Chapter 24 Flashcards

Question

How is oxytocin released

Answer 1

Dilation of the cervix in pregnancy releases it leading to contraction of the uterine smooth muscle, facilitating parturition Nipple stimulation -in postnatal period acts on the smooth muscles surrounding the lactiferous ducts of the mammary gland and facilitates lactation.

Answer 2

Induce labor

Answer 3

Conserve water by restricting diuresis during periods of dehydration and hypovolemia.

Answer 4

Decreased bp sensed by baroreceptors in cardiac atria and carotids Increase in plasma osmotic pressure detected by osmoreceptors also triggers ADH secretion.

Answer 5

Hypovolemia and increased atrial distention result in inhibition

Answer 6

Excess, defiency, mass effects

Answer 7

Arising form excess secretion of tropical hormones

Answer 8

Pituitary adenoma, hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by nonpituitary tumors and certain hypothalamic disorders

Answer 9

Arising from defiency of tropical hormones.

Answer 10

Destructive processes, including ischemic injury, surgery or radiation, inflammatory reactions, and nonfunctional pituitary adenomas

Answer 11

Among the earliest changes referable to mass effects are radiographically abnormalities of the sella turcica, including stellar expansion, bony erosion, and disruption of diaphragma sella.

Answer 12

Decussating fibers int he optic chiasm ....visual field abnormalities, usually bitemporal hemianopsia (both lateral fields) Can get other from asymmetrical growth of tumors

Answer 13

Elevated intracranial pressure, HA, nausea vomiting

Answer 14

Associated with clincial evidence of rapid enlargement of the lesion, a situation called pituitary apoplexy NEUROSURGICAL EMERGENCY, can cause sudden death

Answer 15

Increase or decreased secretion of ADH

Answer 16

Adenoma arising int he anterior lobe

Answer 17

Benign tumors are classified on the basis of the hormones that are produced by the neoplastic cells, which are detected by immunohistochemical stains

Answer 18

GH and prolactin most common combo

Answer 19

Hormone excess and clincial manifestations

Answer 20

Without clincial symtpoms of hormone excess

Answer 21

Pituitary carcinomas and some hypothalamic disorders. Large pituitary adenomas, and particularly nonfunctioning ones, may cause hypopituitarism by encroaching on and destroying the adjacent pituitary parenchyma

Answer 22

Prolactin Lactotroph adenoma, silent lactotroph adenoma Galactorrhea and amenorrhea ( in females) sexual dysfunction, infertility

Answer 23

GH Densely granulated somatotroph adenoma, sparsely granulated somatotroph adenoma, silent somatotroph adenoma Gigantism (children) acromegaly (adult)

Answer 24

Prolactin GH Mammosomatotroph adenomas Combined features of GH and prolactin excess

Answer 25

ACTH and other POMC derived peptides Densely granulated corticotroph adenoma, sparsely granulated corticotroph adenoma, silent corticotroph adenoma Cushing syndrome, Nelson syndrome

Answer 26

TSH Thyrotroph adenomas Silent thyrotroph Adenomas Hyperthyroidism

Answer 27

FSH LH Gonadotroph adenomas Silent gonadotroph Adenomas (null cell) Hypogonadism, mass effects, and hypopituitarism

Answer 28

Express corresponding hormones within the neoplastic cells, as determined by special immunohistochemical staining on tissues. However do not produce the associated clinical syndrome, and present with mass effects accompanied by hypopituitarism due to destruction of normal pituitary parenchyma. These features are particularly common with gonadotroph adenomas

Answer 29

Less than 1 cm

Answer 30

Over 1 cm in diameter 14% of population most ae clinically silent macroadenomas (pituitary incidentaloma)

Answer 31

Later stage than endocrine abnormalities and are more likely to be macroadenomas

Answer 32

G protein mutations

Answer 33

Gs , the a subunit is encoded by the GNAS gene, located on chromosome 20q13

Answer 34

GHRH, TSH, PTH, Has a, b and y subunit Activate AC increase cAMP to proliferate, synthesize hormones and secretion

Answer 35

Inactive with GDP bound to the guanine nucleotide binding site of Gsa

Answer 36

GDP dissociates and GTP binds to Gsa, activating the G protein

Answer 37

Results in the generation of cAMP, which is a potent mitogen for a variety of endocrine cell types , promoting cellular proliferation and hormone synthesis and secretion

Answer 38

Bc an intrinsic GTPase activity in the a subunit, which hydrolyzes GTP into GDP

Answer 39

Somatotroph

Answer 40

Their respective hypothalamic release hormones do not act via cAMP dependent pathways

Answer 41

Sporadic 5% are inherited

Answer 42

MEN1, CDKN1B, PRKAR1A and AIP -not in sporadic

Answer 43

Overexpression of cyclin D1, mutations of TP53, and epigenetic silencing of the retinoblastoma gene (RB) -HRAS activating in pituitary carcinomas

Answer 44

Soft, well circumscribed Small adenomas may be confined to the sella turcica, but with expansion they frequently erode the sella turcica and anterior Clinic processes. Larger 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 CN.

Answer 45

Adenomas ae not grossly encapsulated and infiltrate neighboring tissues such as the cavernous and sphenoid sinuses, sure, and on occasion, the brain itself

Answer 46

Foci of hemorrhage or necrosis

Answer 47

Uniform, polygonal cells arrayed in sheets or cords. Supporting CT, or reticulum is sparse, accounting for the soft gelatinous consistency of many of these tumors. Little mitosis Cytoplasm is acidophilus, basophils, or chromophobe depending not he type and amount of secretory product within the cells, but is generally uniform throughout the tumor

Answer 48

Cellular monomorphism and absence of a significant reticulin network

Answer 49

Correlated with the presence of TP53 mutations. These tumors have a higher propensity for aggressive behavior including invasion and recurrence and are termed ATYPICAL ADENOMAS

Answer 50

Encodes for alpha subunit of stimulators G protein, Gsa. Oncogene mutation of GNAS constitutively activates Gsa, leading to upregulation of intracellular cyclic AMP (cAMP) activity

Answer 51

Activating mutation most common in GN adenomas

Answer 52

Encodes for a negative regulator of protein kinase a (PKA), a downstream mediator of cAMP signaling. Loss of PKA regulation leads to inappropriate cAMP activity

Answer 53

Germline inactivating mutations of PRKARIA are present in AD carney complex GH and prolactin adenomas

Answer 54

Cell cycle regulatory protein promotes G1-A transition

Answer 55

Overexpression Aggressive adenomas

Answer 56

Ras regulates multiple concogenic pathways including proliferation, cell survival and metabolism

Answer 57

Activativating mutation Pituitary carcinomas

Answer 58

MEN1 encodes for menin, a protein with protean roles in tumor suppression, includingrepression of oncogenic transcription factor JunD, and in histone modification

Answer 59

Germline inactivating mutations of CDKN1B (MEN1 like syndrome) ACTH adenomas

Answer 60

Receptor for Arya hydrocarbons and a ligand activated transcription factor

Answer 61

Germline mutations of AIP cause pituitary adenoma predisposition (PAP) syndrome GH adenomas (espicially in patients younger than 35 years old)

Answer 62

Retinoblastoma protein is a negative regulator of the cell cycle

Answer 63

Methylation of RB gene promoter Aggressive adenomas

Answer 64

Related to endocrine abnormalities and mass effects.

Answer 65

Radiographically abnormalities of the sella turcica, visual field abnormalities, signs and symtpoms of elevated ICP, and hypopituitarism Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy as noted earlier

Answer 66

Prolactin secreting lactotroph adenomas are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized cases . These lesions range from small macroadenomas to large, expansive tumors associated with substantial mass effect

Answer 67

Chromophobe cells with juxtanuclear localization of transcription factor PIT-1; these are known as sparsely granulated lactotroph adenomas Much rarer are the acidophilus densely granulated lactotroph adenomas, characterized by diffuse cytoplasmic PIT-1 expression localization Prolactin can be seen with stain Lactotroph adenomas have a propensity to undergo dystrophic calcification of virtually the entire tumor mass Prolactin secretion by functioning adenomas is usually efficient and proportional in that serum prolactin concentrations tend to correlate with the size of the adenoma

Answer 68

Size of adenoma

Answer 69

Amenorrhea, glactorrhea, loss of libido, infertility.

Answer 70

More readily in women espicially between 20-40, presumably bc of the sensitivity of messes to disruption o fhyperprolactinemia. Lactotroph adenoma underlies almost a quarter of cases of amenorrhea. In contrast, in men and older women, the hormonal manifestations may be subtle, allowing the tumors to reach considerable size before being detected CLINCIALLY

Answer 71

Physiologic hyperprolactinemia in pregnancy Nipple stimulation, as occurs during suckling in lactating women and as a response to. Many types of stress Lactotroph hyperplasia cause by loss of dopamine mediated inhibiton of prolactin secretion -with damage of the dopaminergi neurons of the hypothalamus, damage of the pituitary stalk may disturb the normal inhibitors influence of the hypothalamus on prolactin secretion, resulting in hyperprolactinemia. Therefore, a mild elevation ins drum prolactin in a person with a pituitary adenoma does not necessarily indicate a prolactin secreting tumor. Renal failure and hypothyroidism

Answer 72

Surgery or bromocriptine, a dopamine receptor agonist that causes the lesions to diminish in size

Answer 73

GH secreting somatotroph adenomas are the second most common type of functioning pituitary adenoma, and cause gigantism in children and acromegaly in adults

Answer 74

Manifestations of excessive GH may be subtle

Answer 75

Densely granulated and sparsely granulated subtypes

Answer 76

Monomorphic, acidophilus cells that have strong cytoplasmic GH reactivity on immunohistochemical you.

Answer 77

Composed of chromophobe cells with considerable nuclear and cytologic pleomorphism and focal, weak staining for GH

Answer 78

May synthesize both GH and prolactin are being increasingly recognized -have reactivity for prolactin as well as GH

Answer 79

Persistently elevated GH stimulate the hepati secretion of insulin like growth factor 1 which causes many of the clincial manifestations

Answer 80

The elevated levels of GH results in gigantism | -increase in body size with disproportionately long arms and legs

Answer 81

Acromegaly -growth is most conscious in skin and soft tissues, viscera, and the bones of the face, hands and feet Bone density ma increase (hyperostosis) in both the spine and the hips Enlargement of jaw results in its protrusion (prognathism) and broadening of the lower face Feet and hand enlarge and fingers are sausage like Acromegaly as well Slowly over time allowing adenoma to reach big sister

Answer 82

Gonadal dysfunction, DM, muscle weakness, HTN, arthritis, CHF, and increased risk of GI cancer

Answer 83

Document elevated serum GH and IGF-1 levels Failure to suppress GH production in response to an oral load of glucose is one of the most sensitive tests for acromegaly

Answer 84

Surgery or treated via pharmacology (somatostatin which inhibits secretion of GH) or gh receptor antagonists

Answer 85

Yup and metabolic abnormalities improve

Answer 86

Excess production of ACTH by functioning corticotroph adenomas leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (Cushing)

Answer 87

Micro at diagnosis Basophils (densely granulated) but occasionally chromophobe cells 9sparsely granulated). Both variants stain positively with PAS bc of carbohydrate in POMVC, the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivitiy for POMC and its derivatives, including ACHT and B endorphin

Answer 88

Cushing syndrome. (See adrenal) -can be caused by lots of things in addition to pituitary tumor Called Cushing when due to ACTH excess from pituitary

Answer 89

Large destructive pituitary adenomas can develop in patients after surgical removal of the adrenal glands for treatment of cushing -NELSON SYNDROME —-from loss of the inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma. Bc adrenals are absent , hypercortisolism does not develop, and patients present with mass effects due to the pituitary tumor and there can be hyperpigmentation bc of the stimulators effect of other products of the catch precursor molecule on melanocytes

Answer 90

LH and FS producing

Answer 91

Secrete hormones inefficiently and variably and the secretory products usually do not cause a recognizable clincial syndrome (nonfunctioning adenoma)

Answer 92

Middle aged men and women when large enough to cause neurologic symptoms, such as impaired vision, HA, diploid or pituitary apoplexy Or pituitary hormone defiencies (impaired LH)-decrease libido in men and amenorrhea in premenopausal women.

Answer 93

Demonstrate immunoreactivity for the common gonadotropin a subunit and the specific b-fsh and b-lh subunits; fsh is usually the predominant secreted hormone. Gonadotroph adenomas usually express steroidogenic factor-1 (SF-1) and GATA-2, transcription factors associated with normal gonadotroph differentiation

Answer 94

TSH-producing) adenomas are uncommon, accounting for approximately 1% of all pituitary adenomas. Thyrotroph adenomas are a rare cause of hyperthyroidism

Answer 95

s are a heterogeneous group that constitutes approximately 25% to 30% of all pituitary tumors. Their lineage can be established by immunohistochemical staining for hormones or by biochemical demonstration of cell type-specific transcription factors. In the past, many such tumors have been called silent variants or null-cell adenomas . Not surprisingly, nonfunctioning adenomas typically present with symptoms stemming from mass effects. These lesions may also compromise the residual anterior pituitary sufficiently to cause hypopituitarism, which may appear slowly due to gradual enlargement of the adenoma or abruptly because of acute intratumoral hemorrhage (pituitary apoplexy

Answer 96

is rare, accounting for less than 1% of pituitary tumors. The presence of craniospinal or systemic metastases is a sine qua non of a pituitary carcinoma. Most pituitary carcinomas are functional, with prolactin and ACTH being the most common secreted products. Metastases usually appear late in the course, following multiple local recurrences

Answer 97

Anterior lobe pituitary adenoma

Answer 98

▪ The two distinctive morphologic features of most adenomas are their cellular monomorphism and absence of a reticulin network

Answer 99

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 later) is almost always of hypothalamic origin .

Answer 100

Tumors and other mass lesions Traumatic brain injury and subarachnoid hemorrhage Pituitary surgery or radiation Pituitary apoplexy Ischemic necrosis of the pituitary and Sheehan syndrome Rather cleft cyst Empty sella syndrome Hypothalamus lesions Inflammatory disorders Genetic defects

Answer 101

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

Answer 102

A re among the most common causes of pituitary hypofunction

Answer 103

Surgical excision of a pituitary adenoma may inadvertently extend to the nonadenomatous pituitary. Radiation of the pituitary, used to prevent regrowth of residual tumor after surgery, can damage the nonadenomatous pituitary

Answer 104

As mentioned earlier, this is caused by 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 due to pressure on the oculomotor nerves, and hypopituitarism. In severe cases, it can cause cardiovascular collapse, loss of consciousness, and even sudden death. The combination of mass effects from the hemorrhage and the acute hypopituitarism makes pituitary apoplexy a true neurosurgical emergency

Answer 105

Sheehan syndrome, also known as 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 hypoxia. Any further reduction in blood supply caused by obstetric hemorrhage or shock may precipitate infarction of the anterior lobe. Because the posterior pituitary receives its blood directly from arterial branches, it is much less susceptible to ischemic injury 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.

Answer 106

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

Answer 107

Any condition or treatment 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 and the empty sella syndrome . There are two types: (1) In a primary empty sella, a defect in the diaphragma sella allows the arachnoid mater and cerebrospinal fluid to herniate into the sella, expanding the sella and compressing the pituitary. Classically, this occurs in obese women with a history of multiple pregnancies. Affected individuals often present with visual field defects and occasionally with endocrine anomalies, such as hyperprolactinemia , due to interruption of inhibitory hypothalamic inputs. Sometimes the loss of functioning parenchyma is sufficient to produce hypopituitarism. (2) In secondary empty sella, a mass, such as a pituitary adenoma, enlarges the sella and is then either surgically removed or undergoes infarction, leading to loss of pituitary function

Answer 108

: As mentioned earlier, hypothalamic lesions can also affect the pituitary by interfering with the delivery of pituitary hormone-releasing factors. In contrast to diseases that involve the pituitary directly, hypothalamic abnormalities can also diminish the secretion of ADH, resulting in diabetes insipidus (discussed later). Hypothalamic lesions that cause hypopituitarism include tumors , which may be benign (e.g., craniopharyngioma) or malignant; most of the latter are metastases from tumors such as breast and lung carcinoma. Hypothalamic insufficiency can also appear following irradiation of brain or nasopharyngeal tumors

Answer 109

such as sarcoidosis or tuberculous meningitis, can involve the hypothalamus and cause deficiencies of anterior pituitary hormones and diabetes insipidus

Answer 110

Congenital deficiency of transcription factors required for normal pituitary function is a rare cause of hypopituitarism. For example, mutation of the pituitary-specific gene PIT-1 results in combined pituitary hormone deficiency, characterized by deficiencies of GH, prolactin, and TSH

Answer 111

• Children can develop growth failure (pituitary dwarfism) due to growth hormone deficiency

Answer 112

onadotropin (LH and FSH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men

Answer 113

• TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter

Answer 114

• Prolactin deficiency results in failure of postpartum lactation

Answer 115

• The anterior pituitary is also a rich source of 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 melanocytes

Answer 116

The clinically relevant posterior pituitary syndromes involve ADH and include diabetes insipidus and secretion of inappropriately high levels of ADH

Answer 117

Diabetes insipidus can occur in a variety of conditions, including head trauma, tumors, inflammatory disorders of the hypothalamus and pituitary, and surgical complications. The condition can also arise spontaneously, in the absence of an identifiable 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 these two disorders are similar and include the excretion of large volumes of dilute urine with a lower than normal specific gravity. Serum sodium and osmolality are increased by the excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water generally compensate for the urinary losses, but patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration

Answer 118

The most frequent causes of SIADH are the secretion of ectopic ADH by malignant neoplasms (particularly small-cell carcinoma of the lung), drugs that increase ADH secretion, and a variety of central nervous system disorders, including infections and trauma. 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.

Answer 119

Neoplasms in this location may induce hypofunction or hyperfunction of the anterior pituitary, diabetes insipidus, or combinations of these manifestations

Answer 120

Gliomas and craniopharyngiomas

Answer 121

The craniopharyngioma is thought to arise from vestigial remnants of Rathke pouch. These slow-growing tumors account for 1% to 5% of intracranial tumors. A small minority of these lesions occurs within the sella, but most are suprasellar, with or without intrasellar extension. A bimodal age distribution is observed, with one peak in childhood (5 to 15 years) and a second peak in adults 65 years or older. Patients usually come to attention because of headaches and visual disturbances, while children sometimes present with growth retardation due to pituitary hypofunction and GH deficiency.

Answer 122

A bnormalities of the WNT signaling pathway , including activating mutations of the gene encoding β-catenin, have been reported in craniopharyngiomas

Answer 123

Craniopharyngiomas average 3 to 4 cm in diameter; they may be encapsulated and solid, but more commonly they are cystic and sometimes multiloculated. 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

Answer 124

Two distinct histologic variants are recognized: adamantinomatous craniopharyngioma (most often observed in children) and papillary craniopharyngioma (most often observed in adults). The adamantinomatous type frequently contains radiologically demonstrable calcifications; the papillary variant calcifies only rarely.

Answer 125

Adamantinomatous craniopharyngioma consists of nests or cords of stratified squamous epithelium embedded in a spongy “reticulum” that becomes more prominent in the internal layers. “Palisading” of the squamous epithelium is frequently observed at the periphery. Compact, lamellar keratin formation (“wet keratin”) is a diagnostic feature of this tumor ( Fig. 24-7 ). As mentioned earlier, dystrophic calcification is a frequent finding. Additional features include cyst formation, fibrosis, and chronic inflammation. The cysts of adamantinomatous craniopharyngiomas often contain a cholesterol-rich, thick brownish-yellow fluid that has been compared to “machine oil.” These tumors extend fingerlets of epithelium into adjacent brain, where they elicit a brisk glial reaction

Answer 126

Papillary craniopharyngiomas 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 lack the peripheral palisading and do not typically generate a spongy reticulum in the internal layers

Answer 127

Patients with craniopharyngiomas, especially those less than 5 cm in diameter, have an excellent recurrence-free and overall survival. Larger lesions are more invasive but this does not impact on the prognosis. Malignant transformation of craniopharyngiomas into squamous carcinomas is exceptionally rare and usually occurs after irradiation

Answer 128

The thyroid gland, usually located below and anterior to the larynx, consists of two bulky lateral lobes connected by a relatively thin isthmus. The thyroid is divided by thin fibrous septae into lobules composed of about 20 to 40 evenly dispersed follicles, lined by a cuboidal to low columnar epithelium, and filled with PAS-positive thyroglobulin. In response to hypothalamic factors, 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 of the receptor, allowing it to associate with a G s protein ( Fig. 24-8 ). Activation of the G protein stimulates downstream events that result in an increase in intracellular cAMP levels, which stimulates thyroid growth and thyroid hormone synthesis and release via cAMP-dependent protein kinases

Answer 129

Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T 4 ) and lesser amounts of triiodothyronine (T 3 ) . T 4 and T 3 are released into the systemic circulation, where most of these peptides are reversibly bound to circulating plasma proteins, such as thyroxine-binding globulin and transthyretin. The binding proteins act as a buffer that maintains the serum unbound (“free”) T 3 and T 4 concentrations within narrow limits, while ensuring that the hormones are readily available to the tissues. In the periphery, the majority of free T 4 is deiodinated to T 3 ; the latter binds to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does T 4 and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor (TR) results in the assembly of a multiprotein hormone-receptor complex on thyroid hormone response elements (TREs) in target genes, up regulating their transcription ( Fig. 24-8 ). Thyroid hormone has diverse cellular effects, including the stimulation of carbohydrate and lipid catabolism and protein synthesis in a wide range of cells. The net result is an increase in the basal metabolic rate. In addition, thyroid hormone has a critical role in brain development in the fetus and neonate (see later

Answer 130

Goitrogens

Answer 131

Because they suppress T 3 and T 4 synthesis, the level of TSH increases, and subsequent hyperplastic enlargement of the gland ( goiter ) follows.

