The Endocrine System

Introduction

Pituitary Diseases

Thyroid gland diseases

Adrenal gland diseases

INTRODUCTION

The endocrine system consists of an integrated system of ductless glands that produce hormones. Hormones (from the Greek "to set in motion") are secreted into the bloodstream and serve to maintain homeostasis by acting on one or more end organs.

Endocrine diseases usually present clinically as over production or underproduction of one or more hormones. The etiologies are varied and include: idiopathic (primary dysfunction), autoimmune, infectious, atrophic, congenital/developmental and genetic. Neoplasms may cause hormone excess, deficiency or no hormonal alteration. A clinical syndrome may have several possible etiologies. Likewise, one pathologic processes may produce several clinical syndromes.

Objectives:

1. Describe the following causes of hypopituitarism: pituitary adenoma, Sheehan syndrome, empty sella syndrome.

2. Review the physiologic relationship between the thyroid gland, hypothalamus, and anterior pituitary gland.

3. List the major causes of hyperthyroidism. Describe clinical and pathologic findings and the pathogenesis of multinodular goiter.

4. Compare and contrast primary hypothyroidism with secondary hypothyroidism. List the major causes of each.

5. Define cretinism and myxedema.

6. List the common causes of Cushing syndrome.

7. Understand the classification of diabetes mellitus as defined by the National Diabetes Data Group.

8. Be able to differentiate between insulin-dependent diabetes mellitus (Type 1 diabetes, IDDM) and non-insulin-dependent diabetes mellitus (Type 2 diabetes, NIDDM) with respect to pathogenesis and presentation.

9. Describe the pathogenesis of the two acute metabolic complications of diabetes.

10. Describe the pathogenesis of the long-term complications of diabetes, especially the vascular complications. List the major organs involved by microvascular and macrovascular disease.

11. Describe the major cause and clinical manifestations of hypoparathyroidism.

Key words:

Hypersecretion/hyperfunction, Hyposecretion/hypofunction. Pituitary: adenomata; giantism or gigantism; acromegaly; Pituitary Cushing's Thyroid: Grave's disease; nodular goiter; thyrotoxicosis; myxedema; Hashimoto's thyroiditis; Cretinism. Parathyroid: hyperparathyroidism. Adrenals: Adrenal Cushing's syndrome; adrenal crisis; autoimmune adrenalitis; acute adrenal insufficiency; Addison's disease; Waterhouse-Friderichsen syndrome, Adrenal Medulla: neuroblastoma; pheochromocytoma, Multiple Endocrine Neoplasia,

Clinical objectives:

1. Describe the morphologic, molecular, and clinical features of pituitary adenomas, including: gross and microscopic appearances of adenomas, manifestations related to mass effect, endocrine manifestations, especially those related to the production of: growth hormone, ACTH, prolactin.

2. In a patient with a solitary thyroid nodule, list at least four clinical features favoring carcinoma over a goitrous nodule.

3. Compare and contrast the major gross, microscopic, and clinical features of the following thyroid neoplasms: follicular adenoma, papillary carcinoma, follicular, carcinoma, medullary carcinoma.

4. Know the most common causes of primary hyperparathyroidism. Describe gross and microscopic features of each of these parathyroid diseases.

5. Describe clinical and pathologic findings and the pathogenesis of Graves disease as a prototype of hyperthyroidism.

6. Compare and contrast the pathogenesis of the various causes of Cushing syndrome

7. Describe the morphologic changes in various organs, particularly: pancreas, blood vessels, small and large, kidneys, retina in Diabetes mellitus.

Clinical Manifestations of Pituitary Disease

The manifestations of pituitary disorders are as follows:

· Hyperpituitarism: Arising from excess secretion of trophic hormones. The causes of hyperpituitarism include pituitary adenoma, hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by nonpituitary tumors, and certain hypothalamic disorders. The symptoms of hyperpituitarism are discussed in the context of individual tumors below.

· Hypopituitarism: Arising from deficiency of trophic hormones. This may be caused by destructive processes, including ischemic injury, surgery or radiation, and inflammatory reactions. In addition, nonfunctional pituitary adenomas may encroach upon and destroy adjacent normal anterior pituitary parenchyma and cause hypopituitarism.

· Local mass effects: Among the earliest changes referable to mass effect are radiographic abnormalities of the sella turcica, including sellar expansion, bony erosion, and disruption of the diaphragma sella. Because of the close proximity of the optic nerves and chiasm to the sella, expanding pituitary lesions often compress decussating fibers in the optic chiasm. This gives rise to visual field abnormalities, classically in the form of defects in the lateral (temporal) visual fields, so-called bitemporal hemianopsia. In addition, a variety of other visual field abnormalities may be caused by asymmetric growth of many tumors. Like any expanding intracranial mass, pituitary adenomas can produce signs and symptoms of elevated intracranial pressure, including headache, nausea, and vomiting. On occasion, acute hemorrhage into an adenoma is associated with clinical evidence of rapid enlargement of the lesion, a situation appropriately termed pituitary apoplexy. Acute pituitary apoplexy is a neurosurgical emergency, since it can cause sudden death (see below).

Diseases of the posterior pituitary often come to clinical attention because of increased or decreased secretion of one of its products, ADH.

Pituitary Adenomas and Hyperpituitarism

Classification of Pituitary Adenomas

1. Prolactin cell (lactotroph) adenoma

2. Growth hormone cell (somatotroph) adenoma

3. Densely granulated GH cell adenoma

4. Sparsely granulated GH cell adenoma with fibrous bodies

5. Thyroid-stimulating hormone cell (thyrotroph) adenomas

6. ACTH cell (corticotroph) adenomas

7. Gonadotroph cell adenomas

8. Silent gonadotroph adenomas include most so-called null cell and oncocytic adenomas

9. Mixed growth hormone-prolactin cell (mammosomatotroph) adenomas

10. Other plurihormonal adenomas

11. Hormone-negative adenomas

The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe. Other, less common, causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders. Pituitary adenomas can be functional (i.e., associated with hormone excess and clinical manifestations thereof) or silent (i.e., immunohistochemical and/or ultrastructural demonstration of hormone production at the tissue level only, without clinical symptoms of hormone excess). Both functional and silent pituitary adenomas are usually composed of a single cell type and produce a single predominant hormone, although exceptions are known to occur. Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections. Some pituitary adenomas can secrete two hormones (GH and prolactin being the most common combination), and rarely, pituitary adenomas are plurihormonal. Finally, pituitary adenomas may be hormone-negative, based on absence of immunohistochemical reactivity and ultrastructural demonstration of lineage-specific differentiation. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma.

Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using high-resolution computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more in diameter, usually a silent adenoma.1 Pituitary adenomas are usually found in adults, with a peak incidence from the thirties to the fifties. Most pituitary adenomas occur as isolated lesions. In about 3% of cases, however, adenomas are associated with multiple endocrine neoplasia (MEN) type 1 (discussed later). Pituitary adenomas are designated, somewhat arbitrarily, microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter. Silent and hormone-negative adenomas are likely to come to clinical attention at a later stage than those associated with endocrine abnormalities and are therefore more likely to be macroadenomas.

With recent advances in molecular techniques, substantial insight has been gained into the genetic abnormalities associated with pituitary adenomas:

· The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell. Some plurihormonal tumors may arise from clonal expansion of primitive stem cells, which then differentiate in several directions simultaneously.

