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Pathology Pre-test: Endocrine System

Terms in this set (29)

e. Sheehan's syndrome
Hypopituitarism results from destructive processes that involve the adeno-hypophysis (anterior pituitary). These processes may be acute (sudden) or chronic. Sheehan's syndrome, also known as postpartum pituitary necrosis, results from the sudden infarction of the anterior lobe of the pituitary. This can occur with obstetric complications, such as hemorrhage or shock. The pituitary gland normally doubles in size during pregnancy; hypovolemia during delivery decreases blood flow and may result in infarction of the anterior pituitary. Sheehan's syndrome produces symptoms of hypopituitarism. The initial sign is cessation of lactation, which may be followed by secondary amenorrhea due to the loss of gonadotropins. Other signs of hypopituitarism include hypothyroidism and decreased functioning of the adrenal gland. Acute destruction of the pituitary is also associated with DIC and thrombosis of the cavernous sinus. Chronic causes of hypopituitarism include nonsecretory chromophobe pituitary adenomas, empty sella syn- drome, and suprasellar (hypothalamic) tumors. Nonsecretory chromophobe adenomas present as space-occupying lesions that cause decreased hormone production. The gonadotropins are lost first, which results in signs of hypogonadism. Types of chromophobe adenomas include null cell adenomas (no cytoplasmic granules), chromophobes (sparse granules), and oncocytic adenomas (increased cytoplasmic mitochondria). The term pituitary apoplexy refers to spontaneous hemorrhage into a pituitary tumor, while the empty sella syndrome is caused by a defective diaphragma sellae, which permits CSF from the third ventricle to enter the sella. It may also be secondary to infarction or necrosis. A CT scan reveals the sella to be enlarged or to appear empty.
a. Euthyroid individual with increased thyroid-binding globulin
Tests used to determine thyroid function include serum thyroxine (T4), resin T3 uptake (RTU), thyroxine uptake (TU), free thyroxine index (FTI), and thyroid-stimulating hormone (TSH) levels. Serum T4 measures the total T4, which includes T4 bound to thyroid-binding globulin (TBG) and free T4. Therefore, increased total serum T4 levels can be from increased free T4 (such as Graves' disease) or from increased TBG. The resin T3 uptake (RTU) essentially measures the TBG concentration by measuring the binding of radioactive T3 to TBG; note that this is not the serum T3 concentration. The same thing is essentially determined using the thyroxine uptake (TU). These values then can be used to artificially determine the free thyroxine index (FTI), which is an estimate of the free thyroxine. The FTI (T7) can be determined using either T4 times TU or T4 times T3U.
To illustrate, consider the following. If a person is euthyroid, then their free T4 will be within normal limits. If the TBG in this person is normal, then the serum T4 will also be normal, but if their TBG is increased, which can be the result of increased estrogen from birth control pills or pregnancy, then the total serum T4 will be increased. Because the TBG is increased, however, the resin triiodothyronine uptake will be decreased. Because they are euthyroid and their free T4 is normal, then their TSH will also be normal. Note that the measurement of serum TSH levels is the best test to determine if thyroid function is normal or abnormal. A normal TSH level indicates that free T3 and free T4 levels in the serum are normal. Increased serum TSH indicates low free T3 and T4 levels (primary hypothyroidism), while decreased serum TSH levels indicate either decreased production by the pituitary (hypopituitarism) or increased thyroid production by the thyroid gland (hyperthyroidism).