Answer 132

The antithyroid agent propylthiouracil inhibits the oxidation of iodide and thus blocks the production of thyroid hormones; parenthetically, propylthiouracil also inhibits the peripheral deiodination of circulating T 4 into T 3 , thus ameliorating symptoms of thyroid hormone excess (see later). Iodide, when given in large doses to individuals with thyroid hyperfunction, also blocks the release of thyroid hormones by inhibiting the proteolysis of thyroglobulin. Thus, thyroid hormone is synthesized and incorporated into colloid, but it is not released into the blood.

Answer 133

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 osteoclasts

Answer 134

Diseases of the thyroid include conditions associated with excessive release of thyroid hormones (hyperthyroidism), thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. We will first consider the clinical consequences of disturbed thyroid function, and then turn to the disorders that generate these problems

Answer 135

Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T 3 and T 4 . 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 24-3 ). Thus, strictly speaking, hyperthyroidism is only 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, respectively. With this caveat, we follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably

Answer 136

Diffuse hyperplasia of the thyroid associated with Graves disease (approximately 85% of cases) • Hyperfunctional multinodular goiter • Hyperfunctional thyroid adenoma

Answer 137

Diffuse hyperplasia (graves) Hyperfunctioning (toxic) multinodular goiter Hyperfunctioning (toxic) adenoma Iodine-induced hyperthyroidism Neonatal thyrotoxicosis associated with maternal Graves’ disease

Answer 138

TSH secreting pituitary adenoma

Answer 139

Granulomatous (de Quervain) thyroiditis ( painful ) Subacute lymphocytic thyroiditis ( painless ) Struma ovarii (ovarian teratoma with ectopic thyroid) Factitious thyrotoxicosis (exogenous thyroxine intake

Answer 140

The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone and to overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic “tone”

Answer 141

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, adaptations that serve to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Heightened catabolic metabolism results in weight loss despite increased appetite

Answer 142

Individuals with hyperthyroidism can have elevated cardiac contractility and cardiac output, in response to 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, especially in older patients with preexisting cardiac disease. Myocardial changes, such as focal lymphocytic and eosinophilic infiltrates, mild fibrosis, myofibril fatty change, and an increase in size and number of mitochondria, have been described. Some individuals with thyrotoxicosis develop reversible left ventricular dysfunction and “low-output” heart failure, so-called thyrotoxic or hyperthyroid cardiomyopathy

Answer 143

Overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle weakness and decreased muscle mass are common (thyroid myopathy) . In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, diarrhea, and malabsorption

Answer 144

Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the superior tarsal muscle (also known as Müller's muscle ), which functions alongside the levator palpebrae superioris muscle to raise the upper eyelid ( Fig. 24-9 ). However, true thyroid ophthalmopathy associated with proptosis occurs only in Graves disease (see later).

Answer 145

A person 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

Answer 146

Thyroid hormone stimulates bone resorption, increasing porosity of cortical bone and reducing the volume of trabecular bone. The net effect is osteoporosis and an increased risk of fractures in patients with chronic hyperthyroidism. Other findings 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 and lymphadenopathy in patients with Graves’ disease

Answer 147

Thyroid storm refers to 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 cardiac arrhythmias

Answer 148

refers to thyrotoxicosis occurring in older adults, in whom advanced age and various co-morbidities may blunt the features of thyroid hormone excess that typically bring younger patients to attention. The diagnosis of thyrotoxicosis in these individuals is often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease

Answer 149

A diagnosis of hyperthyroidism is made using both clinical and laboratory findings. The measurement of serum TSH concentration is the most useful single screening test for hyperthyroidism, because 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 T 4 , which is predictably increased. In occasional patients, hyperthyroidism results predominantly from increased circulating levels of T 3 (“T 3 toxicosis”). In these cases, free T 4 levels may be decreased, and direct measurement of serum T 3 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 thyrotropin-releasing hormone (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 TSH assays and free thyroid hormone levels, measurement of radioactive iodine uptake by the thyroid gland can help to determine 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

Answer 150

The therapeutic options for hyperthyroidism include several medications, each with a different mechanism of action. Typically, these include a β-blocker to control symptoms induced by increased adrenergic tone, a thionamide to block new hormone synthesis, an iodine solution to block the release of thyroid hormone, and agents that inhibit peripheral conversion of T 4 to T 3 . 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

Answer 151

Hypothyroidism is a condition caused by a structural or functional derangement that interferes with the production of thyroid hormone. Hypothyroidism is a fairly common disorder

Answer 152

Hypothyroidism is a fairly common disorder. By some estimates the population prevalence of overt hypothyroidism is 0.3%, while subclinical hypothyroidism can be found in greater than 4%. The prevalence increases with age, and it is nearly tenfold more common in women than in men

Answer 153

. 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 forms, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid itself, or occurs as a result of pituitary and hypothalamic disease ( Table 24-4 ). Primary hypothyroidism accounts for the vast majority of cases, and may be accompanied by an enlargement in the size of the thyroid gland (goiter

Answer 154

Congenital, autoimmune, iatrogenic Genetic defects in thyroid development ( PAX8, FOXE1 , TSH receptor mutations) (rare) Thyroid hormone resistance syndrome ( THRB mutations) (rare) Postablative Surgery, radioiodine therapy, or external irradiation Autoimmune hypothyroidism Hashimoto thyroiditis * Iodine deficiency * Drugs (lithium, iodides, p -aminosalicylic acid) * Congenital biosynthetic defect (dyshormonogenetic goiter) (rare)

