seen
in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves,
and placenta. By both light and electron microscopy, the basal lamina separating
parenchymal or endothelial cells from the surrounding
Figure 24-36 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole.
The amorphous nature of the thickened vascular wall is evident. (Periodic acid-Schiff [PAS] stain;
courtesy of M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health Science
102. Center at San Antonio, TX.)
tissue is markedly thickened by concentric layers of hyaline material composed
predominantly of type IV collagen ( Fig. 24-37 and Fig. 24-38 ). It should be noted that
despite the increase in the thickness of basement membranes, diabetic capillaries are
more leaky than normal to plasma proteins. The microangiopathy underlies the
development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
An indistinguishable microangiopathy can be found in aged nondiabetic patients but
rarely to the extent seen in patients with long-standing diabetes.
The kidneys are prime targets of diabetes. (See also Chapter 20 .) Renal failure is second
only to myocardial infarction as a cause of death from this disease. Three lesions are
encountered: (1) glomerular lesions; (2) renal vascular lesions, principally
arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis.
The most important glomerular lesions are capillary basement membrane
thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis. These are
described in detail in Chapter 20 . The glomerular capillary basement membranes are
thickened throughout their entire length (see Fig. 24-38 ). This change can be detected by
electron microscopy within a few years of the onset of diabetes, sometimes without any
associated change in renal function.
Diffuse mesangial sclerosis consists of a diffuse increase in mesangial matrix and is
always associated with basement membrane thickening. It is found in most patients with
disease of more than 10 years' duration. When glomerulosclerosis becomes marked,
patients manifest the nephrotic syndrome ( Chapter 20 ), characterized by proteinuria,
hypoalbuminemia, and edema.
Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-like
deposits of a laminated matrix situated in the periphery of the glomerulus. These nodules
are PAS positive and usually contain trapped mesangial cells. This distinctive change has
been called the Kimmelstiel-Wilson lesion, after the pathologists who described it.
Nodular glomerulosclerosis is encountered in approximately 15% to 30% of long-term
diabetics and is a major cause of morbidity and mortality. Diffuse
103. Figure 24-37 Renal cortex showing thickening of tubular basement membranes in a diabetic patient (PAS
Figure 24-38 Electron micrograph of a renal glomerulus showing markedly thickened glomerular basement
membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space. (Courtesy of Dr. Michael
Kashgarian, Department of Pathology, Yale University School of Medicine, New Haven, CT.)
mesangial sclerosis may also be seen in association with old age and hypertension; on the
contrary, the nodular form of glomerulosclerosis, once certain unusual forms of
nephropathies have been excluded (see Chapter 20 ), is essentially pathognomonic of
diabetes. Both the diffuse and nodular forms of glomerulosclerosis induce sufficient
ischemia to cause overall fine scarring of the kidneys, marked by a finely granular
cortical surface ( Fig. 24-39 ).
104. Renal atherosclerosis and arteriolosclerosis constitute part of the macrovascular disease
in diabetics. The kidney is one of the most frequently and severely affected organs;
however, the changes in the arteries and arterioles are similar to those found throughout
the body. Hyaline arteriolosclerosis affects not only the afferent but also the efferent
arteriole. Such efferent arteriolosclerosis is rarely, if ever, encountered in individuals who
do not have diabetes.
Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in
the interstitial tissue and then spreads to affect the tubules. Both the acute and chronic
forms of this disease occur in nondiabetics as well as in diabetics but are more common
in diabetics than in the general population, and, once affected, diabetics tend to have
more severe involvement. One special pattern of acute pyelonephritis, necrotizing
papillitis (or papillary necrosis), is much more prevalent in diabetics than in
Diabetic Ocular Complications.
The ocular involvement may take the form of retinopathy, cataract formation, or
glaucoma. The morphologic features are discussed further in Chapter 29 .
The central and peripheral nervous systems are not spared by diabetes. The effects of
diabetes on the nervous system are described further in Chapter 27 and Chapter 28 .
Figure 24-39 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to
demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the cortical
tissue (right). Additional features include some irregular depressions, the result of pyelonephritis, and an
105. incidental cortical cyst (far right).
CLINICAL FEATURES OF DIABETES
It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus.
Only a few characteristic patterns will be presented.
Type 1 diabetes was traditionally thought to occur primarily in those under age 18 but is
now known to occur at any age. In the initial 1 or 2 years following manifestation of
overt type 1 diabetes, the exogenous insulin requirements may be minimal because of
ongoing endogenous insulin secretion (referred to as the honeymoon period), but shortly
thereafter, any residual β-cell reserve is exhausted and insulin requirements increase
dramatically. Although β-cell destruction is a long-standing process, the transition from
impaired glucose tolerance to overt diabetes may be abrupt, heralded by an event with
increased insulin requirements, such as infection.
The onset is marked by polyuria, polydipsia, polyphagia, and, with extreme derangement,
ketoacidosis, all resulting from metabolic derangements. As insulin is a major anabolic
hormone in the body, deficiency of insulin results in a catabolic state that affects not only
glucose metabolism but also fat and protein metabolism. Unopposed secretion of counter-
regulatory hormones (glucagon, growth hormone, epinephrine) also plays a role in these
metabolic derangements. The assimilation of glucose into muscle and adipose tissue is
sharply diminished or abolished. Not only does storage of glycogen in liver and muscle
cease, but also reserves are depleted by glycogenolysis. The resultant hyperglycemia
exceeds the renal threshold for reabsorption, and glycosuria ensures. The glycosuria
induces an osmotic diuresis and thus polyuria, causing a profound loss of water and
electrolytes ( Fig. 24-40 ). The obligatory renal water loss combined with the
hyperosmolarity resulting from the increased levels of glucose in the blood tends to
deplete intracellular water, triggering the osmoreceptors of the thirst centers of the brain.
In this manner, intense thirst (polydipsia) appears. With a deficiency of insulin, the scales
swing from insulin-promoted anabolism to catabolism of proteins and fats. Proteolysis
follows, and the gluconeogenic amino acids are removed by the liver and used as
building blocks for glucose. The catabolism of proteins and fats tends to induce a
negative energy balance, which in turn leads to increasing appetite (polyphagia), thus
completing the classic triad of diabetes: polyuria, polydipsia, and polyphagia. Despite the
increased appetite, catabolic effects prevail, resulting in weight loss and muscle
weakness. The combination of polyphagia and weight loss is paradoxical and should
always raise the suspicion of diabetes.
Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes but may also
occur in type 2 diabetes, though not as commonly and not to as marked an extent. These
patients have marked insulin deficiency, and the release of the catecholamine hormone
epinephrine blocks any residual insulin action and stimulates the release of glucagon. The
insulin deficiency coupled with glucagon excess decreases peripheral utilization of
glucose while increasing gluconeogenesis, severely exacerbating hyperglycemia (the
plasma glucose levels are usually in the range of 500 to 700 mg/dL). The hyperglycemia
106. causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. The
second major effect of an alteration in the insulin:glucagon ratio is activation of the
ketogenic machinery. Insulin deficiency stimulates lipoprotein lipase, with resultant
excessive breakdown of adipose stores, and an increase in levels of free fatty acids. When
these free fatty acids reach the liver, they are esterified to fatty acyl CoA. Oxidation of
fatty acyl CoA molecules within the hepatic mitochondria produces ketone bodies
(acetoacetic acid and β-hydroxybutyric acid). The rate at which ketone bodies are formed
may exceed the rate at which acetoacetic acid and β-hydroxybutyric acid can be utilized
by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of
ketones is compromised by dehydration, the plasma hydrogen ion concentration
increases, and systemic metabolic ketoacidosis results. Release of ketogenic amino acids
by protein catabolism aggravates the ketotic state.
Type 2 diabetes mellitus may also present with polyuria and polydipsia, but unlike in type
1 diabetes, patients are often older (over 40 years) and frequently obese. However, with
the increase in obesity and sedentary lifestyle in our society, type 2 diabetes is now seen
in children and adolescents with increasing frequency. In some cases, medical attention is
sought because of unexplained weakness or weight loss. Most frequently, however, the
diagnosis is made after routine blood or urine testing in asymptomatic persons. The
absence of ketoacidosis and milder presentation in type 2 diabetes is presumably because
of higher portal vein insulin levels in these patients than in type 1 diabetics, which
prevents unrestricted hepatic fatty acid oxidation and keeps the formation of ketone
bodies in check. In the decompensated state, these patients may develop hyperosmolar
nonketotic coma, a syndrome engendered by the severe dehydration resulting from
sustained osmotic diuresis in patients who do not drink enough water to compensate for
urinary losses from chronic hyperglycemia. Typically, the patient is an elderly diabetic
who is disabled by a stroke or an infection and is unable to maintain adequate water
intake. Furthermore, the absence of ketoacidosis and its symptoms (nausea, vomiting,
respiratory difficulties) delays the seeking of medical attention until severe dehydration
and coma occur. In Table 24-8 , we have summarized some of the
107. Figure 24-40 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An
absolute insulin deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume
depletion. These cause sufficient central nervous system compromise to lead to coma and eventual death if
TABLE 24-8 -- Type 1 Versus Type 2 Diabetes Mellitus (DM)
Type 1 DM Type 2 DM
Clinical Onset: <20 years Onset: >30 years
Normal weight Obese
Markedly decreased blood Increased blood insulin (early);normal to
insulin moderate decreased insulin (late)
Anti-islet cell antibodies No anti-islet cell antibodies
Ketoacidosis common Ketoacidosis rare; nonketotic
Genetics 30–70% concordance in twins 50–90% concordance in twins
Linkage to MHC Class II HLA No HLA linkage
Linkage to candidate diabetogenic genes
(PPARγ, calpain 10)
Pathogenesis Autoimmune destruction of β- Insulin resistance in skeletal muscle,
cells mediated by T cells and adipose tissue and liver
humoral mediators (TNF, IL-1,
β-cell dysfunction and relative insulin
Absolute insulin deficiency
Islet cells Insulitis early No insulitis
Marked atrophy and fibrosis Focal atrophy and amyloid deposition
β-cell depletion Mild β-cell depletion
pertinent clinical, genetic, and histopathologic features that distinguish type 1 and type 2
108. In both forms, it is the long-term effects of diabetes, more than the acute metabolic
complications, that are responsible for the overwhelming proportion of morbidity and
mortality. In most instances, these complications appear approximately 15 to 20 years
after the onset of hyperglycemia. Cardiovascular events such as myocardial infarction,
renal vascular insufficiency, and cerebrovascular accidents are the most common causes
of mortality in long-standing diabetics. The impact of cardiovascular disease can be
gauged from the fact that it accounts for up to 80% of deaths in type 2 diabetes; in fact,
diabetics have a 3 to 7.5 times greater incidence of death from cardiovascular causes
compared to the nondiabetic population ( Fig. 24-41 ). The hallmark of cardiovascular
disease is accelerated atherosclerosis of the large and medium-sized arteries (i.e.,
macrovascular disease). The pathogenesis of accelerated atherosclerosis involves
multiple factors. We have previously
Figure 24-41 Incidence of death from cardiovascular causes in diabetic and nondiabetic individuals after a
7-year follow up. MI, myocardial infarction. (Reproduced with permission from Haffner et al: Mortality
from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without
myocardial infarction. N Engl J Med 339:229, 1998.)
mentioned the contribution of AGEs to endothelial dysfunction and vascular disease in
diabetes. You will recall that the binding of AGE-modified plasma proteins to AGE
receptors on endothelial and vascular smooth muscle leads to generation of a variety of
proatherogenic cytokines and growth factors. Blockade of one such receptor—receptor
for AGE, or RAGE—suppressed macrovascular disease in an atherosclerosis-prone
animal model, underscoring the importance of this pathway in atherogenesis. 