· G-protein mutations are possibly the best-characterized molecular abnormalities in pituitary adenomas. G-proteins are described in Chapter 3; here we will review their function in the context of endocrine neoplasms. G-proteins play a critical role in signal transduction, transmitting signals from cell-surface receptors (e.g., GHRH receptor) to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (e.g., cyclic AMP, cAMP). These are heterotrimeric proteins, composed of a specific α-subunit that binds guanine nucleotide and interacts with both cell surface receptors and intracellular effectors (Fig. 24-3); the β- and γ-subunits are noncovalently bound to the specific α-subunit. Gs is a stimulatory G-protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. The α-subunit of Gs (Gsα) is encoded by the GNAS1 gene, located on chromosome 20q13. In the basal state, Gs exists as an inactive protein, with GDP bound to the guanine nucleotide-binding site of the α-subunit of Gs. On interaction with the ligand-bound cell-surface receptor, GDP dissociates, and GTP binds to Gsα, activating the G-protein. The activation of Gsα results in the generation of cAMP, which acts as a potent mitogenic stimulus for a variety of endocrine cell types (such as pituitary somatotrophs and corticotrophs, thyroid follicular cells, parathyroid cells), promoting cellular proliferation and hormone synthesis and secretion. The activation of Gsα, and resultant generation of cAMP, are transient because of an intrinsic GTPase activity in the α-subunit, which hydrolyzes GTP into GDP. A mutation in the α-subunit that interferes with its intrinsic GTPase activity will therefore result in constitutive activation of Gsα, persistent generation of cAMP, and unchecked cellular proliferation. Approximately 40% of somatotroph cell adenomas bear GNAS1 mutations that abrogate the GTPase activity of Gsα. The mutant form of GNAS1 is also known as the gsp oncogene because of its effects on tumorigenesis. In addition, GNAS1 mutations have also been described in a minority of corticotroph adenomas; in contrast, GNAS1 mutations are absent in thyrotroph, lactotroph, and gonadotroph adenomas, since their respective hypothalamic release hormones do not mediate their action via cAMP-dependent pathways.

· Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a familial disorder associated with tumors and hyperplasias of multiple endocrine organs, including the pituitary. A subtype of MEN syndrome, known as MEN-1, is caused by germ line mutations of the gene MEN1, on chromosome 11q13. While MEN1 mutations are, by definition, present in pituitary adenomas arising in context of the MEN-1 syndrome, they are uncommon in sporadic pituitary adenomas.

· Additional molecular abnormalities present in aggressive or advanced pituitary adenomas include activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events are linked to disease progression.

Morphology. The common pituitary adenoma is a soft, well-circumscribed lesion that may be confined to the sella turcica. Larger lesions typically extend superiorly through the diaphragm sella into the suprasellar region, where they often compress the optic chiasm and adjacent structures, such as some of the cranial nerves.

The adenoma has grown far beyond the confines of the sella turcica, has markedly distorted the left lateral ventricle, and encases the internal carotid artery. The neoplasm contains several small areas of hemorrhage.

As these adenomas expand, they frequently erode the sella turcica and anterior clinoid processes. They may also extend locally into the cavernous and sphenoid sinuses. In up to 30% of cases, the adenomas are not grossly encapsulated and infiltrate adjacent bone, dura, and (rarely) brain, but they do not demonstrate the ability for distant metastasis. Such lesions are termed invasive adenomas. Foci of hemorrhage and necrosis are common in larger adenomas.

Histologically, pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets or cords. Supporting connective tissue, or reticulin, is sparse, accounting for the soft, gelatinous consistency of many of these lesions. The nuclei of the neoplastic cells may be uniform or pleomorphic. Mitotic activity is usually modest. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on the type and amount of secretory product within the cells, but it is generally uniform throughout the cytoplasm. This cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma. The functional status of the adenoma cannot be reliably predicted from its histologic appearance.

Clinical Course. The signs and symptoms of pituitary adenomas include endocrine abnormalities and mass effects. The abnormalities associated with the secretion of excessive quantities of anterior pituitary hormones are mentioned below, when we describe the specific types of pituitary adenoma. Local mass effects may be encountered in any type of pituitary tumor and have been discussed previously under clinical manifestations of pituitary disease. Briefly, these include radiographic abnormalities of the sella turcica, visual field abnormalities, signs and symptoms of elevated intracranial pressure, and occasionally hypopituitarism. Acute hemorrhage into an adenoma is sometimes associated with pituitary apoplexy, as was noted previously.

With this general introduction to pituitary adenomas, we proceed to a discussion of the individual types of tumors.

Prolactinomas

Prolactinomas (lactotroph adenomas) are the most frequent type of hyperfunctioning pituitary adenoma, accounting for about 30% of all clinically recognized pituitary adenomas. These lesions range from small microadenomas to large, expansile tumors associated with substantial mass effect. Microscopically, the overwhelming majority of prolactinomas are composed of weakly acidophilic or chromophobic cells (sparsely granulated prolactinoma); rare prolactinomas are strongly acidophilic (densely granulated prolactinoma). Prolactin can be demonstrated within the secretory granules in the cytoplasm of the cells using immunohistochemical approaches. Prolactinomas have a propensity to undergo dystrophic calcification, ranging from isolated psammoma bodies to extensive calcification of virtually the entire tumor mass ("pituitary stone"). Prolactin secretion by functioning adenomas is characterized by its efficiency-even microadenomas secrete sufficient prolactin to cause hyperprolactinemia-and by its proportionality, in that serum prolactin concentrations tend to correlate with the size of the adenoma.

Increased serum levels of prolactin, or prolactinemia, cause amenorrhea, galactorrhea, loss of libido, and infertility. The diagnosis of an adenoma is made more readily in women than in men, especially between the ages of 20 and 40 years, presumably because of the sensitivity of menses to disruption by hyperprolactinemia. This tumor underlies almost a quarter of cases of amenorrhea. In contrast, in men and older women, the hormonal manifestations may be subtle, allowing the tumors to reach considerable size (macroadenomas) before being detected clinically.

Hyperprolactinemia may result from causes other than prolactin-secreting pituitary adenomas. Physiologic hyperprolactinemia occurs in pregnancy; serum prolactin levels increase throughout pregnancy, reaching a peak at delivery. Prolactin levels are also elevated by nipple stimulation, as occurs during suckling in lactating women, and as a response to many types of stress. Pathologic hyperprolactinemia can also result from lactotroph hyperplasia, such as when there is interference with normal dopamine inhibition of prolactin secretion. This may occur as a result of damage to the dopaminergic neurons of the hypothalamus, pituitary stalk section (e.g., owing to head trauma), or drugs that block dopamine receptors on lactotroph cells. Any mass in the suprasellar compartment may disturb the normal inhibitory influence of the hypothalamus on prolactin secretion, resulting in hyperprolactinemia, a phenomenon called the stalk effect. Therefore, a mild elevation in serum prolactin in a patient with a pituitary adenoma does not necessarily indicate a prolactin-secreting tumor. Several classes of drugs can cause hyperprolactinemia, including dopamine receptor antagonists such as the neuroleptic drugs (phenothiazines, haloperidol) and older antihypertensive drugs, such as reserpine, which inhibit dopamine storage. Other causes of hyperprolactinemia include estrogens, renal failure, and hypothyroidism. Prolactinomas are treated by surgery or, more commonly, with bromocriptine, a dopamine receptor agonist, which causes the lesions to diminish in size.