Answer 155

``` Pituitary failure (rare) Hypothalamic failure (rare ```

Answer 156

Worldwide, congenital hypothyroidism is most often the result of endemic iodine deficiency in the diet (see later). Other rare forms of congenital hypothyroidism include inborn errors of thyroid metabolism (dyshormonogenetic goiter) , wherein any one of the multiple steps leading to thyroid hormone synthesis may be defective, such as (1) iodide transport into thyrocytes, (2) “organification” of iodine (binding of iodine to tyrosine residues of the storage protein, thyroglobulin), and (3) iodotyrosine coupling to form hormonally active T 3 and T 4 . In rare instances there may be complete absence of thyroid parenchyma (thyroid agenesis) , or the gland may be greatly reduced in size (thyroid hypoplasia) due to germline mutations in genes responsible for thyroid development

Answer 157

Autoimmune hypothyroidism is the most common cause of hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-microsomal , antithyroid peroxidase , and antithyroglobulin antibodies, are found in this disorder, and the thyroid is typically enlarged (goitrous). Autoimmune hypothyroidism can occur in isolation or in conjunction with autoimmune polyendocrine syndrome (APS), types 1 and 2 (see discussion in “Adrenal Glands

Answer 158

This can be caused by either surgical or radiation-induced ablation . A large resection of the gland (total thyroidectomy) for the treatment of hyperthyroidism or 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 hyperthyroidism, or exogenous irradiation, such as external radiation therapy to the neck. Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can also cause acquired hypothyroidism, as can agents used to treat nonthyroid conditions (e.g., lithium, p -aminosalicylic acid

Answer 159

Secondary (or central) hypothyroidism is caused by deficiencies of TSH or, far more uncommonly, TRH. Any of the causes of hypopituitarism (for example, pituitary tumor, postpartum pituitary necrosis, trauma, and nonpituitary tumors), or of hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases can cause central hypothyroidism.

Answer 160

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 regions of the world where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. It is now much less prevalent as a result of the widespread supplementation of foods with iodine. On rare occasions, cretinism may also result from genetic defects that interfere with the biosynthesis of thyroid hormone (dyshormonogenetic goiter, see earlier

Answer 161

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 seems to be related to the time at which thyroid deficiency occurs in utero. Normally, maternal T 3 and T 4 cross the placenta and are critical for fetal brain development. If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. In contrast, maternal thyroid hormone deficiency later in pregnancy, after the fetal thyroid has become functional, does not affect normal brain development

Answer 162

The term myxedema is applied to hypothyroidism developing in the older child or adult . Myxedema was first linked with thyroid dysfunction in 1873 by Sir William Gull in an article addressing the development of a “cretinoid state” in adults. The clinical manifestations vary with the age of onset of the deficiency. Older children show 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 before arousing clinical suspicion

Answer 163

Myxedema is marked by a slowing of physical and mental activity . The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic depression. Speech and intellectual functions are slowed. Patients with myxedema are listless, cold intolerant , and frequently overweight. Decreased sympathetic activity results in constipation and decreased sweating. The skin is cool and pale because of decreased blood flow. Reduced cardiac output probably contributes to shortness of breath and decreased exercise capacity, two frequent complaints. Thyroid hormones regulate the transcription of several sarcolemmal genes, such as calcium ATPases and the β adrenergic receptor, and lowered expression of these genes results in a decrease in cardiac output. In addition, hypothyroidism promotes an atherogenic profile—an increase in total cholesterol and low-density lipoprotein (LDL) levels—that probably contributes to the increased cardiovascular mortality in this disease. 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 nonpitting edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice

Answer 164

Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism because of the nonspecific nature of symptoms. Patients with unexplained increases in body weight or hypercholesterolemia should be assessed for potential hypothyroidism. Measurement of the serum TSH level is the most sensitive screening test for this disorder. The TSH level is increased in primary hypothyroidism as a result of a loss of feedback inhibition of TRH and TSH production by the hypothalamus and pituitary, respectively. The TSH level is not increased in persons with hypothyroidism due to primary hypothalamic or pituitary disease. T 4 levels are decreased in individuals with hypothyroidism of any origin.

Answer 165

Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation

Answer 166

Although multiple entities exist under the diagnostic umbrella of “thyroiditis,” this discussion focuses on the three most common and clinically significant subtypes: (1) Hashimoto thyroiditis, (2) granulomatous (de Quervain) thyroiditis, and (3) subacute lymphocytic thyroiditis

Answer 167

Hashimoto thyroiditis is an autoimmune disease that results in destruction of the thyroid gland and gradual and progressive thyroid failure. It is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. The name is derived from the 1912 report by Hashimoto describing patients with goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa) . It 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. It can also occur in children and is a major cause of nonendemic goiter in the pediatric population

Answer 168

Hashimoto thyroiditis is caused by a breakdown in self-tolerance to thyroid autoantigens. This is exemplified by the presence of circulating autoantibodies against thyroglobulin and thyroid peroxidase in the vast majority of Hashimoto patients. The inciting events have not been elucidated, but possibilities include abnormalities of regulatory T cells (Tregs), or exposure of normally sequestered thyroid antigens ( Chapter 6 ). Similar to other autoimmune diseases, Hashimoto thyroiditis has a strong genetic component. Increased susceptibility to Hashimoto thyroiditis is associated with polymorphisms in immune regulation-associated genes, including cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase-22 (PTPN22) , both of which code for regulators of T-cell responses. Susceptibility to other autoimmune diseases, such as type 1 diabetes (see later), is also associated with polymorphisms in both CTLA4 and PTPN22

Answer 169

* CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may destroy thyroid follicular cells. * Cytokine-mediated cell death: Activation of CD4+ T cells leads to the production of inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles. * A less likely mechanism involves binding of antithyroid antibodies (antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity

Answer 170

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. There is extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers ( Fig. 24-11 ). 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 biopsy samples, 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. Unlike Reidel thyroiditis (see later), the fibrosis does not extend beyond the capsule of the gland

Answer 171

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

Answer 172

Hashimoto thyroiditis most often 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 the suspicion of a neoplasm. In the usual case, hypothyroidism develops gradually. In some patients, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, leading to release of thyroid hormones (“ hashitoxicosis ”). During this phase, free T 4 and T 3 levels are elevated, TSH is diminished, and radioactive iodine uptake is decreased. As hypothyroidism supervenes, T 4 and T 3 levels fall, accompanied by a compensatory increase in TSH

Answer 173

Individuals with Hashimoto thyroiditis are at increased risk for developing other autoimmune diseases, both endocrine (type 1 diabetes, autoimmune adrenalitis) and nonendocrine (systemic lupus erythematosus, myasthenia gravis, and Sjögren syndrome; Chapter 6 ). They are also at increased risk for the development of extranodal marginal zone B-cell lymphomas within the thyroid gland ( Chapter 13 ). The relationship between Hashimoto disease and thyroid epithelial cancers remains controversial, with some morphologic and molecular studies suggesting a predisposition to papillary carcinomas

Answer 174

Subacute lymphocytic thyroiditis , which is also referred to as painless thyroiditis , 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. A disease process resembling painless thyroiditis can occur during the postpartum period in up to 5% of women (postpartum thyroiditis) . Painless and postpartum thyroiditides are variants of autoimmune thyroiditis. Most of the patients have circulating antithyroid peroxidase antibodies or a family history of other autoimmune disorders. As many as a third of cases can evolve into overt hypothyroidism over time, and the thyroid histology may resemble Hashimoto thyroiditis

Answer 175

Except for possible mild symmetric enlargement, the thyroid appears grossly normal. Microscopic examination reveals lymphocytic infiltration with large germinal centers within the thyroid parenchyma and patchy disruption and collapse of thyroid follicles. Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell metaplasia are not prominent

Answer 176

Affected individuals may present with a painless goiter, transient overt hyperthyroidism, or both. Some patients transition from hyperthyroidism to hypothyroidism before recovery. As stated, as many as a third of affected individuals eventually progress to overt hypothyroidism over a 10-year period

Answer 177

Granulomatous thyroiditis (also called De Quervain thyroiditis ) occurs much less frequently than does Hashimoto disease. The disorder is most common between the ages of 40 and 50 and, like other forms of thyroiditis, affects women considerably more often than men (4 : 1

Answer 178

Granulomatous thyroiditis is believed to be triggered by a viral infection. 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 infections. Although the pathogenesis of the disease is unclear, one model suggests that it results from a viral infection that leads to exposure to a viral or thyroid antigen 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

Answer 179

The gland may be unilaterally or bilaterally enlarged and firm, with an intact capsule that may adhere 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. Histologic changes are patchy and depend on the stage of the disease. Early in the active inflammatory phase, scattered follicles may be disrupted and replaced by neutrophils forming microabscesses. Later, more characteristic features appear in the form of aggregates of lymphocytes, activated macrophages, and plasma cells associated with collapsed and damaged thyroid follicles. Multinucleate giant cells enclose naked pools or fragments of colloid ( Fig. 24-12 ), 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

Answer 180

Granulomatous thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right

Answer 181

Granulomatous thyroiditis is the most common cause of thyroid pain . There is a variable enlargement of the thyroid. Inflammation of the thyroid and hyperthyroidism are transient, usually diminishing in 2 to 6 weeks, even if the patient is not treated. Nearly all patients have high serum T 4 and T 3 levels and low serum TSH levels during this phase. 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

Answer 182

a rare disorder 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 fibrosis in other sites in the body, such as the retroperitoneum, and appears to be another manifestation of a systemic autoimmune IgG4-related disease, which is associated with fibrosis and tissue infiltration by plasma cells producing IgG4

Answer 183

Hashimoto thyroiditis

Answer 184

▪ Hashimoto thyroiditis is an autoimmune thyroiditis characterized by progressive destruction of thyroid parenchyma, Hürthle cell change, and mononuclear (lymphoplasmacytic) infiltrates, with germinal centers and with or without extensive fibrosis.

Answer 185

bacute lymphocytic thyroiditis often occurs after a pregnancy ( postpartum thyroiditis ), typically is painless, and is characterized by lymphocytic inflammation in the thyroid. It is also a type of autoimmune thyroiditis

Answer 186

▪ Granulomatous (de Quervain) thyroiditis is a self-limited disease, probably secondary to a viral infection, and is characterized by pain and the presence of a granulomatous inflammation in the thyroid

Answer 187

Graves disease is the most common cause of endogenous hyperthyroidism. 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

Answer 188

* Hyperthyroidism associated with diffuse enlargement of the gland * Infiltrative ophthalmopathy with resultant exophthalmos * Localized, infiltrative dermopathy , sometimes called pretibial myxedema , which is present in a minority of patients

Answer 189

Graves disease has a peak incidence between 20 and 40 years of age. Women are affected as much as 10 times more frequently than men . This disorder is said to affect 1.5% to 2% of women in the United States

Answer 190

. A variety of antibodies that can either stimulate or block the TSH receptor are detected in the circulation. The most common antibody subtype, known as thyroid-stimulating immunoglobulin (TSI), is observed in approximately 90% of patients with Graves disease. In contrast to antibodies reactive with thyroglobulin and thyroid peroxidase, TSI is almost never observed in other autoimmune diseases of the thyroid. TSI binds to the TSH receptor and mimics its actions, stimulating adenyl cyclase and increasing the release of thyroid hormones. As stated, some patients also have TSH receptor blocking antibodies in the circulation, and in a minority of patients these may lead to hypothyroidism

Answer 191

Graves disease (hyperthyroidism) and Hashimoto thyroiditis (hypothyroidism) represent two extremes of autoimmune thyroid disorders, and not surprisingly share many underlying features. For example, as with Hashimoto thyroiditis, genetic factors are important in the etiology of Graves disease. The concordance rate in monozygotic twins is 30% to 40%, compared with less than 5% among dizygotic twins, and like Hashimoto thyroiditis, genetic susceptibility is linked to polymorphisms in immune-function genes like CTLA4 and PTPN22 and the HLA-DR3 allele

Answer 192

Autoimmunity also plays a role in the development of the infiltrative ophthalmopathy that is characteristic of Graves disease. In Graves ophthalmopathy, the protrusion of the eyeball (exopthalmos) is associated with increased volume of the retroorbital connective tissues and extraocular muscles, for several reasons. These include (1) marked infiltration of the retroorbital space by mononuclear cells, predominantly T cells; (2) inflammation with edema and swelling of extraocular muscles; (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans 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. Studies performed in animal models suggest that orbital preadipocyte fibroblasts, which express the TSH receptor, appear to stimulate the autoimmune reaction. Activated CD4+ helper T cells secrete cytokines that stimulate fibroblast proliferation and synthesis of extracellular matrix proteins (glycosaminoglycans), leading to progressive infiltration of the retroorbital space and ophthalmopathy

Answer 193

The thyroid gland is usually symmetrically enlarged due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells ( Fig. 24-13 A ). Increases in weight to over 80 gm are not uncommon. On cut section, the parenchyma has a soft, meaty appearance resembling muscle. Histologically, 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. 24-13 B ). Such papillae lack fibrovascular cores, in contrast to those of papillary carcinoma (see later). The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, along with scattered B cells and mature plasma cells, are present throughout the interstitium. Germinal centers are common.

Answer 194

Graves disease. A, There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. Compare with gross photograph of multinodular goiter in Figure 24-15 . B, 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

Answer 195

Preoperative therapy alters the morphology of the thyroid in Graves disease. 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

Answer 196

Changes in extrathyroidal tissue include lymphoid hyperplasia, especially enlargement of the thymus in younger patients. The heart may be hypertrophied, and ischemic changes may be present, particularly in patients with preexisting coronary artery disease. In patients with ophthalmopathy, the 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

Answer 197

The clinical findings in Graves disease include some changes associated with thyrotoxicosis and others associated uniquely with Graves disease, such as 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 enlargement of the thyroid is present in all cases. 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. The basis of such localization is not clear, and it is present only in a minority of patients. Sometimes individuals spontaneously develop thyroid hypofunction. Patients are at increased risk for other autoimmune diseases, such as systemic lupus erythematosus, pernicious anemia, type 1 diabetes, and Addison disease

Answer 198

Laboratory findings in Graves disease include elevated free T 4 and T 3 levels and depressed TSH levels. Because of ongoing stimulation of the thyroid follicles by thyroid-stimulating immunoglobulins, radioiodine scans show a diffusely increased uptake of iodine

Answer 199

Graves disease is treated with β-blockers, which address symptoms related to the increased β-adrenergic tone (e.g., tachycardia, palpitations, tremulousness, and anxiety), and by measures aimed at decreasing thyroid hormone synthesis, such as the administration of thionamides (e.g., propylthiouracil), radioiodine ablation, and thyroidectomy. Surgery is used mostly in patients who have large goiters that are compressing surrounding structures

Answer 200

▪ Graves disease, the most common cause of endogenous hyperthyroidism, is characterized by the triad of thyrotoxicosis, ophthalmopathy, and dermopathy. ▪ Graves disease is an autoimmune disorder caused by activation of thyroid epithelial cells by autoantibodies to the TSH receptor that mimic TSH action ( thyroid-stimulating immunoglobulins ). ▪ The thyroid in Graves disease is characterized by diffuse hypertrophy and hyperplasia of follicles and lymphoid infiltrates; glycosaminoglycan deposition and lymphoid infiltrates are responsible for the ophthalmopathy and dermopathy. ▪ Laboratory features include elevations in serum free T 3 and T 4 and decreased serum TSH

Answer 201

Enlargement of the thyroid, or goiter is caused by impaired synthesis of thyroid hormone, which is most often the result of dietary iodine deficiency

Answer 202

mpairment 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 overcomes the hormone deficiency, ensuring a euthyroid metabolic state in most individuals. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect or endemic iodine deficiency, discussed later), the compensatory responses may be inadequate, resulting in goitrous hypothyroidism . The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. Goiters can broadly be divided into two types: diffuse nontoxic and multinodular

Answer 203

Diffuse nontoxic (simple) goiter causes enlargement of 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

Answer 204

occurs in geographic areas where the soil, water, and food supply contain 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 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, although as many as 200 million people worldwide continue to be at risk for severe iodine deficiency. 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 vegetables belonging to the Brassicaceae (Cruciferae) family (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 deficiency

Answer 205

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 several 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 earlier). In most cases, however, the cause of sporadic goiter is not apparent.

Answer 206

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

Answer 207

As stated earlier, the vast majority of persons with simple goiters are clinically euthyroid. Therefore, the clinical manifestations are primarily related to mass effects from the enlarged thyroid gland ( Fig. 24-14 ). Although serum T 3 and T 4 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

Answer 208

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. Multinodular goiters produce the most extreme thyroid enlargements and are more frequently mistaken for neoplasms 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.

Answer 209

It is believed that multinodular goiters arise because of variations among follicular cells in their response 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, such cells can give rise to clones of proliferating cells. This may result in the formation of a nodule whose continued growth is 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 because of the acquisition of a genetic abnormality favoring growth. Not surprisingly, activating mutations affecting proteins of the TSH-signaling pathway have been identified in a subset of autonomous thyroid nodules (TSH-signaling pathway mutations and their implications are discussed under “Adenomas”). The uneven follicular hyperplasia, generation of new follicles, and accumulation of colloid produce physical stress that may lead to rupture of follicles and vessels followed by hemorrhages, scarring, and sometimes calcifications. With scarring, nodularity appears, which may be accentuated by the preexisting stromal framework of the gland

Answer 210

Multinodular goiters are multilobulated, asymmetrically enlarged glands that can reach weights of more than 2000 gm. The pattern of enlargement is quite unpredictable and 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 stand out, imparting the clinical appearance of a solitary nodule. On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid are present ( Fig. 24-15A ). Older lesions have areas of hemorrhage, fibrosis, calcification, and cystic change. The microscopic appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular hyperplasia , accompanied by degenerative changes related to physical stress. In contrast to follicular neoplasms, a prominent capsule between the hyperplastic nodules and residual compressed thyroid parenchyma is not present

Answer 211

The dominant clinical features of multinodular goiter are those caused by mass effects . In addition to the obvious cosmetic effects, goiters may cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax (superior vena cava syndrome) . Most patients are euthyroid or have subclinical hyperthyroidism (identified only by reduced TSH levels), but in a substantial minority of patients an autonomous nodule may develop within a long-standing goiter and produce hyperthyroidism (toxic multinodular goiter) . This condition, known as Plummer syndrome , is not accompanied by the infiltrative ophthalmopathy and dermopathy of Graves disease. It is estimated that clinically apparent autonomous nodules develop in approximately 10% of multinodular goiters over a 10-year follow-up. The incidence of malignancy in long-standing multinodular goiters is low (<5%) but not zero, and concern for malignancy arises in goiters that demonstrate sudden changes in size or symptoms (e.g., hoarseness). Dominant nodules in a multinodular goiter can present as a “solitary thyroid nodule”, mimicking a thyroid neoplasm. A radioiodine scan demonstrates uneven iodine uptake (including the occasional “hot” autonomous nodule) consistent with the diffuse parenchymal involvement, and an admixture of hyperplastic and involuting nodules. A fine-needle aspiration biopsy is helpful and can often, albeit not always, facilitate the distinction of follicular hyperplasia from a thyroid neoplasm (see later

Answer 212

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%, but 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

Answer 213

From a clinical standpoint, the major concern in persons who present with thyroid nodules is the possibility of a malignant neoplasm. Fortunately, the overwhelming majority of solitary nodules of the thyroid prove to be localized, nonneoplastic lesions (e.g., a dominant nodule in multinodular goiter, simple cysts, or foci of thyroiditis) or benign neoplasms such as follicular adenoma. In fact, benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10 : 1 . While less than 1% of solitary thyroid nodules are malignant, this still represents about 15,000 new cases of thyroid carcinoma per year in the United States. Fortunately, most of these cancers are indolent; more than 90% of affected patients are alive 20 years after being diagnosed

Answer 214

• Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules.

Answer 215

• Nodules in younger patients are more likely to be neoplastic than are those in older patients

Answer 216

• Nodules in males are more likely to be neoplastic than are those in females.

Answer 217

• A history of radiation treatment to the head and neck region is associated with an increased incidence of thyroid malignancy

Answer 218

• Functional nodules that take up radioactive iodine in imaging studies (hot nodules) are much more likely to be benign than malignant

Answer 219

These associations and statistics, however, are of little comfort to a patient, in whom the timely recognition of a malignancy can be lifesaving. Ultimately, morphologic evaluation of a given thyroid nodule, by fine-needle aspiration and surgical resection, provides the most definitive information about its nature. The following sections consider the major thyroid tumors, including adenoma and carcinoma in its various forms

Answer 220

Adenomas of the thyroid are typically discrete, solitary masses, derived from follicular epithelium, and hence they are also known as follicular adenomas . Clinically, follicular adenomas can be difficult to distinguish from dominant nodules of follicular hyperplasia or from the less common follicular carcinomas. In general, follicular adenomas are not forerunners to carcinomas; nevertheless, shared genetic alterations support the possibility that at least of subset of follicular carcinomas arises in preexisting adenomas (see later). Although the vast majority of adenomas are nonfunctional, a small subset produces thyroid hormones and causes clinically apparent thyrotoxicosis. Hormone production in functional adenomas (“toxic adenomas”) is independent of TSH stimulation.

Answer 221

Somatic mutations of the TSH receptor signaling pathway are found in toxic adenomas, as well as in toxic multinodular goiter. Gain-of-function mutations in one of two components of this signaling system—most often the gene encoding the TSH receptor (TSHR) or the α-subunit of G s ( GNAS )—cause follicular cells to secrete thyroid hormone independent of TSH stimulation (“thyroid autonomy”). This leads to symptoms of hyperthyroidism and produces a functional “hot” nodule on imaging. Overall, mutations in the TSH receptor signaling pathway are present in slightly over half of toxic thyroid nodules. Notably, TSHR and GNAS mutations are rare in follicular carcinomas; thus, toxic adenomas and toxic multinodular goiter do not seem to be forerunners of malignancy

Answer 222

A minority (<20%) of nonfunctioning follicular adenomas have mutations of RAS or PIK3CA , which encodes a subunit of the PI-3 kinase, or bear a PAX8-PPARG fusion gene, genetic alterations that are shared with follicular carcinomas. These are discussed in further detail under “Carcinomas” (see later

Answer 223

The typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is demarcated from the surrounding thyroid parenchyma by a well-defined, intact capsule ( Fig. 24-16A ). These features are important in making the distinction from multinodular goiters, which contain multiple nodules even in patients presenting clinically with a solitary dominant nodule. Follicular adenomas average about 3 cm in diameter, but some are much larger (≥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. Areas of hemorrhage, fibrosis, calcification, and cystic change, similar to those encountered in multinodular goiters, are common in follicular adenomas, particularly within larger lesions.

Answer 224

Microscopically, the constituent cells often form uniform-appearing follicles that contain colloid ( Fig. 24-16 B ). The follicular growth pattern is usually quite distinct from the adjacent nonneoplastic thyroid. The neoplastic cells show little variation in cell size, cell shape, or nuclear morphology, and mitotic figures are rare. Occasionally the neoplastic cells acquire brightly eosinophilic granular cytoplasm ( oxyphil or H ü rthle cell change ) ( Fig. 24-17 ). 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 later). Extensive mitotic activity, necrosis, or high cellularity also warrants close inspection to exclude follicular carcinoma and the follicular variant of papillary carcinoma (see later

Answer 225

Many follicular adenomas present as unilateral painless masses that are discovered during a routine physical examination. Larger masses may produce local symptoms, such as difficulty in swallowing. Nonfunctioning adenomas take up less radioactive iodine than does normal thyroid parenchyma. On radionuclide scanning, therefore, nonfunctioning adenomas appear as cold nodules relative to the adjacent thyroid tissue. However, as many as 10% of cold nodules are malignant. Other techniques used to evaluate suspected adenomas are ultrasonography and fine-needle aspiration biopsy. Because of 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. Follicular adenomas do not recur or metastasize and have an excellent prognosis

Answer 226

Carcinomas of the thyroid are relatively uncommon in the United States, accounting for about 1.5% of all cancers. A female predominance has been noted among patients who develop thyroid carcinoma in the early and middle adult years. In contrast, cases presenting in childhood and late adult life are distributed equally among males and females

Answer 227

* Papillary carcinoma (>85% of cases) * Follicular carcinoma (5% to 15% of cases) * Anaplastic (undifferentiated) carcinoma (<5% of cases) * Medullary carcinoma (5% of cases

Answer 228

Most thyroid carcinomas (except medullary carcinomas) are derived from the thyroid follicular epithelium, and of these, the vast majority are well-differentiated lesions. Because of the unique clinical, molecular and biologic features associated with each variant of thyroid carcinoma, these subtypes are described separately. We begin with a discussion of the molecular pathogenesis of all thyroid cancers

Answer 229

Distinct genetic events are involved in the pathogenesis of the four major histologic variants of thyroid cancer. As stated, medullary carcinomas do not arise from the follicular epithelium. Genetic alterations in the three follicular cell–derived malignancies are in growth factor receptor signaling pathways ( Fig. 24-18 ) . You will recall that in normal cells, these pathways are transiently activated by binding of soluble growth factor ligands to the extracellular domain of receptor tyrosine kinases, which results in autophosphorylation of the cytoplasmic domain of the receptor. This in turn sets in motion events that lead to activation of RAS and two downstream signaling arms involving MAP kinase (MAPK) and PI-3 kinase (PI3K). In thyroid carcinomas, as with many cancers ( Chapter 7 ), gain-of-function mutations in components of these pathways lead to their constitutive activation, driving excessive cellular proliferation and increased cell survival

Answer 230

Most papillary carcinomas have gain-of-function mutations involving the genes encoding the RET or NTRK1 receptor tyrosine kinases, or in the serine/threonine kinase BRAF, which you will recall lies in the MAPK pathway

Answer 231

• The RET gene is located on chromosome 10q11, and the receptor tyrosine kinase it encodes is normally not expressed in thyroid follicular cells. In papillary 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 genes that are constitutively expressed in the thyroid epithelium. The novel fusion genes that are so formed are known as RET/PTC (RET/papillary thyroid carcinoma) and are present in approximately 20% to 40% of papillary thyroid cancers. There are more than 15 fusion partners of RET , and two—designated as PTC1 and PTC2 —are most commonly observed in sporadic papillary cancers. The frequency of RET / PTC rearrangements is significantly higher in papillary cancers arising in the backdrop of radiation exposure. The RET/PTC rearrangements produce genes that encode fusion proteins with constitutive tyrosine kinase activity. Similarly, paracentric inversions or translocations of NTRK1 on chromosome 1q21 are present in 5% to 10% of papillary thyroid cancers. These genetic events also produce constitutively active NTRK1 fusion proteins

Answer 232

• BRAF encodes an intermediate signaling component in the MAP kinase pathway. One third to one half of papillary thyroid carcinomas harbor a gain-of-function mutation in the BRAF gene, which is most commonly a valine-to-glutamate change in codon 600 ( BRAF V600E ). The presence of BRAF mutations in papillary carcinomas correlates with adverse prognostic factors like metastatic disease and extrathyroidal extension. As discussed in other chapters, a similar BRAF mutation is found in some other cancers as well, including melanomas, hairy cell leukemia and a subset of colon cancers, suggesting that diverse tumors may share a similar pathway to malignancy

Answer 233

Because chromosomal rearrangements of the RET or NTRK1 genes and mutations of BRAF have redundant effects on MAP kinase signaling, it is not surprising that they are usually (but not always) mutually exclusive events. The histologic variants of papillary carcinoma demonstrate some unique characteristics vis-à-vis the frequency or nature of BRAF mutation (see later). Of further interest, RET / PTC rearrangements and BRAF point mutations are not observed in follicular adenomas or carcinomas

Answer 234

In contrast to papillary carcinomas, follicular carcinomas are associated with acquired mutations that activate RAS or the PI-3K/AKT arm of the receptor tyrosine kinase signaling pathway. It is evident from Figure 24-18 that activated mutations in RAS would be expected to stimulate both the MAPK and PI3K signaling pathways. Why RAS mutations produce follicular neoplasms, rather than papillary neoplasms, is not understood, a point that highlights our lack of insight into the nuances of intracellular signaling. Approximately one third to one half of follicular thyroid carcinomas harbor gain-of-function point mutations of RAS or PIK3CA (the gene that encodes PI-3 kinase), PIK3CA amplifications, or loss-of-function mutations of PTEN , a tumor suppressor gene and negative regulator of this pathway ( Fig. 24-18 ). These genetic alterations are almost always mutually exclusive in follicular carcinomas, in line with their functional equivalence. The progressive increase in the prevalence of RAS and PIK3CA mutations from benign follicular adenomas to follicular carcinomas to anaplastic carcinomas (see later) suggests a shared histogenesis and molecular evolution among these follicular tumors.

Answer 235

A unique (2;3)(q13;p25) translocation has been described in one third to one half of follicular carcinomas. This translocation creates a fusion gene composed of portions of PAX8 , a paired homeobox gene that is important in thyroid development, and the peroxisome proliferator-activated receptor gene ( PPARG ), whose gene product is a nuclear hormone receptor implicated in terminal differentiation of cells. Fewer than 10% of follicular adenomas harbor PAX8-PPARG fusion genes, and these have not been documented thus far in other thyroid neoplasms

Answer 236

These highly aggressive and lethal tumors can arise de novo, or more commonly, by “dedifferentiation” of a well-differentiated papillary or follicular carcinoma. Molecular alterations present in anaplastic carcinomas include those also seen in well-differentiated carcinomas (e.g., RAS or PIK3CA mutations). Other genetic “hits,” such as inactivation of TP53 or activating mutations of β-catenin, are essentially restricted to anaplastic carcinomas and may contribute to their aggressive behavior

Answer 237

Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2, see later) and are associated with germline RET mutations that lead to constitutive activation of the receptor. RET mutations are also seen in approximately one half of 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

Answer 238

The major risk factor predisposing to thyroid cancer is exposure to ionizing radiation , particularly during the first 2 decades of life. In keeping with this, there was a marked increase in the incidence of papillary carcinomas among children exposed to ionizing radiation after the Chernobyl nuclear disaster in 1986. Deficiency of dietary iodine (and by extension, an association with goiter) is linked with a higher frequency of follicular carcinomas.

Answer 239

Papillary carcinomas are the most common form of thyroid cancer, accounting for nearly 85% of primary thyroid malignancies in the United States. They occur throughout life but most often between the ages of 25 and 50, and account for the majority of thyroid carcinomas associated with previous exposure to ionizing radiation. The diagnosis of papillary carcinoma has increased markedly in the last 30 years, partly because of the recognition of follicular variants (see later) that were misclassified in the past

Answer 240

Papillary carcinomas may be solitary or multifocal. Some tumors are well circumscribed and even encapsulated; others infiltrate the adjacent parenchyma and have ill-defined margins. The tumors may contain areas of fibrosis and calcification and are often cystic. The cut surface sometimes reveals papillary foci that point to the diagnosis. The microscopic hallmarks of papillary neoplasms include the following

Answer 241

• Papillary carcinomas may 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 being more complex and having dense fibrovascular cores

Answer 242

he 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 give the appearance of intranuclear inclusions (“pseudo-inclusions”) or intranuclear grooves. The diagnosis of papillary carcinoma can be made based on these nuclear features, even in the absence of papillary architecture

Answer 243

• Concentrically calcified structures termed psammoma bodies are often present, usually within the cores of papillae. These structures are almost never found in follicular and medullary carcinomas, and so, when present in fine-needle aspiration material, they are a strong indication that the lesion is a papillary carcinoma

Answer 244

• 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 occur in up to half of cases

Answer 245

. The most common variant, and the one most liable to misdiagnosis, is the follicular variant, which has the characteristic nuclear features of papillary carcinoma and an almost totally follicular architecture. Follicular variant papillary carcinomas can be either encapsulated or poorly circumscribed and infiltrative. The encapsulated follicular variant of papillary carcinoma has a generally favorable prognosis, while the poorly circumscribed and infiltrative lesions need to be treated more aggressively. The genetic alterations in the follicular variant, especially the encapsulated tumors, demonstrate several distinctions from conventional papillary carcinomas, including a lower frequency of RET / PTC rearrangements, a lower frequency and different spectrum of BRAF mutations, and a significantly higher frequency of RAS mutations. When considered in conjunction with their higher propensity for angioinvasion and lower incidence of lymph node metastases, it has become evident that at least a subset of the encapsulated follicular variant display biological features that are more comparable to minimally invasive follicular carcinomas (see later) than conventional papillary carcinomas

Answer 246

The tall-cell variant has tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures. These tumors tend to occur in older individuals and have higher frequencies of vascular invasion, extrathyroidal extension, and cervical and distant metastases than conventional papillary thyroid carcinoma. Tall-cell variant papillary carcinomas harbor BRAF mutations in most (55% to 100%) cases, and often have RET / PTC translocations as well. The occurrence of these two aberrations together may synergistically enhance MAPK signaling, contributing to the aggressive behavior of this variant

Answer 247

An unusual diffuse sclerosing variant of papillary carcinoma occurs in younger individuals, including children. The tumor has a prominent papillary growth pattern intermixed with solid areas containing nests of squamous metaplasia. As the name suggests, there is extensive, diffuse fibrosis throughout the thyroid gland, often associated with a prominent lymphocytic infiltrate, simulating Hashimoto thyroiditis. Lymph node metastases are present in almost all cases. The diffuse sclerosing variant carcinomas lack BRAF mutations, but RET / PTC translocations are found in approximately half the cases

Answer 248

Finally, the papillary microcarcinoma is defined as an otherwise conventional papillary carcinoma less than 1 cm in size. These lesions most commonly come to attention as an incidental finding in patients undergoing surgery, and may be precursors of typical papillary carcinomas

Answer 249

Most conventional 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 have a significant influence on prognosis, which is generally good. Most carcinomas are single nodules that move freely with the thyroid gland during swallowing and are not distinguishable on examination from benign nodules. 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

Answer 250

A variety of diagnostic tests have been used to help separate benign from malignant thyroid nodules, including radionuclide scanning and fine-needle aspiration. Papillary carcinomas 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 demonstrated nicely in aspirated specimens

Answer 251

Papillary thyroid cancers have an excellent prognosis, with a 10-year survival rate in excess of 95%. Between 5% and 20% of patients have local or regional recurrences, and 10% to 15% have distant metastases. The prognosis of someone with papillary thyroid cancers is dependent on several factors including age (in general, being less favorable among patients older than 40 years), the presence of extrathyroidal extension, and presence of distant metastases (stage

Answer 252

Follicular carcinomas account for 5% to 15% of primary thyroid cancers, but are more frequent in areas with dietary iodine deficiency, where they constitute 25% to 40% of thyroid cancers. They are more common in women (3 : 1) and present more often in older patients than do papillary carcinomas; the peak incidence is between 40 and 60 years of age

Answer 253

Follicular carcinomas are single nodules that may be well circumscribed or widely infiltrative ( Fig. 24-20 A ). Sharply demarcated lesions may be exceedingly difficult to distinguish from follicular adenomas by gross examination. Larger lesions may penetrate the capsule and infiltrate well beyond the thyroid capsule into the adjacent neck. They are gray to tan to pink on cut section and may be somewhat translucent due to the presence of large, colloid-filled follicles. Degenerative changes, such as central fibrosis and foci of calcification, are sometimes present

Answer 254

Microscopically, most follicular carcinomas are composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid ( Fig. 24-20 B ). In other cases follicular differentiation may be less apparent, and there may be nests or sheets of cells without colloid. Occasional tumors are dominated by cells with abundant granular, eosinophilic cytoplasm (Hürthle cell or oncocytic variant of follicular carcinoma) . Whatever the pattern, the nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not present. While nuclear features (optically clear nuclei, nuclear grooves) are helpful in distinguishing papillary from follicular neoplasms, there is no reliable cytologic difference between follicular adenomas and minimally invasive follicular carcinomas . Making this distinction requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular invasion ( Fig. 24-21 ). The criterion for vascular invasion is applicable only to capsular vessels and vascular spaces beyond the capsule; the presence of tumor plugs within intra-tumoral blood vessels has little prognostic significance. Unlike in papillary cancers, lymphatic spread is uncommon in follicular cancers

Answer 255

In contrast to minimally invasive follicular cancers, the diagnosis of carcinoma is obvious in widely invasive follicular carcinomas, which infiltrate the thyroid parenchyma and extrathyroidal soft tissues . Histologically, these cancers tend to have a greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, and increased mitotic activity.

Answer 256

Follicular carcinomas present as slowly enlarging painless nodules. Most frequently they are cold nodules on scintigrams, although rare, better-differentiated lesions may be hyperfunctional, take up radioactive iodine and appear warm on scintiscan. Because follicular carcinomas have little propensity for invading lymphatics, regional lymph nodes are rarely involved, but vascular (hematogenous) dissemination is common, with metastases to bone, lungs, liver, and elsewhere.

Answer 257

The prognosis depends largely on the extent of invasion and stage at presentation. Widely invasive follicular carcinoma often presents with systemic metastases, and as many as half of affected patients succumb to their disease within 10 years. This is in sharp contrast to minimally invasive follicular carcinomas, which have a 10-year survival rate of greater than 90%. Most follicular carcinomas are treated with total thyroidectomy followed by the administration of radioactive iodine, which can be used to identify metastases and to 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 endogenous TSH levels. Serum thyroglobulin levels are used for monitoring tumor recurrence, because this thyroid protein should be barely detectable in a patient who is free of disease

Answer 258

Anaplastic carcinomas are undifferentiated tumors of the thyroid follicular epithelium, accounting for less than 5% of thyroid tumors. They are aggressive, with a mortality rate approaching 100%. Patients with anaplastic carcinoma are older than those with other types of thyroid cancer, with a mean age of 65 years. Approximately a quarter of patients with anaplastic thyroid carcinomas have a past history of a well-differentiated thyroid carcinoma, and another quarter harbors a concurrent well-differentiated tumor in the resected specimen

Answer 259

variable morphology, including (1) large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells; (2) spindle cells with a sarcomatous appearance; and (3) mixed spindle and giant cells. Foci of papillary or follicular differentiation may be present in some tumors, suggesting an origin from a better-differentiated carcinoma. The neoplastic cells express epithelial markers like cytokeratin, but are usually negative for markers of thyroid differentiation, like thyroglobulin

Answer 260

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. Symptoms related to compression and invasion, such as dyspnea, dysphagia, hoarseness, and cough, are common. There are no effective therapies, 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

Answer 261

Medullary carcinomas of the thyroid are neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid, and account for approximately 5% of thyroid neoplasms. 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 serotonin, ACTH, and vasoactive intestinal peptide (VIP). About 70% of tumors arise sporadically. 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; see “ Multiple Endocrine Neoplasia Syndromes ”). Recall that activating point mutations in the RET proto-oncogene play an important role in the development of both familial and sporadic medullary carcinomas. Cases associated with MEN types 2A or 2B occur in younger patients, and may even arise during the first decade of life. In contrast, sporadic as well as familial medullary carcinomas are lesions of adulthood, with a peak incidence in the 40s and 50s

Answer 262

Sporadic medullary thyroid carcinomas present as a solitary nodule ( Fig. 24-22 A ). 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

Answer 263

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 calcitonin polypeptides are present in the stroma in many cases ( Fig. 24-22 B ). Calcitonin is readily demonstrable within the cytoplasm of the tumor cells as well as in the stromal amyloid by immunohistochemical methods. As with all neuroendocrine tumors, electron microscopy reveals variable numbers of membrane-bound electron-dense granules within the cytoplasm of the neoplastic cells ( Fig. 24-23 ). One of the 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, and that is believed to be a precursor lesion in familial cases. Thus, the presence of multiple prominent clusters of C cells scattered throughout the parenchyma should raise the specter of an inherited predisposition, even if a family history is not present

Answer 264

Sporadic cases of medullary carcinoma come to medical attention most often as a mass in the neck, sometimes associated with dysphagia or hoarseness. In some instances, the initial manifestations are those of a paraneoplastic syndrome caused by the secretion of a peptide hormone (e.g., diarrhea due to the secretion of VIP, or Cushing syndrome due to ACTH). Notably, hypocalcemia is not a prominent feature, despite the presence of raised calcitonin levels. In addition to circulating calcitonin, secretion of carcinoembryonic antigen by the neoplastic cells is a useful biomarker, especially for presurgical assessment of tumor load and in calcitonin-negative tumors

Answer 265

Patients with familial syndromes may come to attention because of symptoms localized to the thyroid or as a result of endocrine neoplasms in other organs (e.g., adrenal or parathyroid glands). Medullary carcinomas arising in the context of MEN-2B are generally more aggressive and metastasize more frequently than those occurring in patients with sporadic tumors, MEN-2A, or FMTC. As will be discussed later, asymptomatic MEN-2 patients carrying germline RET mutations are offered prophylactic thyroidectomy as early as possible to prevent the otherwise inevitable development of medullary carcinomas, the major risk factor for poor outcome in these individuals. 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. Several small-molecule inhibitors of RET tyrosine kinase have recently been developed, and are being tested in individuals with medullary carcinomas.

Answer 266

▪ Most thyroid neoplasms manifest as solitary thyroid nodules ; only 1% of all thyroid nodules are neoplastic. ▪ Follicular adenomas are the most common benign neoplasms, while papillary carcinoma is the most common malignancy. ▪ Multiple genetic pathways are involved in thyroid carcinogenesis. Some of the genetic abnormalities that are fairly unique to thyroid cancers include PAX8/PPARG fusion genes or mutations that activate RAS or PI-3K (in follicular carcinomas), chromosomal rearrangements involving the RET oncogene or mutations in BRAF (in papillary carcinomas), and mutations of RET (in medullary carcinomas). ▪ Follicular adenomas and carcinomas both are composed of well-differentiated follicular epithelial cells; the latter are distinguished by evidence of capsular and/or vascular invasion. ▪ Papillary carcinomas are recognized based on nuclear features (ground-glass nuclei, pseudoinclusions) even in the absence of papillae. Psammoma bodies are a characteristic feature of papillary cancers; these neoplasms often metastasize by way of lymphatics, but the prognosis is excellent. ▪ Anaplastic carcinomas are thought to arise by dedifferentiation of more differentiated neoplasms. They are highly aggressive, uniformly lethal cancers. ▪ Medullary cancers are neoplasms arising from the parafollicular C cells and can occur in either sporadic (70%) or familial (30%) settings. Multicentricity and C cell hyperplasia are features of familial cases. Amyloid deposits are a characteristic histologic finding

Answer 267

Thyroglossal duct cyst is the most common clinically significant congenital anomaly of the thyroid. A sinus tract may persist as a vestige 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 the cysts to form either spherical masses or fusiform swellings, rarely over 2 to 3 cm in diameter, that 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 resembling the covering of the posterior portion of the tongue in the region of the foramen cecum. 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

Answer 268

The four parathyroid glands are composed of two cell types: chief cells and oxyphil cells. Chief cells predominate; they are polygonal, 12 to 20 µm in diameter, and have central, round, uniform nuclei and light to dark pink cytoplasm. Sometimes these cells take on a water-clear appearance due to the presence of large amounts of cytoplasmic glycogen. In addition, they have secretory granules containing parathyroid hormone (PTH) . 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

Answer 269

The function of the parathyroid glands is to regulate calcium homeostasis. The activity of the parathyroid glands is controlled by the level of free (ionized) calcium in the bloodstream. Normally, decreased levels of free calcium stimulate the synthesis and secretion of PTH. The metabolic functions of PTH that regulate serum calcium levels are several. S

Answer 270

* Increases the renal tubular reabsorption of calcium, thereby conserving free calcium * Increases the conversion of vitamin D to its active dihydroxy form in the kidneys * Increases urinary phosphate excretion, thereby lowering serum phosphate levels * Augments gastrointestinal calcium absorption

Answer 271

The net result of these activities is to elevate the level of free calcium, which, in turn, inhibits further PTH secretion in a classic feedback loop. Similar to the other endocrine organs, abnormalities of the parathyroid glands include both hyperfunction and hypofunction. Tumors of the parathyroid glands, in contrast to thyroid tumors, usually come to attention because of excessive secretion of PTH rather than mass effects.

Answer 272

Hyperparathyroidism is caused by elevated parathyroid hormone and is classified into primary, secondary, and least commonly, tertiary types

Answer 273

• Primary hyperparathyroidism : an autonomous overproduction of parathyroid hormone (PTH), usually resulting from an adenoma or hyperplasia of parathyroid tissue

Answer 274

• Secondary hyperparathyroidism : compensatory hypersecretion of PTH in response to prolonged hypocalcemia, most commonly from chronic renal failure

Answer 275

• Tertiary hyperparathyroidism : persistent hypersecretion of PTH even after the cause of prolonged hypocalcemia is corrected, for example after renal transplant

Answer 276

Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an important cause of hypercalcemia

Answer 277

* Adenoma: 85% to 95% * Primary hyperplasia (diffuse or nodular): 5% to 10% * Parathyroid carcinoma: ~1%

Answer 278

Primary hyperparathyroidism is usually a disease of adults and is more common in women than in men by a ratio of nearly 4 : 1. The annual incidence is now estimated to be about 25 cases per 100,000 in the United States and Europe; as many as 80% of patients with this condition are identified in the outpatient setting, when hypercalcemia is discovered incidentally on a serum electrolyte panel. Most cases occur in the 50s or later in life.

Answer 279

ig. 24-24 ). Most, if not all, sporadic parathyroid adenomas are monoclonal, consistent with their being neoplasms. As with nodules in goitrous thyroids, 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 later), suggesting that these lesions lie in the gray zone between reactive hyperplasias and neoplasia. There are two molecular defects that have an established role in the development of sporadic adenomas:

Answer 280

Cyclin D1 gene inversions leading to overexpression of cyclin D1, a major regulator of the cell cycle. A pericentromeric inversion on chromosome 11 results in relocation of the cyclin D1 gene (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, causing the cells to proliferate. Between 10% and 20% of adenomas have this clonal rearrangement. In addition, cyclin D1 is overexpressed in approximately 40% of parathyroid adenomas, suggesting that mechanisms other than cyclin D1 gene inversion can lead to its overexpression

Answer 281

Approximately 20% to 30% of sporadic parathyroid tumors have mutations in both copies of the MEN1 gene, a tumor suppressor gene on chromosome 11q13. Germline mutations of MEN1 are also found in patients with familial parathyroid adenomas (see later). The spectrum of MEN1 mutations in sporadic tumors is virtually identical to that in familial parathyroid adenomas

Answer 282

Familial syndromes are a distant second to sporadic adenomas as causes of primary hyperparathyroidism. The genetic syndromes associated with familial parathyroid adenomas include Multiple Endocrine Neoplasia, types 1 and 2, caused by germline mutations of MEN1 and RET , respectively (both are discussed in further detail later), and familial hypocalciuric hypercalcemia, a rare autosomal-dominant disorder caused by loss-of-function mutations in the parathyroid calcium-sensing receptor gene ( CASR ), which results in decreased sensitivity to extracellular calcium

Answer 283

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 PTH and 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 gm and consists of a well-circumscribed, soft, tan to reddish-brown nodule invested by a delicate capsule. In contrast to primary hyperplasia, the glands outside the adenoma are usually normal in size or somewhat shrunken because of feedback inhibition by elevated levels of serum calcium. Microscopically, parathyroid adenomas are mostly composed of uniform, polygonal chief cells with small, centrally placed nuclei ( Fig. 24-25 ). At least a few nests of larger oxyphil cells are present as well; uncommonly, adenomas are composed entirely of this cell type (oxyphil adenomas) . These may resemble Hürthle cell tumors in the thyroid. A rim of compressed, nonneoplastic parathyroid tissue, generally separated by a fibrous capsule, is often visible at the edge of the adenoma. Mitotic figures are rare, but it is not uncommon to find bizarre and pleomorphic nuclei even within adenomas (so-called endocrine atypia ); this is not a criterion for malignancy. In contrast to the normal parathyroid parenchyma, adipose tissue is inconspicuous

Answer 284

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 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 hyperplastic glands

Answer 285

Parathyroid carcinomas may be 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 are usually uniform and resemble normal parathyroid cells, and are arrayed in nodular or trabecular patterns. The mass is usually enclosed by a dense, fibrous capsule. Diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only reliable criteria. Local recurrence occurs in one third of cases, and more distant dissemination occurs in another third.

Answer 286

Morphologic changes of hyperparathyroidism in the skeletal system ( Chapter 26 ) and the urinary tract deserve special mention. Symptomatic, untreated primary hyperparathyroidism manifests with three interrelated skeletal abnormalities: osteoporosis, brown tumors and osteitis fibrosa cystica. The osteoporosis results in decreased bone mass, with preferential involvement of the phalanges, vertebrae and proximal femur. For unknown reasons, the increased osteoclast activity in hyperparathyroidism affects cortical bone (subperiosteal and endosteal surfaces) more severely than medullary bone. In medullary bone, osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks and producing what is known as dissecting osteitis ( Fig. 24-26 ). The marrow spaces around the affected surfaces are replaced by fibrovascular tissue. The correlative radiographic finding is a decrease in bone density or osteoporosis

Answer 287

The bone loss predisposes to microfractures and secondary hemorrhages that elicit an influx of macrophages and an ingrowth of reparative fibrous tissue, creating a mass of reactive tissue, known as a brown tumor ( Fig. 26-16 , Chapter 26 ). The brown color is the result of the vascularity, hemorrhage, and hemosiderin deposition, and it is not uncommon for the lesions to undergo cystic degeneration. The combination of increased osteoclast activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica (von Recklinghausen disease of bone ). Osteitis fibrosa cystica is now rarely encountered because hyperparathyroidism is usually diagnosed on routine blood tests and treated at an early, asymptomatic stage (see later)

Answer 288

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.

Answer 289

Primary hyperparathyroidism may be (1) asymptomatic and identified on routine blood chemistry profile, or (2) associated with the classic clinical manifestations of primary hyperparathyroidism

Answer 290

Because serum calcium levels are routinely assessed, most patients with primary hyperparathyroidism are diagnosed incidentally, on the basis of clinically silent hypercalcemia. In fact, primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia. Hence, many of the classic manifestations, particularly those referable to bone and renal disease, are now seen infrequently in clinical practice.

Answer 291

Among other causes of hypercalcemia ( Table 24-5 ), malignancy stands out as the most frequent cause of symptomatic hypercalcemia in adults, and must be excluded by appropriate clinical and laboratory investigations.

Answer 292

The most common mechanism (in ~80% of cases) through which osteolytic tumors induce hypercalcemia is by secretion of PTH-related peptide (PTHrP), whose functions are similar to PTH in inducing osteoclastic bone resorption and hypercalcemia; the remaining 20% induce hypercalcemia through metastases to the bone and subsequent cytokine-induced bone resorption.

Answer 293

individuals with primary hyperparathyroidism, serum PTH levels are inappropriately elevated for the level of serum calcium, whereas PTH levels are low to undetectable in hypercalcemia caused by of nonparathyroid diseases ( Table 24-5 ).

Answer 294

Radioimmunoassays specific for PTH and PTHrP are available and can be useful in distinguishing primary hyperparathyroidism and malignancy-associated hypercalcemia

Answer 295

adioimmunoassays specific for PTH and PTHrP are available and can be useful in distinguishing primary hyperparathyroidism and malignancy-associated hypercalcemia. Other laboratory alterations referable to PTH excess include hypophosphatemia and increased urinary excretion of both calcium and phosphate.

Answer 296

Secondary renal disease may lead to phosphate retention with normalization of serum phosphate levels.

Answer 297