b. Cretinism
The consequences of excess or inadequate thyroid hormone are directly attributed to abnormalities involving the normal functioning of thyroid hormones, such as regulation of body processes. For example, excess thy- roid hormone (hyperthyroidism) results in weight loss (increased lipolysis) despite increased food intake, heat intolerance, increased heart rate, tremor, nervousness, and weakness (due to loss in muscle mass). Inade- quate levels of thyroid hormone (hypothyroidism) produce different signs and symptoms in children than in older children and adults. In young chil- dren hypothyroidism produces cretinism, a disease that is characterized by marked retardation of physical and mental growth (severe mental retarda- tion). Patients develop dry, rough skin and a protuberant abdomen. Char- acteristic facial features include periorbital edema; a flattened, broad nose; and a large, protuberant tongue. In contrast, hypothyroidism in older chil- dren and adults produces myxedema. This disease is characterized by a decrease in the metabolic rate, which can result in multiple signs and symptoms, such as cold intolerance and weight gain. Neurologic features of this abnormality include slowing of intellectual and motor function (fatigue, lethargy, and slow speech), apathy, sleepiness, depression, para- noia, and prolonged relaxation phase in deep tendon reflexes ("hung-up" reflexes). Other signs and symptoms of hypothyroidism include dry skin and brittle hair, which can produce hair loss; decreased erythropoiesis, which produces a normochromic normocytic anemia; increased choles- terol, which increases the risk of atherosclerosis; and myxedema, which is the increased interstitial deposition of mucopolysaccharides. The latter abnormality can result in diffuse nonpitting edema of the skin, hoarseness, and enlargement of the heart. Other systems affected by hypothyroidism include the heart, the GI tract, and the GU tract. Patients may develop a slowed heart rate and decreased stroke volume (resulting in cool, pale skin) and constipation, as well as impotence (in men) or menorrhagia and anovulatory cycles (in women).
d. Lymphoid infiltrate with scattered Hurthle cells
Hashimoto's thyroiditis, one of the autoimmune thyroid diseases, is associ- ated with the HLA-B8 haplotype and high titers of circulating autoantibod- ies, including antimicrosomal, antithyroglobulin, and anti-TSH receptor antibodies. This abnormality, which is not uncommon in the United States, is characterized histologically by an intense lymphoplasmacytic infiltrate, with the formation of lymphoid follicles and germinal centers. This pro- duces destruction and atrophy of the follicles and transforms the thyroid follicular cells into acidophilic cells. There are many different names for these cells, including oxyphilic cells, oncocytes, and Hürthle cells. Not uncommonly, patients develop hypothyroidism as a result of follicle dis- ruption, and the manifestations consist of fatigue, myxedema, cold intoler- ance, hair coarsening, and constipation. Rarely, cases of Hashimoto's thyroiditis may develop hyperthyroidism (Hashitoxicosis), while the com- bination of Hashimoto's disease, pernicious anemia, and type I diabetes mellitus is called Schmidt's syndrome. This is one type of multiglandular syndrome.
Although subacute thyroiditis and Riedel's thyroiditis may have similar symptoms to Hashimoto's thyroiditis, biopsy findings in these disorders are distinctly different. Subacute (de Quervain's, granulomatous, or giant cell) thyroiditis is a self-limited viral infection of the thyroid. It typically follows an upper respiratory tract infection. Patients develop the acute onset of fever and painful thyroid enlargement and may develop a transient hypothyroidism. Histologically there is destruction of the follicles with a granulomatous reaction and multinucleated giant cells that surround frag- ments of colloid. One-half of patients with Riedel's thyroiditis are hypothy- roid, but, in contrast to the other types of thyroiditis, microscopic examination reveals dense fibrosis of the thyroid gland, often extending into extrathyroidal soft tissue. This fibrosis produces a rock-hard enlarged thyroid gland that may produce the feeling of suffocation. This combina- tion of signs and symptoms may be mistaken clinically for a malignant process. Additionally, these patients may develop similar fibrosis in the mediastinum or retroperitoneum. Subacute lymphocytic thyroiditis is also a self-limited, painless enlargement of the thyroid that is associated with hypothyroidism, but that lacks antithyroid antibodies or lymphoid germi- nal centers within the thyroid. Finally, follicular cell hyperplasia with scal- loping of colloid is characteristic of hyperthyroidism due to Graves' disease, while the extracellular deposition of amyloid in the thyroid gland is characteristic of medullary thyroid carcinoma.
e. Follicular carcinoma
Follicular carcinoma is the second most common malignancy of the thyroid gland. These tumors present as slowly enlarging painless nodules that usually are found to be "cold" (nonfunctioning) nodules with thyroid scans. The histology of follicular carcinoma is similar to follicular adenoma and this type of malignancy may have a well-defined capsule. Invasion into blood vessels or the capsule must be present to diagnosis follicular carcinoma. There are two basic pathways that lead to the development of follicular carcinomas of the thyroid. One involves mutations of the RAS family of oncogenes, while the other involves a unique translocation between PAX8 and the peroxisome proliferator-activated receptor gamma (PPAR gamma), which forms a PAX8-PPAR-gamma fusion gene.
