Increased urinary phosphate excretion, thereby lowering serum phosphate levels (since phosphate binds to ionized calcium)
Increased conversion of vitamin D to its active dihydroxy form in the kidneys, which in turn augments lesions underlying primary hyperparathyroidism is as follows: • Adenoma—85% to 95% • Primary hyperplasia (diffuse or nodular)—5% to 10% • Parathyroid carcinoma—1%
Abnormalities in two genes are commonly associated with parathyroid tumors:
Cyclin D1 gene rearrangements. Cyclin D1 is a positive regulator of the cell cycle. An inversion on chromosome 11 repositions the cyclin D1 gene (normally on 11q), so that it resides adjacent to genomic elements that regulate the PTH gene (on 11p). These elements drive abnormal expression of cyclin D1 in PTH-producing cells, leading to increased proliferation of these cells. Between 10% and 20% of adenomas have this acquired genetic defect. Cyclin D1 is overexpressed in approximately 40% of parathyroid adenomas, indicating the existence of additional mechanisms that lead to its dysregulation.
MEN1 mutations. Approximately 20% to 30% of sporadic parathyroid tumors have mutations in both copies of the MEN1 tumor suppressor gene (see later). The spectrum of MEN1 mutations in the sporadic tumors is virtually identical to that in familial parathyroid adenomas.
• Enhanced osteoclastic activity (i.e., bone resorption,
MORPHOLOGYthus releasing ionized calcium), mediated indirectly by promoting the differentiation of osteoclast progenitor cells into mature osteoclasts
The net result of these activities is an increase in the level of free calcium in the blood, which inhibits PTH secretion from chief cells. Abnormalities of the parathyroids include both hyperfunction and hypofunction. Tumors of the parathyroid glands, unlike thyroid tumors, usually come to attention because of excessive secretion of PTH, rather than mass effects.
Hyperparathyroidism occurs in two major forms, primary and secondary, and, less commonly, as tertiary hyperparathyroidism. The first condition represents an autonomous, spontaneous overproduction of PTH, while the latter two conditions typically occur as secondary phenomena in patients with chronic renal insufficiency.
Primary hyperparathyroidism is a common endocrine disorder and an important cause of hypercalcemia. There was a dramatic increase in the detection of cases in the latter half of the 20th century, mainly due to routine performance of serum calcium assays in hospitalized patients. The frequency of occurrence of the various parathyroid
Themorphologicchangesinprimaryhyperparathyroidismincludethoseintheparathyroidglandsandinotherorgansaffectedbyhypercalcemia.In75%to80%ofcases,oneoftheparathyroidglandsharborsasolitaryadenoma.Thetypicalparathyroidadenomaisawell-circumscribed,soft,tannodule,investedbyadelicatecapsule.Bydefinition,parathyroidadenomasareconfinedtoasinglegland(
Fig.20.19 ).Theotherglandsarenormalinsizeorsomewhatshrunken,asaresultoffeedbackinhibitionbyelevatedserumcalcium.Mostparathyroidadenomasweighbetween0.5and5g.Onmicroscopicexamination,parathyroidadenomasarecomposedpredominantlyofchiefcells(