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PARATHYROID GLANDS Derived from the developing pharyngeal pouches The four glands normally lie in close proximity to the upper and lower poles of each thyroid lobe 10% of individuals have only two or three glands.
In the adult, the parathyroid is a yellowbrown, ovoid encapsulated nodule weighing approximately 35 to 40 mg. Most of the gland is composed of chief cells. They contain secretory granules of parathyroid hormone (PTH). Oxyphil cells and transitional oxyphils are found throughout the normal parathyroid, either singly or in small clusters.
The amount of stromal fat increases up to age 25, reaching a maximum of approximately 30% of the gland. The activity of the parathyroid glands is controlled by the level of free (ionized) calcium in the bloodstream rather than by trophic hormones secreted by the hypothalamus and pituitary.
The metabolic functions of PTH in supporting serum calcium levels can be summarized as follows: PTH activates osteoclasts, thereby mobilizing calcium from bone. It increases the renal tubular reabsorption of calcium, thereby conserving free calcium. It increases the conversion of vitamin D to its active dihydroxy form in the kidneys. It increases urinary phosphate excretion, thereby lowering serum phosphate levels. It augments gastrointestinal calcium absorption.
Hypercalcemia of malignancy is due to increased bone resorption and subsequent release of calcium. There are two major mechanisms by which this can occur: (1) osteolytic metastases and local release of cytokines (2) release of PTH-related protein (PTHr. P).
Recently, a critical osteoclastogenic pathway has been discovered that involves the osteoblast cell-surface receptor RANK (receptor activator of nuclear factor κB), its ligand, RANKL, and a decoy receptor for RANKL, osteoprotegerin. RANKL is also known as "osteoclast differentiation factor, " and by binding with the RANK receptor, it promotes all aspects of osteoclast function, including proliferation, differentiation, fusion, and activation. RANKL is secreted by tumor cells and peritumoral stromal cells in metastatic foci and causes osteolysis.
PTH-related protein: The most frequent cause of hypercalcemia in nonmetastatic solid tumors-particularly squamous cell cancers PTHr. P-induced hypercalcemia was known as "humoral hypercalcemia of malignancy" to distinguish it from hypercalcemia arising from osteolytic metastases.
Hyperparathyroidism PRIMARY HYPERPARATHYROIDISM Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an important cause of hypercalcemia. The frequency of the various parathyroid lesions underlying the hyperfunction is as follows: Adenoma: 75% to 80% Primary hyperplasia (diffuse or nodular): 10% to 15% Parathyroid carcinoma: less than 5%
Primary hyperparathyroidism is usually a disease of adults and is more common in women than in men by a ratio of nearly 3: 1. In more than 95% of cases, the disorder is caused by sporadic parathyroid adenomas or sporadic hyperplasia :
Cardinal features of hyperparathyroidism. With routine evaluation of calcium levels in most patients, primary hyperparathyroidism is often detected at a clinically silent stage. Hypercalcemia from any other cause can also give rise to the same symptoms. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 20 February 2006 11: 38 PM) © 2005 Elsevier
The genetic syndromes associated with familial primary hyperparathyroidism include the following: Multiple endocrine neoplasia-1 (MEN-1) Multiple endocrine neoplasia-2 (MEN-2) Familial hypocalciuric hypercalcemia (FHH) is an autosomal-dominant disorder characterized by enhanced parathyroid function due to decreased sensitivity to extracellular calcium. Sporadic parathyroid hyperplasia is also monoclonal in many instances,
Morphology Parathyroid adenomas solitary -similar to the normal parathyroid glands, may lie in close proximity to the thyroid gland or in an ectopic site (e. g. , the mediastinum). The typical parathyroid adenoma averages 0. 5 to 5. 0 gm; is a well-circumscribed, soft, tan to reddish-brown nodule; and is invested by a delicate capsule In contrast to primary hyperplasia, the glands outside the adenoma are usually normal in size or somewhat shrunken because of feedback inhibition by elevations in serum calcium.
Microscopically, parathyroid adenomas are often composed predominantly of fairly uniform, polygonal chief cells with small, centrally placed nuclei Mitotic figures are rare. A rim of compressed, non-neoplastic parathyroid tissue, generally separated by a fibrous capsule, is often visible at the edge of the adenoma.