The PAX (paired box) genes are a family of related genes that code for transcription factors important for tissue development. Abnormalities of these PAX genes are associated with various diseases: PAX-2 with the "renal- coloboma" syndrome; PAX-3 with the Waardenburg syndrome (white forelocks of hair; eye colors don't match); PAX-5 with lymphoplasmacytoid lymphoma; PAX-6 with aniridia and Wilm's tumor; PAX-8 with follicular thyroid carcinoma; and PAX-9 with congenital absence of teeth.
Note that the clinical term goiter is used to describe any enlargement of the thyroid. Most patients with goiter are euthyroid (nonfunctional goiter), as hyperthyroidism (toxic goiter) is relatively rare. In the early stages of goiter formation, there is diffuse hyperplasia of the small thyroid follicles, which histologically resembles the changes of Graves' disease. This early stage is called a diffuse nontoxic goiter or simple goiter. The thyroid gland then undergoes repeated episodes of involution and hyperplasia. Over time this produces an enlarged multinodular goiter that histologically consists of multiple nodules, some of which consist of colloid-filled enlarged follicles and others of which show hyperplasia of small follicles lined by active epithelium. There are also areas of fibrosis, hemorrhage, calcification, and cystic degeneration. The last stage of goiter formation consists of nodules composed primarily of enlarged colloid-filled follicles. This stage is called a colloid goiter. Finally, note that colloid carcinoma is a type of malignancy of the breast, not the thyroid gland.
c. Optically clear nuclei with longitudinal nuclear grooves
The four major histologic subtypes of thyroid carcinoma are papillary carcinoma, follicular carcinoma, medullary carcinoma, and undifferentiated (anaplastic) carcinoma. Papillary carcinomas of the thyroid are composed of papillary structures with fibrovascular cores, while follicular carcinomas typically show a microfollicular pattern. It is important prognostically to differentiate papillary carcinomas from follicular carcinomas, as papillary carcinomas tend to be indolent (up to 80% survival at 10 years), while follicular carcinomas are much more aggressive (5-year mortality of up to 70%). Follicular areas may be present within a papillary carcinoma and in fact may be quite extensive. If present, these changes can make diagnosis difficult. It is important to recognize this follicular variant of papillary carcinoma because its behavior remains similar to that of indolent papillary carcinoma. Features consistent with papillary carcinoma, even in predominantly follicular areas, include optically clear nuclei ("ground glass," "Orphan Annie eyes"), nuclear grooves, calcospherites (psammoma bodies), and intranuclear cytoplasmic pseudoinclusions.
In contrast to the histologic features of papillary carcinoma, follicular carcinoma of the thyroid has a histology that is similar to a follicular adenoma, but capsular and blood vessel invasion is present. Medullary carcinoma is characterized by its amyloid stroma, its genetic (familial) associations, and its elaboration of calcitonin and other substances. It is a malignancy that originates from the parafollicular C cells. Undifferentiated (anaplastic) carcinoma, seen in individuals over the age of 50, is characterized by anaplastic spindle or giant cells with frequent mitoses. This tumor is characterized by rapid growth and a poor prognosis.
