4.1 Introduction

Calcium is one of the most tightly regulated ions in the body, highlighting its critical role in everything from intracellular signaling to muscular contraction. Thus, even small deviations in calcium values outside the normal range usually signify some underlying pathology. Disorders involving hypercalcemia are more common than those involving hypocalcemia because of all of the compensatory systems that respond to a drop in serum calcium. In an outpatient setting the most common cause of hypercalcemia is primary hyperparathyroidism. The diagnosis of early primary hyperparathyroidism increased dramatically with the advent of automated multiple sample blood chemistry analysis. The corollary of this fact is that we rarely encounter patients as dramatic as Captain Martell anymore. ¹ Therefore, to be able to better diagnose and treat patients with diseases of the parathyroid gland, who often do not have significant clinical signs or symptoms, it is important to have a clear understanding of the factors involved in the regulation and secretion of parathyroid hormone (PTH) to avoid misdiagnosis.

4.2 History

The comparative anatomical description and naming of parathyroid glands are credited to Sandstroem in 1880, ^{2 , 3} who examined the necks of humans and other mammals (dog, cat, rabbit, horse, and ox) for the glands he eventually named glandulae parathyroidea ⁴ (Fig. 4.1). As a medical student in the Department of Anatomy in the University of Uppsala he examined the necks of human cadavers and identified the same organs he had observed in animals in 43 of 50 cadavers: “Found on both sides of the inferior border of the thyroid an organ of the size of a small pea which judging from its exterior, did not appear to be a lymph gland, or an accessory thyroid gland and which upon histological examination showed a rather peculiar structure.” ⁴ At that time only two parathyroid glands were recognized to be present in humans. Interestingly, the description of parathyroid glands as distinct organs in animals had been made as far back as 1852 by Owen, who identified “a small compact yellow glandular body attached to the thyroid” in the Indian rhinoceros. ^{2 , 5} A potential role of these organs was not clear until the French physiologist Eugene Gley demonstrated that tetany did not occur after thyroidectomy in experimental animals if the parathyroid glands were excluded. ⁴ However, it was felt that the parathyroid gland’s role was to remove toxins (such as methyl guanidine) from the body and that it was the accumulation of these toxins that was precipitating the tetany. ⁶ It was not until almost 20 years later that MacCallum and Voegtlin demonstrated that removal of the parathyroid glands was associated with hypocalcemia and that infusion of calcium prevented tetany. ^{6 , 7}

A connection between overproduction of PTH and a specific disease was proposed in 1915 when the pathologist Friedrich Schlagenhaufer, based on two autopsies he was performing on patients with hyperparathyroidism, speculated that an enlarged parathyroid gland (adenoma) could result in parathyroid bone disease (osteitis fibrosa cystica). ^{4 , 6} Subsequently, in 1925 this hypothesis was put to the test when Dr. Felix Mandl successfully removed an enlarged parathyroid gland in a patient, with marked improvement in the accompanying bone disease. ⁶

Around this time, Fuller Albright and colleagues at the Massachusetts General Hospital began careful metabolic studies to characterize calcium and phosphate turnover. ^{8 , 9 , 10 , 11 , 12} A New England sea captain by the name of Charles Martell had developed severe parathyroid bone disease and was operated on by Dr. Edward Richardson, head of the Department of Surgery at the Massachusetts General Hospital. No abnormal parathyroid tissue was located in the neck despite repeated surgeries. Dr. Oliver Cope, then a surgical resident, undertook a study on normal variations in the parathyroid glands. In 1932, Dr. Edward Churchill, together with Dr. Cope, in Captain Martell’s seventh surgery, extended the incision to the chest with a sternotomy and successfully removed a parathyroid adenoma from the mediastinum. ¹³ Unfortunately, Captain Martell went on to die from renal failure related to kidney stone disease from the many years of severe hyperparathyroidism.