Parathyroid adenomas are almost always solitary lesions. Technetium-99 msestamibi radionuclide scan demonstrates an area of increased uptake corresponding to the left inferior parathyroid gland (arrow). This patient had a parathyroid adenoma. Preoperative scintigraphy is useful in localizing and distinguishing adenomas from parathyroid hyperplasia, where more than one gland would demonstrate increased uptake. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 20 February 2006 11: 38 PM) © 2005 Elsevier
Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma (lowpower photomicrograph) revealing clear delineation from the residual gland below. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 20 February 2006 11: 38 PM) © 2005 Elsevier
Parathyroid adenoma. B, High-power detail of a chief cell parathyroid adenoma. There is some slight variation in nuclear size but no anaplasia and some slight tendency to follicular formation. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 20 February 2006 11: 38 PM) © 2005 Elsevier
Primary hyperplasia Sporadically or as a component of MEN syndrome. Classically all four glands are involved, there is frequently asymmetry with apparent sparing of one or two glands, making the distinction between hyperplasia and adenoma difficult. The combined weight of all glands rarely exceeds 1. 0 gm and is often less. Microscopically, the most common pattern seen is that of chief cell hyperplasia, which may involve the glands in a diffuse or multinodular pattern.
Parathyroid carcinomas Circumscribed lesions that are difficult to distinguish from adenomas, or they may be clearly invasive neoplasms. These tumors enlarge one parathyroid gland consist of gray-white, irregular masses that sometimes exceed 10 gm in weight.
The cells of parathyroid carcinomas are usually uniform and resemble normal parathyroid cells. They are arrayed in nodular or trabecular patterns with a dense, fibrous capsule enclosing the mass. diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only reliable criteria of malignancy. Local recurrence occurs in one third of cases, and more distant dissemination occurs in another third.
Skeletal changes include prominence of osteoclasts, which, in turn, erode bone matrix and mobilize calcium salts, particularly in the metaphyses of long tubular bones In more severe cases, the cortex is grossly thinned, and the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cyst formation (osteitis fibrosa cystica). Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasms (brown tumors of hyperparathyroidism).
PTH-induced hypercalcemia favors formation of urinary tract stones (nephrolithiasis) as well as calcification of the renal interstitium and tubules (nephrocalcinosis). Metastatic calcification secondary to hypercalcemia may also be seen in other sites, including the stomach, lungs, myocardium, and blood vessels.
Clinical Course. Primary hyperparathyroidism presents in one of two general ways: (1) It may be asymptomatic and be identified after a routine chemistry profile, (2) Patients may have the classic clinical manifestations of primary hyperparathyroidism
Raised PTH Decreased PTH Hyperparathyro idism Primary (adenoma > hyperplasia)* Secondary† Tertiary† Familial hypocalciuric hypercalcemia Hypercalcemia of malignancy Osteolytic metastases (RANKL-mediated) PTH-r. P-mediated Vitamin D toxicity Immobilization Thiazide diuretics Granulomatous disease (sarcoidosis)
Primary hyperparathyroidism is the most common cause of hyper-calcemia overall. Malignancy is the most common cause of symptomatic hypercalcemia. Primary hyperparathyroidism and malignancy account for nearly 90% of cases of hypercalcemia. Secondary and tertiary hyperparathyroidism are most commonly associated with progressive renal failure.
Asymptomatic Hyperparathyroidism Because serum calcium levels are routinely assessed in the work-up of most patients who need blood tests for unrelated conditions, clinically silent hyperparathyroidism is often detected early. The most common manifestation of primary hyperparathyroidism is an increase in the level of serum ionized calcium; in fact, primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia.
Symptomatic Primary Hyperparathyroidism The signs and symptoms of hyperparathyroidism reflect the combined effects of increased PTH secretion and hypercalcemia. The symptomatic presentation involves a diversity of clinical manifestations: Bone disease includes bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica. Nephrolithiasis (renal stones) occurs in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and a variety of abnormalities in renal function are found, including polyuria and secondary polydipsia. Gastrointestinal disturbances include constipation, nausea, peptic ulcers, pancreatitis, and gallstones. Central nervous system alterations include depression, lethargy, and eventually seizures. Neuromuscular abnormalities include complaints of weakness and fatigue. Cardiac manifestations include aortic or mitral valve calcifications (or both).
SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism is caused by any condition associated with a chronic depression in the serum calcium level because low serum calcium leads to compensatory overactivity of the parathyroid glands. Renal failure is by far the most common cause of secondary hyperparathyroidism, although a number of other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin D deficiency, may also cause this disorder.
Morphology: The parathyroid glands in secondary hyperparathyroidism are hyperplastic. As in the case of primary hyperplasia, the degree of glandular enlargement is not necessarily symmetric. Microscopically, the hyperplastic glands contain an increased number of chief cells, or cells with more abundant, clear cytoplasm (so-called water-clear cells) in a diffuse or multinodular distribution. Fat cells are decreased in number. Bone changes similar to those seen in primary hyperparathyroidism may also be present. Metastatic calcification may be seen in many tissues, including lungs, heart, stomach, and blood vessels.
Clinical Course The clinical features of secondary hyperparathyroidism are usually dominated by those associated with chronic renal failure. Bone abnormalities (renal osteodystrophy) and other changes associated with PTH excess are, in general, less severe than are those seen in primary hyperparathyroidism.
In a minority of patients, parathyroid activity may become autonomous and excessive, with resultant hypercalcemia, a process that is sometimes termed tertiary hyperparathyroidism. Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients.
Hypoparathyroidism is far less common than is hyperparathyroidism. There are many possible causes of deficient PTH secretion resulting in hypoparathyroidism: Surgically induced hypoparathyroidism occurs with inadvertent removal of all the parathyroid glands during thyroidectomy, excision of the parathyroid glands in the mistaken
Congenital absence of all glands, as in certain developmental abnormalities, such as thymic aplasia and cardiac defects (22 q 11. 2 syndrome) Familial hypoparathyroidism is often associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency; this syndrome is known as autoimmune polyendocrine syndrome type 1 (APS 1) and is caused by mutations in the autoimmune regulator (AIRE) gene. İdiopathic hypoparathyroidism most likely represents an autoimmune disease with isolated atrophy of the glands.
The major clinical manifestations of hypoparathyroidism are referable to hypocalcemia and are related to the severity and chronicity of the hypocalcemia. The hallmark of hypocalcemia is tetany, which is characterized by neuromuscular irritability Mental status changes can include emotional instability, anxiety and depression, confusional states, hallucinations, and frank psychosis.
Intracranial manifestations include calcifications of the basal ganglia, parkinsonian-like movement disorders Ocular disease results in calcification of the lens leading to cataract formation. Cardiovascular manifestations include a conduction defect, which produces a characteristic prolongation of the QT interval in the electrocardiogram. Dental abnormalities occur when hypocalcemia is present during early development. These findings are highly characteristic of hypoparathyroidism and include dental hypoplasia, failure of eruption, defective enamel and root
Pseudohypoparathyroidism Hypoparathyroidism occurs because of endorgan resistance to the actions of PTH. Serum PTH levels are normal or elevated. Central to the understanding of PTH resistance are two key concepts: (1) G-proteins, principally Gs, mediate the cellular actions of PTH on bone and kidney, and (2) GNAS 1 is a selectively imprinted gene, with tissue-specific patterns of imprinting
Two types of pseudohypoparathyroidism have been identified depending on the parent of origin of the mutant allele: 1 -Pseudohypoparathyroidism type 1 A is associated with multihormone resistance and Albright hereditary osteodystrophy (AHO), a syndrome characterized by skeletal and developmental defects. Patients with AHO often have short stature, obesity, short metacarpal and metatarsal bones, and variable mental deficits. The multihormone resistance involves three hormones (PTH, TSH, and LH/FSH),
2 -Pseudopseudohypoparathyroidism: In this disorder, the mutation is inherited on the paternal allele, and it is characterized by AHO without accompanying multihormonal resistance. As a result, serum calcium, phosphate and PTH levels are normal.