``` Raised [PTH] Decreased [PTH] Hyperparathyroidism Primary (adenoma > hyperplasia) * Secondary † Tertiary † ``` Familial hypocalciuric hypercalcemia

Answer 298

Hypercalcemia of malignancy * Vitamin D toxicity Immobilization Thiazide diuretics Granulomatous disease (sarcoidosis)

Answer 299

The signs and symptoms of hyperparathyroidism reflect the combined effects of increased PTH secretion and hypercalcemia. Primary hyperparathyroidism is associated with “painful bones, renal stones, abdominal groans, and psychic moans

Answer 300

Bone disease and bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica. • Nephrolithiasis (renal stones) in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and abnormalities in renal function lead to polyuria and secondary polydipsia. • Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones. • Central nervous system alterations, including depression, lethargy, and eventually seizures. • Neuromuscular abnormalities, including weakness and fatigue. • Cardiac manifestations, including aortic or mitral valve calcifications (or both).

Answer 301

The abnormalities most directly related to hyperparathyroidism are nephrolithiasis and bone disease, whereas those attributable to hypercalcemia include fatigue, weakness, pancreatitis, metastatic calcifications, and constipation

Answer 302

Secondary hyperparathyroidism is caused by any condition that gives rise to chronic hypocalcemia, which in turn leads to compensatory overactivity of the parathyroid glands

Answer 303

Renal failure is by far the most common cause of secondary hyperparathyroidism , although several 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 ). Because vitamin D has suppressive effects on parathyroid growth and PTH secretion, its relative deficiency compounds the hyperparathyroidism in renal failure.

Answer 304

The parathyroid glands in secondary hyperparathyroidism are hyperplastic. As in primary hyperparathyroidism, 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. Metastatic calcification may be seen in many tissues, including lungs, heart, stomach, and blood vessels

Answer 305

The clinical features of secondary hyperparathyroidism are usually dominated by the inciting chronic renal failure. Secondary hyperparathyroidism per se is usually not as severe or as prolonged as primary hyperparathyroidism, hence the skeletal abnormalities (referred to as renal osteodystrophy) tend to be milder. Control of the hyperparathyroidism allows the bony changes to regress significantly or disappear completely. 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 . Patients with secondary hyperparathyroidism often respond to dietary vitamin D supplementation, as well as phosphate binders, which decrease the prevailing hyperphosphatemia.

Answer 306

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

Answer 307

▪ Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia. ▪ In a majority of cases, primary hyperparathyroidism is caused by a sporadic parathyroid adenoma and, less commonly, by parathyroid hyperplasia. ▪ Parathyroid adenomas are solitary, while hyperplasia typically is a multiglandular process. ▪ Skeletal manifestations of hyperparathyroidism include bone resorption, osteitis fibrosa cystica, and brown tumors. Renal changes include nephrolithiasis (stones) and nephrocalcinosis. ▪ The clinical manifestations of hyperparathyroidism can be summarized as “painful bones, renal stones, abdominal groans, and psychic moans.” ▪ Secondary hyperparathyroidism most often is caused by renal failure, which lowers serum calcium levels, resulting in reactive hyperplasia of parathyroid glands. ▪ Malignancies are the most important cause of symptomatic hypercalcemia, which results from osteolytic metastases or release of PTH-related protein from nonparathyroid tumors.

Answer 308

Hypoparathyroidism is far less common than is hyperparathyroidism. Acquired hypoparathyroidism is almost always an inadvertent consequence of surgery; in addition, there are several genetic causes of hypoparathyroidism

Answer 309

• 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

Answer 310

• Autoimmune 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 under “Adrenal Glands

Answer 311

• Autosomal-dominant hypoparathyroidism is caused by gain-of-function mutations in the calcium-sensing receptor ( CASR ) gene. Inappropriate CASR activity due to heightened calcium sensing suppresses PTH, resulting in hypocalcemia and hypercalciuria . Recall that loss-of-function CASR mutations are a rare cause of familial parathyroid adenomas.

