Clinical Information

Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands, which are located along the posterior aspect of the thyroid gland. The hormone is synthesized as a 115-amino acid precursor (pre-pro-PTH), cleaved to pro-PTH, and then to the 84-amino acid molecule, PTH (numbering, by universal convention, starting at the amino terminus). The precursor forms generally remain within the parathyroid cells.

Secreted PTH undergoes cleavage and metabolism to form carboxyl-terminal fragments (PTH-C), amino-terminal fragments (PTH-N), and mid-molecule fragments (PTH-M). Only those portions of the molecule that carry the amino terminus (ie, the whole molecule and PTH-N) are biologically active. The active forms have half-lives of approximately 5 minutes. The inactive PTH-C fragments, with half-lives of 24 to 36 hours, make up more than 90% of the total circulating PTH and are primarily cleared by the kidneys. In patients with kidney failure, PTH-C fragments can accumulate to very high levels. PTH 184 is also elevated in these patients, with mild elevations being considered a beneficial compensatory response to end organ PTH resistance, which is observed in kidney failure.

The serum calcium level regulates PTH secretion via negative feedback through the parathyroid calcium sensing receptor (CASR). Decreased calcium levels stimulate PTH release. Secreted PTH interacts with its specific type II G-protein receptor, causing rapid increases in renal tubular reabsorption of calcium and decreased phosphorus reabsorption. It also participates in long-term calciostatic functions by enhancing mobilization of calcium from bone and increasing kidney synthesis of 1,25-dihydroxy vitamin D, which, in turn, increases intestinal calcium absorption. In rare inherited syndromes of parathyroid hormone resistance or unresponsiveness, and in kidney failure, PTH release may not increase serum calcium levels.

Hyperparathyroidism causes hypercalcemia, hypophosphatemia, hypercalcuria, and hyperphosphaturia. Long-term consequences are dehydration, kidney stones, hypertension, gastrointestinal disturbances, osteoporosis, and sometimes neuropsychiatric and neuromuscular problems. Hyperparathyroidism is most commonly primary and caused by parathyroid adenomas. It can also be secondary in response to hypocalcemia or hyperphosphatemia. This is most commonly observed in kidney failure. Long-standing secondary hyperparathyroidism can result in tertiary hyperparathyroidism, which represents the secondary development of autonomous parathyroid hypersecretion. Rare cases of mild, benign hyperparathyroidism can be caused by inactivating CASR genetic variants.

Hypoparathyroidism is most commonly secondary to thyroid surgery but can also occur on an autoimmune basis or due to activating CASR genetic variants. The symptoms of hypoparathyroidism are primarily those of hypocalcemia with weakness, tetany, and possible optic nerve atrophy.