Activation of protein kinase C, with resultant impairment of vasodilation and increased
109. procoagulant PAI-1 activity, may also contribute to the endothelial injury and accelerated
atherosclerosis in diabetes.
The importance of obesity in the pathogenesis of insulin resistance has already been
discussed, but it is also an independent risk factor for development of atherosclerosis
( Chapter 11 ). Additional risk factors for atherosclerosis that are present in many type 2
diabetics include hypertension, dyslipidemia, and platelet dysfunction. Hypertension is
approximately twice as frequent in diabetics as in those without the disease. Similar to
atherosclerosis, the increased frequency of hypertension may be a manifestation of
hyperglycemia-induced endothelial dysfunction. Dyslipidemias include both increased
triglycerides and LDL levels and decreased levels of the "protective" lipoprotein, HDL
( Chapter 11 ); hepatic insulin resistance combined with peripheral activation of
lipoprotein lipase plays a key role in maintaining a "proatherogenic" lipoprotein profile in
diabetic individuals. Finally, increased platelet adhesiveness to the vessel wall is
observed in states of insulin resistance, possibly owing to increased thromboxane A2
synthesis and reduced prostacyclin.
Diabetic nephropathy is a leading cause of end-stage renal disease in the United States. 
Approximately 30% to 40% of all diabetics develop clinical evidence of nephropathy, but
a considerably smaller fraction of patients with type 2 diabetes progress to end-stage
renal disease. However, because of the much greater prevalence of type 2 diabetes, these
patients constitute slightly over half the diabetic patients starting dialysis each year. The
frequency of diabetic nephropathy is greatly influenced by the genetic makeup of the
population in question; for example, Native Americans, Hispanics, and African
Americans have a greater risk of developing end-stage renal disease than do non-
Hispanic whites with type 2 diabetes. The
earliest manifestation of diabetic nephropathy is the appearance of low amounts of
albumin in the urine (>30 mg/day, but <300 mg/day), that is, microalbuminuria. Of note,
microalbuminuria is also a marker for greatly increased cardiovascular morbidity and
mortality for patients with either type 1 or type 2 diabetes. Therefore, all patients with
microalbuminuria should be screened for macrovascular disease, and aggressive
intervention should be undertaken to reduce cardiovascular risk factors. Without specific
interventions, approximately 80% of type 1 diabetics and 20% to 40% of type 2 diabetics
will develop overt nephropathy with macroalbuminuria (>300 mg of urinary albumin per
day) over 10 to 15 years, usually accompanied by the appearance of hypertension. The
progression from overt nephropathy to end-stage renal disease can be highly variable. By
20 years, more than 75% of type 1 diabetics and approximately 20% of type 2 diabetics
with overt nephropathy will develop end-stage renal disease, requiring dialysis or renal
transplantation. Diabetic nephropathy is also discussed in Chapter 20 .
Visual impairment, sometimes even total blindness, is one of the more feared
consequences of long-standing diabetes. This disease is currently the fourth leading cause
of acquired blindness in the United States. Approximately 60% to 80% of patients
110. develop some form of diabetic retinopathy approximately 15 to 20 years after diagnosis
( Chapter 29 ). As was previously stated, the fundamental lesion of retinopathy—
neovascularization—is probably attributable to VEGF signaling in the retina. In 
addition to retinopathy, diabetics also have an increased propensity for glaucoma and
cataract formation, both of which contribute to visual impairment in diabetes. Diabetic
neuropathy can elicit a variety of clinical syndromes, afflicting the central nervous
system, peripheral sensorimotor nerves, and the autonomic nervous system; these are
discussed further in Chapter 27 and Chapter 28 .
Diabetics are plagued by enhanced susceptibility to infections of the skin and to
tuberculosis, pneumonia, and pyelonephritis. Such infections cause the deaths of about
5% of diabetic patients. In an individual with diabetic neuropathy, a trivial infection in a
toe may be the first event in a long succession of complications (gangrene, bacteremia,
pneumonia) that may ultimately lead to death.
In recent years, increasingly sedentary lifestyles and poor eating habits have contributed
to the simultaneous escalation of diabetes and obesity worldwide, which some have
termed as "diabesity." Sadly, this "epidemic" of diabetes and obesity has percolated
even to children. As the incidence of communicable diseases has declined and expected
life span has increased, diabetes has become a major public health problem, and it
continues to be one of the top 10 "killers" in the United States. There is hope, however,
since the role of primary prevention of type 2 diabetes by lifestyle and dietary alterations
and secondary prevention of diabetic complications by strict glycemic control has
become increasingly recognized. It is also hoped that islet cell transplantation will result
in a cure for those afflicted with type 1 diabetes.
Pancreatic Endocrine Neoplasms
The preferred term for tumors of the pancreatic islet cells, referred to as "islet cell
tumors" in common medical parlance, is pancreatic endocrine neoplasms. They are
rare in comparison with tumors of the exocrine pancreas, accounting for only 2% of all
pancreatic neoplasms. They are most common in adults and can occur anywhere along
the length of the pancreas, embedded in the substance of the pancreas or arising in the
immediate peripancreatic tissues. They resemble in appearance their counterparts,
carcinoid tumors, found elsewhere in the alimentary tract ( Chapter 17 ). Pancreatic
endocrine neoplasms may be single or multiple and benign or malignant, the latter
metastasizing to lymph nodes and liver. When multiple, each tumor may be composed of
a different cell type. Pancreatic endocrine neoplasms have a propensity to elaborate
pancreatic hormones, but some may be totally nonfunctional.
Like any other endocrine neoplasms in the body (see below), it is difficult to predict the
biologic behavior of a pancreatic endocrine neoplasm based on light microscopic criteria
alone. Unequivocal criteria for malignancy include (1) metastases to regional lymph
nodes or distant organs (including the liver), (2) vascular invasion, and (3) gross invasion
of adjacent viscera. Other features suggestive of malignancy include infiltration beyond
the tumor capsule into the pancreatic parenchyma, a high mitotic index, tumor necrosis,
111. and significant cellular atypia. In general, tumors less than 2 cm in diameter tend to
behave in an indolent manner, but there are significant exceptions to this rule. Finally, the
functional status of the tumor might have some import on prognosis, as approximately
90% of insulinomas are benign, while 60% to 90% of other functioning and
nonfunctioning pancreatic endocrine neoplasms tend to be malignant. Fortunately,
insulinomas are also the most common subtype of pancreatic endocrine neoplasms.
The three most common and distinctive clinical syndromes associated with functional
pancreatic endocrine neoplasms are (1) hyperinsulinism, (2) hypergastrinemia and the
Zollinger-Ellison syndrome, and (3) multiple endocrine neoplasia (the last is described in
β-cell tumors (insulinomas) are the most common of pancreatic endocrine neoplasms and
may be responsible for the elaboration of sufficient insulin to induce clinically significant
hypoglycemia. There is a characteristic clinical triad resulting from these pancreatic
lesions: (1) Attacks of hypoglycemia occur with blood glucose levels below 50 mg/dL of
serum; (2) the attacks consist principally of such central nervous system manifestations as
confusion, stupor, and loss of consciousness; and (3) the attacks are precipitated by
fasting or exercise and are promptly relieved by feeding or parenteral administration of
Insulinomas are most often found within the pancreas and are generally benign. Most are
solitary lesions, although multiple tumors or tumors ectopic to the pancreas may be
encountered. Bona fide carcinomas, making up only about 10% of cases, are diagnosed
on the basis of criteria for malignancy listed above. On rare occasions, an insulinoma
may arise in ectopic pancreatic tissue.
Solitary tumors are usually small (often less than 2 cm in diameter) and are encapsulated,
pale to red-brown
nodules located anywhere in the pancreas. Histologically, these benign tumors look
remarkably like giant islets, with preservation of the regular cords of monotonous cells
and their orientation to the vasculature. Not even the malignant lesions present much
evidence of anaplasia ( Fig. 24-42A ), and they may be deceptively encapsulated. By
immunocytochemistry, insulin can be localized in the tumor cells ( Fig. 24-42B ). Under
the electron microscope, neoplastic β cells, like their normal counterparts, display
distinctive round granules that contain polygonal or rectangular dense crystals separated
from the enclosing membrane by a distinct halo. It should be cautioned that granules may
be present in the absence of clinically significant hormone activity.
112. Hyperinsulinism may also be caused by diffuse hyperplasia of the islets. This change is
found occasionally in adults but is usually encountered in neonates and infants. Several
clinical scenarios may result in diffuse islet hyperplasia (previously known as
nesidioblastosis), including maternal diabetes, Beck-with-Wiedemann syndrome
( Chapter 10 ), and rare metabolic disorders. In maternal diabetes, the fetus, long exposed
to the hyperglycemia of maternal blood, responds by an increase in the size and number
of its islets. In the postnatal period, these hyperactive islets may be responsible for
serious episodes of hypoglycemia. This phenomenon is usually transient, although
persisting problems may result from mutations in the glucose-sensing mechanism or
insulin-secreting mechanisms within the β cell.
While up to 80% of islet cell tumors may demonstrate excessive insulin secretion, the
hypoglycemia is mild in all but about 20%, and many cases never become clinically
symptomatic. The critical laboratory findings in insulinomas are high circulating levels of
insulin and a high insulin-glucose ratio. Surgical removal of the tumor is usually followed
by prompt reversal of the hypoglycemia.
It is important to note that there are many other causes of hypoglycemia besides
insulinomas. The differential diagnosis of this frequently obscure metabolic abnormality
Figure 24-42 Pancreatic endocrine tumor ("islet cell tumor"). A, The neoplastic cells are monotonous and
demonstrate minimal pleomorphism or mitotic activity (H & E stain). B, Immunoreactivity for insulin
confirms the neoplasm is an insulinoma. Clinically, the patient had episodic hypoglycemia.
conditions as abnormal insulin sensitivity, diffuse liver disease, inherited glycogenoses,
and ectopic production of insulin by certain retroperitoneal fibromas and fibrosarcomas.
ZOLLINGER-ELLISON SYNDROME (GASTRINOMAS)
Marked hypersecretion of gastrin usually has its origin in gastrin-producing tumors
(gastrinomas), which are just as likely to arise in the duodenum and peripancreatic soft
tissues as in the pancreas (so-called gastrinoma triangle). There has been lack of
113. agreement regarding the cell of origin for these tumors, although it appears likely that
endocrine cells of either the gut or the pancreas could be the source. Zollinger and Ellison
first called attention to the association of pancreatic islet cell lesions with hypersecretion
of gastric acid and severe peptic ulceration, which are present in 90% to 95% of
Gastrinomas may arise in the pancreas, the peripancreatic region, or the wall of the
duodenum. Over half of gastrin-producing tumors are locally invasive or have
already metastasized at the time of diagnosis. In approximately 25% of patients,
gastrinomas arise in conjunction with other endocrine tumors, thus conforming to the
MEN-1 syndrome (see below); MEN-1-associated gastrinomas are frequently multifocal,
while sporadic gastrinomas are usually single. As with insulin-secreting tumors of the
pancreas, gastrin-producing tumors are histologically bland and rarely exhibit marked
In the Zollinger-Ellison syndrome, hypergastrinemia from a pancreatic or duodenal tumor
stimulates extreme gastric acid secretion, which in turn causes peptic ulceration. The
duodenal and gastric ulcers are often multiple; although they are identical to those found
in the general population, they are often unresponsive to usual modalities of therapy. In
addition, ulcers may also occur in unusual locations such as the jejunum;
when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be
considered. More than 50% of the patients have diarrhea; in 30%, it is the presenting
Treatment of Zollinger-Ellison syndrome involves control of gastric acid secretion by use
of H+ /K+ -ATPase inhibitors ( Chapter 17 ) and excision of the neoplasm. Total resection
of the neoplasm, when possible, eliminates the syndrome. Patients with hepatic
metastases have a significantly shortened life expectancy, with progressive tumor growth
leading to liver failure usually within 10 years.