Answer 312

• Familial isolated hypoparathyroidism (FIH) is a rare condition with either autosomal dominant or autosomal recessive patterns of inheritance. Autosomal-dominant FIH is caused by a mutation in the gene encoding PTH precursor peptide, which impairs its processing to the mature hormone. Autosomal-recessive FIH is caused by loss-of-function mutations in the transcription factor gene glial cells missing-2 ( GCM2 ), which is essential for development of the parathyroid.

Answer 313

• Congenital absence of parathyroid glands can occur in conjunction with other malformations, such as thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome. As discussed in Chapter 6 , when thymic defects are present, the condition is called DiGeorge syndrome

Answer 314

The major clinical manifestations of hypoparathyroidism are related to the severity and chronicity of the hypocalcemia

Answer 315

he hallmark of hypocalcemia is tetany , which is characterized by neuromuscular irritability , resulting from decreased serum calcium levels. The symptoms 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 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. Trousseau sign refers to carpal spasms produced by occlusion of the circulation to the forearm and hand with a blood pressure cuff for several minutes

Answer 316

• Mental status changes include emotional instability, anxiety and depression, confusional states, hallucinations, and frank psychosis

Answer 317

• Intracranial manifestations include calcifications of the basal ganglia, parkinsonian-like movement disorders, and increased intracranial pressure with resultant papilledema. The paradoxical association of hypocalcemia with calcifications may be because of an increase in phosphate levels, resulting in tissue deposits with calcium that exists in local extracellular milieu.

Answer 318

• Ocular disease takes the form of calcification of the lens and cataract formation

Answer 319

Cardiovascular manifestations include a conduction defect that produces a characteristic prolongation of the QT interval in the electrocardiogram

Answer 320

• 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

Answer 321

In this condition, hypoparathyroidism occurs because of end-organ resistance to the actions of PTH. Indeed, serum PTH levels are normal or elevated. In one form of pseudohypoparathyroidism, there is end-organ resistance to TSH and FSH/LH as well as PTH. All of these hormones signal via G-protein–coupled receptors, and the disorder results from genetic defects in components of this pathway that are shared across endocrine tissues. PTH resistance is the most obvious clinical manifestation. It presents as hypocalcemia, hyperphosphatemia, and elevated circulating PTH. TSH resistance is generally mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in females

Answer 322

The endocrine pancreas consists of about 1 million clusters of cells, the islets of Langerhans , which contain four major and two minor cell types. The four main types are β, α, δ, and PP (pancreatic polypeptide) cells. They can be differentiated by the ultrastructural characteristics of their granules, and by their hormone content ( Fig. 24-27 ). The β cells produce insulin , which regulates glucose utilization in tissues and reduces blood glucose levels, as will be detailed in the discussion of diabetes. α cells secrete glucagon , which stimulates glycogenolysis in the liver and thus increases blood sugar. δ cells secrete somatostatin , which suppresses both insulin and glucagon release. PP cells secrete pancreatic polypeptide , which exerts several gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility. These cells 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

Answer 323

Diabetes mellitus is a group of metabolic disorders sharing the common 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. In the United States, diabetes is the leading cause of end-stage renal disease, adult-onset blindness and non-traumatic lower extremity amputations resulting from atherosclerosis of the arteries

Answer 324

Diabetes and related disorders of glucose metabolism are extremely common. According to the American Diabetes Association, diabetes affects more than 25 million children and adults, or more than 8% of the population, in the United States, nearly a third of whom are currently unaware that they have hyperglycemia. Approximately 1.9 million new cases of adult diabetes are diagnosed each year in the United States. Furthermore, a staggering 79 million adults in this country have impaired glucose tolerance or “prediabetes,” which is defined as elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of diabetes (see later), and individuals with prediabetes are at high risk for developing frank diabetes. Compared to non-Hispanic whites, Native Americans, African Americans, and Hispanics are 1.5 to 2 times more likely to develop diabetes in their lifetimes. The World Health Organization estimates that as many as 346 million people suffer from diabetes worldwide, with India and China being the largest contributors to the world's diabetic load. Increasingly sedentary life styles and poor eating habits have contributed to the simultaneous escalation of diabetes and obesity, which some have called the diabesity epidemic . Sadly, obesity and diabetes have now extended even to children who subsist on “junk” food and lack adequate exercise

Answer 325

The mortality rate from diabetes varies across countries, with middle- and low-income nations accounting for almost 80% of diabetes-related deaths and nearly double the mortality rates observed in developed nations. Nonetheless, diabetes continues to be one of the top 10 “killers” in the United States. The total yearly costs related to diabetes in the United States are estimated to be an astounding 174 billion dollars, including $116 billion in direct medical costs and the additional $58 billion in indirect costs such as disability, work loss, and premature mortality

Answer 326

Blood glucose is normally maintained in a very narrow range of 70 to 120 mg/dL. According to the ADA and WHO, diagnostic criteria for diabetes include : 1. A fasting plasma glucose ≥ 126 mg/dL, 2. A random plasma glucose ≥ 200 mg/dL (in a patient with classic hyperglycemic signs, as discussed later), 3. 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) with a loading dose of 75 gm, and 4. A glycated hemoglobin (Hb A1C ) level ≥ 6.5% (glycated hemoglobin is further discussed under chronic complications of diabetes

Answer 327

All tests, except the random blood glucose test in a patient with classic hyperglycemic signs, need to be repeated and confirmed on a separate day. If there is discordance between two assays (e.g., fasting glucose and Hb A1C level), then the result with greater degree of abnormality is considered the “readout.” Of note, many acute stresses, such as severe infections, burns or trauma, can lead to transient hyperglycemia due to secretion of hormones like catecholamines and cortisol that oppose the action of insulin. The diagnosis of diabetes requires persistence of hyperglycemia following resolution of the acute illness.

Answer 328

1. A fasting plasma glucose between 100 and 125 mg/dL (“impaired fasting glucose”), 2. 2-hour plasma glucose between 140 and 199 mg/dL following a 75-gm glucose OGTT, and/or 3. A glycated hemoglobin (Hb A1C ) level between 5.7% and 6.4%

Answer 329

As many as one-fourth of individuals with impaired glucose tolerance will develop overt diabetes over 5 years, with additional factors such as obesity and family history compounding the risk. In addition, individuals with prediabetes also harbor a significant risk for cardiovascular complications

Answer 330

• Type 1 diabetes is an autoimmune disease characterized by pancreatic β cell destruction and an absolute deficiency of insulin . It accounts for approximately 5% to 10% of all cases, and is the most common subtype diagnosed in patients younger than 20 years of age

Answer 331

• 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 90% to 95% of diabetic patients have type 2 diabetes, and the vast majority of such individuals are overweight. Although classically considered “adult-onset,” the prevalence of type 2 diabetes in children and adolescents has been increasing at an alarming pace due to the increasing rates of obesity in these age groups. One piece of encouraging news is that the incidence of obesity in the U.S. in children ages 2-5 years fell by over 40% during the period of 2004 to 2012, a tipping of the scales that may signal a reversal of a troubling trend

Answer 332

Immune mediated Idiopathic

Answer 333

Maturity-onset diabetes of the young (MODY), caused by mutations in: Hepatocyte nuclear factor 4α ( HNF4A ), MODY1 Glucokinase ( GCK ), MODY2 Hepatocyte nuclear factor 1α ( HNF1A ), MODY3 Pancreatic and duodenal homeobox 1 ( PDX1 ), MODY4 Hepatocyte nuclear factor 1β ( HNF1B ), MODY5 Neurogenic differentiation factor 1 ( NEUROD1 ), MODY6 Neonatal diabetes (activating mutations in KCNJ11 and ABCC8 , encoding Kir6.2 and SUR1, respectively) Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A→G) Defects in proinsulin conversion Insulin gene mutations

Answer 334

Type a insulin resistance Lipoatrophic diabetes

Answer 335

``` Chronic pancreatitis Pancreatectomy/trauma Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy ```

Answer 336