During that time, work was also proceeding on the purification of parathyroid hormone (called “parathyrin” at that time). Hanson, ¹⁴ and later Collip, ¹⁵ were able to successfully make a purified extract of PTH from bovine parathyroids. James Collip, who had previously assisted in the preparation of an insulin extract with Drs. Banting and McLeod, demonstrated that administration of his extract successfully prevented the development of tetany in a patient. ¹⁶ Further characterization of the PTH molecule required more pure preparations, which was eventually accomplished by Aurbach ¹⁷ and Rasmussen and Craig ¹⁸ in 1959.

4.3 Parathyroid Physiology

Evolutionarily, parathyroid glands are known to be present in amphibians and mammals but not fish. In view of calcium’s multiple essential roles in the body, it has been hypothesized that, as organisms migrated from the ocean (with a high calcium content) to land they required a mechanism for regulating this key ion, and thus those organisms that developed parathyroid glands were at a selective advantage. ¹⁹ In humans, the parathyroid glands develop from the endoderm of the third and fourth pharyngeal pouches. A key transcription factor in the development of the parathyroid glands is Gcm-2. ²⁰ This transcription factor appears to be exclusively expressed in the parathyroid glands. Phylogenetic studies have also shown it to be expressed in pharyngeal pouches in fish (from which the internal gill buds develop). ²¹ Thus Graham et al ²² speculate that the evolution of the parathyroid glands was a natural progression from the gills in fish to their present form and thus the reason for the glands’ location in the neck.

4.3.1 Calcium Receptors

Calcium is the key regulator of PTH secretion. Until recently, it was not clear how this cation regulated PTH secretion. It is now known that there is a distinct calcium receptor that belongs to the G-protein coupled seven-​transmembrane-​domain receptor family. ²³ In addition to the chief cells in the parathyroid gland, the calcium receptor is expressed in multiple other tissues, including C cells in the thyroid, kidney, bone cells, cartilage, intestine, placenta, ²⁴ brain, lung, and keratinocytes, ²⁵ where it plays a key role in regulating calcium balance (Fig. 4.2). Although this receptor has the highest affinity for calcium, it will also bind other polyvalent cations, like magnesium, and aromatic amino acids, such as L-phenylalanine and L-tryptophan. ²⁶ In fact, the presence of the calcium receptor on antral G cells (which secrete gastrin), gastric parietal cells (which secrete acid), and renal cortical thick ascending limb cells (which regulate urinary calcium) may explain why ingestion of protein or amino acids results in increased gastrin, acid secretion, and urinary calcium excretion, respectively. ²⁶

Binding of calcium to the calcium receptor in the parathyroid glands results in suppression of PTH secretion. Stimulation of PTH secretion because of hypocalcemia follows a sigmoidal curve, with large increases in PTH secretion occurring with only small drops in serum calcium. The parathyroid tissue expresses very high levels of the calcium receptor, and calcium binding results in activation of phosphoinositide-specific phospholipase C (PI-PLC) and activation of protein kinase C (PKC). In addition to this signal transduction pathway, calcium binding to its receptor also activates the phospholipase A₂ (PLA₂), phospholipase D (PLD), and mitogen-activated protein kinase (MAPK) pathways. These calcium receptor–regulated proliferative pathways have a major impact on parathyroid cell mitosis. Under normal conditions there is very little proliferative activity in parathyroid tissue; however, hypocalcemia markedly stimulates parathyroid cell division, as seen in patients with renal failure. Calcium receptor binding in parathyroid tissue also activates the inhibitory G protein (G_i) and inhibits adenylate cyclase and lowers cyclic adenosine monophosphate (cAMP) levels. Interestingly, these signal transduction pathways can also be modulated by other cations. It has long been known that hypomagnesemia inhibits PTH secretion. It has recently been shown that this hypomagnesemic-induced inhibition of PTH secretion is secondary to an increased activation of the phosphoinositide pathway and greater inhibition of cAMP.

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