Growth hormone (somatotroph cell) adenomas

GH-secreting tumors are the second most common type of functioning pituitary adenoma. Somatotroph cell adenomas may be quite large by the time they come to clinical attention because the manifestations of excessive GH may be subtle. Histologically, GH-containing adenomas are also classified into two subtypes: densely granulated and sparsely granulated. The densely granulated adenomas are composed of cells that are monomorphic and acidophilic in routine sections, retain strong cytoplasmic GH reactivity on immunohistochemistry, and demonstrate cytokeratin staining in a perinuclear distribution. In contrast, the sparsely granulated variants are composed of chromophobe cells with considerable nuclear and cytologic pleomorphism, and retain focal and weak GH reactivity. Bihormonal mammosomatotroph adenomas that are reactive for both GH and prolactin are being increasingly recognized with the availability of better reagents for immunohistochemical analysis; morphologically, most bihormonal adenomas resemble the densely granulated pure somatotroph adenomas.

Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (IGF-I or somatomedin C), which causes many of the clinical manifestations. If a somatotrophic adenoma appears in children before the epiphyses have closed, the elevated levels of GH (and IGF-1) result in gigantism. This is characterized by a generalized increase in body size with disproportionately long arms and legs. If the increased levels of GH are present after closure of the epiphyses, patients develop acromegaly. In this condition, growth is most conspicuous in skin and soft tissues; viscera (thyroid, heart, liver, and adrenals); and bones of the face, hands, and feet. Bone density may be increased (hyperostosis) in both the spine and the hips. Enlargement of the jaw results in protrusion (prognathism) with broadening of the lower face. The hands and feet are enlarged with broad, sausage-like fingers. In most instances, gigantism is also accompanied by evidence of acromegaly. These changes develop for decades before being recognized, hence the opportunity for the adenomas to reach substantial size. GH excess is also correlated with a variety of other disturbances, including gonadal dysfunction, diabetes mellitus, generalized muscle weakness, hypertension, arthritis, congestive heart failure, and an increased risk of gastrointestinal cancers.

The diagnosis of pituitary GH excess relies on documentation of elevated serum GH and IGF-1 levels. In addition, failure to suppress GH production in response to an oral load of glucose is one of the most sensitive tests for acromegaly. The goals of treatment are to restore GH levels to normal and to decrease symptoms referable to a pituitary mass lesion while not causing hypopituitarism. To achieve these goals, the tumor can be removed surgically or destroyed by radiation therapy, or GH secretion can be reduced by drug therapy. When effective control of GH hypersecretion is achieved, the characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities improve.

Corticotroph cell adenomas

Corticotroph adenomas are usually small microadenomas at the time of diagnosis. These tumors are most often basophilic (densely granulated) and occasionally chromophobic (sparsely granulated). Both variants stain positively with periodic acid-Schiff (PAS) because of the presence of carbohydrate in pre-opiomelanocorticotropin (POMC), the ACTH precursor molecule; in addition, they demonstrate variable immunoreactivity for POMC and its derivatives, including ACTH and β-endorphin.

Excess production of ACTH by the corticotroph adenoma leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (also known as Cushing syndrome). This syndrome is discussed in more detail later with the diseases of the adrenal gland. It can be caused by a wide variety of conditions in addition to ACTH-producing pituitary tumors. When the hypercortisolism is due to excessive production of ACTH by the pituitary, the process is designated Cushing disease. Large destructive adenomas can develop in patients after surgical removal of the adrenal glands for treatment of Cushing syndrome. This condition, known as Nelson syndrome, occurs most often because of a loss of the inhibitory effect of adrenal corticosteroids on a pre-existing corticotroph microadenoma. Because the adrenals are absent in patients with this disorder, hypercortisolism does not develop. In contrast, patients present with mass effects of the pituitary tumor. In addition, there can be hyperpigmentation because of the stimulatory effect of other products of the ACTH precursor molecule on melanocytes.

Hypopituitarism

Hypopituitarism refers to decreased secretion of pituitary hormones, which can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or absent. This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary. Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (see below) is almost always of hypothalamic origin. Most cases of hypofunction arise from destructive processes directly involving the anterior pituitary, although other mechanisms have been identified:

· Tumors and other mass lesions: Pituitary adenomas, other benign tumors arising within the sella, primary and metastatic malignancies, and cysts can cause hypopituitarism. Any mass lesion in the sella can cause damage by exerting pressure on adjacent pituitary cells.

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

· Pituitary apoplexy: As has been mentioned, this is a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma. In its most dramatic presentation, apoplexy causes the sudden onset of excruciating headache, diplopia owing to pressure on the oculomotor nerves, and hypopituitarism. In severe cases, it can cause cardiovascular collapse, loss of consciousness, and even sudden death. Thus, pituitary apoplexy is a true neurosurgical emergency.

· Ischemic necrosis of the pituitary and Sheehan syndrome: Ischemic necrosis of the anterior pituitary is an important cause of pituitary insufficiency. Sheehan syndrome, or postpartum necrosis of the anterior pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary.6 During pregnancy, the anterior pituitary enlarges to almost twice its normal size. This physiologic expansion of the gland is not accompanied by an increase in blood supply from the low-pressure venous system; hence, there is relative anoxia of the pituitary. Further reduction in blood supply caused by obstetric hemorrhage or shock may precipitate infarction of the anterior lobe. The posterior pituitary, because it receives its blood directly from arterial branches, is much less susceptible to ischemic injury in this setting and is therefore usually not affected. Pituitary necrosis may also be encountered in other conditions, such as disseminated intravascular coagulation and (more rarely) sickle cell anemia, elevated intracranial pressure, traumatic injury, and shock of any origin. Whatever the pathogenesis, the ischemic area is resorbed and replaced by a nubbin of fibrous tissue attached to the wall of an empty sella.

· Rathke cleft cyst: These cysts, lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland.

· Empty sella syndrome: Any condition that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation, can result in an empty sella. The empty sella syndrome refers to the presence of an enlarged, empty sella turcica that is not filled with pituitary tissue. There are two types: (1) In a primary empty sella, there is a defect in the diaphragma sella that allows the arachnoid mater and cerebrospinal fluid to herniate into the sella, resulting in expansion of the sella and compression of the pituitary. Classically, affected patients are obese women with a history of multiple pregnancies. The empty sella syndrome may be associated with visual field defects and occasionally with endocrine anomalies, such as hyperprolactinemia, owing to interruption of inhibitory hypothalamic effects. Loss of functioning parenchyma can be severe enough to result in hypopituitarism. (2) In a secondary empty sella, a mass, such as a pituitary adenoma, enlarges the sella, but then it is either surgically removed or undergoes spontaneous necrosis, leading to loss of pituitary function. Hypopituitarism can result from the treatment or spontaneous infarction.

· Genetic defects: Rare congenital deficiencies of one or more pituitary hormones have been recognized in children. For example, mutations in pit-1, a pituitary transcription factor, result in combined deficiency of GH, prolactin, and TSH.

Less frequently, disorders that interfere with the delivery of pituitary hormone-releasing factors from the hypothalamus, such as hypothalamic tumors, may also cause hypofunction of the anterior pituitary. Any disease involving the hypothalamus can alter secretion of one or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones. In contrast to diseases that involve the pituitary directly, any of these conditions can also diminish the secretion of ADH, resulting in diabetes insipidus (discussed later). Hypothalamic lesions that cause hypopituitarism include:

· Tumors, including benign lesions that arise in the hypothalamus, such as craniopharyngiomas, and malignant tumors that metastasize to that site, such as breast and lung carcinomas. Hypothalamic hormone deficiency can ensue when brain or nasopharyngeal tumors are treated with radiation.

· Inflammatory disorders and infections, such as sarcoidosis or tuberculous meningitis, can cause deficiencies of anterior pituitary hormones and diabetes insipidus.