``` A cromegaly Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma ```

Answer 337

Cytomegalovirus Coxsackie B virus Congenital rubella

Answer 338

``` Glucocorticoids Thyroid hormone Interferon-α Protease inhibitors β-adrenergic agonists Thiazides Nicotinic acid Phenytoin (Dilantin) Vacor ```

Answer 339

D own syndrome Klinefelter syndrome Turner syndrome Prader-Willi syndrome

Answer 340

1: childhood and adolescence 2: adult; increasing incidence in childhood and adolescence

Answer 341

1 normal weight or weight loss 2 vast majority obese

Answer 342

1 progressive decrease in insulin levels 2 increased blood insulin (early); normal or moderate decrease in insulin (late)

Answer 343

1 circulating islet autoantibodies (anti insulin, anti-GAD, anti-ICA512) 2 no islet autoantibodies

Answer 344

1. Diabetic ketoacidosis in absence of insulin therapy | 2. Nonketotic hyperosmolar coma more common

Answer 345

1. Major linkage to MHC class II genes; also linked to polymorphism in CTLA4 and PTPN22 and insulin gene VNTRs 2 no HLA linkage; linkage to candidate diabetogenic and obesity-related genes (TCF7L2, PPARG, FTO, etc)

Answer 346

1. Dysfunction in T cell selection and regulation leading to breakdown in self tolerance to islet auoantigens 2. Insulin resistance in peripheral tissues, failure of compensation by B cells - multiple obesity associated factors linked to pathogenesis of insulin resistance

Answer 347

1. Insulitis 9inflammatory infiltrate of T cells and macrophages) B cell depletion , islet atrophy 2 no insults; amyloid deposition in islets mild B cell deposition

Answer 348

. It should be stressed that while the major types of diabetes have different pathogenic mechanisms, the long-term complications affecting the 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. We will first briefly review normal insulin secretion and the mechanism of insulin action since these are critical to understanding the pathogenesis of diabetes

Answer 349

Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counterregulatory hormones, including glucagon, on glucose uptake and metabolism. 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.

Answer 350

Insulin is produced in the β cells of the pancreatic islets ( Fig. 24-27 ) as a precursor protein and is proteolytically cleaved in the Golgi complex to generate the mature hormone and a peptide byproduct, C-peptide . Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; thus, C-peptide levels serve as a surrogate for β-cell function, decreasing with loss of β-cell mass in type 1 diabetes, or increasing with insulin resistance-associated hyperinsulinemia

Answer 351

The most important stimulus for insulin synthesis and release is glucose itself. An increase in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulin-independent glucose-transporter, GLUT-2 ( Fig. 24-28 ). β cells express an ATP-sensitive K + channel on the membrane, which comprises two subunits: an ATP-sensitive K + channel and the sulfonylurea receptor, the latter being the binding site for oral hypoglycemic agents (sulfonylureas), one of the several classes of drugs used in the treatment of diabetes (see later). Metabolism of glucose generates ATP, which inhibits the activity of the ATP-sensitive K + channel, leading to membrane depolarization and the influx of Ca 2+ . The resultant increase in intracellular Ca 2+ 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

Answer 352

Of these, the most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding is the incretins. Two incretins have been identified: glucose-dependent insulinotropic polypeptide (GIP) , secreted by enteroendocrine “K cells” in the proximal small bowel, and glucagon-like peptide-1 (GLP-1) , secreted by “L cells” in the distal ileum and colon. The elevation in GIP and GLP-1 levels following oral food intake is known as the “incretin effect.” In addition to increased insulin secretion from β cells, these hormones also reduce glucagon secretion and delay gastric emptying, which promotes satiety. Once released, circulating GIP and GLP-1 are degraded in circulation by a class of enzymes known as dipeptidyl peptidase (DPPs), especially DPP-4. The “incretin effect” is significantly blunted in patients with type 2 diabetes, and efforts to restore incretin function can lead to improved glycemic control and loss of weight (through restoration of satiety). These observations have resulted in the development of two new classes of drugs for patients with type 2 diabetes: GLP-1 receptor agonists , which are synthetic GLP-1 mimetics that bind to, and activate the GLP-1 receptor on islet and extrapancreatic sites, and DPP-4 inhibitors, which enhance levels of endogenous incretins by delaying their degradation.

Answer 353

Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-promoting effects ( Fig. 24-29 ). The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body, thus increasing a major source of energy as well as metabolic intermediates that are used in the biosynthesis of cellular building blocks such as lipids, nucleotides, and amino acids. These cells are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, which together represent about two thirds of the entire body weight. Glucose uptake in other peripheral tissues, most notably the brain, is insulin independent. In muscle cells, glucose is then either stored as glycogen or oxidized to 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

Answer 354

e more pertinent mediators are summarized in Fig. 24-30 . The insulin receptor is a tetrameric protein composed of two α- and two β-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 autophosphorylation of the receptor and the phosphorylation (activation) of several intracellular substrate proteins, such as the family of insulin receptor substrates (IRS), which includes IRS1-IRS4 and GAB1. The substrate proteins, in turn, activate multiple downstream signaling cascades, including the PI3K and the MAP kinase pathways, which mediate the metabolic and mitogenic activities of insulin on the cell. Insulin signaling also facilitates the trafficking and docking of vesicles containing the insulin-sensitive glucose transporter protein GLUT-4 to the plasma membrane, which promotes glucose uptake. This process is mediated by AKT, the principal effector of the PI3K pathway, but also independently by the cytoplasmic protein CBL, which is a direct phosphorylation target of the insulin receptor.

Answer 355

Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous β- cell antigens . Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age. Because the disease can develop at any age, including late adulthood, the previously used appellation “juvenile diabetes” is now considered inaccurate. Similarly, the older moniker “insulin-dependent diabetes mellitus” has been excluded from the current classification of diabetes because all forms of diabetes may be treated with insulin. Nevertheless, most patients with type 1 diabetes require insulin for survival; without insulin they develop serious metabolic complications such as ketoacidosis and coma. As with most autoimmune diseases, the pathogenesis of type 1 diabetes involves an interplay of genetic and environmental factors

Answer 356

Epidemiologic studies, such as those demonstrating higher concordance rates for disease in monozygotic vs dizygotic twins, have convincingly established a genetic basis for type 1 diabetes. More recently, genome-wide association studies have identified multiple genetic susceptibility loci for type 1 diabetes, as well as for type 2 diabetes (see later). More than 30 susceptibility loci for type 1 diabetes are now known. Of these, the most important locus is the HLA gene cluster on chromosome 6p21, which according to some estimates contributes as much as 50% of the genetic susceptibility to type 1 diabetes . Ninety percent to 95% of Caucasians with this disease have either an HLA-DR3 or HLA-DR4 haplotype, in contrast to about 40% of normal subjects; moreover, 40% to 50% of patients with type 1 diabetes are combined DR3/DR4 heterozygotes, in contrast to 5% of normal subjects. Individuals who have either DR3 or DR4 concurrently with a DQ8 haplotype (which corresponds to DQA1*0301-DQB1*0302 alleles) demonstrate one of the highest inherited risks for type 1 diabetes in sibling studies. Predictably, the polymorphisms in the HLA molecules are located in or adjacent to the peptide-binding pockets, consistent with the notion that disease-associated alleles code for molecules that have the capacity to display particular antigens. However, as discussed in Chapter 6 , it is still not known if these HLA-disease associations reflect the ability of specific HLA molecules to present self islet antigens or if they are related to the role of HLA molecules in T-cell selection and tolerance. Several non-HLA genes also confer susceptibility to type 1 diabetes. The first disease-associated non-MHC gene to be identified was insulin , with variable number of tandem repeats (VNTRs) in the promoter region being associated with disease susceptibility. The mechanism underlying this association is unknown. It is possible that these polymorphisms influence the level of expression of insulin in the thymus, thus affecting the negative selection of insulin-reactive T cells ( Chapter 6 ). The association between polymorphisms in CTLA4 and PTPN22 and autoimmune thyroiditis was mentioned earlier; not surprisingly, these genes have also been linked with susceptibility to type 1 diabetes. The relationship of type 1 diabetes to altered T-cell selection and regulation is also underscored by the striking prevalence of this disease in individuals with rare germline defects in genes that code for immune regulators, such as AIRE , mutations of which cause autoimmune polyendocrinopathy syndrome, type 1 (APS, type 1) (see Adrenal Gland later

Answer 357

As in other autoimmune diseases, genetic susceptibility contributes to only a part of diabetes risk, and environmental factors must play a role. The nature of these environmental influences remains an enigma. Although antecedent viral infections have been suggested as triggers for development of the disease, neither the type of virus nor how it promotes islet-specific autoimmunity is established. Some studies suggest that viruses might share epitopes with islet antigens, and the immune response to the virus results in cross-reactivity and destruction of islet tissues, a phenomenon known as molecular mimicry . On the other hand, infections are also known to be protective against type 1 diabetes

Answer 358

Although the clinical onset of type 1 diabetes is often abrupt, there is a lengthy lag period between initiation of the autoimmune process and the appearance of disease, during which there is progressive loss of insulin reserves ( 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 destroyed

Answer 359

. This failure of tolerance may be a result of some combination of defective clonal deletion of self-reactive T cells in the thymus, as well as defects in the functions of regulatory T cells or resistance of effector T cells to suppression by regulatory cells. Thus, autoreactive T cells not only survive but are poised to respond to self-antigens. The initial activation of these cells is thought to occur in the peripancreatic lymph nodes, perhaps in response to antigens that are released from damaged islets. The activated T cells then traffic to the pancreas, where they cause β-cell injury. Multiple T-cell populations have been implicated in this damage, including T H 1 cells (which may secrete cytokines, including IFN-γ and TNF, that injure β cells), and CD8+ CTLs (which kill β cells directly). The islet autoantigens that are the targets of immune attack may include insulin, the β cell enzyme glutamic acid decarboxylase (GAD), and islet cell autoantigen 512 (ICA512

Answer 360

Type 2 diabetes is a complex disease that involves an interplay of genetic and environmental factors and a pro-inflammatory state. Unlike type 1 diabetes, there is no evidence of an autoimmune basis

Answer 361

Genetic susceptibility contributes to the pathogenesis, as evidenced by the disease concordance rate of greater than 90% in monozygotic twins. Furthermore, first-degree relatives have 5- to 10-fold higher risk of developing type 2 diabetes than those without a family history, when matched for age and weight. Genome-wide association studies (GWAS) performed over the last decade have identified at least 30 loci that individually confer a minimal to modest increase in the lifetime risk for type 2 diabetes. The detailed description of these susceptibility loci is beyond the scope of this chapter, although many of the polymorphisms identified are in genes associated with insulin secretion . Elucidating the biochemical mechanisms through which these and other linked genes contribute to diabetes pathogenesis is a work in progress

Answer 362

The most important environmental risk factor for type 2 diabetes is obesity, particularly central or visceral obesity. Greater than 80% of individuals with type 2 diabetes are obese, and the incidence of diabetes worldwide has risen in proportion to obesity. Obesity contributes to the cardinal metabolic abnormalities of diabetes (see later) and to insulin resistance early in disease. In fact, even modest weight loss through dietary modifications can reduce insulin resistance and improve glucose tolerance. A sedentary lifestyle (typified by lack of exercise) is another risk factor for diabetes, independent of obesity. Weight loss and exercise usually have additive effects on improving insulin sensitivity and are often the first non-pharmacological measures attempted in patients with milder type 2 diabetes

Answer 363

The two cardinal metabolic defects that characterize type 2 diabetes are: * Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin ( insulin resistance ) * Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β- cell dysfunction

Answer 364

Insulin resistance predates the development of hyperglycemia and is usually accompanied by compensatory β-cell hyperfunction and hyperinsulinemia in the early stages of the evolution of diabetes ( Fig. 24-32 ). Over time, the inability of β cells to adapt to increasing secretory needs for maintaining a euglycemic state results in chronic hyperglycemia and the resulting long-standing complications of diabetes

Answer 365

* Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver, which contributes to high fasting blood glucose levels * Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal, which contributes to high post-prandial blood glucose level * Failure to inhibit activation of “hormone-sensitive” lipase in adipose tissue, leading to excess triglyceride breakdown in adipocytes and excess circulating free fatty acids (FFAs)

Answer 366

For example, reduced tyrosine phosphorylation of the insulin receptor and IRS proteins is observed in peripheral tissues, which compromises insulin signaling and reduces the level of the glucose transporter GLUT-4 on the cell surface ( Fig. 24-30 ). In fact, one of the mechanisms by which exercise can improve insulin sensitivity is through increased translocation of GLUT-4 to the surface of skeletal muscle cells

Answer 367

Multiple factors contribute to insulin resistance, of which obesity is probably the most important. The risk for 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

Answer 368

Free fatty acids (FFAs). Cross-sectional studies have demonstrated an inverse correlation between fasting plasma FFAs and insulin sensitivity. Central adipose tissue is more “lipolytic” than peripheral sites, which might explain the particularly deleterious consequences of this pattern of fat distribution. Excess FFAs overwhelm the intracellular fatty acid oxidation pathways, leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG). These “toxic” intermediates can attenuate signaling through the insulin receptor pathway. In liver cells, insulin normally inhibits gluconeogenesis by blocking the activity of phosphoenolpyruvate carboxykinase, the first enzymatic step in this process. Attenuated insulin signaling allows phosphoenolpyruvate carboxykinase to “ramp up” gluconeogenesis. Excess FFAs also compete with glucose for substrate oxidation, leading to feedback inhibition of glycolytic enzymes, thereby further exacerbating the existing glucose imbalance.

Answer 369

• Adipokines. You will recall that adipose tissue is not merely a passive storage depot for fat but is a functional endocrine organ that releases hormones in response to changes in metabolic status ( Chapter 9 ). A variety of proteins secreted into the systemic circulation by adipose tissue have been identified, and these are collectively termed adipokines (or adipose cytokines). Some of these promote hyperglycemia, and other adipokines (such as leptin and adiponectin) decrease blood glucose, in part by increasing insulin sensitivity in peripheral tissues. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance

Answer 370

Inflammation: Over the past several years, inflammation has emerged as an important factor in the pathogenesis of type 2 diabetes. It is now known that an inflammatory milieu—mediated not by an autoimmune process such as type 1 diabetes but rather by proinflammatory cytokines that are secreted in response to excess nutrients such as free fatty acid (FFAs) and glucose—results in both insulin resistance and β-cell dysfunction. Excess FFAs within macrophages and β cells can activate the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin IL-1β ( Chapter 3 ). IL-1β, in turn, mediates the secretion of additional pro-inflammatory cytokines from macrophages, islet cells, and other cells. IL-1 and other cytokines are released into the circulation and act on the major sites of insulin action to promote insulin resistance. Thus, excess FFAs can impede insulin signaling directly within peripheral tissues, as well as indirectly through the release of pro-inflammatory cytokines

Answer 371

While insulin resistance by itself can lead to impaired glucose tolerance , β- cell dysfunction is virtually a requirement for the development of overt diabetes . In contrast to the severe genetic defects in β-cell function that occur in monogenic forms of diabetes (see later), β-cell function actually increases early in the disease process in most patients with “sporadic” type 2 diabetes, mainly as a compensatory measure to counter insulin resistance and maintain euglycemia. Eventually, however, β cells seemingly exhaust their capacity to adapt to the long-term demands of peripheral insulin resistance, and the hyperinsulinemic state gives way to a state of relative insulin deficiency.

Answer 372

* Excess free fatty acids that compromise β cell function and attenuate insulin release (“ lipotoxicity ”) * The impact of chronic hyperglycemia (“ glucotoxicity ”) * An abnormal “ incretin effect, ” leading to reduced secretion of GIP and GLP-1, hormones that promote insulin release (see earlier) * Amyloid deposition within islets. This is a characteristic finding in individuals with long-standing type 2 diabetes, being present in more than 90% of diabetic islets examined, but it is unclear whether it is a cause or an effect of β-cell “burnout.” * Finally, the impact of genetics cannot be discounted, as many of the polymorphisms associated with an increased lifetime risk for type 2 diabetes occur in genes that control insulin secretion (see earlier

Answer 373

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. These forms of diabetes result from either a primary defect in β-cell function or a defect in insulin receptor signaling (described later

Answer 374

Approximately 1% to 2% of patients with diabetes harbor a primary defect in β-cell function that occurs without β-cell loss, affecting either β-cell mass and/or insulin production. This form of monogenic diabetes is caused by a heterogeneous group of genetic defects. The largest subgroup of patients in this category was traditionally designated as having “maturity-onset diabetes of the young” (MODY) because of its superficial resemblance to type 2 diabetes and its occurrence in younger patients. MODY can result from germline loss-of-function mutations in one of six genes ( Table 24-6 ), of which mutations of glucokinase ( GCK ) are the most common. Glucokinase is a rate limiting step in oxidative glucose metabolism, which in turn, is coupled to insulin secretion within islet β cells ( Fig. 24-28 ). Other rare genetic causes for primary defects in β cell function include mutations of genes that code for the two subunits of the ATP-sensitive K + -channel, defects in mitochondrial DNA (which can impede ATP synthesis), and mutations of the insulin gene itself

Answer 375

Rare insulin receptor mutations that affect receptor synthesis, insulin binding, or receptor tyrosine kinase activity can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance). Such patients often show a velvety hyperpigmentation of the skin, known as acanthosis nigricans . Females with type A insulin resistance frequently have polycystic ovaries and elevated androgen levels. Lipoatrophic diabetes , as the name suggests, is hyperglycemia accompanied by loss of adipose tissue, the latter occurring selectively in the subcutaneous fat. This rare group of genetic disorders has in common insulin resistance, diabetes, hypertriglyceridemia, acanthosis nigricans, and abnormal fat deposition in the liver (hepatic steatosis). Multiple subtypes of lipoatrophic diabetes, each ascribed to a different causal mutation, have been reported

Answer 376

Pregnancy can be complicated by diabetes in one of two settings: when women with preexisting diabetes become pregnant (“pregestational” or overt diabetes), or women who were previously euglycemic develop impaired glucose tolerance and diabetes for the first time during pregnancy (“gestational” diabetes). Approximately 5% of pregnancies occurring in the United States are complicated by hyperglycemia, and the incidence of both pregestational and gestational diabetes is rising in parallel with the rising incidence of obesity and diabetes in the general population. Pregnancy is a “diabetogenic” state in which the prevailing hormonal milieu favors a state of insulin resistance. In a previously euglycemic woman who is otherwise susceptible due to concurrent genetic and environmental factors, the consequence may be gestational diabetes. Women with pregestational diabetes (where hyperglycemia is already present in the periconception period) have an increased risk of stillbirth and congenital malformations in the fetus. Poorly controlled diabetes that arises later in pregnancy, regardless of prior history, can lead to excessive birth weight in the newborn ( macrosomia ), as well as long-term sequelae for the child exposed to a diabetic environment in utero, including obesity and diabetes later in life. Gestational diabetes typically resolves following delivery; however, the majority of women with this condition will develop overt diabetes over the next 10 to 20 years.

Answer 377

It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus. We will discuss the most common initial presentation or mode of diagnosis for each of the two major subtypes, followed by a discussion of acute, and then chronic (long-term) complications of diabetes

Answer 378

Type 1 diabetes was formerly thought to occur primarily in persons younger than age 18 but is now known to occur at any age. In the initial 1 or 2 years following the onset of overt type 1 diabetes, the exogenous insulin requirements may be minimal because of ongoing endogenous insulin secretion (referred to as the honeymoon period ). Thereafter, any residual β-cell reserve is exhausted and insulin requirements increase dramatically. Although β-cell destruction is a prolonged process, the transition from impaired glucose tolerance to overt diabetes may be abrupt and is often brought on by an event, such as infection, that is also associated with increased insulin requirements

Answer 379

In contrast to type 1 diabetes, patients with type 2 diabetes are typically older than 40 years and frequently obese. However, with the increase in obesity and sedentary lifestyle in this society, type 2 diabetes is being seen in children and adolescents with increasing frequency. In some cases, medical attention is sought because of unexplained fatigue, dizziness, or blurred vision. Most frequently, however, the diagnosis of type 2 diabetes is made after routine blood testing in asymptomatic persons. In fact, in light of the large number of asymptomatic individuals with undiagnosed hyperglycemia in the United States, routine glucose testing is recommended for everyone older than 45 years of age.

Answer 380

The onset of type 1 diabetes is usually marked by the triad of polyuria, polydipsia, polyphagia, and, when severe, diabetic ketoacidosis, all resulting from metabolic derangements.

Answer 381

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 ensues. The glycosuria induces an osmotic diuresis and thus polyuria , causing a profound loss of water and electrolytes ( Fig. 24-33 ). 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

Answer 382

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.

Answer 383

Diabetic ketoacidosis is a severe acute metabolic complication of type 1 diabetes, but may also occur in type 2 diabetes, though not as commonly and not to as marked an extent. The most common precipitating factor is a failure to take insulin, although other stressors such as intercurrent infections, illness, trauma and certain drugs might also lead to this complication. Many of these factors are associated with the release of the catecholamine epinephrine , which blocks any residual insulin action and stimulates the secretion 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 250 to 600 mg/dL). The hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state.

Answer 384

The second major effect of insulin deficiency is activation of the ketogenic machinery . Insulin deficiency stimulates hormone sensitive lipase, with resultant 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 coenzyme A. Oxidation of fatty acyl coenzyme A 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 result is a systemic metabolic ketoacidosis . Release of ketogenic amino acids by protein catabolism aggravates the ketotic state.

Answer 385

The clinical manifestations of diabetic ketoacidosis include fatigue, nausea and vomiting, severe abdominal pain, a characteristic fruity odor, and deep, labored breathing (also known as Kussmaul breathing ). Persistence of the ketotic state eventually leads to depression in cerebral consciousness and coma. Reversal of ketoacidosis requires administration of insulin, correction of metabolic acidosis, and treatment of the underlying precipitating factors such as infection

Answer 386

In contrast to type 1 diabetes, the frequency of ketoacidosis is significantly lower in type 2 diabetes, presumably because of higher portal vein insulin levels in these patients, which prevents unrestricted hepatic fatty acid oxidation and keeps the formation of ketone bodies in check. Instead, type 2 diabetics may develop a condition known as hyperosmolar hyperosmotic syndrome (HHS) due to severe dehydration resulting from sustained osmotic diuresis (particularly in patients who do not drink enough water to compensate for urinary losses from chronic hyperglycemia). Typically, the patient is an older 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, Kussmaul breathing) delays the seeking of medical attention until severe dehydration and impairment of mental status occur. The hyperglycemia is usually more severe than in diabetic ketoacidosis, in the range of 600 to 1200 mg/dL

Answer 387

Ironically, the most common acute metabolic complication in either type of diabetes is hypoglycemia, usually as a result of having missed a meal, excessive physical exertion, an excess insulin administration, or during the phase of dose finding for antidiabetic agents. The signs and symptoms of hypoglycemia include dizziness, confusion, sweating, palpitations, and tachycardia; if hypoglycemia persists, loss of consciousness may occur. Reversal of hypoglycemia through oral or intravenous glucose intake prevents the onset of permanent neurological damage

Answer 388

The morbidity associated with longstanding diabetes of either type is due to damage induced in large- and medium-sized muscular arteries ( diabetic macrovascular disease ) and in small vessels ( diabetic macrovascular disease ) by chronic hyperglycemia. Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lower extremity ischemia. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively (see later

Answer 389

Persistent hyperglycemia (“glucotoxicity”) seems to be responsible for the long term complications of diabetes . Much of the evidence supporting a role for glycemic control in ameliorating the long-term complications of diabetes has come from large randomized trials. The assessment of glycemic control in these trials has been based on the percentage of glycated hemoglobin , also known as Hb A1C , which is formed by nonenzymatic covalent addition of glucose moieties to hemoglobin in red cells. Unlike blood glucose levels, Hb A1C provides a measure of glycemic control over the lifespan of a red cell (120 days) and is affected little by day-to-day variations. It is recommended that Hb A1C be maintained below 7% in diabetic patients. It is important to stress that hyperglycemia is not the only factor responsible for the long-term complications of diabetes, and that other underlying abnormalities, such as insulin resistance, and co-morbidities like obesity, also play an important role

Answer 390

In each of the proposed mechanisms, increased glucose flux through various intracellular metabolic pathways is thought to generate harmful precursors that contribute to end organ damage

Answer 391

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 groups of both intracellular and extracellular proteins. The natural rate of AGE formation is greatly accelerated in the presence of hyperglycemia. AGEs bind to a specific receptor (RAGE) that is expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle. The detrimental effects of the AGE-RAGE signaling axis within the vascular compartment include

Answer 392

• Release of cytokines and growth factors , including transforming growth factor β (TGFβ), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy (see later

Answer 393

* Release of cytokines and growth factors , including transforming growth factor β (TGFβ), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy (see later) * Generation of reactive oxygen species (ROS) in endothelial cells * Increased procoagulant activity on endothelial cells and macrophages * Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix

Answer 394

In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins. Cross-linking of 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 extravasation of fluid. Proteins cross-linked by AGEs 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 of 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 bind to the glycated basement membrane, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy.

Answer 395