OTHER RARE PANCREATIC ENDOCRINE NEOPLASMS
α-cell tumors (glucagonomas) are associated with increased serum levels of glucagon and
a syndrome consisting of mild diabetes mellitus, a characteristic skin rash (necrolytic
migratory erythema), and anemia. They occur most frequently in perimenopausal and
postmenopausal women and are characterized by extremely high plasma glucagon levels.
δ-cell tumors (somatostatinomas) are associated with diabetes mellitus, cholelithiasis,
steatorrhea, and hypochlorhydria. They are exceedingly difficult to localize
preoperatively. High plasma somatostatin levels are required for diagnosis.
114. VIPoma (watery diarrhea, hypokalemia, achlorhydria, or WDHA syndrome) is an
endocrine tumor that induces a characteristic syndrome, caused by release of vasoactive
intestinal peptide (VIP) from the tumor. Some of these tumors are locally invasive and
metastatic. A VIP assay should be performed on all patients with severe secretory
diarrhea. Neural crest tumors, such as neuroblastomas, ganglioneuroblastomas, and
ganglioneuromas ( Chapter 10 ) and pheochromocytomas (see below) can also be
associated with the VIPoma syndrome.
Pancreatic carcinoid tumors producing serotonin and an atypical carcinoid syndrome are
exceedingly rare. Pancreatic polypeptide-secreting endocrine tumors are
endocrinologically asymptomatic, despite the presence of high levels of the hormone in
Some pancreatic and extrapancreatic endocrine tumors produce two or more hormones,
usually simultaneously and occasionally in sequence. In addition to insulin, glucagon,
and gastrin, pancreatic endocrine tumors may produce adrenocorticotropic hormone,
melanocyte-stimulating hormone, vasopressin, serotonin, and norepinephrine. These
multihormonal tumors are to be distinguished from the multiple endocrine neoplasias (see
below), in which a multiplicity of hormones is produced by tumors in several different
The adrenal glands are paired endocrine organs consisting of both cortex and medulla,
which differ in their development, structure, and function. In the adult, the normal
adrenal gland weighs about 4 gm; but with acute stress, lipid depletion may reduce the
weight, or prolonged stress, such as dying after a long chronic illness, can induce
hypertrophy and hyperplasia of the cortical cells and more than double the weight of the
normal gland. Beneath the capsule of the adrenal is the narrow layer of zona glomerulosa.
An equally narrow zona reticularis abuts the medulla. Intervening is the broad zona
fasciculata, which makes up about 75% of the total cortex. The adrenal cortex
synthesizes three different types of steroids: (1) glucocorticoids (principally cortisol),
which are synthesized primarily in the zona fasciculata with a small contribution from the
zona reticularis; (2) mineralocorticoids, the most important being aldosterone, which is
generated in the zona glomerulosa; and (3) sex steroids (estrogens and androgens), which
are produced largely in the zona reticularis. The adrenal medulla is composed of
115. chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine.
Catecholamines have many effects that allow rapid adaptations to changes in the
Diseases of the adrenal cortex can be conveniently divided into those associated with
cortical hyperfunction and those characterized by cortical hypofunction.
ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM)
Just as there are three basic types of corticosteroids elaborated by the adrenal cortex
(glucocorticoids, mineralocorticoids, and sex steroids), so there are three distinctive
hyperadrenal clinical syndromes: (1) Cushing syndrome, characterized by an excess of
cortisol; (2) hyperaldosteronism; and (3) adrenogenital or virilizing syndromes caused by
an excess of androgens. The clinical features of these syndromes overlap somewhat
because of the overlapping functions of some of the adrenal steroids.
Hypercortisolism (Cushing Syndrome)
This disorder is caused by any condition that produces an elevation in glucocorticoid
levels. There are four possible sources of excess cortisol ( Fig. 24-43 ). In clinical
practice, most causes of Cushing syndrome are the result of the administration of
exogenous glucocorticoids. The other
116. Figure 24-43 A schematic representation of the various forms of Cushing syndrome, illustrating the three
endogenous forms as well as the more common exogenous (iatrogenic) form. ACTH, adrenocorticotropic
three sources of the hypercortisolism can be categorized as endogenous Cushing
• Primary hypothalamic-pituitary diseases associated with hypersecretion of
• Hypersecretion of cortisol by an adrenal adenoma, carcinoma, or nodular
• The secretion of ectopic ACTH by a nonendocrine neoplasm
Primary hypersecretion of ACTH accounts for 70% to 80% of cases of endogenous
hypercortisolism. In recognition of the neurosurgeon who first published the full
description of this syndrome and related it to a pituitary lesion, this pituitary form of
Cushing syndrome is referred to as Cushing disease. The disorder affects women about
five times more frequently than men, and it occurs most frequently during the twenties
and thirties. In the vast majority of cases, the pituitary gland contains an ACTH-
producing microadenoma that does not produce mass effects in the brain; some
corticotroph tumors qualify as macroadenomas (>10 mm). In most of the remaining
cases, the anterior pituitary contains areas of corticotroph cell hyperplasia without a
discrete adenoma. Corticotroph cell hyperplasia may be primary or may arise secondarily
from excessive stimulation of ACTH release by a hypothalamic corticotropin releasing
hormone (CRH)-producing tumor. The adrenal glands in patients with Cushing disease
117. are characterized by variable degrees of nodular cortical hyperplasia (discussed later),
caused by the elevated levels of ACTH. The cortical hyperplasia, in turn, is responsible
Primary adrenal neoplasms, such as adrenal adenoma and carcinoma, and primary
cortical hyperplasia are responsible for about 10% to 20% of cases of endogenous
Cushing syndrome. This form of Cushing syndrome is also designated ACTH-
independent Cushing syndrome or adrenal Cushing syndrome because the adrenals
function autonomously. The biochemical sine qua non of adrenal Cushing syndrome is
elevated serum levels of cortisol with low levels of ACTH.
• Adenomas and carcinomas are about equally common in adults; in children,
carcinomas predominate. The cortical carcinomas tend to produce more marked
hypercortisolism than the adenomas or hyperplastic processes. In instances of a
unilateral neoplasm, the uninvolved adrenal cortex and that in the opposite gland
undergo atrophy because of suppression of ACTH secretion.
• The overwhelming majority of hyperplastic adrenals arise from secondary
influences, and primary cortical hyperplasia is uncommon. Two types of primary
bilateral adrenocortical hyperplasia have been described in association with
Cushing syndrome. In massive macronodular adrenocortical disease (MMAD),
the nodules are usually greater than 3 mm in diameter. MMAD affects older
adults, and there is no known genetic component. The second variant of primary
nodular hyperplasia, seen more often in children than in adults, is a familial
condition known as primary pigmented nodular adrenal disease (PPNAD). The 
in PPNAD demonstrate diffuse bilateral micronodules (<3 mm in diameter) that
are usually darkly pigmented (brown to black).
Secretion of ectopic ACTH by nonpituitary tumors accounts for most of the remaining
cases (∼ 10%) of Cushing syndrome. In many instances, the responsible tumor is a small
cell carcinoma of the lung, although other neoplasms, including carcinoid tumors,
medullary carcinomas of the thyroid, and islet cell tumors of the pancreas, have been
associated with the syndrome. In addition to tumors that elaborate ectopic ACTH, an
occasional neuroendocrine neoplasm produces ectopic corticotropin-releasing hormone,
which, in turn, causes ACTH secretion and hypercortisolism. As in the pituitary variant,
the adrenal glands undergo bilateral cortical hyperplasia, but often the rapid downhill
course of the patients with these cancers cuts short the adrenal enlargement. This variant
of Cushing syndrome is more common in men and usually occurs in the forties and
The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. The
pituitary in Cushing syndrome shows changes regardless of the cause. The most
118. common alteration, resulting from high levels of endogenous or exogenous
glucocorticoids, is termed Crooke hyaline change. In this condition, the normal
granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is
replaced by homogeneous, lightly basophilic material. This alteration is the result of the
accumulation of intermediate keratin filaments in the cytoplasm.
The morphology of the adrenal glands depends on the cause of the hypercortisolism.
The adrenals have one of the following abnormalities: (1) cortical atrophy; (2) diffuse
hyperplasia; (3) nodular hyperplasia; and (4) an adenoma, rarely a carcinoma. In patients
in whom the syndrome results from exogenous glucocorticoids, suppression of
endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of
the zonae fasciculata and reticularis by ACTH. The zona glomerulosa is of normal
thickness in such cases because this portion of the cortex functions independently of
ACTH. In cases of endogenous hypercortisolism, in contrast, the adrenals either are
hyperplastic or contain a cortical neoplasm. Diffuse hyperplasia is found in 60% to 70%
of cases of Cushing syndrome. Both glands are enlarged, either subtly or markedly,
weighing up to 25 to 40 gm. The adrenal cortex is diffusely thickened and yellow, owing
to an increase in the size and number of lipid-rich cells in the zonae fasciculata and
reticularis. Some degree of nodularity is common but is pronounced in nodular
hyperplasia. This takes the form of bilateral, 0.5- to 2.0-cm, yellow nodules scattered
throughout the cortex, separated by intervening areas of widened cortex. The uninvolved
cortex and nodules are composed of a mixture of lipid-laden clear cells and lipid-poor
compact cells showing some variability in cell and nuclear size with occasional
binucleate forms. The combined adrenals may weigh up to 30 to 50 gm. Most cases of
hyperplasia are associated with elevated serum levels of ACTH, whether of pituitary or
ectopic origin. Primary adrenocortical neoplasms causing Cushing syndrome may be
malignant or benign. Adenomas or carcinomas of the adrenal cortex as the source of
cortisol secretion are not macroscopically distinctive from nonfunctioning adrenal
neoplasms to be described later. Both the benign and the malignant lesions are more
common in women in their thirties to fifties. The adrenocortical adenomas are yellow
tumors surrounded by thin or well-developed capsules, and most weigh less than 30 gm.
Microscopically, they are composed of cells that are similar to those encountered in the
normal zona fasciculata. Their morphology is identical to that of nonfunctional adenomas
and of adenomas associated with hyperaldosteronism (see below). The carcinomas
associated with Cushing syndrome, by contrast, tend to be larger than the adenomas.
These tumors are unencapsulated masses frequently exceeding 200 to 300 gm in weight,
having all of the anaplastic characteristics of cancer, as will be detailed later. With
functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of
the contralateral adrenal gland are atrophic, owing to suppression of endogenous ACTH
by high cortisol levels.