a. Primary hyperparathyroidism
Hyperparathyroidism is caused by excess production of parathyroid hormone (PTH). In patients with hyperparathyroidism, it is important to distinguish primary hyperparathyroidism from secondary hyperparathyroidism. Both forms may be associated with the development of bone lesions, but excess PTH production in primary hyperparathyroidism leads to different laboratory values than those seen with secondary hyperparathyroidism. Increased levels of PTH in primary hyperparathyroidism result in increased serum calcium (hypercalcemia) and decreased serum phosphorus. The serum calcium levels are elevated because of increased bone resorption and increased intestinal calcium absorption, the result of increased activity of vitamin D. PTH also increases calcium reabsorption in the distal renal tubule, but, because the filtered load of calcium exceeds the ability for reabsorption, calcium is increased in the urine (hypercalciuria). PTH also increases urinary excretion of phosphate. The excess calcium in the urine predisposes to renal stone formation, especially calcium oxalate or calcium phosphate stones. Urinary stones can produce flank pain and hematuria. This is the most common presentation for patients with hyperparathyroidism. The hypercalcemia of hyperparathyroidism may also cause peptic ulcer disease due to the stimulation of gastrin release and increased acid secretion from the parietal cells. The hypercalcemia also results in muscle weakness, fatigue, and hypomotility of the GI tract, which can lead to constipation and nausea. Alterations of mental status are also common.
In contrast to primary hyperparathyroidism, secondary hyper-parathyroidism results from hypocalcemia. This causes secondary hyper- secretion of PTH and produces the combination of hypocalcemia and increased PTH production. It is primarily found in patients with chronic renal failure. Patients with hypoparathyroidism develop hypocalcemia and hyperphosphatemia but have normal serum creatinine levels. Primary hypo- parathyroidism and pseudohypoparathyroidism also result in decreased 24-h excretion of calcium and phosphate.
c. Box C
To summarize the diseases of the parathyroid glands, since serum calcium levels are affected by serum PTH levels, plotting serum calcium levels and serum PTH on a graph will separate the different abnormalities of PTH functioning into different areas of the graph. Increased levels of PTH (hyperparathyroidism) may be either primary or secondary. Primary hyperparathyroidism is associated with increased PTH and increased calcium (area B), while secondary hyperparathyroidism is associated with increased PTH and decreased or normal calcium levels (boxes E and D, respectively). This can be seen in patients with a deficiency of 1-α-hydroxylase, because decreased active vitamin D levels produce decreased absorption of calcium, hypocalcemia, and resultant hyperparathyroidism.
Primary hypoparathyroidism refers to decreased levels of PTH and decreased levels of calcium (box C). Causes of primary hypoparathyroidism include iatrogenic factors, such as surgical accident during thyroidectomy, congenital abnormalities (DiGeorge's syndrome), and type I polyglandular autoimmune syndrome. Patients with the latter abnormality have at least two of the triad of Addison's disease, hypoparathyroidism, and mucocutaneous candidiasis. Pseudo-hypoparathyroidism refers to decreased levels of calcium and increased levels of PTH (box E, which is the same as hyperparathyroidism). Pseudo-hyperparathyroidism would theoretically refer to decreased levels of PTH and increased levels of calcium (box A). This combination does not occur with diseases of the parathyroid glands, but instead can be seen in patients with hypercalcemia as the result of production of a substance with parathyroid hormone like function (paraneoplastic syndrome). This substance is called parathyroid-hormone-related protein. In these patients, serum levels of PTH are decreased because of the high levels of calcium.
d. 21-hydroxylase
In the adrenal cortex, cholesterol is converted into either mineralocorticoids (aldosterone) in the zona glomerulosa, glucocorticoids (cortisol) in the zona fasciculata, or sex steroid precursors in the zona reticularis. Congenital adrenal hyperplasia (CAH) is a syndrome that results from a defect in the synthesis of cortisol. This leads to excess ACTH secretion by the anterior pituitary and resultant adrenal hyperplasia. The defect in the synthesis of cortisol is the result of a deficiency in one of the enzymes in the normal pathway of cortisol synthesis, such as 21-hydroxylase or 11-hydroxylase. Most cases of CAH result from a deficiency of 21-hydroxylase. Two forms of this deficiency include salt-wasting adrenogenitalism and simple virilizing adrenogenitalism. The salt-wasting syndrome results from a complete lack of the hydroxylase. There is no synthesis of mineralocorticoids or glucocorticoids in the adrenal cortex. Decreased mineralocorticoids cause marked sodium loss in the urine, hyponatremia, hyperkalemia, acidosis, and hypotension.