Calcium-dependent activation of intracellular protein kinase C (PKC) and the second messenger diacyl glycerol (DAG) is an important signal transduction pathway. Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence causes excessive PKC activation. The downstream effects of PKC activation are numerous, including production of VEGF, TGF-β, and the procoagulant protein plasminogen activator inhibitor-1 (PAI-1) ( Chapter 4 ) by the vascular endothelium. It should be evident that some effects of AGEs and activated PKC are overlapping, and both likely contribute to diabetic microangiopathy

Answer 396

Even in some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular glucose. This excess glucose is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor. NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH). GSH is one of the important antioxidant mechanisms in the cell ( Chapter 2 ), and any reduction in GSH increases cellular susceptibility to ROS (“oxidative stress”). In the face of sustained hyperglycemia, progressive depletion of intracellular NADPH by aldol reductase compromises GSH regeneration, increasing cellular susceptibility to oxidative stress. Sorbitol accumulation in the lens contributes to cataract formation

Answer 397

Finally, it is postulated that hyperglycemia-induced flux through the hexosamine pathway increases intracellular levels of fructose-6-phosphate , which is a substrate for glycosylation of proteins, leading to generation of excess proteoglycans. These glycosylation changes are accompanied by abnormal expression of TGFβ or PAI-1, which further exacerbate the end-organ damage

Answer 398

The important morphologic changes are related to the many late systemic complications of diabetes. As previously discussed, these changes are seen in both type 1 and type 2 diabetes ( Fig. 24-34 ). We will first discuss the morphologic changes and then describe the clinical manifestations resulting from the altered morphology

Answer 399

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

Answer 400

* 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. * Leukocytic infiltrates in the islets (insulitis) are principally composed of T lymphocytes, and are also seen in animal models of autoimmune diabetes ( Fig. 24-35 A ). Lymphocytic infiltrates may be present in type 1 diabetics at the time of clinical presentation. The distribution of insulitis may be strikingly uneven in infants who fail to survive the immediate postnatal period

Answer 401

* In type 2 diabetes there may be a subtle reduction in islet cell mass, demonstrated only by special morphometric studies. * Amyloid deposition within islets in type 2 diabetes begins in and around capillaries and between cells. At advanced stages, the islets may be virtually obliterated ( Fig. 24-35 B ); fibrosis may also be observed. Similar lesions may be found in older nondiabetics, apparently as part of normal aging

Answer 402

• 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

Answer 403

iabetes exacts a heavy toll on the vascular system. Endothelial dysfunction ( Chapter 11 ), which predisposes to atherosclerosis and other cardiovascular morbidities, is widespread in diabetes, as a consequence of the deleterious effects of persistent hyperglycemia and insulin resistance on the vascular compartment. 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. 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 is discussed later

Answer 404

Hyaline arteriolosclerosis , the vascular lesion associated with hypertension ( Chapters 11 and 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 older 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 pressure

Answer 405

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. 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

Answer 406

The kidneys are prime targets of diabetes. 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

Answer 407

Widespread thickening of the glomerular capillary basement membrane (GBM) occurs in virtually all cases of diabetic nephropathy and is part and parcel of the diabetic microangiopathy. Pure capillary basement membrane thickening can be detected only by electron microscopy ( Fig. 24-37 ). Careful morphometric studies demonstrate that this thickening begins as early as 2 years after the onset of type 1 diabetes and by 5 years amounts to about a 30% increase. The thickening continues progressively and usually concurrently with mesangial widening. Simultaneously, there is thickening of the tubular basement membranes

Answer 408

This lesion consists of diffuse increase in mesangial matrix . There can be mild proliferation of mesangial cells early in the disease process, but cell proliferation is not a prominent part of this injury. The mesangial increase is typically associated with the overall thickening of the GBM. The matrix depositions are PAS-positive ( Fig. 24-39 ). As the disease progresses, the expansion of mesangial areas can extend to nodular configurations. The progressive expansion of the mesangium has been shown to correlate well with measures of deteriorating renal function such as increasing proteinuria.

Answer 409

This is also known as intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease . The glomerular lesions take the form of ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus. The nodules are PAS-positive. They lie within the mesangial core of the glomerular lobules and can be surrounded by patent peripheral capillary loops ( Fig. 24-39 ) or loops that are markedly dilated. The nodules often show features of mesangiolysis with fraying of the mesangial/capillary lumen interface and disruption of sites at which the capillaries are anchored into the mesangial stalks. The latter may produce capillary microaneurysms as the untethered capillaries distend outward due to force imparted by intracapillary blood pressure and flow. Usually, not all the lobules in individual glomeruli are involved by nodular lesions, but even uninvolved lobules and glomeruli show striking diffuse mesangial sclerosis. As the disease advances, the individual nodules enlarge and may eventually compress and engulf capillaries, obliterating the glomerular tuft. These nodular lesions are frequently accompanied by prominent accumulations of hyaline material in capillary loops (“ fibrin caps ”) or adherent to Bowman capsules (“ capsular drops ”). Both afferent and efferent glomerular hilar arterioles show hyalinosis. As a consequence of the glomerular and arteriolar lesions, the kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes overall contraction in size ( Fig. 24-40 ). Approximately 15% to 30% of individuals with long-term diabetes develop nodular glomerulosclerosis, and in most instances it is associated with renal failure

Answer 410

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 in other tissues. 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

Answer 411

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 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 nondiabet

Answer 412

The eye is profoundly affected by diabetes mellitus . The architecture and microanatomy of the eye are discussed in Chapter 29 . Diabetes-induced hyperglycemia leads to acquired opacification of the lens, a condition known as cataract . Long-standing diabetes is also associated with increased intraocular pressure ( glaucoma ) (see later), and resulting damage to the optic nerve. The most profound histopathologic changes of diabetes are seen in the retina . The retinal vasculopathy of diabetes mellitus can be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy

Answer 413

The prevalence of peripheral neuropathy in individuals with diabetes depends on the duration of the disease; up to 50% of diabetics overall have peripheral neuropathy clinically, and up to 80% of those who have had the disease for more than 15 years. This is discussed further

Answer 414

Table 24-7 summarizes some of the pertinent clinical, genetic, and histopathologic features that distinguish type 1 and type 2 diabetes. In both types it is the long-term effects of diabetes, more than the acute metabolic complications, that are responsible for the overwhelming majority of the morbidity and mortality . In most instances these complications appear approximately 15 to 20 years after the onset of hyperglycemia. The severity of chronic complications is related to both the degree and the duration of hyperglycemia, as evidenced by the attenuation of end-organ damage by effective glycemic control in prospective studies

Answer 415

Diabetics have a two to four times greater incidence of coronary artery disease, and a fourfold higher risk of dying from cardiovascular complications than nondiabetics. An elevated risk for cardiovascular disease is even observed in prediabetics. Significantly, myocardial infarction is almost as common in diabetic women as in diabetic men. In contrast, myocardial infarction is uncommon in nondiabetic women of reproductive age. Diabetes is often accompanied by underlying conditions that favor the development of adverse cardiovascular events. For example, hypertension is found in approximately 75% of individuals with type 2 diabetes and potentiates the effects of hyperglycemia and insulin resistance on endothelial dysfunction and atherosclerosis. Another cardiovascular risk frequently seen in diabetics is dyslipidemia , which includes both increased triglycerides and LDL levels and decreased levels of the “protective” lipoprotein, high-density lipoprotein ( Chapter 11 ). Insulin resistance is believed to contribute to “diabetic dyslipidemia” by favoring the hepatic production of atherogenic lipoproteins and by suppressing the uptake of circulating lipids in peripheral tissues. Finally, diabetics have elevated levels of PAI-1, which is an inhibitor of fibrinolysis and therefore acts as a procoagulant in the formation of atherosclerotic plaques

Answer 416

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 . Notably, microalbuminuria is also a marker for greatly increased cardiovascular morbidity and mortality for persons 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 is highly variable, but 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

Answer 417

. Approximately 60% to 80% of patients develop some form of diabetic retinopathy approximately 15 to 20 years after diagnosis. The fundamental lesion of retinopathy—neovascularization—is attributable to hypoxia-induced overexpression of VEGF in the retina. Current treatment for this condition includes administration of antiangiogenic agents. As stated earlier, diabetics also have an increased propensity for glaucoma and cataract formation , both of which contribute to visual impairment in diabetes

Answer 418

can elicit a variety of clinical syndromes, afflicting the central nervous system, peripheral sensorimotor nerves, and the autonomic nervous system. The most frequent pattern of involvement is a distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function . Over time the upper extremities may be involved as well, thus approximating a “glove and stocking” pattern of polyneuropathy. Other forms include autonomic neuropathy , which produces disturbances in bowel and bladder function and sometimes erectile dysfunction, and diabetic mononeuropathy , which may manifest as sudden footdrop, wristdrop, or isolated cranial nerve palsies.

Answer 419

. Such infections cause the deaths of about 5% of diabetics. 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. The basis of enhanced susceptibility is multifactorial, and includes decreased neutrophil functions (chemotaxis, adherence to the endothelium, phagocytosis, and microbicidal activity), and impaired cytokine production by macrophages. The vascular compromise also reduces delivery of circulating cells and molecules that are required for host defense

Answer 420

▪ Type 1 diabetes is an autoimmune disease characterized by progressive destruction of islet β cells, leading to absolute insulin deficiency. The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells, and circulating autoantibodies to islet cell antigens (including insulin) often are detected in affected patients. ▪ Type 2 diabetes has no autoimmune basis; instead, features central to its pathogenesis are insulin resistance and β- cell dysfunction , resulting in relative insulin deficiency. ▪ Obesity has an important relationship with insulin resistance (and hence type 2 diabetes), mediated through multiple factors including excess free fatty acids, cytokines released from adipose tissues (adipocytokines), and inflammation. ▪ Monogenic forms of diabetes are uncommon and are caused by single-gene defects that result in primary β-cell dysfunction (e.g., glucokinase mutation) or lead to abnormalities of insulin-insulin receptor signaling (e.g., insulin receptor gene mutations). ▪ The long-term complications of diabetes are similar in both types and involve four potential mechanisms resulting from sustained hyperglycemia: formation of advanced glycation end products (AGEs), activation of protein kinase C (PKC), disturbances in the polyol pathways leading to oxidative stress, and overload of the hexosamine pathway. ▪ Long term complications of diabetes include both large vessel disease ( macroangiopathy ), such as atherosclerosis, ischemic heart disease and lower extremity ischemia, as well as small vessel disease ( microangiopathy ), the latter manifesting mainly as retinopathy, nephropathy and neuropathy

Answer 421

The preferred term for tumors of the pancreatic islet cells (“islet cell tumors”) is pancreatic neuroendocrine tumors or PanNETs . They are rare in comparison with tumors of the exocrine pancreas, accounting for only 2% of all pancreatic neoplasms. PanNETs 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 their counterparts, carcinoid tumors, found elsewhere in the alimentary tract ( Chapter 17 ). These tumors may be single or multiple and benign or malignant. Pancreatic endocrine neoplasms often elaborate pancreatic hormones, or may be nonfunctional

Answer 422

Like other endocrine neoplasms, it is difficult to predict the behavior of a pancreatic endocrine neoplasm based on their light microscopic appearance. Unequivocal criteria for malignancy include metastases, vascular invasion, and local infiltration. The functional status of the tumor has some impact on prognosis, in that approximately 90% of insulin producing tumors are benign, while 60% to 90% of other functioning and nonfunctioning pancreatic endocrine neoplasms are malignant. Fortunately, insulinomas are the most common subtype of pancreatic endocrine neoplasms

Answer 423

* MEN1 , which causes familial MEN syndrome, type 1, also is mutated in a number of sporadic neuroendocrine tumors * Loss-of-function mutations in tumor suppressor genes such PTEN and TSC2 ( Chapter 7 ) , which result in activation of the oncogenic mammalian TOR (mTOR) signaling pathway. * Inactivating mutations in two genes, alpha-thalassemia/mental retardation syndrome, X-linked ( ATRX ) and death-domain associated protein ( DAXX ) , which have multiple cellular functions, including telomere maintenance. Of note, nearly half of PanNETs have a somatic mutation in either ATRX or DAXX, but not both, suggesting that the encoded proteins function in a critical common pathway

Answer 424

(1) hyperinsulinism , (2) hypergastrinemia and the Zollinger-Ellison syndrome , and (3) multiple endocrine neoplasia (MEN) (described in detail later

Answer 425

β-cell tumors (insulinomas) are the most common of pancreatic endocrine neoplasms, and may produce sufficient insulin to induce clinically significant hypoglycemia. The characteristic clinical picture is dominated by hypoglycemic episodes, which occur if the blood glucose level falls below 50 mg/dL of serum. The clinical manifestations include confusion, stupor, and loss of consciousness. These episodes are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose

Answer 426

Insulinomas are most often found within the pancreas and are generally benign. Most are solitary, although multiple tumors may be encountered. Bona fide carcinomas, making up only about 10% of cases, are diagnosed on the basis of local invasion and distant metastases. On rare occasions an insulinoma may arise in ectopic pancreatic tissue. In such cases, electron microscopy reveals the distinctive granules of β-cells

Answer 427

Solitary tumors are usually small (often < 2 cm in diameter), 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, and they may be deceptively encapsulated. Deposition of amyloid is a characteristic feature of many insulinomas

Answer 428

. This change is found occasionally in adults but is far more commonly encountered as congenital hyperinsulinism with hypoglycemia in neonates and infants. Several clinical scenarios may result in islet hyperplasia (previously known as nesidioblastosis ), including maternal diabetes, Beckwith-Wiedemann syndrome ( Chapter 10 ), and rare mutations in the β-cell K + -channel protein or sulfonylurea receptor. In maternal diabetes, the fetal islets respond to hyperglycemia by increasing their size and number. In the postnatal period, these hyperactive islets may be responsible for serious episodes of hypoglycemia. This phenomenon is usually transient

Answer 429

While up to 80% of islet cell tumors 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-to-glucose ratio. Surgical removal of the tumor is usually followed by prompt reversal of the hypoglycemia

Answer 430

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 agreement regarding the cell of origin of these tumors, although it seems 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, hypersecretion of gastric acid and severe peptic ulceration , which are present in 90% to 95% of patients

Answer 431

More than 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, as part of the MEN-1 syndrome (see later); 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 show marked anaplasia. In the Zollinger-Ellison syndrome, hypergastrinemia gives rise to extreme gastric acid secretion, which in turn causes peptic ulceration ( Chapter 17 ). The duodenal and gastric ulcers are often multiple; although they are identical to those found in the general population, they are often unresponsive to therapy. In addition, ulcers may occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered

Answer 432

More than 50% of the patients have diarrhea; in 30%, it is the presenting symptom. Treatment of Zollinger-Ellison syndrome involves control of gastric acid secretion by use of H + K + -ATPase inhibitors and excision of the neoplasm. Total resection of the neoplasm, when possible, eliminates the syndrome. Patients with hepatic metastases have a shortened life expectancy, with progressive tumor growth leading to liver failure usually within 10 years

Answer 433

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

Answer 434

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

Answer 435

VIPoma (watery diarrhea, hypokalemia, achlorhydria, or WDHA syndrome) induces a characteristic syndrome that is 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, ganglioneuroblastoma, and ganglioneuromas ( Chapter 10 ) and pheochromocytomas (see later) can also be associated with the VIPoma syndrome

Answer 436

Pancreatic carcinoid tumors producing serotonin and an atypical carcinoid syndrome are exceedingly rare. Pancreatic polypeptide-secreting endocrine tumors present as mass lesions as even high plasma levels of this hormone fail to cause symptoms

Answer 437

In addition to insulin, glucagon, and gastrin, pancreatic endocrine tumors may produce ACTH, MSH, ADH, serotonin, and norepinephrine. These multihormonal tumors are to be distinguished from the MEN syndromes (discussed later), in which a multiplicity of hormones is produced by tumors in several different glands

Answer 438

The adrenal glands are paired endocrine organs consisting of a cortex and a medulla, which differ in their development, structure, and function. In essence the cortex and medulla are two glands packaged as one structure. The adrenal cortex has three zones. Beneath the capsule 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 and to a lesser degree in 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 chromaffin cells, which synthesize and secrete catecholamines , mainly epinephrine. Catecholamines have many effects that allow rapid adaptations to changes in the environment

Answer 439

hyperfunction and those associated with hypofunction

Answer 440

The syndromes of adrenal hyperfunction are caused by overproduction of the three major hormones of the adrenal cortex (1) Cushing syndrome , characterized by an excess of cortisol; (2) hyperaldosteronism as a result of excessive aldosterone; 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

Answer 441

This disorder is caused by conditions that produce elevated glucocorticoid levels. Cushing syndrome can be broadly divided into exogenous and endogenous causes. The vast majority of cases of Cushing syndrome are the result of the administration of exogenous glucocorticoids (“iatrogenic” Cushing syndrome). The endogenous causes can, in turn, be divided into those that are ACTH dependent and those that are ACTH independent

Answer 442

I n recognition of Harvey Cushing, the neurosurgeon who first published the full description of this syndrome, the pituitary form is referred to as Cushing disease . The disorder affects women about four times more frequently than men and occurs most frequently in young adults. In the vast majority of cases it is caused by an ACTH-producing pituitary microadenoma . In some cases there is an underlying macroadenoma and rarely there is corticotroph cell hyperplasia without a discrete adenoma. Corticotroph cell hyperplasia may be primary or arise secondarily from excessive stimulation of ACTH release by a hypothalamic corticotrophin-releasing hormone (CRH)-producing tumor. The adrenal glands in individuals with Cushing disease 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 for hypercortisolism

Answer 443

c ACTH by nonpituitary tumors accounts for about 10% of ACTH-dependent Cushing syndrome. In many instances the responsible tumor is a small-cell carcinoma of the lung , although other neoplasms, including carcinoids, medullary carcinomas of the thyroid, and islet cell tumors, have been associated with the syndrome. In addition to tumors that elaborate ectopic ACTH, occasionally a neuroendocrine neoplasm may produce ectopic corticotrophin releasing hormone (CRH), which, in turn, causes ACTH secretion and hypercortisolism. As in the pituitary variant, the adrenal glands undergo bilateral cortical hyperplasia, but the rapid downhill course of patients with these cancers often limits the extent of the adrenal enlargement. This variant of Cushing syndrome is more common in men and usually occurs in the 40s and 50s

Answer 444

The biochemical sine qua non of ACTH-independent Cushing syndrome is elevated serum levels of cortisol with low levels of ACTH. Cortical carcinomas tend to produce more marked hypercortisolism than adenomas or hyperplasias. In instances of a unilateral neoplasm, the uninvolved adrenal cortex and the cortex in the opposite gland undergo atrophy because of suppression of ACTH secretion

Answer 445

In macronodular hyperplasia the nodules are usually greater than 3 mm in diameter. Macronodular hyperplasia is typically a sporadic (nonsyndromic) condition observed in adults. It is now known that, although the condition is ACTH independent, it is not entirely “autonomous.” Specifically, cortisol production is regulated by non-ACTH circulating hormones, because of ectopic overexpression of their corresponding receptors in the adrenocortical cells. Such non-ACTH hormones include gastric inhibitory peptide, LH and ADH; their receptors are overexpressed on hyperplastic adrenal cortical cells. The mechanism by which these receptors for non-ACTH hormones are overexpressed in adrenocortical tissues is not known. A subset of macronodular hyperplasia arises in the setting of McCune-Albright syndrome ( Chapter 26 ), characterized by somatic mutations that activate GNAS , which encodes a stimulatory G s α. This G s α mutation causes hyperplasia by increasing intracellular levels of cAMP, which you will recall is an important second messenger in many endocrine cell types. Given this, it is not surprising that mutations in several other proteins that are involved in cAMP signaling, such as the regulatory subunit of cAMP-dependent protein kinase (encoded by the PRKAR1A gene) and a phosphodiesterase (an enzyme that breaks down cAMP, encoded by the PDE11A gene), are also associated with primary cortical hyperplasia

Answer 446

The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. The pituitary shows changes regardless of the cause. The most 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 becomes homogeneous and paler. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm.

Answer 447

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 contrast, in cases of endogenous hypercortisolism, the adrenals either are hyperplastic or contain a cortical neoplasm.

Answer 448

Diffuse hyperplasia is found in individuals with ACTH-dependent Cushing syndrome ( Fig. 24-42 ). Both glands are enlarged, either subtly or markedly, weighing up to 30 gm. The adrenal cortex is diffusely thickened and variably nodular, although the latter is not as pronounced as seen in cases of ACTH-independent nodular hyperplasia. Microscopically, the hyperplastic cortex demonstrates an expanded “lipid-poor” zona reticularis, comprising compact, eosinophilic cells, surrounded by an outer zone of vacuolated “lipid-rich” cells, resembling those seen in the zona fasciculata. Any nodules present are usually composed of vacuolated “lipid-rich” cells, which account for the yellow color of diffusely hyperplastic glands.

Answer 449

contrast, in macronodular hyperplasia the adrenals are almost entirely replaced by prominent nodules of varying sizes (≤3 cm), which contain an admixture of lipid-poor and lipid-rich cells. Unlike diffuse hyperplasia, the areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity.

Answer 450

Micronodular hyperplasia is composed of 1- to 3-mm darkly pigmented (brown to black) micronodules, with atrophic intervening areas ( Fig. 24-43 ). The pigment is believed to be lipofuscin, a wear-and-tear pigment ( Chapter 2 ).

Answer 451

Primary adrenocortical neoplasms causing Cushing syndrome may be malignant or benign. Functional adenomas or carcinomas of the adrenal cortex as the source of cortisol are not morphologically distinct from nonfunctioning adrenal neoplasms (described later). Both the benign and the malignant lesions are more common in women in their 30s to 50s. 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. The carcinomas associated with Cushing syndrome, by contrast, tend to be larger than the adenomas. These tumors (detailed later) are unencapsulated masses frequently exceeding 200 to 300 gm in weight that have all of the anaplastic characteristics of cancer. With functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of the contralateral adrenal gland are atrophic, as a result of suppression of endogenous ACTH by high cortisol levels

Answer 452

Cushing syndrome develops slowly and 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 in the form of 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 (secondary diabetes) . The catabolic effects 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 ( Fig. 24-44 ). Bone resorption results in the development of osteoporosis , with consequent backache and increased susceptibility to fractures. Persons with Cushing syndrome are at increased risk for a variety of infections, because glucocorticoids suppress the immune response. Additional manifestations include several mental disturbances , including mood swings, depression, and frank psychosis, as well as hirsutism and menstrual abnormalities

Answer 453

A patient with Cushing syndrome demonstrating central obesity, “moon facies,” and abdominal striae. (Reproduced with permission from Lloyd RV, et al (eds): Atlas of Nontumor Pathology: Endocrine Diseases. Washington, DC, American Registry of Pathology, 2002

Answer 454

The laboratory diagnosis of Cushing syndrome is based on the following: (1) the 24-hour urine free-cortisol concentration, which is increased, and (2) loss of normal diurnal pattern of cortisol secretion. Determining the cause of Cushing syndrome depends on the serum ACTH and measurement of urinary steroid excretion after administration of dexamethasone (dexamethasone suppression test). The results of these tests fall into three general patterns

Answer 455

* 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-hydroxycorticosteroids. After higher doses of injected dexamethasone, however, the pituitary responds by reducing ACTH secretion, which is reflected by suppression of urinary steroid secretion. * Ectopic ACTH secretion results in an elevated level of ACTH, but its secretion is completely insensitive to low or high doses of exogenous dexamethasone. * 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 excretion

Answer 456

▪ The most common cause of hypercortisolism is exogenous administration of steroids. ▪ Endogenous hypercortisolism most often is secondary to an ACTH-producing pituitary microadenoma ( Cushing disease ), followed by primary adrenal neoplasms ( ACTH-independent hypercortisolism) and paraneoplastic ACTH production by tumors (e.g., small cell lung cancer). ▪ The morphologic features in the adrenal vary from bilateral cortical atrophy (in exogenous steroid-induced disease), to bilateral diffuse or nodular hyperplasia (most common finding in endogenous Cushing syndrome), to an adrenocortical neoplasm.

Answer 457

Hyperaldosteronism is the generic term for a group of closely related conditions characterized by chronic excess aldosterone secretion. Hyperaldosteronism may be primary, or it may be secondary to an extra-adrenal cause. Primary hyperaldosteronism stems from an autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity . Blood pressure elevation is the most common manifestation of primary hyperaldosteronism , which is caused by one of three mechanisms

Answer 458

, characterized by bilateral nodular hyperplasia of the adrenal glands, is the most common underlying cause of primary hyperaldosteronism, accounting for about 60% of cases. Individuals with idiopathic hyperaldosteronism tend to be older and to have less severe hypertension than those presenting with adrenal neoplasms. The pathogenesis of idiopathic hyperaldosteronism remains unclear, although recent studies suggest that a subset of patients with familial idiopathic hyperaldosteronism harbor germline mutations of KCNJ5 , encoding a potassium channel

Answer 459

either an aldosterone-producing adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 35% 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 patient. Somatic mutations of KCNJ5 are also present in a subset of aldosterone-secreting adenomas

Answer 460

is an uncommon cause of primary familial hyperaldosteronism. In some families, it stems from a rearrangement involving chromosome 8 that places CYP11B2 (the gene that encodes aldosterone synthase ) under the control of the ACTH responsive CYP11B1 gene promoter. ACTH thus stimulates the production of aldosterone synthase, the enzyme that is responsible for the last step in aldosterone synthesis. Because in this unusual circumstance aldosterone production is under the control of ACTH, it is suppressible by

Answer 461