Developing slowly over time, Cushing syndrome, similar to many other endocrine
abnormalities, can be quite subtle in its early manifestations. Early stages of the disorder
may present with hypertension and weight gain ( Table 24-9 ). With time, the more
characteristic central pattern of adipose tissue deposition becomes apparent, with
119. resultant truncal obesity, moon facies, and accumulation of fat in the posterior neck and
back (buffalo hump). Hypercortisolism causes selective atrophy of fast-twitch (type 2)
myofibers, resulting in decreased muscle mass and proximal limb weakness.
Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells, with
resultant hyperglycemia, glucosuria, and polydipsia; Cushing syndrome is an important
cause of secondary diabetes. The catabolic effects on proteins cause loss of collagen and
resorption of bones. Consequently, the skin is thin, fragile, and easily bruised; wound
healing is poor; and cutaneous striae are particularly common in the abdominal area.
Bone resorption results in the development of osteoporosis, with consequent backache
and increased susceptibility to fractures. Patients with Cushing syndrome are at increased
risk for a variety of infections
TABLE 24-9 -- Major Features of Cushing Syndrome with Approximate Frequency
Clinical Features Percentages
Central obesity (about trunk and upper back) 85–90%
Moon facies 85%
Weakness and fatigability 85%
Glucose intolerance/diabetes 75/20%
Neuropsychiatric abnormalities 75–80%
Menstrual abnormalities 70%
Skin striae (sides of lower abdomen) 50%
because glucocorticoids suppress the immune response. Additional manifestations
include a number of mental disturbances, including mood swings, depression, and frank
psychosis, as well as hirsutism and menstrual abnormalities.
Cushing syndrome is diagnosed in the laboratory with the following: (1) the 24-hour
urine free cortisol level, which is increased, and (2) loss of normal diurnal pattern of
cortisol secretion. Determining the cause of Cushing syndrome depends on the level of
serum ACTH and measurement of urinary steroid excretion after administration of
dexamethasone. Three general patterns can be obtained: 
120. 1. In pituitary Cushing syndrome, the most common form, ACTH levels are elevated
and cannot be suppressed by the administration of a low dose of dexamethasone.
Hence, there is no reduction in urinary excretion of 17-hydroxy-corticosteroids.
After higher doses of injected dexamethasone, however, the pituitary responds by
reducing ACTH secretion, which is reflected by suppression of urinary steroid
2. Ectopic ACTH secretion results in an elevated level of ACTH, but its secretion is
completely insensitive to low or high doses of exogenous dexamethasone.
3. When Cushing syndrome is caused by an adrenal tumor, the ACTH level is quite
low because of feedback inhibition of the pituitary. As with ectopic ACTH
secretion, both low-dose and high-dose dexamethasone fail to suppress cortisol
Hyperaldosteronism is the generic term for a small group of closely related, uncommon
syndromes, all characterized by chronic excess aldosterone secretion. Excessive levels of
aldosterone cause sodium retention and potassium excretion, with resultant hypertension
and hypokalemia. Hyperaldosteronism may be primary, or it may be a secondary event
resulting from an extra-adrenal cause.
Primary hyperaldosteronism indicates an autonomous overproduction of aldosterone,
with resultant suppression of the renin-angiotensin system and decreased plasma renin
activity. Primary hyperaldosteronism is caused by one of three mechanisms ( Fig. 
• Adrenocortical neoplasm, either an aldosterone-producing adrenocortical
adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In
approximately 80% of cases, primary hyperaldosteronism is caused by a solitary
aldosterone-secreting adenoma, a condition referred to as Conn syndrome. This
syndrome occurs most frequently in adult middle life and is more common in
women than in men (2:1). Multiple adenomas may be present in an occasional
• Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism),
characterized by bilateral nodular hyperplasia of the adrenal glands, highly
reminiscent of those found in the nodular hyperplasia of Cushing syndrome. The
genetic basis of idiopathic hyperaldosteronism is not clear, although it is possibly
caused by an overactivity of the aldosterone synthase gene, CYP11B2. 
• Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of
primary hyperaldosteronism that is familial and genetic. In some families, it is
caused by a chimeric gene resulting from fusion between CYP11B1 (the 11β-
hydroxylase gene) and CYP11B2 (the aldosterone synthase gene). This leads to
a sustained production of hybrid steroids in addition to both cortisol and
aldosterone. The activation of aldosterone secretion is under the influence of
ACTH and hence is suppressible by exogenous administration of dexamethasone.
121. In secondary hyperaldosteronism, in contrast, aldosterone release occurs in response to
activation of the renin-angiotensin system ( Chapter 4 ). It is characterized by increased
levels of plasma renin and is encountered in conditions such as the following:
• Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
• Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic
• Pregnancy (due to estrogen-induced increases in plasma renin substrate).
Aldosterone-producing adenomas are almost always solitary, small (<2 cm in
diameter), well-circumscribed lesions, more often found on the left than on the right.
They tend to occur in the thirties and forties, and in women more often than in men.
These lesions are often buried within the gland and do not produce visible enlargement, a
point to be remembered in interpreting sonographic or scanning images. They are bright
yellow on cut section ( Fig. 24-45 ) and, surprisingly, are composed of lipid-laden
cortical cells that more closely resemble fasciculata cells than glomerulosa cells (the
normal source of aldosterone). In general, the cells tend to be uniform in size and shape
and resemble mature cortical cells; occasionally, there is some nuclear and cellular
pleomorphism but no evidence of anaplasia ( Fig. 24-46 ). A characteristic feature of
aldesterone-producing adenomas is the presence of eosinophilic, laminated cytoplasmic
inclusions, known as spironolactone bodies, found after treatment with the anti-
hypertensive drug spironolactone. In contrast to cortical adenomas associated with
Cushing syndrome, those associated with hyperaldosteronism do not usually suppress
ACTH secretion. Therefore, the adjacent adrenal cortex and that of the contralateral gland
are not atrophic.
Bilateral idiopathic hyperplasia ( Fig. 24-47 ) is marked by diffuse and focal
hyperplasia of cells resembling those of the normal zona glomerulosa. The hyperplasia is
often wedge-shaped, extending from the periphery toward the center of the gland.
Bilateral enlargement can be subtle in idiopathic hyperplasia, and as a rule, an
adrenocortical adenoma should be carefully excluded as the cause for
The clinical manifestations of primary hyperaldosteronism are hypertension and
hypokalemia. Serum renin, as was mentioned previously, is low. Hypokalemia results
from renal potassium wasting and can cause a variety of neuromuscular manifestations,
including weakness, paresthesias, visual disturbances, and occasionally frank tetany.
Sodium retention increases the total body sodium and
122. Figure 24-44 The major causes of primary hyperaldosteronism and its principal effects on the kidney.
expands the extracellular fluid volume, leading to elevation of the serum sodium
concentration and an increase in intracellular sodium with increased vascular reactivity.
The hypertension is, in part, a result of the sodium retention. The expanded extracellular
123. fluid volume and hypokalemia both impose a burden on the heart, sometimes causing
electrocardiographic changes and cardiac decompensation. The diagnosis of primary
hyperaldosteronism is confirmed by the elevated levels of aldosterone and depressed
levels of renin in the circulation. Even when the diagnosis of primary hyperaldosteronism
is made, it is necessary to distinguish among the various causes, particularly the
differentiation of an adenoma, which is amenable to surgical excision. Primary adrenal
hyperplasia associated with hyperaldosteronism occurs more often in children and young
adults than in older adults; surgical intervention is not very beneficial in these patients,
who are best managed with medical therapy with an aldosterone antagonist such as
spironolactone. Uncommon as primary hyperaldosteronism is, it should not be
overlooked clinically, because it provides an opportunity to cure a form of hypertension.
The treatment of secondary hyperaldosteronism rests on correcting the underlying cause
stimulating the renin-angiotensin system.
Disorders of sexual differentiation, such as virilization or feminization, can be caused by
primary gonadal disorders ( Chapter 22 ) and several primary adrenal disorders. The
adrenal cortex secretes two compounds—dehydroepiandrosterone and androstenedione—
that require conversion to testosterone in peripheral tissues for their androgenic effects.
Unlike gonadal androgens, ACTH regulates adrenal androgen formation ( Fig. 24-48 );
thus, excess secretion can occur either as a "pure" syndrome or as a component of
Cushing disease. The adrenal causes of androgen excess include adrenocortical
124. Figure 24-45 Adrenal cortical adenoma. The adenoma is distinguished from nodular hyperplasia by its
solitary, circumscribed nature. The functional status of an adrenal cortical adenoma cannot be predicted
from its gross or microscopic appearance.
neoplasms and a group of disorders that have been designated congenital adrenal
Adrenocortical neoplasms associated with virilization are more likely to be androgen-
secreting adrenal carcinomas than adenomas. Conversely, functioning adrenal cortical
carcinomas are most often associated with a virilization syndrome, usually in
combination with hypercortisolism ("mixed syndrome"). These tumors are
morphologically identical to other cortical neoplasms and will be discussed later.
Congenital adrenal hyperplasia (CAH) represents a group of autosomal-recessive,
inherited metabolic errors, each characterized by a deficiency or total lack of a particular
enzyme involved in the biosynthesis of cortical steroids, particularly cortisol. 
Steroidogenesis is then channeled into other pathways, leading to increased production of
androgens, which accounts for virilization. Simultaneously, the deficiency of cortisol
results in increased secretion of ACTH, resulting in adrenal hyperplasia. Certain enzyme
defects may also impair aldosterone secretion, adding salt wasting to the virilizing
syndrome. Other enzyme deficiencies may be incompatible with life or, in rare instances,
may involve only the aldosterone pathway without involving cortisol synthesis. Thus,
there is a spectrum of these syndromes, and with each one, there may be a total lack of a
particular enzyme or a mutation that only mildly impairs the effectiveness of the enzyme.
The following remarks focus on the most common of these disorders.
Defective conversion of progesterone to 11-deoxycorticosterone by 21-hydroxylase
(CYP21B) accounts for over 90% of cases of congenital adrenal hyperplasia. Figure 
24-48 illustrates normal adrenal steroidogenesis and the consequences of 21-hydroxylase
deficiency. 21-Hydroxylase deficiency may range from a total lack to a mild loss,
depending on the nature of the CYP21B mutation. Three distinctive syndromes have been
125. Figure 24-46 Histologic features of an adrenal cortical adenoma. The neoplastic cells are vacuolated
because of the presence of intracytoplasmic lipid. There is mild nuclear pleomorphism. Mitotic activity and
necrosis are not seen.
salt-wasting (classic) adrenogenitalism, (2) simple virilizing adrenogenitalism, and (3)
nonclassic adrenogenitalism, which implies mild disease that may be entirely
asymptomatic or associated only with symptoms of androgen excess during childhood or
The carrier frequency of the classic form is approximately 1 in 60, while the carrier
frequency of the nonclassic or mild form is 1 in 5 to 1 in 50, depending on the ethnic
group; Hispanics and Ashkenazi Jewish populations have the highest carrier frequencies.
The incidence of classic 21-hydroxylase deficiency varies somewhat between
populations, with a
126. Figure 24-47 Nodular hyperplasia of the adrenal contrasted with normal adrenal gland. In cross-section,
the adrenal cortex is yellow, thickened, and multinodular, owing to hypertrophy and hyperplasia of the
lipid-rich zonae fasciculata and reticularis.
