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The precise regulation of the serum ionized calcium concentration is necessary to sustain human life. The calcium cation is central to a myriad of reactions, from enzymatic function to the coagulation cascade to muscle fiber contraction and neurotransmission to the dynamic buildup and breakdown of the scaffolding that houses it all. The majority of calcium in the human body is found in the skeleton and comprises approximately 2% of the average individual's body weight. Serum calcium levels are precisely maintained through an intricate interplay of checks and balances that begin and end with the parathyroid glands. The regulatory axis of calcium consists of the parathyroid glands, parathyroid hormone (PTH), membrane calcium receptors, the kidneys, the gut, and bone. Membrane calcium receptors on the cells of the parathyroid glands sense minute decreases in serum ionized calcium levels, triggering a cascade beginning with the secretion of PTH. This stimulates mobilization of calcium from bone, a reduction in renal calcium excretion, and an increase in renal hydroxylation of vitamin D, indirectly affecting calcium absorption in the duodenum and proximal jejunum. When calcium increases to within an acceptable range, calcium receptor-based stimulation of the parathyroids ceases, and secretion of PTH is inhibited. Thus, under normal conditions, the defining relationship between serum calcium and serum PTH is inverse: that is, high serum calcium begets low serum PTH and vice versa.


Diseases of the parathyroid are manifest almost exclusively as derangements in calcium metabolism. Hypercalcemia is the most common presentation, although the differential diagnosis of isolated hypercalcemia may be broad and complex. When hypercalcemia is associated with inappropriately high serum PTH, it is considered primary hyperparathyroidism (PHPT). This presupposes no antecedent renal disease, lithium therapy, or malabsorptive syndrome. In PHPT, the calcium level is generally high-normal to significantly elevated, and PTH levels are moderately elevated. PHPT may come in the form of single- or multigland adenoma, four-gland hyperplasia, or (rarely) parathyroid carcinoma.


Secondary hyperparathyroidism (SHPT) refers to the situation in which a derangement in calcium homeostasis (of a nonparathyroid cause) leads to a compensatory increase in PTH secretion. Unlike with PHPT, in SHPT, the elevation of serum PTH is an appropriate physiologic response to a perceived calcium deficit. The serum calcium level is generally in the low-normal range, and PTH is proportionately elevated. This is seen most often in the setting of end-stage renal disease (ESRD) (Figure 10-1) but may also result from other disorders of bone metabolism and the gastrointestinal (GI) tract.

Figure 10-1.
Graphic Jump Location

Pathogenesis of secondary hyperparathyroidism. PTH = parathyroid hormone; SPO4 = serum phosphate (Reproduced with permission from Wesseling K, Coburn JW, Salusky IB. In: DeGroot LJ, Jameson J, DeKretser DM, eds. Endocrinology, 5th ed. Philadelphia: Elsevier Saunders; 2006:1697-1712.)


On occasion, after prolonged secondary stimulation, the hyperfunctioning parathyroids are rendered unresponsive to serum calcium concentrations via a loss of calcium-sensing ...

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