The clinical manifestations of anterior pituitary hypofunction depend on the specific hormone(s) that are lacking. Children can develop growth failure (pituitary dwarfism) due to growth hormone deficiency. Gonadotropin (GnRH) deficiency leads to amenorrhea and infertility in women and decreased libido, impotence, and loss of pubic and axillary hair in men. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism, respectively, and are discussed later in the chapter. Prolactin deficiency results in failure of postpartum lactation. The anterior pituitary is also a rich source of melanocyte-stimulating hormone (MSH), synthesized from the same precursor molecule that produces ACTH; therefore, one of the manifestations of hypopituitarism includes pallor due to a loss of stimulatory effects of MSH on melanocytes.

Posterior Pituitary Syndromes

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

· Diabetes insipidus. ADH deficiency causes diabetes insipidus, a condition characterized by excessive urination (polyuria) owing to an inability of the kidney to resorb water properly from the urine. It can result from a variety of processes, including head trauma, tumors, and inflammatory disorders of the hypothalamus and pituitary as well as surgical procedures involving these organs. The condition can also arise spontaneously, in the absence of an underlying disorder. Diabetes insipidus from ADH deficiency is designated as central to differentiate it from nephrogenic diabetes insipidus, which is a result of renal tubular unresponsiveness to circulating ADH. The clinical manifestations of the two diseases are similar and include the excretion of large volumes of dilute urine with an inappropriately low specific gravity. Serum sodium and osmolality are increased owing to excessive renal loss of free water, resulting in thirst and polydipsia. Patients who can drink water can generally compensate for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may develop life-threatening dehydration.

· Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremia. The most frequent causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), non-neoplastic diseases of the lung, and local injury to the hypothalamus or posterior pituitary (or both). The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction. Although total body water is increased, blood volume remains normal, and peripheral edema does not develop.

Thyroid gland

Diseases of the thyroid are of great importance because most are amenable to medical or surgical management. They include conditions associated with excessive release of thyroid hormones (hyperthyroidism), those associated with thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. We first consider the clinical consequences of disturbed thyroid function, then focus on the disorders that generate these problems.

Hyperthyroidism

Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4. Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to as hyperthyroidism. However, in certain conditions the oversupply is related to either excessive release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than hyperfunction of the gland. 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. With this disclaimer, we will follow the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably. The three most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following:

· Diffuse hyperplasia of the thyroid associated with Graves disease (accounts for 85% of cases)

· Hyperfunctional multinodular goiter

· Hyperfunctional adenoma of the thyroid

Clinical Course. The clinical manifestations of hyperthyroidism are protean and include changes referable to the hypermetabolic state induced by excess thyroid hormone as well as those related to overactivity of the sympathetic nervous system (i.e., an increase in the β-adrenergic "tone").

Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss. Heat intolerance is common. Sweating is increased because of higher levels of calorigenesis. Increased basal metabolic rate also results in characteristic weight loss despite increased appetite.

Cardiac manifestations are among the earliest and most consistent features of hyperthyroidism. Patients with hyperthyroidism can have an increase in cardiac output, owing to both increased cardiac contractility and increased peripheral oxygen requirements. Tachycardia, palpitations, and cardiomegaly are common. Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. Congestive heart failure may develop, particularly in elderly patients with pre-existing cardiac disease. Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria, have been described. Some patients with thyrotoxicosis develop a reversible diastolic dysfunction and a "low-output" failure, so-called thyrotoxic dilated cardiomyopathy

In the neuromuscular system, overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle weakness is common with decreased muscle mass (thyroid myopathy).

Ocular changes often call attention to hyperthyroidism. A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris. However, true thyroid ophthalmopathy associated with proptosis is a feature seen only in Graves disease (see below).

In the gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility, malabsorption, and diarrhea.

The skeletal system is also affected in hyperthyroidism. Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone. The net effect is osteoporosis and an increased risk of fractures in patients with chronic hyperthyroidism.

Other findings throughout the body include atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in the hepatocytes; and generalized lymphoid hyperplasia with lymphadenopathy in patients with Graves disease.

Thyroid storm is used to designate the abrupt onset of severe hyperthyroidism. This condition occurs most commonly in patients with underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress. Patients are often febrile and present with tachycardia out of proportion to the fever. Thyroid storm is a medical emergency: A significant number of untreated patients die of cardiac arrhythmias.

Apathetic hyperthyroidism refers to thyrotoxicosis occurring in the elderly, in whom old age and various comorbidities may blunt the typical features of thyroid hormone excess seen in younger patients. The diagnosis of thyrotoxicosis in these patients is often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease.

Hypothyroidism

Hypothyroidism is caused by any structural or functional derangement that interferes with the production of adequate levels of thyroid hormone. It can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. As in the case of hyperthyroidism, this disorder is divided into primary and secondary categories, depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or occurs as a result of pituitary disease; rarely, hypothalamic failure is a cause of tertiary hypothyroidism. Primary hypothyroidism accounts for the vast majority of cases of hypothyroidism. Primary hypothyroidism can be thyroprivic (due to absence or loss of thyroid parenchyma) or goitrous (due to enlargement of the thyroid gland under the influence of TSH). The causes of primary hypothyroidism include the following.

Causes of Hypothyroidism

Primary

Developmental

Thyroid hormone resistance syndrome

Postablative

Surgery, radioiodine therapy, or external radiation

Autoimmune hypothyroidism

Hashimoto thyroiditis

Iodine deficiency

Drugs (lithium, iodides, p-aminosalicylic acid)

Congenital biosynthetic defect (dyshormonogenetic goiter)

Secondary

Pituitary failure

Tertiary

Hypothalamic failure (rare)

Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-TSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis. Some patients with hypothyroidism have circulating anti-TSH antibodies, but they usually do not have the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto thyroiditis. In the past, many of these patients were classified as having primary "idiopathic" hypothyroidism, but the disease is now recognized as a type of autoimmune disorder of the thyroid, occurring either in isolation or in conjunction with other autoimmune endocrine manifestations.

Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can cause hypothyroidism, as can agents used to treat nonthyroid conditions (e.g., lithium, p-aminosalicylic acid

Inborn errors of thyroid metabolism are an uncommon cause of goitrous hypothyroidism (dyshormonogenetic goiter). Any one of the multiple steps leading to thyroid hormone synthesis may be deficient: (1) iodide transport defect, (2) organification defect, (3) dehalogenase defect, and (4) iodotyrosine coupling defect. Organification of iodine involves binding of oxidized iodide with tyrosyl residues in thyroglobulin, and this process is deficient in patients with Pendred syndrome, wherein goitrous hypothyroidism is accompanied by sensorineural deafness.

Thyroid hormone resistance syndrome is a rare autosomal-dominant disorder caused by inherited mutations in the thyroid hormone receptor (TR), which abolish the ability of the receptor to bind thyroid hormones. Patients demonstrate a generalized resistance to thyroid hormone, despite high circulating levels of T3 and T4. Since the pituitary is also resistant to feedback from thyroid hormones, TSH levels tend to be high as well. In rare instances, there may be complete absence of thyroid parenchyma (thyroid agenesis), or the gland may be greatly reduced in size (thyroid hypoplasia). Mutations in the TSH receptor are a newly recognized cause of congenital hypothyroidism associated with a hypoplastic thyroid gland. Recently, mutations in two transcription factors that are expressed in the developing thyroid and regulate follicular differentiation-thyroid transcription factor-2 (TTF-2) and Paired Homeobox-8 (PAX-8) -have been reported in patients with thyroid agenesis. Thyroid agenesis caused by TTF-2 mutations is usually associated with a cleft palate.