in contrast, aldosterone release occurs in response to activation of the renin-angiotensin system ( Chapter 11 ). 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 syndrome) * Pregnancy (due to estrogen-induced increases in plasma renin substrate

Answer 462

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 30s and 40s, and in women more often than in men. They 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 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; occasionally, there is modest nuclear and cellular pleomorphism (see Fig. 24-51 ). A characteristic feature of aldosterone-producing adenomas is the presence of eosinophilic, laminated cytoplasmic inclusions, known as spironolactone bodies , found after treatment with the antihypertensive 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

Answer 463

Bilateral idiopathic hyperplasia 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. The enlargement may be subtle, and as a rule an adrenocortical adenoma must be carefully excluded as the cause for hyperaldosteronism

Answer 464

The most important clinical consequence of hyperaldosteronism is hypertension . With an estimated prevalence rate of 5% to 10% among nonselected hypertensive patients, primary hyperaldosteronism may be the most common cause of secondary hypertension (i.e., hypertension secondary to an identifiable cause). The prevalence of hyperaldosteronism increases with the severity of hypertension, reaching nearly 20% in patients who are classified as having treatment-resistant hypertension. Through its effects on the renal mineralocorticoid receptor, aldosterone promotes sodium reabsorption, which secondarily increases the reabsorption of water, expanding the extracellular fluid volume and elevating cardiac output

Answer 465

The long-term effects of hyperaldosteronism-induced hypertension are cardiovascular compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) and an increase in the prevalence of adverse events such as stroke and myocardial infarction. Hypokalemia was considered a mandatory feature of primary hyperaldosteronism, but increasing numbers of normokalemic patients are now diagnosed. Hypokalemia results from renal potassium wasting and, when present, can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally frank tetany

Answer 466

The diagnosis of primary hyperaldosteronism is confirmed by elevated ratios of plasma aldosterone concentration to plasma renin activity; if this screening test is positive, a confirmatory aldosterone suppression test must be performed, because many unrelated causes can alter the plasma aldosterone and renin ratios

Answer 467

In primary hyperaldosteronism, the therapy varies according to cause. Adenomas are amenable to surgical excision. In contrast, surgical intervention is not very beneficial in patients with primary hyperaldosteronism due to bilateral hyperplasia, which often occurs in children and young adults. These patients are best managed medically with an aldosterone antagonist such as spironolactone. The treatment of secondary hyperaldosteronism rests on correcting the underlying cause stimulating the renin-angiotensin system

Answer 468

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 can be converted to testosterone in peripheral tissues. Unlike gonadal androgens, ACTH regulates adrenal androgen formation ( Fig. 24-46 ); 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 neoplasms and a group of disorders that have been designated congenital adrenal hyperplasia (CAH

Answer 469

Such tumors are often also associated with hypercortisolism (“mixed syndrome”). They are morphologically identical to other cortical neoplasms and will be discussed later

Answer 470

teroid precursors that build behind the defective step in the pathway are channeled into other pathways, resulting in increased production of androgens, which accounts for virilization. Simultaneously, the deficiency of cortisol leads to increased secretion of ACTH, culminating 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

Answer 471

21-hydroxylase deficiency (caused by mutations of CYP21A2 ) is by far the most common, accounting for over 90% of cases. Figure 24-46 illustrates normal adrenal steroidogenesis and the consequences of 21-hydroxylase deficiency, which may range from a total lack to a mild loss, depending on the nature of the CYP21A2 mutation. Three distinctive syndromes have been described: (1) salt-wasting (“classic”) adrenogenitalism, (2) simple virilizing adrenogenitalism, and (3) “nonclassic” adrenogenitalism

Answer 472

• 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 resulting in 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. 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

Answer 473

• Simple virilizing adrenogenital syndrome without salt wasting (presenting as genital ambiguity) occurs in approximately a third of patients with 21-hydroxylase deficiency. These patients generate sufficient mineralocorticoid to prevent a salt-wasting “crisis.” However, the lowered glucocorticoid level fails to cause feedback inhibition of ACTH secretion. Thus, the level of testosterone is increased, with resultant progressive virilization

Answer 474

• Nonclassic or late-onset adrenal virilism is significantly more common than the classic patterns already described. There is only a partial deficiency in 21-hydroxylase function, which accounts for the later onset. Individuals with this syndrome may be virtually asymptomatic or have mild manifestations, such as hirsutism, acne, and menstrual irregularities. Nonclassic CAH cannot be diagnosed on routine newborn screening, and the diagnosis is usually rendered by demonstration of biosynthetic defects in steroidogenesis

Answer 475

In all cases of CAH the adrenals are bilaterally hyperplastic, sometimes increasing 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, because of 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 persons with CAH

Answer 476

The clinical features of these disorders are determined by the specific enzyme deficiency and include abnormalities related to androgen excess , with or without aldosterone and glucocorticoid deficiency . CAH affects not only adrenal cortical enzymes but also products synthesized in the 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

Answer 477

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.

Answer 478

. Severe enzyme deficiency in infancy can be a life-threatening condition with vomiting, dehydration, and salt wasting. Individuals with CAH 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

Answer 479

The adrenal cortex can secrete excess androgens in either of two settings: adrenocortical neoplasms (usually virilizing carcinomas) or congenital adrenal hyperplasia (CAH). ▪ CAH consists of a group of autosomal recessive disorders characterized by defects in steroid biosynthesis, usually cortisol; the most common subtype is caused by deficiency of the enzyme 21-hydroxylase. ▪ Reduction in cortisol production causes a compensatory increase in ACTH secretion, which in turn stimulates androgen production. Androgens have virilizing effects, including masculinization in females (ambiguous genitalia, oligomenorrhea, hirsutism), precocious puberty in males, and in some instances, salt (sodium) wasting and hypotension. ▪ Bilateral hyperplasia of the adrenal cortex is characteristic, and a subset of 21-hydroxylase-deficient patients also demonstrates adrenomedullary dysplasia.

Answer 480

Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals due 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

Answer 481

* As a crisis in individuals 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 precipitate an adrenal crisis, because of the inability of the atrophic adrenals to produce glucocorticoid hormones * As a result of massive adrenal hemorrhage , which damages the adrenal cortex sufficiently to cause acute adrenocortical insufficiency—as occurs in newborns following prolonged and difficult delivery with considerable trauma and hypoxia. It also occurs in some patients maintained on anticoagulant therapy, in postsurgical patients who develop disseminated intravascular coagulation and consequent hemorrhagic infarction of the adrenals, and as a complication of disseminated bacterial infection; in this last setting, it is called Waterhouse-Friderichsen syndrome

Answer 482

This uncommon but catastrophic syndrome is characterized by the following: * Overwhelming bacterial infection, classically Neisseria meningitidis septicemia but occasionally caused by other highly virulent organisms, such as Pseudomonas species, pneumococci, Haemophilus influenzae , or even staphylococci * Rapidly progressive hypotension leading to shock * Disseminated intravascular coagulation associated with widespread purpura * Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage

Answer 483

The basis for the adrenal hemorrhage is uncertain but could be due to direct bacterial seeding of small vessels in the adrenal, the development of disseminated intravascular coagulation, or endothelial dysfunction caused by microbial products and inflammatory mediators. Whatever the basis, the adrenals are converted to sacs of clotted blood, which obscures virtually all of the underlying detail. Histologic examination reveals that the hemorrhage starts within the medulla near thin-walled venous sinusoids, then suffuses peripherally into the cortex, often leaving islands of recognizable cortical cells ( Fig. 24-48 ). Prompt recognition and appropriate therapy must be instituted immediately, or death follows within hours to a few days

Answer 484

Prompt recognition and appropriate therapy must be instituted immediately, or death follows within hours to a few days

Answer 485

In an article 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 modern parlance, 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 (e.g., autoimmune adrenalitis) are much more common in whites and in women

Answer 486

A large number of diseases may affect 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, AIDS, or metastatic cancers

Answer 487

• Autoimmune adrenalitis accounts for 60% to 70% of cases; 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. Autoantibodies to several key steroidogenic enzymes (21-hydroxylase, 17-hydroxylase) have been detected in these patients. Autoimmune adrenalitis can occur in one of two clinical settings

Answer 488

• Autoimmune polyendocrine syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED), is characterized by chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy) 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 on chromosome 21q22. AIRE is expressed primarily in the thymus, where it functions as a transcription factor that promotes the expression of many peripheral tissue antigens. Self-reactive T cells that recognize these antigens are eliminated ( Chapter 6 ). In the absence of AIRE function, central T-cell tolerance to peripheral tissue antigens is compromised, promoting autoimmunity. Individuals with APS1 develop autoantibodies against IL-17 and IL-22, which are the principal effector cytokines secreted by T H 17 T-cells ( Chapter 6 ). Because these two T H 17-derived cytokines are crucial for defense against fungal infections, it is not surprising that patients develop chronic mucocutaneous candidiasis

Answer 489

• Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early adulthood and presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes. Unlike in APS1, mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not develop

Answer 490

• 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 cases 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 fungi, disseminated infections caused by Histoplasma capsulatum and Coccidioides immitis may result in chronic adrenocortical insufficiency. AIDS sufferers are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium avium-intracellulare ) and noninfectious (Kaposi sarcoma) complications

Answer 491

• Metastatic neoplasms involving the adrenals are another 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, although many other neoplasms, including gastrointestinal carcinomas, malignant melanoma, and hematopoietic neoplasms, may also metastasize to the adrenals

Answer 492

• Genetic causes of adrenal insufficiency include congenital adrenal hypoplasia ( adrenal hypoplasia congenita ) and adrenoleukodystrophy . Adrenoleukodystrophy is described in Chapter 28 . Congenital adrenal hypoplasia is a rare X-linked disease caused by mutations in a gene that encodes a transcription factor implicated in adrenal development

Answer 493

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 adjacent medulla, although the medulla is otherwise preserved ( Fig. 24-49 ). 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 the normal architecture is obscured by the infiltrating neoplasm

Answer 494

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 adjacent medulla, although the medulla is otherwise preserved ( Fig. 24-49

Answer 495

. 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

Answer 496

. When hypoadrenalism is caused by metastatic carcinoma , the adrenals are enlarged and the normal architecture is obscured by the infiltrating neoplasm

Answer 497

Addison disease begins insidiously and does not come to attention until 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 individuals with primary adrenal disease, hyperpigmentation of the skin, particularly of sun-exposed areas and at pressure points, such as the neck, elbows, knees, and knuckles, is quite characteristic. This is caused by elevated levels of pro-opiomelanocortin (POMC), which is derived from the anterior pituitary and is a precursor of both ACTH and melanocyte stimulating hormone (MSH). By contrast, hyperpigmentation is not seen in persons with adrenocortical insufficiency caused by primary pituitary or hypothalamic disease. Decreased mineralocorticoid activity in persons with primary adrenal insufficiency results in potassium retention 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 immediately.

Answer 498

▪ Primary adrenocortical insufficiency can be acute (Waterhouse-Friderichsen syndrome) or chronic (Addison disease) ▪ Chronic adrenal insufficiency in the developed world most often is secondary to autoimmune adrenalitis , which occurs in the context of one of two autoimmune polyendocrine syndromes: APS1 (caused by mutations in the AIRE gene) or APS2. APS1 is characterized by autoimmune attack against multiple endocrine organs and autoantibodies against IL-17. ▪ Tuberculosis and infections due to opportunistic pathogens associated with the human immunodeficiency virus and tumors metastatic to the adrenals are the other important causes of chronic hypoadrenalism. ▪ Patients typically present with fatigue, weakness, and gastrointestinal disturbances. Primary adrenocortical insufficiency also is characterized by high ACTH levels with associated skin pigmentation

Answer 499

ny disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that 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 levels of melanocyte-stimulating hormone are not elevated . 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

Answer 500

Secondary disease can be differentiated from Addison disease by demonstration of low levels of plasma ACTH in the former. In patients with primary disease the destruction of the adrenal cortex reduces the response to exogenously administered ACTH, whereas in those with secondary hypofunction there is a prompt rise in plasma cortisol levels

Answer 501

In cases of hypoadrenalism secondary to hypothalamic or pituitary disease (secondary hypoadrenalism) , depending on the severity of ACTH deficiency, the adrenals may be moderately to markedly decreased in size. The small, flattened glands usually retain their yellow color as a result of a small amount of residual lipid. The cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The medulla is unaffected

Answer 502

It should be evident from the preceding sections that functional adrenal neoplasms may be responsible for any of the various forms of hyperadrenalism. Adenomas and carcinomas are about equally common in adults; in children, carcinomas predominate. While most cortical neoplasms are sporadic, two familial cancer syndromes are associated with a predisposition for developing adrenocortical carcinomas: Li-Fraumeni syndrome, in patients who harbor germline TP53 mutations ( Chapter 7 ), and Beckwith-Wiedemann syndrome, a disorder of epigenetic imprinting

Answer 503

Functional adenomas are most commonly associated with hyperaldosteronism and Cushing syndrome, whereas a virilizing neoplasm is more likely to be a carcinoma. However, not all adrenocortical neoplasms elaborate steroid hormones. Functional and nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of morphologic features. Determination of functionality is based on clinical evaluation, and measurement of hormones or hormone metabolites in the blood

Answer 504

Most adrenocortical adenomas are clinically silent and are usually incidental findings at autopsy or during abdominal imaging for an unrelated cause (see the discussion of adrenal “incidentalomas” later). The typical cortical adenoma is a well-circumscribed, nodular lesion up to 2.5 cm in diameter that expands the adrenal ( Fig. 24-50 ). In contrast to functional adenomas, which are associated with atrophy of the adjacent cortex, the cortex adjacent to nonfunctional adenomas is normal. On cut surface, adenomas are usually yellow to yellow-brown because of the presence of lipid

Answer 505

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. 24-51 ). Mitotic activity is generally inconspicuous.

Answer 506

Adrenocortical carcinomas are rare neoplasms that can occur at any age, including childhood. They are more likely to be functional than adenomas and are often associated with virilism or other clinical manifestations of hyperadrenalism. In most cases adrenocortical carcinomas are large, invasive lesions, many exceeding 20 cm in diameter, which efface the native adrenal gland ( Fig. 24-52 ). 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. Adrenal cancers have a strong tendency to invade the adrenal vein, vena cava, and lymphatics. Metastases to regional and periaortic nodes are common, as is distant hematogenous spread to the lungs and other viscera. The median patient survival is about 2 years

Answer 507

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 may be difficult to differentiate from primary cortical carcinomas. Of note, metastases to the adrenal cortex are significantly more common than primary adrenocortical carcinomas

Answer 508

Adrenal cysts are relatively uncommon; however, with the use of sophisticated abdominal imaging techniques, the frequency of detection of these lesions is increasing. 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.”

Answer 509

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

Answer 510

he 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. The estimated population prevalence of “incidentalomas” discovered by imaging is approximately 4%, with an age-dependent increase in prevalence. Fortunately, the vast majority of adrenal incidentalomas are small nonsecreting cortical adenomas of no clinical importance.

Answer 511

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 adrenal medulla is the major source of catecholamines (epinephrine, norepinephrine) in the body. 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. 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

Answer 512

Pheochromocytomas are neoplasms composed of chromaffin cells, which synthesize and release catecholamines and in some instances peptide hormones. It is important to recognize these tumors because they are a rare cause of surgically correctable hypertension. Traditionally, the features of pheochromocytomas have been summarized by the “rule of 10s

Answer 513

• Ten percent of pheochromocytomas are extra-adrenal , occurring in sites such as the organs of Zuckerkandl and the carotid body. Pheochromocytomas that develop in extra-adrenal paraganglia are designated paragangliomas and are discussed in

Answer 514

• Ten percent of sporadic adrenal pheochromocytomas are bilateral ; this figure may rise to as high as 50% in cases that are associated with familial tumor syndromes (see later

Answer 515

• Ten percent of adrenal pheochromocytomas are biologically malignant , defined by the presence of metastatic disease. Malignancy is more common (20% to 40%) in extra-adrenal paragangliomas, and in tumors arising in the setting of certain germline mutations (see later

Answer 516

Ten percent of adrenal pheochromocytomas are not associated with hypertension . Of the 90% that present with hypertension, approximately two thirds have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations, which can, on occasion, be fatal

Answer 517

One “traditional” 10% rule that has now been modified pertains to familial cases. It is now recognized that as many as 25% of individuals with pheochromocytomas and paragangliomas harbor a germline mutation in one one of at least six known genes ( Table 24-11 ). Patients with germline mutations are typically younger at presentation than those with sporadic tumors and more often harbor bilateral disease. The affected genes fall into two broad classes, those that enhance growth factor receptor pathway signaling (e.g., RET, NF1 ), and those that increase the activity of the transcription factor HIF-1α. You will recall that the VHL gene encodes a tumor suppressor protein that is needed for the oxygen-dependent degradation of HIF-1α and is mutated in patients with von Hippel-Lindau (VHL) syndrome, which is associated with a number of tumors, including pheochromocytoma. Other familial cases of pheochromocytoma are associated with germline mutations in genes encoding components of the succinate dehydrogenase complex ( SDHB, SDHC, and SDHD ). This complex is involved in mitochondrial electron transport and oxygen sensing, and it is believed that these mutations also lead to upregulation of HIF-1α, which appears to be a key oncogenic driver in this type of tumor.

Answer 518

heochromocytomas range from small, circumscribed lesions confined to the adrenal ( Fig. 24-54 ) to large hemorrhagic masses weighing kilograms. The average weight of a pheochromocytoma is 100 gm, but weights 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 within the tumor 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 due to oxidation of stored catecholamines, thus the term chromaffin

Answer 519

The histologic pattern in pheochromocytoma is quite variable. The tumors are composed of clusters of polygonal to spindle-shaped chromaffin cells or chief cells that are surrounded by supporting sustentacular cells, creating small nests or alveoli (zellballen) that are supplied by a rich vascular network ( Fig. 24-55 ). Uncommonly, the dominant cell type is a spindle or small cell; various patterns can be found in any one tumor. The cytoplasm has a finely granular appearance, best demonstrated with silver stains, due to the presence of granules containing catecholamines. The nuclei are usually round to ovoid, with a stippled “salt and pepper” chromatin that is characteristic of neuroendocrine tumors. Electron microscopy reveals variable numbers of membrane-bound, electron-dense secretory granules ( Fig. 24-56 ). Immunoreactivity for neuroendocrine markers (chromogranin and synaptophysin) is seen in the chief cells, while the peripheral sustentacular cells stain with antibodies against S-100, a calcium-binding protein expressed by a variety of mesenchymal cell types

Answer 520

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 are not entirely reliable. 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. 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

Answer 521

RET gene Pheochromocytoma Medullary thyroid carcinoma, parathyroid hyperplasia

Answer 522

RET gene Pheochromocytoma Medullary thyroid carcinoma Marfanoid habitus , mucocutaneous , GNs

Answer 523

NF1 gene Pheochromocytoma Neurofibromatosis, cafe at lait spots, optic nerve glioma

Answer 524

VHL gene Pheochromocytoma, paraganglioma Renal cell carcinoma, hemangioblastomas, pancreatic endocrine neoplasm

Answer 525

SDHD gene Pheochromocytoma, paraganglioma

Answer 526

SDHC Paraganglioma

Answer 527

SDHB Pheochromocytoma, paraganglioma

Answer 528

The dominant clinical manifestation of pheochromocytoma is hypertension , observed in 90% of patients. Approximately two thirds of patients with hypertension demonstrate paroxysmal episodes , which are 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. Isolated paroxysmal episodes of hypertension occur in fewer than half of patients; more commonly, patients demonstrate chronic, sustained elevation in blood pressure punctuated by the aforementioned paroxysms. The paroxysms may be precipitated by emotional stress, exercise, changes in posture, and palpation in the region of the tumor; patients with urinary bladder paragangliomas occasionally precipitate a paroxysm during micturition. The elevations of blood 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

Answer 529

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 either to ischemic damage secondary to catecholamine-induced constriction of myocardial blood vessels 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 peptide hormones. The laboratory diagnosis of pheochromocytoma is based on the demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines

Answer 530

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

Answer 531

The MEN syndromes are a group of 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

Answer 532

Tumors occur at a younger age than sporadic tumors. • 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 hyperplasia involving the cell of origin. For example, individuals with MEN-2 almost universally demonstrate C-cell hyperplasia in the thyroid parenchyma adjacent to medullary thyroid carcinomas. • These tumors are usually more aggressive and recur in a higher proportion of cases than do similar sporadic endocrine tumors

Answer 533

MEN-1, or Wermer syndrome , is a rare heritable disorder with a prevalence of about 2 per 100,000. MEN-1 is characterized by abnormalities involving the parathyroid , pancreas , and pituitary glands ; thus the mnemonic device, the 3Ps

Answer 534

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

Answer 535

• Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity and mortality in persons with MEN-1. These tumors are usually aggressive and often present with metastatic disease. It is not uncommon to find multiple “microadenomas” scattered throughout the pancreas in conjunction with one or two dominant lesions. MEN-1-associated pancreatic endocrine tumors are often functional; however, because pancreatic polypeptide is the most commonly secreted product, many tumors fail to produce an endocrine hypersecretion syndrome. Among those that do, Zollinger-Ellison syndrome (associated with gastrinomas) and hypoglycemia and neurologic manifestations (associated with insulinomas) are most common

Answer 536

• Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a prolactinoma ; some patients develop acromegaly from somatotrophin-secreting tumors.

Answer 537

• It is now recognized that the spectrum of this disease extends 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

Answer 538

MEN-1 syndrome is caused by germline mutations in the MEN1 tumor suppressor gene, which encodes a protein called menin . Menin is a component of several different transcription factor complexes, which (depending on the specific binding partner) may either promote or inhibit tumorigenesis. This dichotomy in menin function is best exemplified in the interactions of menin with two oncogenic transcription factors—JunD and the mixed-lineage leukemia (MLL) protein. When menin partners with JunD, it blocks transcriptional activation by JunD; in fact, loss of this tumor suppressor interaction is believed to contribute to the multiple endocrine neoplasia observed in the setting of MEN1 inactivating mutations. On the contrary, the association of wild-type menin with MLL leads to the formation of a tumor promoting transcriptional complex in a subset of leukemias

Answer 539

The dominant clinical manifestations of MEN-1 usually result from the peptide hormones that are overproduced and include such abnormalities as recurrent hypoglycemia due to insulinomas, intractable peptic ulcers in persons 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 death

Answer 540

MEN-2 is subclassified into three distinct syndromes: MEN-2A, MEN-2B, and familial medullary thyroid cancer

Answer 541

• MEN-2A , or Sipple syndrome , is characterized by pheochromocytoma , medullary carcinoma of the thyroid , and parathyroid hyperplasia ( Table 24-11 ). 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. Among individuals with MEN-2A, 40% to 50% have pheochromocytomas, which are often bilateral and may arise in extra-adrenal sites. Parathyroid hyperplasia and evidence of hypercalcemia or renal stones occur in 10% to 20% of patients. MEN-2A is clinically and genetically distinct from MEN-1 and is caused by germline gain-of-function mutations in the RET proto-oncogene on chromosome 10q11.2 . As was noted earlier, the RET proto-oncogene encodes a receptor tyrosine kinase that binds glial-derived 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), germline mutations constitutively activate the RET receptor

Answer 542

• 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 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 ( Table 24-11 ). A germline mutation leading to a single amino acid change in RET, distinct from the mutations that are seen in MEN-2A, seems to be responsible for virtually all cases of MEN-2B. This point substitution affects a critical region of the tyrosine kinase domain of the protein and leads to constitutive activation of RET in the absence of ligand. Of note, approximately a third of sporadic medullary thyroid carcinomas harbor the identical mutation, and these cases are associated with aggressive disease and an adverse prognosis.

Answer 543

• 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

Answer 544

In contrast to MEN-1, in which the long-term benefit of early diagnosis by 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. Now, routine genetic testing identifies RET mutation carriers earlier and more reliably in MEN-2 kindreds; all individuals carrying germline RET mutations are advised to undergo prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomas .

Answer 545

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. The principal secretory product of the pineal gland is melatonin, which is involved in the control of circadian rhythms, including the sleep-wake cycle; hence the popular use of melatonin for the treatment of jet lag

Answer 546

All tumors involving the pineal are rare; most (50% to 70%) arise from sequestered embryonic germ cells ( Chapter 28 ). 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 debated, but most “pinealophiles” favor restricting the term pinealoma to neoplasms arising from the pineocytes.

Answer 547

These neoplasms are divided into two categories, pineoblastomas and pineocytomas, based on their level of differentiation, which, in turn, correlates with their aggressiveness. These tumors are rare, and are described in specialized texts