Because of the enzyme block there is increased formation of 17- hydroxyprogesterone, which is then shunted into the production of testosterone. This may cause virilism (pseudohermaphroditism) in female infants. That is, XX females with CAH develop ovaries, female ductal structures, and external male genitalia. Much more often there is only a partial deficiency of 21-hydroxylase, which leads to decreased production of both aldosterone and cortisol. The decreased cortisol levels cause increased production of ACTH by the pituitary, which results in adrenal hyperplasia, enough to maintain adequate serum levels of aldosterone and cortisol. In contrast to a complete deficiency of 21-hydroxylase, there is no sodium loss with a partial deficiency of 21-hydroxylase. The excess stimulation by ACTH, however, leads to increased production of androgens, which may cause virilism in female infants.
A deficiency of 11-hydroxylase, which is rare, also leads to decreased cortisol production and increased ACTH secretion. This in turn leads to the accumulation of deoxycorticosterone (DOC) and 11-deoxycortisol, both of which are strong mineralocorticoids. This results in increased sodium retention by the kidneys and hypertension. Patients also develop hypokalemia and virilization due to androgen excess. Patients with a deficiency of 17- hydroxylase also exhibit impaired cortisol production, increased ACTH, and secondary increased DOC. These patients, however, cannot synthesize normal amounts of androgens and estrogens. This is because the gene that codes for 17-hydroxylase is the same for the enzyme in the adrenal cortex and the gonads, and the deficiency is the same in both organs. Because of decreased sex hormones, genotypic females develop primary amenorrhea and fail to develop secondary sex characteristics, while genotypic males present as pseudohermaphrodites. Additionally, the plasma LH levels are increased due to decreased feedback inhibition.
d. Cushing's syndrome
The clinical effects of excess cortisol are called Cushing's syndrome. Many of the symptoms of Cushing's syndrome that result from excess cortisol production can be directly related to the normal function of cortisol. Because cortisol is a glucocorticoid, its major function involves the maintenance of normal blood glucose levels. In this regard cortisol increases gluconeogenesis and glycogen storage in the liver. To provide the protein for liver gluconeogenesis, muscle is broken down. Because muscle is primarily located in the extremities, patients lose muscle in the extremities. This produces muscle wasting and proximal muscle weakness. Cortisol, in contrast to insulin, inhibits glucose uptake by many tissues. Therefore, excess cortisol causes symptoms of glucose intolerance, hyperglycemia, and diabetes mellitus. Cortisol also stimulates the appetite and lipogenesis in certain adipose tissues (the face and trunk), while promoting lipolysis in the extremities. Therefore, excess cortisol is associated with truncal obesity, "moon" face, and "buffalo hump." Excess cortisol inhibits fibroblasts, which in turn leads to loss of collagen and connective tissue. This produces thinning of the skin and weakness of blood vessels, which in turn results in easy bruising (ecchymoses), purple abdominal striae, and impaired wound healing. Cortisol also decreases the intestinal absorption of calcium, decreases the renal reabsorption of calcium and phosphorus, and increases the urinary excretion of calcium (hypercalcinuria). The combination of decreased bone formation and increased bone resorption with excess cortisol produces osteoporosis (decreased bone mass). Hypertension also occurs in a majority of patients with Cushing's syndrome; the exact mechanism is unknown. Cortisol enhances erythropoietin function, resulting in secondary polycythemia, which is seen clinically as plethora. Cortisol also normally functions to inhibit many inflammatory and immune reactions. Hypercortisolism produces decreased neutrophil adhesion in blood vessels and increased destruction of lymphocytes and eosinophils. This results in an absolute neutrophilia, absolute lymphopenia, eosinopenia, and increased vulnerability to microbial infections. Patients with Cushing's syndrome also develop psychiatric symptoms that include euphoria, mania, and psychosis. Gonadal dysfunction also is frequent, which in pre- menopausal women leads to hirsutism, acne, amenorrhea, and infertility.