Secondary hypothyroidism is caused by TSH deficiency, and tertiary (central) hypothyroidism is caused by TRH deficiency. Secondary hypothyroidism can result from any of the causes of hypopituitarism. Frequently, the cause is a pituitary tumor; other causes include postpartum pituitary necrosis, trauma, and nonpituitary tumors, as was previously discussed. Tertiary (central) hypothyroidism can be caused by any disorder that damages the hypothalamus or interferes with hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary. This can result from hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases. Classic clinical manifestations of hypothyroidism include cretinism and myxedema.

Cretinism

Cretinism refers to hypothyroidism that develops in infancy or early childhood. The term cretin was derived from the French chrétien, meaning Christian or Christlike, and was applied to these unfortunates because they were considered to be so mentally retarded as to be incapable of sinning. In the past, this disorder occurred fairly commonly in areas of the world where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. It has become much less frequent in recent years, owing to the widespread supplementation of foods with iodine. On rare occasions, cretinism may also result from inborn errors in metabolism (e.g., enzyme deficiencies) that interfere with the biosynthesis of normal levels of thyroid hormone (sporadic cretinism).

Clinical features of cretinism include impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia. The severity of the mental impairment in cretinism appears to be related to the time at which thyroid deficiency occurs in utero. Normally, maternal hormones, including T3 and T4, cross the placenta and are critical to fetal brain development. If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. In contrast, reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allows normal brain development.

Myxedema

The term myxedema is applied to hypothyroidism developing in the older child or adult. Myxedema, or Gull disease, was first linked with thyroid dysfunction in 1873 by Sir William Gull in a paper addressing the development of a "cretinoid state" in adults. The clinical manifestations vary with the age of onset of the deficiency. The older child shows signs and symptoms intermediate between those of the cretin and those of the adult with hypothyroidism. In the adult, the condition appears insidiously and may take years to reach the level of clinical suspicion.

Clinical features of myxedema are characterized by a slowing of physical and mental activity. The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which may mimic depression in the early stages of the disease. Speech and intellectual functions become slowed. Patients with myxedema are listless, cold-intolerant, and frequently overweight. Reduced cardiac output probably contributes to shortness of breath and decreased exercise capacity, two frequent complaints in patients with hypothyroidism. Decreased sympathetic activity results in constipation and decreased sweating. The skin in these patients is cool and pale because of decreased blood flow. Histologically, there is an accumulation of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and a number of visceral sites. This results in edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice.

Thyroiditis

Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation. These diseases include conditions that result in acute illness with severe thyroid pain (e.g., infectious thyroiditis, subacute granulomatous thyroiditis) and disorders in which there is relatively little inflammation and the illness is manifested primarily by thyroid dysfunction (subacute lymphocytic thyroiditis and fibrous [Reidel] thyroiditis).

Infectious thyroiditis may be either acute or chronic. Acute infections can reach the thyroid via hematogenous spread or through direct seeding of the gland, such as via a fistula from the piriform sinus adjacent to the larynx. Other infections of the thyroid, including mycobacterial, fungal, and Pneumocystis infections, are more chronic and frequently occur in immunocompromised patients. Whatever the cause, the inflammatory involvement may cause sudden onset of neck pain and tenderness in the area of the gland and is accompanied by fever, chills, and other signs of infection. Infectious thyroiditis can be self-limited or can be controlled with appropriate therapy. Thyroid function is usually not significantly affected, and there are few residual effects except for possible small foci of scarring. This section focuses on the more common and clinically significant types of thyroiditis: (1) Hashimoto thyroiditis (or chronic lymphocytic thyroiditis), (2) subacute granulomatous thyroiditis, and (3) subacute lymphocytic thyroiditis.

Hashimoto thyroiditis

Hashimoto thyroiditis (or chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. It is characterized by gradual thyroid failure because of autoimmune destruction of the thyroid gland. The name Hashimoto thyroiditis is derived from the 1912 report by Hashimoto describing patients with goiter and intense lymphocytic infiltration of the thyroid (struma lymphomatosa). This disorder is most prevalent between 45 and 65 years of age and is more common in women than in men, with a female predominance of 10:1 to 20:1. Although it is primarily a disease of older women, it can occur in children and is a major cause of nonendemic goiter in children.

Pathogenesis. Hashimoto thyroiditis is an autoimmune disease in which the immune system reacts against a variety of thyroid antigens. The overriding feature of Hashimoto thyroiditis is progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis. Multiple immunologic mechanisms may contribute to the death of thyrocytes.

Morphology. The thyroid is often diffusely enlarged, although more localized enlargement may be seen in some cases. The capsule is intact, and the gland is well demarcated from adjacent structures. The cut surface is pale, yellow-tan, firm, and somewhat nodular. Microscopic examination reveals extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers. 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.

At higher power, the lymphocytic and plasma cell infiltrate with germinal center formation is easily appreciated. Hurthle cell metaplasia of atrophic thyroid follicles is represented by cells with increased cytoplasm showing eosinophilic granularity, as well as nuclear enlargement with some reactive atypia.

This is a metaplastic response of the normally low cuboidal follicular epithelium to ongoing injury. In fine-needle aspiration biopsies, the presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes is characteristic of Hashimoto thyroiditis. In "classic" Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant. A fibrous variant is characterized by severe thyroid follicular atrophy and dense "keloid-like" fibrosis, with broad bands of acellular collagen encompassing residual thyroid tissue. Unlike Reidel thyroiditis (see below), the fibrosis does not extend beyond the capsule of the gland. The remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis.

Clinical Course. Hashimoto thyroiditis comes to clinical attention as painless enlargement of the thyroid, usually associated with some degree of hypothyroidism, in a middle-aged woman. The enlargement of the gland is usually symmetric and diffuse, but in some cases, it may be sufficiently localized to raise a suspicion of neoplasm. In the usual clinical course, hypothyroidism develops gradually. In some cases, however, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones ("hashitoxicosis").

Graves Disease

Graves reported in 1835 his observations of a disease characterized by "violent and long continued palpitations in females" associated with enlargement of the thyroid gland. Graves disease is the most common cause of endogenous hyperthyroidism. It is characterized by a triad of clinical findings:

1. Hyperthyroidism owing to hyperfunctional, diffuse enlargement of the thyroid

2. Infiltrative ophthalmopathy with resultant exophthalmos

3. Localized, infiltrative dermopathy, sometimes called pretibial myxedema.

Graves disease has a peak incidence between the ages of 20 and 40, women being affected up to seven times more frequently than men. Genetic factors are important in the etiology of Graves disease. An increased incidence of Graves disease occurs among family members of affected patients, and the concordance rate in monozygotic twins is as high as 60%.

Pathogenesis. Graves disease is an autoimmune disorder in which a variety of antibodies may be present in the serum, including antibodies to the TSH receptor, thyroid peroxisomes, and thyroglobulin. Autoimmune disorders of the thyroid thus span a continuum in which Graves disease, characterized by hyperfunction of the thyroid, lies at one extreme and Hashimoto disease, manifesting as hypothyroidism, occupies the other end. Sometimes hyperthyroidism may supervene on pre-existing

Morphology. The thyroid gland is usually symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. Increases in weight to over 80 gm are not uncommon. The gland is usually smooth and soft, and its capsule is intact. On cut section, the parenchyma has a soft, meaty appearance resembling normal muscle. Histologically, the dominant feature is too many cells. The follicular epithelial cells in untreated cases are tall and more crowded than usual. This crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles. Such papillae lack fibrovascular cores, in contrast to those of papillary carcinoma (see below). The colloid within the follicular lumen is pale, with scalloped margins. Lymphoid infiltrates, consisting predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common.

