Figure 50.1. Calcium-sensing receptor.

THE PARATHYROID GLANDS AND PARATHYROID HORMONE

The four parathyroid glands derive from the third and fourth branchial pouches and reside adjacent to the thyroid gland in the neck. They are very small, each weighing only about 40 g. The predominant epithelial cell in the parathyroid glands is called the “chief cell,” which has a clear cytoplasm and is distinct from the larger oxyphil cell, which has an eosinophilic granular cytoplasm. Both cell types contain PTH.

    The parathyroid cells “sense” the level of ionized calcium by way of the CaSRs that are expressed on the surface of the cells. The relationship between the extracellular ionized calcium concentration and PTH is a steep sigmoid curve in which small changes in ionized calcium produce marked changes in PTH (Figure 50.3).

    The initial effect of a decrease in extracellular ionized calcium is to stimulate the secretion of preformed PTH via exocytosis from storage granules in the parathyroid cells. Interestingly, most cells in the body require calcium to stimulate the process of exocytosis. How, then, can parathyroid cells release PTH via exocytosis in an environment of calcium deficiency? It appears that this critical role is played by intracellular magnesium in the parathyroid cells. This explains why severe prolonged magnesium deficiency essentially paralyzes PTH secretion, inducing reversible hypoparathyroidism. Interestingly, more moderate hypomagnesemia stimulates PTH secretion, whereas hypermagnesemia inhibits it, similar to the effects of hypo- and hypercalcemia.

    Changes in serum calcium regulate both the secretion of preformed PTH and the de novo synthesis of PTH at the level of gene transcription. Vitamin D also plays a role in PTH gene regulation in that high levels of calcitriol [1,25(OH)₂] inhibit PTH gene transcription. This allows calcitriol or vitamin D analogues to be used in the treatment of secondary hyperparathyroidism in patients with renal failure.

HYPERCALCEMIA

The differential diagnosis for hypercalcemia is shown in box 50.1. The first question to ask in any case of hypercalcemia is: what is the PTH level? If PTH is frankly high or even inappropriately “normal” in the setting of hypercalcemia, the diagnosis is primary hyperparathyroidism (PHPT). There are a few other diagnoses that should be considered. These include tertiary hyperparathyroidism (from chronic renal failure) and use of lithium or thiazides, possibilities that are easily eliminated. A fourth possibility is the very rare autosomal dominant condition known as familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH). Individuals with FHH have inactivating mutations of the CaSR, rendering the receptor less sensitive or resistant to the ambient serum calcium concentration at both the parathyroids and kidneys. In other words, these individuals require higher serum calcium levels to maintain normal calcium homeostasis. The hallmark of FHH is an inappropriately low urinary calcium excretion that can be easily calculated using a simple formula:

Urine CaCl/CrCl <0.01 is consistent with FHH. These patients should not be sent for parathyroid surgery. Genetic testing for mutations of the CaSR can be done if the diagnosis is uncertain.

Box 50.1 DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA

PRIMARY HYPERPARATHYROIDISM

Primary hyperparathyroidism (HPT) accounts for 80–90% of hypercalcemia in asymptomatic individuals and is by far the most common cause of hypercalcemia in healthy outpatients. The vast majority (80%) of cases of PHPT are due to solitary adenomas. Around 15% of patients will have four-gland hyperplasia, and 2–4% will have multiple adenomas. Parathyroid hyperplasia is most commonly found in three autosomal-dominant inherited syndromes: multiple endocrine neoplasia (MEN) 1, MEN 2A, and isolated familial hyperparathyroidism. Parathyroid carcinoma represents <0.5% of cases.

    The classic signs and symptoms of PHPT have been referred to as “stones, bones, abdominal groans, and psychic moans.” These are listed in box 50.2. Prior to the introduction of multiphasic chemistry screening, most patients with PHPT presented with renal manifestations (stones, nephrocalcinosis, renal failure) and/or the classic bone disease, osteitis fibrosa cystica. Now, up to 85% of individuals with PHPT are asymptomatic. Kidney stones occur in fewer than 15% of patients with PHPT, whereas the most common bone disorder, osteoporosis, mainly affects skeletal sites rich in cortical bone (such as the distal one-third of the radius). Other manifestations of mild PHPT include dyspepsia, nausea, and constipation (“abdominal groans”) as well as fatigue, lethargy, depression, and difficulty concentrating (“psychic moans”). Myalgias, muscle weakness, chondrocalcinosis, polyuria/polydipsia, and nocturia can also occur. Nonclassical manifestations of PHPT such as cardiovascular and neurological dysfunction are under active investigation at this time.

    Laboratory findings in PHPT typically show elevated serum calcium (corrected for serum albumin) with a simultaneously elevated serum intact PTH. However, many patients with mild PHPT have serum calcium levels that fluctuate in and out of the normal range. Similarly, serum PTH levels may be in the middle or upper level of normal range, although such levels are still “inappropriate” within the context of hypercalcemia. Even “low normal” PTH levels may be associated with PTH-secreting parathyroid adenomas. Serum phosphorus levels tend to be below 3.5 mg/dL due to the phosphaturic effect of PTH on the renal tubules. Note that concomitant vitamin D deficiency is very common in patients with PHPT and in some cases may “mask” the hypercalcemia. Recent guidelines recommend checking 25-hydroxyvitamin D levels in all patients with PHPT and correcting any deficiencies to maintain levels above 20 ng/mL.

Box 50.2 SIGNS AND SYMPTOMS OF PRIMARY HYPERPARATHYROIDISM

    Parathyroidectomy remains the definitive treatment for PHPT. For individuals with mild, asymptomatic PHPT, a 2008 international workshop of experts developed guidelines for surgical intervention (box 50.3). Patients who do not meet any of these criteria (up to 50% in some series) may be monitored with annual serum calcium, serum creatinine, and bone mineral density (BMD) measurements every 1–2 years (see box 50.4). Longitudinal studies of patients with asymptomatic PHPT show remarkable biochemical stability over 10–15 years, although up to 25% ultimately require surgery. Following surgical cure of PHPT, there are dramatic improvements in BMD and 90–95% reduction in renal stone formation in those with previous nephrolithiasis. Recent clinical trials randomizing subjects with PHPT to either parathyroidectomy or observation have found improvements in bone density in the surgical groups but variable effects on quality of life and symptoms.

Box 50.3 THIRD INTERNATIONAL WORKSHOP GUIDELINES FOR SURGERY FOR ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM (PHPT)

Box 50.4 GUIDELINES FOR FOLLOW-UP OF NONSURGICALLY TREATED PATIENTS WITH ASYMPTOMATIC PHPT

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