127. Figure 24-48 Consequences of C-21 hydroxylase deficiency. 21-Hydroxylase deficiency impairs the
synthesis of both cortisol and aldosterone. The resultant decrease in feedback inhibition (dashed line)
causes increased secretion of adrenocorticotropic hormone, resulting ultimately in adrenal hyperplasia and
increased synthesis of testosterone. The sites of action of 11-, 17-, and 21-hydroxylase are shown by the
numbers in circles.
worldwide mean of around 1 in 13,000 newborns. The mechanism of CYP21B gene
inactivation in 21-hydroxylase deficiency involves recombination with a neighboring
pseudogene on chromosome 6p21 called CYP21A (a pseudogene is an inactive
homologous gene created by ancestral duplication in a localized region of the genome).
In the majority of cases of CAH, portions of the CYP21A pseudogene replace all or part
of the active CYP21B gene. The introduction of nonfunctional sequences from CYP21A
into the CYP21B sequence has the same effect as inactivating mutations in CYP21B.
128. The salt-wasting syndrome results from an inability to convert progesterone into
deoxycorticosterone because of a total lack of the hydroxylase. Thus, there is virtually no
synthesis of mineralocorticoids, and concomitantly, there is a block in the conversion of
hydroxyprogesterone into deoxycortisol with deficient cortisol synthesis. This pattern
usually comes to light soon after birth because in utero the electrolytes and fluids can be
maintained by the maternal kidneys. There is salt wasting, hyponatremia, and
hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly
death. The concomitant block in cortisol synthesis and excess production of androgens,
however, lead to virilization, which is easily recognized in the female at birth or in utero
but is difficult to recognize in the male. Various degrees of virilization are encountered,
ranging from mild clitoral enlargement to complete labioscrotal fusion to marked clitoral
enlargement enclosing the urethra, thus producing a phalloid organ. Males with this
disorder are generally unrecognized at birth but come to clinical attention 5 to 15 days
later because of some salt-losing crisis.
Simple virilizing adrenogenital syndrome without salt wasting (presenting as genital
ambiguity) may occur in individuals with a less than total 21-hydroxylase defect because
with less severe deficiencies the level of mineralocorticoid, although reduced, is
sufficient for salt reabsorption, but the lowered glucocorticoid level fails to cause
feedback inhibition of ACTH secretion. Thus, the level of aldosterone is mildly reduced,
testosterone is increased, and ACTH is elevated, with resultant adrenal hyperplasia.
Nonclassic or late-onset adrenal virilism is much more common than the classic patterns
already described. Patients with this syndrome may be virtually asymptomatic or have
mild manifestations, such as hirsutism. The diagnosis can be made only by demonstration
of biosynthetic defects in steroidogenesis and by genetic studies.
In all cases of CAH, the adrenals are bilaterally hyperplastic, sometimes expanding to 10
to 15 times their normal weights because of the sustained elevation in ACTH. The
adrenal cortex is thickened and nodular, and on cut section, the widened cortex appears
brown, owing to total depletion of all lipid. The proliferating cells are mostly compact,
eosinophilic, lipid-depleted cells, intermixed with lipid-laden clear cells. Hyperplasia of
corticotroph (ACTH-producing) cells is present in the anterior pituitary in most CAH
The clinical features of these disorders are determined by the specific enzyme deficiency
abnormalities related to androgen excess and aldosterone and glucocorticoid deficiency.
CAH affects not only adrenal cortical enzymes, but also products synthesized in the
129. medulla. High levels of intra-adrenal glucocorticoids are required to facilitate medullary
catecholamine (epinephrine and norepinephrine) synthesis. In patients with severe salt-
wasting 21-hydroxylase deficiency, a combination of low cortisol levels and
developmental defects of the medulla (adrenomedullary dysplasia) profoundly affects
catecholamine secretion, further predisposing these individuals to hypotension and
circulatory collapse. 
Depending on the nature and severity of the enzymatic defect, the onset of clinical
symptoms may occur in the perinatal period, later childhood, or, less commonly,
adulthood. For example, in 21-hydroxylase deficiency, excessive androgenic activity
causes signs of masculinization in females, ranging from clitoral hypertrophy and
pseudohermaphroditism in infants, to oligomenorrhea, hirsutism, and acne in postpubertal
females. In males, androgen excess is associated with enlargement of the external
genitalia and other evidence of precocious puberty in prepubertal patients and
oligospermia in older males.
CAH should be suspected in any neonate with ambiguous genitalia; severe enzyme
deficiency in infancy can be a life-threatening condition with vomiting, dehydration, and
salt wasting. In the milder variants, women may present with delayed menarche,
oligomenorrhea, or hirsutism. Patients with congenital adrenal hyperplasia are treated
with exogenous glucocorticoids, which, in addition to providing adequate levels of
glucocorticoids, also suppress ACTH levels and thus decrease the excessive synthesis of
the steroid hormones responsible for many of the clinical abnormalities.
Mineralocorticoid supplementation is required in the salt-wasting variants of CAH. With
the availability of routine neonatal metabolic screens for CAH and the feasibility of
molecular testing for antenatal detection of 21-hydroxylase mutations, the outcome for
even the most severe variants has improved significantly.
Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal
disease (primary hypoadrenalism) or decreased stimulation of the adrenals owing to a
deficiency of ACTH (secondary hypoadrenalism) ( Table 24-10 ). The patterns of
adrenocortical insufficiency can be considered under the following headings: (1) primary
acute adrenocortical insufficiency (adrenal crisis), (2) primary chronic adrenocortical
insufficiency (Addison disease), and (3) secondary adrenocortical insufficiency.
Primary Acute Adrenocortical Insufficiency
Acute adrenal cortical insufficiency occurs in a variety of clinical settings (see Table
• As a crisis in patients with chronic adrenocortical insufficiency precipitated by
any form of stress that requires an immediate increase in steroid output from
glands incapable of responding
• In patients maintained on exogenous corticosteroids, in whom rapid withdrawal
of steroids or failure to increase steroid doses in response to an acute stress may
130. precipitate an adrenal crisis, owing to the inability of the atrophic adrenals to
produce glucocorticoid hormones
• As a result of massive adrenal hemorrhage, which destroys the adrenal cortex
sufficiently to cause acute adrenocortical insufficiency. This occurs in newborns
following prolonged and difficult delivery with considerable trauma and hypoxia,
leading to extensive adrenal hemorrhages beginning in the medulla and extending
into the cortex. Newborns are particularly vulnerable because they are often
deficient in prothrombin for at least several days after birth. It also occurs in some
patients maintained on anticoagulant therapy, in postsurgical patients who
develop disseminated intravascular coagulation with consequent hemorrhagic
infarction of the adrenals, and when massive adrenal hemorrhage complicates a
bacteremic infection; in this last setting, it is called Waterhouse-Friderichsen
TABLE 24-10 -- Adrenocortical Insufficiency
Loss of cortex
Congential adrenal   hypoplasia
X-linked adrenal hypoplasia     (DAX-1 gene on Xp21)
"Miniature" type adrenal hypoplasia     (unknown cause)
Adrenoleukodystrophy (  ALD gene on Xq28)
Autoimmune adrenal   insufficiency
Autoimmune polyendocrinopathy     syndrome type 1 (AIRE-1 gene on 21q22)
Autoimmune polyendocrinopathy     syndrome type 2 (polygenic)
Isolated autoimmune adrenalitis     (polygenic)
Acquired immune deficiency     syndrome
Acute hemorrhagic necrosis     (Waterhouse-Friderichsen syndrome)
Amyloidosis, sarcoidosis,   hemochromatosis
Metabolic failure in hormone production
131. Congenital adrenal   hyperplasia (cortisol and aldosterone deficiency with virlization)
Drug- and steroid-induced inhibition of   adrenocorticotropic hormone or cortical cell
Hypothalamic pituitary disease
Neoplasm, inflammation (sarcoidosis,   tuberculosis, pyogens, fungi)
Hypothalamic pituitary suppression
Long-term steroid   administration
This uncommon but catastrophic syndrome is characterized by the following:
• An overwhelming bacterial infection, which is classically associated with
Neisseria meningitidis septicemia but occasionally is caused by other highly
virulent organisms, such as Pseudomonas species, pneumococci, Haemophilus
influenzae, or staphylococci
• Rapidly progressive hypotension leading to shock
• Disseminated intravascular coagulation with widespread purpura, particularly of
• Rapidly developing adrenocortical insufficiency associated with massive
bilateral adrenal hemorrhage
132. Figure 24-49 Waterhouse-Friderichsen syndrome in a child. The dark, hemorrhagic adrenal glands are
distended with blood.
Waterhouse-Friderichsen syndrome can occur at any age but is somewhat more common
in children. The basis for the adrenal hemorrhage is uncertain but could be attributable to
direct bacterial seeding of small vessels in the adrenal, the development of disseminated
intravascular coagulation, endotoxin-induced vasculitis, or some form of hypersensitivity
vasculitis. Whatever the basis, the adrenals are converted to sacs of clotted blood
virtually obscuring all underlying detail ( Fig. 24-49 ). Histologic examination reveals
that the hemorrhage starts within the medulla in relationship to thin-walled venous
sinusoids, then suffuses peripherally into the cortex, often leaving islands of recognizable
cortical cells ( Fig. 24-50 ). When it is recognized promptly and treated effectively with
antibiotics, recovery is possible, but the clinical course is usually devastatingly abrupt,
and prompt recognition and appropriate therapy must be instituted immediately, or death
follows within hours to a few days.
Primary Chronic Adrenocortical Insufficiency (Addison Disease)
133. In a paper published in 1855, Thomas Addison described a group of patients suffering
from a constellation of symptoms, including "general languor and debility, remarkable
feebleness of the heart's action, and a peculiar change in the color of the skin" associated
with disease of the "suprarenal capsules" or, in more current terminology, the adrenal
glands. Addison disease, or chronic adrenocortical insufficiency, is an uncommon
disorder resulting from progressive destruction of the adrenal cortex. In general, clinical
manifestations of adrenocortical insufficiency do not appear until at least 90% of the
adrenal cortex has been compromised. The causes of chronic adrenocortical insufficiency
are listed in Table 24-10 . Although all races and both sexes may be affected, certain
causes of Addison disease (such as autoimmune adrenalitis) are much more common in
whites, particularly in women.
A large number of diseases may attack the adrenal cortex, including lymphomas,
amyloidosis, sarcoidosis, hemochromatosis, fungal infections, and adrenal hemorrhage,
but more than 90% of all cases are attributable to one of four disorders: autoimmune
adrenalitis, tuberculosis, the acquired immune deficiency syndrome (AIDS), or
Autoimmune adrenalitis accounts for 60% to 70% of cases, and it is by far the most
common cause of primary adrenal insufficiency in developed countries. As the name
implies, there is autoimmune destruction of steroidogenic cells, and autoantibodies to
several key steroidogenic enzymes (21-hydroxylase, 17-hydroxylase) have been detected
in these patients. Autoimmune adrenalitis can occur in one of three clinical settings:
• Autoimmune polyendocrine syndrome type 1 (APS1) is also known as
autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy
(APECED). APS1 is characterized by chronic mucocutaneous candidiasis and
abnormalities of skin, dental enamel, and nails (ectodermal dystrophy) occurring
in association with a combination of organ-specific autoimmune disorders
(autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic
hypogonadism, pernicious anemia) that result in immune destruction of target
organs. APS1 is caused by mutations in the autoimmune regulator (AIRE) gene
21q22. The expression of AIRE protein is primarily in the thymus, where it
appears to function as a transcription factor that promotes the expression of many
self-antigens, leading to negative selection (death) of self-reactive T cells
( Chapter 6 ).
• Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early
adulthood and presents as a combination of adrenal insufficiency with
autoimmune thyroiditis or type 1 diabetes. Unlike in APS1, mucocutaneous
candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not
134. occur. APS2, unlike APS1, is not a monogenic disorder, although some studies
have suggested a possible association with polymorphisms in the HLA loci. 
• Isolated autoimmune Addison disease presents with autoimmune destruction
restricted to the adrenal glands. However, in terms of age at presentation and
linkage to HLA and other susceptibility loci, isolated autoimmune adrenalitis
overlaps with APS2, suggesting that the former may be a variant of the latter.
Figure 24-50 Waterhouse-Friderichsen syndrome. At autopsy, the adrenals were grossly hemorrhagic and
shrunken; microscopically, little residual cortical architecture is discernible.
Infections, particularly tuberculosis and those produced by fungi, may also cause primary
chronic adrenocortical insufficiency. Tuberculous adrenalitis, which once accounted for
as much as 90% of Addison disease, has become less common with the development of
antituberculous agents. With the resurgence of tuberculosis in most urban centers and the
persistence of the disease in developing countries, however, this cause of adrenal
insufficiency must be kept in mind. When present, tuberculous adrenalitis is usually
associated with active infection in other sites, particularly in the lungs and genitourinary
tract. Among the fungi, disseminated infections caused by Histoplasma capsulatum and
Coccidioides immitis may also result in chronic adrenocortical insufficiency. Patients
with AIDS are at risk for developing adrenal insufficiency from several infectious
(cytomegalovirus, Mycobacterium avium-intercellulare) and noninfectious complications
Metastatic neoplasms involving the adrenals are another potential cause of adrenal
insufficiency. The adrenals are a fairly common site for metastases in patients with
disseminated carcinomas. Although adrenal function is preserved in most such patients,
the metastatic tumors occasionally destroy enough adrenal cortex to produce a degree of
adrenal insufficiency. Carcinomas of the lung and breast are the source of a majority of
metastases in the adrenals, although many other neoplasms, including gastrointestinal
135. carcinomas, malignant melanoma, and hematopoietic neoplasms, may also metastasize to
Genetic disorders of adrenal insufficiency include adrenal hypoplasia congenital (AHC)
and adrenoleukodystrophy. Technically, these disorders are also associated with chronic
adrenal insufficiency, although they are not commonly included in the causes of Addison
disease. Adrenoleukodystrophy is described in Chapter 28 . Congenital adrenal
hypoplasia is rare, and will not be discussed further.
The anatomic changes in the adrenal glands depend on the underlying disease. Primary
autoimmune adrenalitis is characterized by irregularly shrunken glands, which may be
difficult to identify within the suprarenal adipose tissue. Histologically, the cortex
contains only scattered residual cortical cells in a collapsed network of connective tissue.
A variable lymphoid infiltrate is present in the cortex and may extend into the subjacent
medulla, although the medulla is otherwise preserved ( Fig. 24-51 ). In cases of
tuberculous and fungal disease, the adrenal architecture is effaced by a granulomatous
inflammatory reaction identical to that encountered in other sites of infection. When
hypoadrenalism is caused by metastatic carcinoma, the adrenals are enlarged, and their
normal architecture is obscured by the infiltrating neoplasm.
Addison disease begins insidiously and does not come to attention until at least 90% of
the cortex of both glands is destroyed and the levels of circulating glucocorticoids and
mineralocorticoids are significantly decreased. The initial manifestations include
progressive weakness and easy fatigability, which may be dismissed as nonspecific
complaints. Gastrointestinal disturbances are common and include anorexia, nausea,
vomiting, weight loss, and diarrhea. In patients with primary adrenal disease, increased
circulating levels of ACTH precursor hormone stimulate melanocytes, with resultant
hyperpigmentation of the skin, particularly of sun-exposed areas and at pressure points,
such as the neck, elbows, knees, and knuckles. By contrast, hyperpigmentation is not seen
in patients with adrenocortical insufficiency caused by primary pituitary or hypothalamic
disease. Decreased mineralocorticoid activity in patients with primary adrenal
insufficiency results in potassium and sodium loss, with consequent hyperkalemia,
hyponatremia, volume depletion, and hypotension. Hypoglycemia may occasionally
occur as a result of glucocorticoid deficiency and impaired gluconeogenesis. Stresses
such as infections, trauma, or surgical procedures in such patients can precipitate an acute
adrenal crisis, manifested by intractable vomiting, abdominal pain, hypotension, coma,
and vascular collapse. Death occurs rapidly unless corticosteroid therapy begins
Secondary Adrenocortical Insufficiency
Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection,
infarction, or irradiation, that
136. Figure 24-51 Autoimmune adrenalitis. In addition to loss of all but a subcapsular rim of cortical cells, there
is an extensive mononuclear cell infiltrate.
reduces the output of ACTH leads to a syndrome of hypoadrenalism that has many
similarities to Addison disease. Analogously, prolonged administration of exogenous
glucocorticoids suppresses the output of ACTH and adrenal function. With secondary
disease, the hyperpigmentation of primary Addison disease is lacking because
melanotropic hormone levels are low. The manifestations also differ in that secondary
hypoadrenalism is characterized by deficient cortisol and androgen output but normal or
near-normal aldosterone synthesis. Thus, in adrenal insufficiency secondary to pituitary
malfunction, marked hyponatremia and hyperkalemia are not seen.
ACTH deficiency can occur alone, but in some instances, it is only one part of
panhypopituitarism, associated with multiple primary trophic hormone deficiencies. The
differentiation of secondary disease from Addison disease can be confirmed with
demonstration of low levels of plasma ACTH in the former. In patients with primary
disease, the destruction of the adrenal cortex does not permit a response to exogenously
administered ACTH in the form of increased plasma levels of cortisol, whereas in those
with secondary hypofunction, there is a prompt rise in plasma cortisol levels.
In cases of hypoadrenalism secondary to hypothalamic or pituitary disease (secondary
hypoadrenalism), depending on the extent of ACTH lack, the adrenals may be
moderately to markedly reduced in size. They are reduced to small, flattened structures
that usually retain their yellow color owing to a small amount of residual lipid. The
cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The
medulla is unaffected.
137. It should be evident from the preceding sections that functional adrenal neoplasms may
be responsible for any of the various forms of hyperadrenalism. While functional
adenomas are most commonly associated with hyperaldosteronism and Cushing
syndrome, a virilizing neoplasm is more likely to be a carcinoma. However, not all
adrenocortical neoplasms elaborate steroid hormones. Determination of whether a
cortical neoplasm is functional or not is based on clinical evaluation and measurement of
the hormone or its metabolites in the laboratory. In other words, functional and
nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of
Most adrenocortical adenomas are clinically silent and are usually encountered as
incidental findings at the time of autopsy or during abdominal imaging for an unrelated
cause (see the discussion of adrenal incidentalomas below). Some experts believe that all
adrenal adenomas should, by definition, demonstrate clinical or biochemical evidence of
hyperfunction and that the incidentally discovered "tumors" are best classified as
hyperplastic nodules. In either case, the typical cortical adenoma is a well-
circumscribed, nodular lesion up to 2.5 cm in diameter that expands the adrenal. In
contrast to functional adenomas, which are associated with atrophy of the adjacent cortex,
the cortex adjacent to nonfunctional adenomas is of normal thickness. On cut surface,
adenomas are usually yellow to yellow-brown because of the presence of lipid within the
tumor cells. Microscopically, adenomas are composed of cells similar to those populating
the normal adrenal cortex. The nuclei tend to be small, although some degree of
pleomorphism may be encountered even in benign lesions ("endocrine atypia"). The
cytoplasm of the neoplastic cells ranges from eosinophilic to vacuolated, depending on
their lipid content ( Fig. 24-46 ). Mitotic activity is generally inconspicuous.
Adrenocortical carcinomas are rare neoplasms that can occur at any age, including
childhood. They are more likely to be functional than adenomas are, and carcinomas are
therefore often associated with virilism or other clinical manifestations of
hyperadrenalism. Two rare inherited causes of adrenal cortical carcinomas are Li-
Fraumeni syndrome ( Chapter 7 ) and Beckwith-Wiedemann syndrome ( Chapter 10 ). In
most cases, adrenocortical carcinomas are large, invasive lesions, many exceeding 20 cm
in diameter, that efface the native adrenal gland. The less common, smaller, and better-
circumscribed lesions may be difficult to distinguish from an adenoma. On cut surface,
adrenocortical carcinomas are typically variegated, poorly demarcated lesions containing
areas of necrosis, hemorrhage, and cystic change ( Fig. 24-52 ). Invasion of contiguous
structures, including the adrenal vein and inferior vena cava, is common.
Microscopically, adrenocortical carcinomas may be composed of well-differentiated cells
resembling those seen in cortical adenomas or bizarre, monstrous giant cells ( Fig.
24-53 ), which may be difficult to distinguish from those of an undifferentiated
carcinoma metastatic to the adrenal. Between these extremes are found cancers with
moderate degrees of anaplasia, some composed predominantly of spindle cells.
Carcinomas, particularly those of bronchogenic origin, may metastasize to the adrenals,
and they may be extremely difficult to differentiate from primary cortical carcinomas.
Adrenal cancers have a strong tendency to invade the adrenal vein, vena cava, and
138. lymphatics. Metastases to regional and periaortic nodes are common, as is distant
Figure 24-52 Adrenal carcinoma. The hemorrhagic and necrotic tumor dwarfs the kidney and compresses
the upper pole.
Figure 24-53 Adrenal carcinoma (A) revealing marked anaplasia, contrasted with normal cortical cells (B).
spread to the lungs and other viscera. Bone metastases are unusual. The median patient
survival is about 2 years.
OTHER LESIONS OF THE ADRENAL
Adrenal cysts are relatively uncommon lesions; however, with the use of sophisticated
abdominal imaging techniques, the frequency of detection of these lesions appears to be
139. increasing. The larger cysts may produce an abdominal mass and flank pain. Both
cortical and medullary neoplasms may undergo necrosis and cystic degeneration and may
present as "nonfunctional" cysts.
Adrenal myelolipomas are unusual benign lesions composed of mature fat and
hematopoietic cells. Although most of these lesions represent incidental findings,
occasional myelolipomas may reach massive proportions. Histologically, mature
adipocytes are admixed with aggregates of hematopoietic cells belonging to all three
lineages. Foci of myelolipomatous change may be seen in cortical tumors and in adrenals
with cortical hyperplasia.
The term adrenal incidentaloma is a half-facetious moniker that has crept into the
medical lexicon as advancements in medical imaging have led to the incidental discovery
of adrenal masses in asymptomatic individuals or in individuals in whom the presenting
complaint is not directly related to the adrenal gland. Fortunately, the vast majority of
adrenal incidentalomas are nonsecreting cortical adenomas, but in effect, any adrenal
cortical or medullary neoplasm or hyperplasia, metastatic cancer, or a non-neoplastic
disease (abscess, amyloidosis, sarcoid) can result in an incidentally discovered adrenal
The adrenal medulla is developmentally, functionally, and structurally distinct from the
adrenal cortex. It is composed of specialized neural crest (neuroendocrine) cells, termed
chromaffin cells, and their supporting (sustentacular) cells. The chromaffin cells are
round to oval, have prominent cytoplasmic membrane-bound granules of stored
catecholamines, and are supported by a richly vascularized scant stroma of spindled and
sustentacular cells. These cells, so named because of their brown-black color after
exposure to potassium dichromate (e.g., Zenker fixative), synthesize and secrete
catecholamines in response to signals from preganglionic nerve fibers in the sympathetic
nervous system. The adrenal medulla is the major source of catecholamines (epinephrine,
norepinephrine) in the body. Norepinephrine functions as a local neurotransmitter, chiefly
of sympathetic postganglionic neurons. Only small amounts reach the circulation.