The hyperfunctioning follicular epithelium is tall columnar, representing cellular hypertrophy. Papillary infoldings into the follicular lumens result from epithelial proliferation and overcrowding, representing hyperplasia. Peripheral scalloping of the colloid within follicular lumens represents active pinocytosis by the hyperfunctioning epithelium.

Preoperative therapy alters the morphology of the thyroid in Graves disease. Preoperative administration of iodine causes involution of the epithelium and the accumulation of colloid by blocking thyroglobulin secretion.

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

Clinical Course. The clinical findings in Graves disease include changes referable to thyrotoxicosis as well as those associated uniquely with Graves disease: diffuse hyperplasia of the thyroid, ophthalmopathy, and dermopathy. The degree of thyrotoxicosis varies from case to case and is sometimes less conspicuous than other manifestations of the disease. Diffuse enlargement of the thyroid is present in all cases of Graves disease. The thyroid enlargement may be accompanied by increased flow of blood through the hyperactive gland, often producing an audible bruit. Sympathetic overactivity produces a characteristic wide, staring gaze and lid lag. The ophthalmopathy of Graves disease results in abnormal protrusion of the eyeball (exophthalmos). The extraocular muscles are often weak. The exophthalmos may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. The infiltrative dermopathy, or pretibial myxedema, is most common in the skin overlying the shins, where it presents as scaly thickening and induration of the skin. However, it is present only in a minority of patients. The skin lesions may be slightly pigmented papules or nodules and often have an orange peel texture.

Laboratory findings in Graves disease include elevated free T4 and T3 levels and depressed TSH levels. Because of ongoing stimulation of the thyroid follicles by thyroid-stimulating immunoglobulins, radioactive iodine uptake is increased, and radioiodine scans show a diffuse uptake of iodine.

Diffuse and Multinodular Goiters

Enlargement of the thyroid, or goiter, is the most common manifestation of thyroid disease. Diffuse and multinodular goiters reflect impaired synthesis of thyroid hormone, most often caused by dietary iodine deficiency. Impairment of thyroid hormone synthesis leads to a compensatory rise in the serum TSH level, which, in turn, causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state in the vast majority of individuals. If the underlying disorder is sufficiently severe (e.g., a congenital biosynthetic defect or endemic iodine deficiency, see below), the compensatory responses may be inadequate to overcome the impairment in hormone synthesis, resulting in goitrous hypothyroidism. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency.

Diffuse nontoxic goiter

Diffuse nontoxic (simple) goiter specifies a form of goiter that diffusely involves the entire gland without producing nodularity. Because the enlarged follicles are filled with colloid, the term colloid goiter has been applied to this condition. This disorder occurs in both an endemic and a sporadic distribution.

Endemic goiter occurs in geographic areas where the soil, water, and food supply contain only low levels of iodine. The term endemic is used when goiters are present in more than 10% of the population in a given region. Such conditions are particularly common in mountainous areas of the world, including the Alps, Andes, and Himalayas, where iodine deficiency is widespread.

The mass is relatively symmetric and diffusely enlarges the thyroid gland.

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.

Sporadic goiter occurs less frequently than does endemic goiter. There is a striking female preponderance and a peak incidence at puberty or in young adult life. Sporadic goiter can be caused by a number of conditions, including the ingestion of substances that interfere with thyroid hormone synthesis. In other instances, goiter may result from hereditary enzymatic defects that interfere with thyroid hormone synthesis, all transmitted as autosomal-recessive conditions (dyshormonogenetic goiter; see above). In most cases, however, the cause of sporadic goiter is not apparent.

Morphology. 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.

Clinical Course. The vast majority of patients with simple goiters are clinically euthyroid. Therefore, the clinical manifestations are primarily related to mass effects from the enlarged thyroid gland (discussed in detail with multinodular goiter; see below). Although serum T3 and T4 levels are normal, the serum TSH is usually elevated or at the upper range of normal, as is expected in marginally euthyroid individuals. In children, dyshormonogenetic goiter, caused by a congenital biosynthetic defect, may induce cretinism.

Multinodular goiter

With time, recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter. Virtually all long-standing simple goiters convert into multinodular goiters. They may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter). Multinodular goiters produce the most extreme thyroid enlargements and are more frequently mistaken for neoplastic involvement than any other form of thyroid disease. Because they derive from simple goiter, they occur in both sporadic and endemic forms, having the same female-to-male distribution and presumably the same origins but affecting older individuals because they are late complications.

It is believed that multinodal goiters may arise because of variations among follicular cells in responses to external stimuli, such as trophic hormones. If some cells in a follicle have a growth advantage, perhaps because of intrinsic genetic abnormalities similar to those that give rise to adenomas, those cells will develop into clones of proliferating cells. This may result in the formation of a nodule whose continued growth could even be autonomous, without the external stimulus. Consistent with this model, both polyclonal and monoclonal nodules coexist within the same multinodular goiter, the latter presumably having arisen owing to the acquisition of a genetic abnormality favoring growth.

Morphology. Multinodular goiters are multilobulated, asymmetrically enlarged glands that can achieve a weight 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.

The thyroid gland shows multiple nodules on cut surfaces. Some nodules show cystic degeneration, hemorrhage, fibrosis, and calcification.

Occasionally, most of it is hidden behind the trachea and esophagus; in other instances, one nodule may so stand out as to impart the clinical appearance of a solitary nodule. On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid are present. Regressive changes occur frequently, particularly in older lesions, and include areas of hemorrhage, fibrosis, calcification, and cystic change. The microscopic appearance includes colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular epithelial hypertrophy and hyperplasia, accompanied by the degenerative changes noted previously.

Clinical Course. The dominant clinical features of goiter are those caused by the mass effects of the enlarged gland. In addition to the obvious cosmetic effects of a large neck mass, goiters may cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax. Most patients are euthyroid, but in a substantial minority of patients, a hyperfunctioning nodule may develop within a long-standing goiter, resulting in hyperthyroidism (toxic multinodular goiter). This condition, known as Plummer syndrome, is not accompanied by the infiltrative ophthalmopathy and dermopathy of Graves disease. As was previously mentioned, goiter may be associated with clinical evidence of hypothyroidism in specific clinical settings. Radioiodine uptake is uneven, reflecting varied levels of activity in different regions. Hyperfunctioning nodules concentrate radioiodine and appear "hot." Goiters are also of clinical significance because of their ability to mask or to mimic neoplastic diseases arising in the thyroid.

Neoplasms of the Thyroid

The solitary thyroid nodule is a palpably discrete swelling within an otherwise apparently normal thyroid gland. The estimated incidence of solitary palpable nodules in the adult population of the United States varies between 1% and 10%, although it is significantly higher in endemic goitrous regions. Single nodules are about four times more common in women than in men. The incidence of thyroid nodules increases throughout life.

From a clinical standpoint, the possibility of neoplastic disease is of major concern in patients who present with thyroid nodules. Fortunately, the overwhelming majority of solitary nodules of the thyroid prove to be localized, non-neoplastic conditions (e.g., nodular hyperplasia, simple cysts, or foci of thyroiditis) or benign neoplasms such as follicular adenomas. In fact, benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10:1. Carcinomas of the thyroid are thus uncommon, accounting for well under 1% of solitary thyroid nodules and representing about 15,000 new cancer cases each year.

Adenomas

Adenomas of the thyroid are typically discrete, solitary masses. With rare exception, they are derived from follicular epithelium and so might all be called follicular adenomas. A variety of terms have been proposed for classifying adenomas on the basis of degree of follicle formation and the colloid content of the follicles. Simple colloid adenomas (macrofollicular adenomas), a common form, resemble normal thyroid tissue; others recapitulate stages in the embryogenesis of the normal thyroid (fetal or microfollicular, embryonal or trabecular). There is limited utility in these classifications because mixed patterns are common, and most of these benign tumors are nonfunctional. Clinically, follicular adenomas can be difficult to distinguish from dominant nodules of follicular hyperplasia or from the less common follicular carcinomas.