In contrast to Cushing's syndrome, which results from excess cortisol, Conn's syndrome results from excess aldosterone. Addison's disease results from hypofunctioning, not hyperfunctioning, of the adrenal cortex. It most commonly results from autoimmune destruction of the adrenal cortex. Finally, Schmidt's syndrome, which is a type of polyglandular autoimmune syndrome, is characterized by the combination of Hashimoto's disease, pernicious anemia, and type I diabetes mellitus.
c. Autoimmune destruction of the adrenal cortex
Hypo-functioning of the cortex of the adrenal gland (adrenocortical insufficiency) may be the result of abnormalities involving either the adrenal gland itself (primary adrenocortical insufficiency) or the pituitary gland, which controls the adrenal (secondary adrenocortical insufficiency). Primary insufficiency may arise from either an acute process or a chronic process. Causes of primary acute adrenocortical insufficiency include acute hemorrhagic necrosis of the adrenals, seen in children as Waterhouse-Friderichsen syndrome. This syndrome is most commonly due to Neisseria meningitidis septicemia, which is characterized by meningitis, septicemia, DIC, and hypovolemic shock. Acute adrenocortical insufficiency may also occur with too rapid a withdrawal of steroid therapy if a patient has additional stress. Causes of primary chronic adrenocortical insufficiency (Addison's disease) include autoimmune adrenalitis, infections, amyloidosis, and metastatic cancer. Previously the most common cause of Addison's disease was tuberculosis of the adrenal gland, but now the majority of patients have adrenal autoantibodies and are thought to have autoimmune adrenalitis. Half of these cases involve other autoimmune endocrine diseases, the resulting syndromes being called polyglandular autoimmune (PGA) syndromes.
Secondary adrenocortical insufficiency, such as in decreased functioning of the pituitary or in prolonged suppression of the pituitary by exogenous glucocorticoid therapy, results in decreased ACTH and hypofunctioning of the adrenal. This produces symptoms similar to those of Addison's disease, such as weakness and weight loss. In contrast to the case with Addison's dis- ease, secretion of aldosterone in patients with secondary adrenocortical insufficiency is normal, because aldosterone production is not controlled by the pituitary gland. Therefore these patients do not develop symptoms of aldosterone deficiency such as volume depletion, hypotension, hyperkalemia, or hyponatremia. Additionally, because ACTH levels are not elevated, there is no hyperpigmentation.
c. Ectodermal dystrophy
In 1855, when Thomas Addison first described primary adrenal insufficiency, the most common cause was tuberculosis of the adrenal gland. Now the majority of patients have adrenal autoantibodies and are thought to have autoimmune Addison's disease. Autoimmune adrenalitis may occur by itself (isolated autoimmune Addison's disease) or it may occur with other autoimmune endocrine diseases. Two major patterns of autoimmune poly-endocrine syndromes have been described. In addition to autoimmune adrenitis, patients with autoimmune polyendocrine syndrome type 1 (APS1) have chronic mucocutaneous candidiasis and abnormalities of the skin, nails, and teeth (ectodermal dystrophy). APS1 is also known as APECED (autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy). In addition patients have other autoimmune disorders including autoimmune hypoparathyroidism, idiopathic hypogonadism, and pernicious anemia. APS1 results from mutations of the autoimmune regulator (AIRE) gene, the product of which is expressed primarily in the thymus. Autoimmune polyendocrine syndromes type 2 (APS2) is not associated with candidiasis, ectodermal dysplasia, or autoimmune hypoparathy- roidism. Instead, autoimmune adrenalitis is present with autoimmune thyroiditis (Hashimoto's thyroiditis) or type 1 diabetes mellitus.
Finally, do not confuse autoimmune polyendocrine syndromes with multiple endocrine neoplasia (MEN). Hyperplasia of the parathyroid glands is seen with both type I and type II MEN, while neoplasms of the anterior pituitary are seen with type I MEN only.