Epinephrine (adrenaline) is secreted into the vascular system. It interacts with α-
adrenergic and β-adrenergic receptors in various cells, which then activate second
messengers and a cascade of enzymatic reactions mediating the systemic actions of
epinephrine, for example, increasing the force and rate of myocardial contractions and
140. causing vasoconstriction of most vascular beds. Because the secretory cells are a part of
the neuroendocrine system, they are also capable of synthesizing a variety of bioactive
amines and peptides, such as histamine, serotonin, renin, chromogranin A, and
Neuroendocrine cells similar to chromaffin cells are widely dispersed in an extra-adrenal
system of clusters and nodules that, together with the adrenal medulla, make up the
paraganglion system. These extra-adrenal paraganglia are closely associated with the
autonomic nervous system and can be divided into three groups based on their anatomic
distribution: (1) branchiomeric, (2) intravagal, and (3) aorticosympathetic ( Fig. 24-54 ).
The branchiomeric and intravagal paraganglia associated with the parasympathetic
system are located close to the major arteries and cranial nerves of the head and neck and
include the carotid bodies ( Chapter 16 ). The intravagal paraganglia, as the term implies,
are distributed along the vagus nerve. The aorticosympathetic chain is found in
association with segmental ganglia of the sympathetic system and therefore is distributed
mainly alongside of the abdominal aorta. The organs of Zuckerkandl, close to the aortic
bifurcation, belong to this group. The visceral paraganglia, as the term implies, are
located within organs such as the urinary bladder. They are described in Chapter 16 .
141. Figure 24-54 The paraganglion system. This schematic representation of the paraganglion system
demonstrates sites of paraganglion cell nests, in which neoplasms may form. The extra-adrenal portion of
the paraganglion system is grouped into three families based on anatomic distribution, innervation, and
microscopic structure: (1) branchiomeric, (2) intravagal, and (3) aorticosympathetic. (From Whalen RK, et
al: Extra-adrenal pheochromocytoma. J Urol 147:1–10, 1992; copyright Williams & Wilkins, 1992.)
The most important diseases of the adrenal medulla are neoplasms, which include
neoplasms of chromaffin cells (pheochromocytomas) and neuronal neoplasms (including
neuroblastomas and more mature ganglion cell tumors).
Pheochromocytomas are uncommon neoplasms composed of chromaffin cells, which
synthesize and release catecholamines and in some instances peptide hormones. These
tumors are important because they (similar to aldosterone-secreting adenomas) give rise
to surgically correctable forms of hypertension. Although only about 0.1% to 0.3% of
hypertensive patients have an underlying pheochromocytoma, the hypertension can be
fatal when the pheochromocytoma goes unrecognized. Occasionally, one of these tumors
produces other steroids or peptides and so may be associated with Cushing syndrome or
some other endocrinopathy.
Pheochromocytomas usually subscribe to a convenient "rule of 10s":
• 10% of pheochromocytomas arise in association with one of several familial
syndromes ( Table 24-11 ). These include the MEN-2A and MEN-2B syndromes
(described later), type I neurofibromatosis ( Chapter 5 ), von Hippel-Lindau
syndrome ( Chapter 28 ), and Sturge-Weber syndrome ( Chapter 16 ).
• 10% of pheochromocytomas are extra-adrenal, occurring in sites such as the
organ of Zuckerkandl and the carotid body, where these chromaffin-negative
tumors are usually called paragangliomas to distinguish them from
• 10% of nonfamilial adrenal pheochromocytomas are bilateral; this figure may
rise to 70% in cases that are associated with familial syndromes.
• 10% of adrenal pheochromocytomas are biologically malignant, although the
associated hypertension represents a serious and potentially lethal complication of
even "benign" tumors. Frank malignancy is somewhat more common (20% to
40%) in tumors arising in extra-adrenal sites.
• 10% of adrenal pheochromocytomas arise in childhood, usually the familial
subtypes, and with a strong male preponderance. The nonfamilial
often occur in adults between 40 and 60 years of age, with a slight female
TABLE 24-11 -- Familial Syndromes Associated with Pheochromocytoma
MEN, type 2A Medullary thyroid carcinomas and C-cell hyperplasia
Pheochromocytomas and adrenal medullary hyperplasia
MEN, type 2B Medullary thyroid carcinomas and C-cell hyperplasia
Pheochromocytomas and adrenal medullary hyperplasia
143. TABLE 24-11 -- Familial Syndromes Associated with Pheochromocytoma
von Hippel-Lindau Renal, hepatic, pancreatic, and epididymal cysts
Renal cell carcinomas
von Recklinghausen Neurofibromatosis
Café au lait skin spots
Schwannomas, meningiomas, gliomas
Sturge-Weber Cavernous hemangiomas of fifth cranial nerve distribution
MEN, multiple endocrine neoplasia.
Data from Silverman ML, Lee AK: Anatomy and pathology of the adrenal glands. Urol
Clin North Am 16:417, 1989.
Pheochromocytomas range from small, circumscribed lesions confined to the adrenal
( Fig. 24-55 ) to large hemorrhagic masses weighing kilograms. The average weight of a
pheochromocytoma is 100 gm, but variations from just over 1 gm to almost 4000 gm
have been reported. The larger tumors are well demarcated by either connective tissue or
compressed cortical or medullary tissue. Richly vascularized fibrous trabeculae pass into
the tumor and produce a lobular pattern. In many tumors, remnants of the adrenal gland
can be seen, stretched over the surface or attached at one pole. On section, the cut
surfaces of smaller pheochromocytomas are yellow-tan. Larger lesions tend to be
hemorrhagic, necrotic, and cystic and typically efface the adrenal gland. Incubation of
fresh tissue with a potassium dichromate solution turns the tumor a dark brown color
owing to oxidation of stored catecholamines, thus the term chromaffin.
The histologic pattern in pheochromocytoma is quite variable. The tumors are composed
of polygonal to spindle-shaped chromaffin cells or chief cells, clustered with the
sustentacular cells into small nests or alveoli (zellballen) by a rich vascular network
( Fig. 24-56 ). Uncommonly, the dominant cell type is a spindle or small cell; various
144. patterns can be found in any one tumor. The cytoplasm has a finely granular appearance,
best demonstrated with silver stains, owing to the appearance of granules containing
catecholamines. The nuclei are usually round to ovoid, with a stippled "salt and pepper"
chromatin that is characteristic of most neuroendocrine tumors. Electron microscopy
reveals variable numbers of membrane-bound, electron-dense granules, representing
Figure 24-55 Pheochromocytoma. The tumor is enclosed within an attenuated cortex and demonstrates
areas of hemorrhage. The comma-shaped residual adrenal is seen below.
Figure 24-56 Pheochromocytoma demonstrating characteristic nests of cells ("zellballen") with abundant
cytoplasm. Granules containing catecholamine are not visible in this preparation. It is not uncommon to
145. find bizarre cells even in pheochromocytomas that are biologically benign, and this criterion by itself
should not be used to diagnose malignancy.
catecholamines and sometimes other peptides ( Fig. 24-57 ). Immunoreactivity for
neuroendocrine markers (chromogranin and synaptophysin) is present in the chief cells,
while the peripheral sustentacular cells label with S-100, a calcium-binding protein
expressed by a variety of mesenchymal cell types.
The criteria for determining malignancy in pheochromocytomas can be a vexing issue.
There is no single histologic feature that can reliably predict clinical behavior in
pheochromocytomas. Tumors with "benign" histologic features may metastasize, while
bizarrely pleomorphic tumors may remain confined to the adrenal gland. In fact, cellular
and nuclear pleomorphism, including the presence of giant cells, and mitotic figures are
often seen in benign pheochromocytomas, while cellular monotony is paradoxically
associated with an aggressive behavior (see below).
Figure 24-57 Electron micrograph of pheochromocytoma. This tumor contains membrane-bound secretory
granules in which catecholamines are stored (30,000X).
Even capsular and vascular invasion may be encountered in benign lesions. Therefore,
the definitive diagnosis of malignancy in pheochromocytomas is based exclusively
on the presence of metastases. These may involve regional lymph nodes as well as more
distant sites, including liver, lung, and bone. Several histologic features, such as numbers
of mitoses, confluent tumor necrosis, and spindle cell morphology, have been associated
with an aggressive behavior and increased risk of metastasis, but in and of itself, no
single criterion is entirely reliable. 
146. The dominant clinical feature in patients with pheochromocytoma is hypertension.
Classically, this is described as an abrupt, precipitous elevation in blood pressure,
associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of
apprehension. These episodes may also be associated with pain in the abdomen or chest,
nausea, and vomiting. In practice, isolated paroxysmal episodes of hypertension occur in
fewer than half of patients. In about two-thirds of patients, the hypertension occurs in the
form of chronic, sustained elevation in blood pressure, although an element of labile
hypertension is also present. The paroxysms may be precipitated by emotional stress,
exercise, changes in posture, and palpation in the region of the tumor. The elevations of
pressure are induced by the sudden release of catecholamines that may acutely precipitate
congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation,
and cerebrovascular accidents. The cardiac complications have been attributed to what
has been called catecholamine cardiomyopathy, or catecholamine-induced myocardial
instability and ventricular arrhythmias. Nonspecific myocardial changes, such as focal
necrosis, mononuclear infiltrates, and interstitial fibrosis, have been attributed to
ischemic damage secondary to the catecholamine-induced vasomotor constriction of the
myocardial circulation or to direct catecholamine toxicity. In some cases,
pheochromocytomas secrete other hormones, such as ACTH and somatostatin, and may
therefore be associated with clinical features related to the secretion of these or other
The laboratory diagnosis of pheochromocytoma is based on the demonstration of
increased urinary excretion of free catecholamines and their metabolites, such as
vanillylmandelic acid (VMA) and metanephrines. Isolated benign tumors are treated with
surgical excision, after preoperative and intraoperative medication of patients with
adrenergic-blocking agents to prevent a hypertensive crisis. Multifocal lesions require
long-term medical treatment for hypertension.
TUMORS OF EXTRA-ADRENAL PARAGANGLIA
Pheochromocytomas that develop in paraganglia other than the adrenal medulla are often
designated paragangliomas. Paragangliomas may arise in any organ that contains
paraganglionic tissue. Tumors arising in the carotid body are designated carotid body
tumors, whereas those originating in the jugulotympanic body are sometimes referred to
as chemodectomas because these paraganglia sense the oxygen and carbon dioxide levels
of the blood. The carotid body tumor is a typical paraganglioma, forming a palpable mass
in the neck enveloping the carotid vessels. Paragangliomas are uncommon and occur
about one tenth as frequently as adrenal pheochromocytomas. They are described in
Chapter 16 .