Pathogenesis. The TSH receptor signaling pathway plays an important role in the pathogenesis of toxic adenomas. Activating ("gain of function") somatic mutations in one of two components of this signaling system-most often the TSH receptor itself or the α-subunit of Gs-cause chronic overproduction of cAMP, generating cells that acquire a growth advantage. This results in clonal expansion of follicular epithelial cells that can autonomously produce thyroid hormone and cause symptoms of thyroid excess.

Morphology. The typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is well demarcated from the surrounding thyroid parenchyma. The neoplastic cells are demarcated from the adjacent parenchyma by a well-defined, intact capsule. These features are important in making the distinction from multinodular goiters, which contain multiple nodules on their cut surface (even though the patient may present clinically with a solitary dominant nodule), produce less compression of the adjacent thyroid parenchyma, and lack a well-formed capsule. Areas of hemorrhage, fibrosis, calcification, and cystic change, similar to those encountered in multinodular goiters, are common in follicular adenomas, particularly within larger lesions.

Microscopically, the constituent cells often form uniform-appearing follicles that contain colloid. The follicular growth pattern within the adenoma is usually quite distinct from the adjacent non-neoplastic thyroid.

This neoplastic tissue is very well differentiated, showing follicles containing colloid. The nuclei are uniform and round with some small nucleoli and no mitotic figures, and polarity of the cuboidal cells toward follicular lumens is preserved.

This is another feature distinguishing adenomas from multinodular goiters, in which nodular and uninvolved thyroid parenchyma may have similar growth patterns. The epithelial cells composing the follicular adenoma reveal little variation in cell and nuclear morphology. Mitotic figures are rare, and extensive mitotic activity warrants careful examination of the capsule to exclude follicular carcinoma. Similarly, papillary change is not a typical feature of adenomas and, if extensive, should raise the suspicion of an encapsulated papillary carcinoma (see below). Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change); the clinical presentation and behavior of a follicular adenoma with oxyphilia (Hürthle cell adenoma) is no different from that of a conventional adenoma. Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular carcinomas, which demonstrate capsular and/or vascular invasion (see below).

Clinical Features. Many thyroid adenomas present as a unilateral painless mass, often discovered during a routine physical examination. Larger masses may produce local symptoms, such as difficulty in swallowing.

Most adenomas take up less radioactive iodine than does normal thyroid parenchyma. Thyroid adenomas, including atypical adenomas, have an excellent prognosis and do not recur or metastasize. About 20% of follicular adenomas have point mutations in the RAS family of oncogenes, which have also been identified in 30% to 40% of follicular carcinomas. This finding raises the possibility that some adenomas may progress to carcinomas.

Carcinomas

Most cases occur in adults, although some forms, particularly papillary carcinomas, may present in childhood. A female predominance has been noted among patients who develop thyroid carcinoma in the early and middle adult years, perhaps related to the expression of estrogen receptors on neoplastic thyroid epithelium. In contrast, cases presenting in childhood and late adult life are distributed equally among males and females. Most thyroid carcinomas are well-differentiated lesions.

Most thyroid carcinomas are derived from the follicular epithelium, except for medullary carcinomas; the latter are derived from the parafollicular or C cells. Because of the unique clinical and biologic features associated with each variant of thyroid carcinoma, these subtypes are described separately.

Morphology. Papillary carcinomas are solitary or multifocal lesions. Some tumors may be well-circumscribed and even encapsulated; others may infiltrate the adjacent parenchyma with ill-defined margins. The lesions may contain areas of fibrosis and calcification and are often cystic. On the cut surface, they may appear granular and may sometimes contain grossly discernible papillary foci. Papillary carcinomas can contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells.

Papillae are present within a clear space representing a cystic cavity. The neoplastic papillae are lined by a single row of fairly uniform, columnar epithelial cells and have central, delicate, fibrovascular cores. Examine Image 8 to see nuclear features. Papillary carcinomas may also show numerous calcospherites with concentric lamellae (psammoma bodies).

In most neoplasms, the epithelium covering the papillae consists of well-differentiated, uniform, orderly, cuboidal cells, but at the other extreme are those with fairly anaplastic epithelium showing considerable variation in cell and nuclear morphology. When present, the papillae of papillary carcinoma differ from those seen in areas of hyperplasia. In contrast to hyperplastic papillary lesions, the neoplastic papillae are more complex and have dense fibrovascular cores. The nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground glass or Orphan Annie eye nuclei.

The follicular variant has the characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture. Grossly, the tumor may be encapsulated, and focally, psammoma bodies may be seen. Clinical Course. Most papillary carcinomas present as asymptomatic thyroid nodules, but the first manifestation may be a mass in a cervical lymph node. Interestingly, the presence of isolated cervical nodal metastases does not appear to have a significant influence on the generally good prognosis of these lesions. The carcinoma, which is usually a single nodule, moves freely during swallowing and is not distinguishable from a benign nodule. Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease. In a minority of patients, hematogenous metastases are present at the time of diagnosis, most commonly in the lung.

A variety of diagnostic tests have been employed to help separate benign from malignant thyroid nodules, including radionuclide scanning and fine-needle aspiration. Most papillary lesions are cold masses on scintiscans. Improvements in cytologic analysis have made fine-needle aspiration cytology a reliable test for distinguishing between benign and malignant nodules. The nuclear features are often nicely demonstrable in aspirated specimens.

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

Follicular Carcinoma

Follicular carcinomas are the second most common form of thyroid cancer, accounting for 10% to 20% of all thyroid cancers. They tend to present in women, and at an older age than do papillary carcinomas, with a peak incidence in the forties and fifties. The incidence of follicular carcinoma is increased in areas of dietary iodine deficiency, suggesting that in some cases, nodular goiter may predispose to the development of the neoplasm. The high frequency of RAS mutations in follicular adenomas and carcinomas suggests that the two may be related tumors.

Morphology. Follicular carcinomas are single nodules that may be well circumscribed or widely infiltrative. 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, on occasion, are somewhat translucent when large, colloid-filled follicles are present. Degenerative changes, such as central fibrosis and foci of calcification, are sometimes present.

Microscopically, most follicular carcinomas are composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid. 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 cells). Whatever the pattern, the nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not present. It is important to note the absence of these details because some papillary carcinomas may appear almost entirely follicular. Follicular lesions in which the nuclear features are typical of papillary carcinomas should be treated as papillary cancers. While nuclear features are helpful in distinguishing papillary from follicular neoplasms, they are of little value in distinguishing follicular adenomas from minimally invasive follicular carcinomas. This distinction requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular invasion. The criterion for vascular invasion is applicable only to capsular vessels and vascular spaces beyond the capsule; the presence of tumor plugs within intratumoral blood vessels has little prognostic significance. Unlike in papillary cancers, lymphatic spread is distinctly uncommon in follicular cancers.

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

Clinical Course. Follicular carcinomas present as slowly enlarging painless nodules. Most frequently, they are cold nodules on scintigrams, although in rare cases, the better-differentiated lesions may be hyperfunctional, take up radioactive iodine, and appear warm on scintiscan. Follicular carcinomas have little propensity for invading lymphatics; therefore, regional lymph nodes are rarely involved, but vascular invasion is common, with spread to bone, lungs, liver, and elsewhere. The prognosis is largely dependent on the extent of invasion and stage at presentation. Widely invasive follicular carcinomas not infrequently develop metastases, and up to half succumb to their disease within 10 years.

growth and compromise of vital structures in the neck.

