Parathyroid Hormone

PTH is an 84–amino-acid chain (9,500 d), but its biologic activity resides in the first 34 residues. In the parathyroid gland, a pre-pro-PTH (115-amino-acid chain) and a proparathyroid hormone (90 amino acids) are synthesized. Pre-pro-PTH is converted to pro-PTH and pro-PTH to PTH. PTH(1-84) is the major secretory product of the gland, but it is rapidly cleaved in the liver and kidney into smaller COOH-terminal, mid-region, and NH₂-terminal fragments.

The occurrence of these fragments in serum has led to the development of a variety of assays. The 1-34 amino-terminal (N-terminus) fragments possess biologic activity but are present in low amounts in the circulation; assay of these fragments is most useful for detecting acute secretory changes. The carboxy-terminal (C-terminus) and mid-region fragments, although biologically inert, are cleared more slowly from the circulation and represent 80% of plasma immunoreactive PTH; values of the C-terminal fragment are 50-500 times the level of the active hormone. The C-terminal assays are effective in detecting hyperparathyroidism, but because C-terminal fragments are removed from the circulation by glomerular filtration, these assays are less useful for evaluating the secondary hyperparathyroidism characteristic of renal disease. Only certain sensitive radioimmunoassays for PTH can differentiate the subnormal concentrations that occur in hypoparathyroidism from normal levels.

When serum levels of calcium fall, the signal is transduced through the calcium-sensing receptor, and secretion of PTH increases (Fig. 564-1). PTH stimulates activity of 1α-hydroxylase in the kidney, enhancing production of 1,25-dihydroxycholecalciferol, also written 1,25(OH)₂D₃. The increased level of 1,25(OH)₂D₃ induces synthesis of a calcium-binding protein (calbindin-D) in the intestinal mucosa, with resultant absorption of calcium. PTH also mobilizes calcium by directly enhancing bone resorption, an effect that requires 1,25(OH)₂D₃. The effects of PTH on bone and kidney are mediated through binding to specific receptors on the membranes of target cells and through activation of a transduction pathway involving a G-protein coupled to the adenylate cyclase system (Chapter 566).

Figure 564-1 Some components involved in calcium homeostasis. CaSR and PTH/PTHrP receptor mediate their effects through G-protein-coupled signaling pathways, which in turn activate the adenyl cyclase (AC) and phospholipase C (PLC) systems.

(From Thakker RV: Genetic development in hypoparathyroidism, Lancet 357:974–976, 2001.)

The calcium-sensing receptor regulates the secretion of PTH and the reabsorption of calcium by the renal tubules in response to alterations in serum calcium concentrations. The gene for the receptor is located on chromosome 3q13.3-q21 and encodes a cell surface protein that is expressed in parathyroid glands and kidneys and belongs to the family of G protein–coupled receptors. In the normally functioning calcium-sensing receptor, hypocalcemia induces increased secretion of PTH and hypercalcemia depresses PTH secretion. Loss-of-function mutations cause an increased set point with respect to serum calcium, resulting in hypercalcemia and in the conditions of familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Acquired hypocalciuric hypercalcemia may be due to autoantibodies to the calcium-sensing receptor and manifests with hypercalcemia and hyperparathyroidism. Gain-of-function mutations result in depressed secretion of PTH in response to hypocalcemia, leading to the syndrome of familial hypocalcemia with hypercalciuria (see Fig. 564-1).

Parathyroid Hormone–Related Peptide

PTHrP is homologous to PTH only in the first 13 amino acids of its amino terminus, 8 of which are identical to PTH. Its gene is on the short arm of chromosome 12 and that of PTH is on the short arm of chromosome 11.

PTHrP, like PTH, activates PTH receptors in kidney and bone cells and increases urinary cyclic adenosine monophosphate (cAMP) and renal production of 1,25(OH)₂D₃. It is produced in almost every type of cell of the body, including every tissue of the embryo at some stage of development. PTHrP is critical for normal fetal development. Inactivating mutations of the receptor for PTH/PTHrP result in a lethal bone disorder characterized by short limbs and markedly advanced bone maturation known as Blomstrand chondrodysplasia (see Fig. 564-1). PTHrP appears to have a paracrine or autocrine role because serum levels are low except in a few clinical situations. Cord blood contains levels of PTHrP that are 3-fold higher than in serum from adults; it is produced by the fetal parathyroid glands and appears to be the main agent stimulating maternal-fetal calcium transfer. PTHrP appears to be essential for normal skeletal maturation of the fetus, which requires 30 g of calcium during a normal gestation. During pregnancy, maternal absorption of calcium increases from about 150 mg daily to 400 mg during the second trimester.

As in cord blood, PTHrP levels are increased during lactation and in patients with benign breast hypertrophy. Breast milk and pasteurized bovine milk have levels of PTHrP that is 10,000 times higher than those of normal plasma. Most instances of the hormonal hypercalcemia syndrome of malignancy are caused by elevated concentrations of PTHrP.

Vitamin D

See Chapter 48.

Calcitonin

Calcitonin (CT) is a 32-amino-acid polypeptide. Its gene is on chromosome 11p and is tightly linked to that of PTH. The gene for CT encodes 3 peptides: CT, a 21-amino-acid carboxyterminal flanking peptide (katacalcin), and a CT gene-related peptide. Katacalcin and CT are co-secreted in equimolar amounts by the parafollicular cells (C cells) of the thyroid gland. CT appears to be of little consequence in children and adults because very high levels in patients with medullary carcinoma of the thyroid (a tumor arising from the C cells) do not cause hypercalcemia. In the fetus, however, circulating levels are high and appear to augment bone metabolism and skeletal growth; these high levels are probably stimulated by the normally high fetal calcium levels. Unlike the high levels in cord blood and circulating concentrations in young children, levels in older children and adults are low. Infants and children with congenital hypothyroidism (and presumed deficiency of C cells) have lower levels of CT than do normal children.

Its action appears to be independent of PTH and vitamin D. Its main biologic effect appears to be the inhibition of bone resorption by decreasing the number and activity of bone-resorbing osteoclasts. This action of CT is the rationale for its use in treatment of Paget disease. CT is synthesized in other organs, such as the gastrointestinal tract, pancreas, brain, and pituitary. In these organs, CT is thought to behave as a neurotransmitter to impose a local inhibitory effect on cell function.