Neuroblastoma is the most common extracranial solid tumor of childhood. These
neoplasms occur most commonly during the first 5 years of life and may arise during
infancy. Neuroblastomas may occur anywhere in the sympathetic nervous system and
occasionally within the brain, but they are most common in the abdomen; most cases
arise in either the adrenal medulla or the retroperitoneal sympathetic ganglia. Most
147. neuroblastomas are sporadic, although familial cases also occur. These tumors were
discussed in Chapter 10 , along with other pediatric neoplasms.
Multiple Endocrine Neoplasia Syndromes
The multiple endocrine neoplasia (MEN) syndromes are a group of genetically inherited
diseases resulting in proliferative lesions (hyperplasia, adenomas, and carcinomas) of
multiple endocrine organs. Like other inherited cancer disorders ( Chapter 7 ), endocrine
tumors arising in the context of MEN syndromes have certain distinct features that
contrast with their sporadic counterparts:
• These tumors occur at a younger age than sporadic cancers.
• They arise in multiple endocrine organs, either synchronously (at the same time)
or metachronously (at different times).
• Even in one organ, the tumors are often multifocal.
• The tumors are usually preceded by an asymptomatic stage of endocrine
hyperplasia involving the cell of origin of the tumor. For example, patients with
MEN-1 syndrome develop varying degrees of islet cell hyperplasia, some of
which progress to pancreatic tumors.
• These tumors are usually more aggressive and recur in a higher proportion of
cases than do similar endocrine tumors that occur sporadically.
The salient features of the MEN syndromes are summarized in Table 24-12 and discussed
MULTIPLE ENDOCRINE NEOPLASIA, TYPE 1
MEN-1, or Wermer syndrome, is a rare heritable disorder with a prevalence of about 2
per 100,000. It is characterized by abnormalities involving the parathyroid, pancreas,
and pituitary glands; thus the mnemonic device, the 3Ps:
• Parathyroid: Primary hyperparathyroidism is the most common manifestation of
MEN-1 (80% to 95% of patients) and is the initial manifestation of the disorder in
most patients, appearing in almost all patients by age 40 to 50. Parathyroid
abnormalities include both hyperplasia and adenomas. Hyperplasias arising in the
context of MEN-1 are monoclonal.
• Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity
and mortality in MEN-1 patients. These tumors are usually aggressive and often
present with metastatic disease. It is not uncommon to find multiple
148. "microadenomas" scattered throughout the pancreas in conjunction with one or
two dominant lesions. Pancreatic endocrine tumors are often functional; however,
since pancreatic polypeptide is the most commonly secreted product, these tumors
might not be accompanied by an endocrine hypersecretion syndrome. Among
symptomatic pancreatic tumors, gastrinomas associated with Zollinger-Ellison
syndrome and insulinomas associated with hypoglycemia and neurologic
manifestations are the most common subtypes.
• Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a
prolactinoma; some patients develop acromegaly from somatotrophin-secreting
• The spectrum of this disease has been expanded beyond the 3Ps. The duodenum
is the most common site of gastrinomas in individuals with MEN-1 (far in excess
of the frequency of pancreatic gastrinomas), and synchronous duodenal and
pancreatic tumors may be present in the same individual. In addition, carcinoid
tumors, thyroid and adrenocortical adenomas, and lipomas are more frequent than
in the general population.
TABLE 24-12 -- Multiple Endocrine Neoplasia (MEN) Syndromes
MEN-1 MEN-2A MEN-2B
Parathyroid Hyperplasia ++ Hyperplasia +
Pancreatic islets Hyperplasia ++
Adrenal Cortical Pheochromocytoma + Pheochromocytoma +++
Thyroid C-cell hyperplasia +++ C-cell hyperplasia +++
Medullary carcinoma Medullary carcinoma +++
Mutant gene MEN1 RET RET
Relative frequency: +, uncommon; +++, common.
149. MEN-1 syndrome is caused by germ-line mutations in the MEN1 gene at 11q13. This
gene encodes a 610-amino acid product known as menin, which localizes primarily to the
nucleus. MEN1 is a classic tumor suppressor gene ( Chapter 7 ) in that both alleles are
inactivated in the MEN-1-associated tumors. The precise role of menin in tumor
suppression remains elusive, although recent studies have shown that it may be important
in regulating the cell cycle and transcription.
The dominant clinical manifestations of MEN-1 are usually defined by the peptide
hormones that are overproduced and include such abnormalities as recurrent
hypoglycemia due to insulinomas, intractable peptic ulcers in patients with Zollinger-
Ellison syndrome, nephrolithiasis caused by PTH-induced hypercalcemia, or symptoms
of prolactin excess from a pituitary tumor. As expected, malignant behavior by one or
more of the endocrine tumors arising in these patients is often the proximate cause of
MULTIPLE ENDOCRINE NEOPLASIA, TYPE 2
MEN-2 is subclassified into three distinct syndromes: MEN-2A, MEN-2B, and familial
medullary thyroid cancer.
• MEN-2A, or Sipple syndrome, is characterized by pheochromocytoma,
medullary carcinoma, and parathyroid hyperplasia. Medullary carcinomas of the
thyroid occur in almost 100% of patients. They are usually multifocal and are
virtually always associated with foci of C-cell hyperplasia in the adjacent thyroid.
The medullary carcinomas may elaborate calcitonin and other active products and
are usually clinically aggressive. Forty per cent to 50% of patients with MEN-2A
have pheochromocytomas, which are often bilateral and may arise in extra-
adrenal sites. As in the case of pheochromocytomas in general, they may be
benign or malignant. Ten per cent to 20% of patients have parathyroid hyperplasia
and evidence of hypercalcemia or renal stones. MEN-2A is clinically and
genetically distinct from MEN-1 and has been linked to germ-line mutations in
the RET (rearranged during transfection) protooncogene on chromosome 10q11.2.
As was noted earlier, the RET protooncogene is a receptor tyrosine kinase that
binds glialderived neurotrophic factor (GDNF) and other ligands in the GDNF
family and transmits growth and differentiation signals ( Chapter 7 ). Loss of
function mutations in RET result in intestinal aganglionosis and Hirschsprung
disease ( Chapter 17 ). In contrast, in MEN-2A (as well as in MEN-2B), germ-line
mutations constitutively activate the RET receptor, resulting in gain of function.
This scenario is different from most other inherited predispositions to neoplasia,
which are due to heritable loss of function mutations that inactivate tumor-
suppressor proteins ( Chapter 7 ).
• MEN-2B has significant clinical overlap with MEN-2A. Patients develop
medullary thyroid carcinomas, which are usually multifocal and more aggressive
than in MEN-2A, and pheochromocytomas. However, unlike in MEN-2A,
primary hyperparathyroidism is not present. In addition, MEN-2B is accompanied
150. by neuromas or ganglioneuromas involving the skin, oral mucosa, eyes,
respiratory tract, and gastrointestinal tract, and a marfanoid habitus, with long
axial skeletal features and hyperextensible joints. A single amino acid change in
RET (RETMet918Thr ), distinct from the
mutational spectra that are seen in MEN-2A, appears to be responsible for
virtually all cases of MEN-2B and affects a critical region of the tyrosine kinase
catalytic domain of the protein. 
• Familial medullary thyroid cancer is a variant of MEN-2A, in which there is a
strong predisposition to medullary thyroid cancer but not the other clinical
manifestations of MEN-2A or MEN-2B. A substantial majority of cases of
medullary thyroid cancer are sporadic, but as many as 20% may be familial.
Familial medullary thyroid cancers develop at an older age than those occurring in
the full-blown MEN-2 syndrome and follow a more indolent course.
In contrast to MEN-1, in which the long-term benefit of early diagnosis via genetic
screening is not well established, diagnosis via screening of at-risk family members in
MEN-2A kindred is important because medullary thyroid carcinoma is a life-threatening
disease that can be prevented by early thyroidectomy. Prior to the advent of genetic
testing, family members of patients with the MEN-2 syndrome were screened with
annual biochemical tests, which often lacked sensitivity. Now, routine genetic testing
identifies RET mutation carriers earlier and more reliably in MEN-2 kindred; all
individuals carrying germ-line RET mutations are advised to undergo prophylactic
thyroidectomy to prevent the inevitable development of medullary carcinomas.
The rarity of clinically significant lesions (virtually only tumors) justifies brevity in the
consideration of the pineal gland. It is a minute, pinecone-shaped organ (hence its name),
weighing 100 to 180 mg and lying between the superior colliculi at the base of the brain.
It is composed of a loose, neuroglial stroma enclosing nests of epithelial-appearing
pineocytes, cells with photosensory and neuroendocrine functions (hence the designation
of the pineal gland as the "third eye"). Silver impregnation stains reveal that these cells
have long, slender processes reminiscent of primitive neuronal precursors intermixed
with the processes of astrocytic cells.
All tumors involving the pineal are rare; most (50% to 70%) arise from sequestered
embryonic germ cells. They most commonly take the form of so-called germinomas,
resembling testicular seminoma ( Chapter 21 ) or ovarian dysgerminoma ( Chapter 22 ).
Other lines of germ cell differentiation include embryonal carcinomas; choriocarcinomas;
mixtures of germinoma, embryonal carcinoma, and choriocarcinoma; and, uncommonly,
typical teratomas (usually benign). Whether to characterize these germ cell neoplasms as
pinealomas is still a subject of debate, but most "pinealophiles" favor restricting the term
pinealoma to neoplasma arising from the pineocytes.
These neoplasms are divided into two categories, pineoblastomas and pineocytomas,
based on their level of differentiation, which, in turn, correlates with their neoplastic
Pineoblastomas are encountered mostly in the first two decades of life and appear as
soft, friable, gray masses punctuated with areas of hemorrhage and necrosis. They
typically invade surrounding structures, such as the hypothalamus, midbrain, and lumen
of the third ventricle. Histologically, they are composed of masses of pleomorphic cells
two to four times the diameter of an erythrocyte. Large hyperchromatic nuclei appear to
occupy almost the entire cell, and mitoses are frequent. The cytology is that of primitive
embryonal tumor ("small blue cell neoplasm") similar to medulloblastoma ( Chapter
28 ) or retinoblastoma ( Chapter 29 ).
Pineoblastomas, like medulloblastomas, tend to spread via the cerebrospinal fluid. As
might be expected, the enlarging mass may compress the aqueduct of Sylvius, giving rise
to internal hydrocephalus and all its consequences. Survival beyond 1 or 2 years is rare.
In contrast, pineocytomas occur mostly in adults and are much slower-growing than
pineoblastomas. They tend to be well-circumscribed, gray, or hemorrhagic masses that
compress but do not infiltrate surrounding structures. Histologically, the tumors may be
pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation.
The tumors are composed largely of pineocytes having darkly staining, round-to-oval,
fairly regular nuclei. Necrosis is unusual, and mitoses are virtually absent. The neoplastic
cells resemble normal pineocytes in their strong immunoreactivity for neuro-specific
enolase and synaptophysin. Particularly distinctive are the pineocytomatous
pseudorosettes rimmed by rows of pineocytes. The centers of these rosettes are filled
with eosinophilic cytoplasmic material representing tumor cell processes. These cells are
set against a background of thin, fibrovascular, anastomosing septa, which confer a
lobular growth pattern to the tumor. Glial and retinal differentiation is detectable by
immunoreactivity for glial fibrillary acidic protein and retinal S-antigen, respectively.
The clinical course of patients with pineocytomas is prolonged, averaging 7 years. The
manifestations are the consequence of their pressure effects and consist of visual
disturbances, headache, mental deterioration, and sometimes dementia-like behavior. The
lesions being located where they are, it is understandable that successful excision is at
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