The endocrine pancreas

We now turn to the two main disorders of islet cells: diabetes mellitus and pancreatic endocrine tumors

Diabetes Mellitus

Diabetes mellitus (DM) is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic dysregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. Diabetes is a leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputations.

A variety of monogenic and secondary causes are responsible for the remaining cases, and these will be discussed later. It should be stressed that while the major types of diabetes have different pathogenic mechanisms, the long-term complications in kidneys, eyes, nerves, and blood vessels are the same, as are the principal causes of morbidity and death. The pathogenesis of the two major types is discussed separately, but first we briefly review normal insulin secretion and the mechanism of insulin signaling, since these aspects are critical to understanding the pathogenesis of diabetes.

Pathogenesis of the complications of diabetes

The morbidity associated with long-standing diabetes of either type results from a number of serious complications, involving both large- and medium-sized muscular arteries (macrovascular disease), as well as capillary dysfunction in target organs (microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased risk of myocardial infarction, stroke, and lower-extremity gangrene. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively. Diabetes is the leading cause of blindness and end-stage renal disease in the Western hemisphere, besides contributing substantially to the incidence of cardiovascular events each year. Hence, the basis of long-term complications of diabetes is the subject of a great deal of research. Most of the available experimental and clinical evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia. For example, when kidneys are transplanted into diabetics from nondiabetic donors, the lesions of diabetic nephropathy may develop within 3 to 5 years after transplantation. Conversely, kidneys with lesions of diabetic nephropathy demonstrate a reversal of the lesion when transplanted into normal recipients. Two large multicenter trials to evaluate the effects of plasma glucose concentrations on long-term complications of diabetes-the Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS)-have convincingly demonstrated delayed progression of microvascular complications by strict control of the hyperglycemia. It is important to stress, however, that not all diabetics have long-term complications, irrespective of the level of blood glucose control over time, indicating that there are additional factors that modulate an individual's risk for microvascular disease. It is likely that such disease-modifying elements are genetic, and there is an ongoing search to identify these additional genes.

Morphology of diabetes and its late complications

Pathologic findings in the pancreas are variable and not necessarily dramatic. The important morphologic changes are related to the many late systemic complications of diabetes. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of diabetes, the onset might be delayed. In most patients, however, morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues. These changes are seen in both type 1 and type 2 diabetes.

Morphology.

Pancreas. 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:

· Reduction in the number and size of islets. This is most often seen in type 1 diabetes, particularly with rapidly advancing disease. Most of the islets are small and inconspicuous, and not easily detected.

· Leukocytic infiltration of the islets (insulitis) principally composed of T lymphocytes similar to that in animal models of autoimmune diabetes. This may be seen in type 1 diabetics at the time of clinical presentation. The distribution of insulitis may be strikingly uneven. Eosinophilic infiltrates may also be found, particularly in diabetic infants who fail to survive the immediate postnatal period.

· By electron microscopy, β-cell degranulation may be observed, reflecting depletion of stored insulin in already damaged β cells. This is more commonly seen in patients with newly diagnosed type 1 disease, when some β cells are still present.

· In type 2 diabetes, there may be a subtle reduction in islet cell mass, demonstrated only by special morphometric studies.

· Amyloid replacement of islets in type 2 diabetes appears as deposition of pink, amorphous material beginning in and around capillaries and between cells. At advanced stages, the islets may be virtually obliterated; fibrosis may also be observed.

This low-power view shows pancreatic acini, stroma with blood vessels, and a few islets of Langerhans. Note that the exocrine part of the pancreas is normal.

This change is often seen in long-standing cases of type 2 diabetes. Similar lesions may be found in elderly nondiabetics, apparently as part of normal aging.

· An increase in the number and size of islets is especially characteristic of nondiabetic newborns of diabetic mothers. Presumably, fetal islets undergo hyperplasia in response to the maternal hyperglycemia.

Diabetic Macrovascular Disease. Diabetes exacts a heavy toll on the vascular system. The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. Except for its greater severity and earlier age at onset, atherosclerosis in diabetics is indistinguishable from that in nondiabetics. Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics. Significantly, it is almost as common in diabetic women as in diabetic men. In contrast, myocardial infarction is uncommon in nondiabetic women of reproductive age. Gangrene of the lower extremities, as a result of advanced vascular disease, is about 100 times more common in diabetics than in the general population. The larger renal arteries are also subject to severe atherosclerosis, but the most damaging effect of diabetes on the kidneys is exerted at the level of the glomeruli and the microcirculation. This will be discussed later

Hyaline arteriolosclerosis, the vascular lesion associated with hypertension, is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension. It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen. Not surprisingly, in diabetics, it is related not only to the duration of the disease, but also to the level of blood pressure

Diabetic Microangiopathy. One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla. However, it may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta. By both light and electron microscopy, the basal lamina separating parenchymal or endothelial cells from the surrounding tissue is markedly thickened by concentric layers of hyaline material composed predominantly of type IV collagen. 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

Diabetic Nephropathy. 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. The glomerular capillary basement membranes are thickened throughout their entire length.

This low-power view shows hyaline thickening of the arterial wall and evidence of tubular destruction, seen as an increase in the interstitial fibrous tissue. One of the glomeruli in this field has been totally replaced by scar tissue, and hence, it appears acellular and hyalinized. The two other glomeruli show nodular glomerulosclerosis.

This change can be detected by electron microscopy within a few years of the onset of diabetes, sometimes without any associated change in renal function.

Diffuse mesangial sclerosis consists of a diffuse increase in mesangial matrix and is always associated with basement membrane thickening. It is found in most patients with disease of more than 10 years' duration. When glomerulosclerosis becomes marked, patients manifest the nephrotic syndrome, characterized by proteinuria, hypoalbuminemia, and edema.

Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-like deposits of a laminated matrix situated in the periphery of the glomerulus. These nodules are PAS positive and usually contain trapped mesangial cells. This distinctive change has been called the Kimmelstiel-Wilson lesion, after the pathologists who described it. Nodular glomerulosclerosis is encountered in approximately 15% to 30% of long-term diabetics and is a major cause of morbidity and mortality. Diffuse mesangial sclerosis may also be seen in association with old age and hypertension; on the contrary, the nodular form of glomerulosclerosis, once certain unusual forms of nephropathies have been excluded, is essentially pathognomonic of diabetes. Both the diffuse and nodular forms of glomerulosclerosis induce sufficient ischemia to cause overall fine scarring of the kidneys, marked by a finely granular cortical surface

Renal atherosclerosis and arteriolosclerosis constitute part of the macrovascular disease in diabetics. The kidney is one of the most frequently and severely affected organs; however, the changes in the arteries and arterioles are similar to those found throughout the body. Hyaline arteriolosclerosis affects not only the afferent but also the efferent arteriole. Such efferent arteriolosclerosis is rarely, if ever, encountered in individuals who do not have diabetes.

Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules. Both the acute and chronic forms of this disease occur in nondiabetics as well as in diabetics but are more common in diabetics than in the general population, and, once affected, diabetics tend to have more severe involvement. One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics

Clinical features of diabetes

It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus. Only a few characteristic patterns will be presented.

Type 1 diabetes was traditionally thought to occur primarily in those under age 18 but is now known to occur at any age. In the initial 1 or 2 years following manifestation of overt type 1 diabetes, the exogenous insulin requirements may be minimal because of ongoing endogenous insulin secretion