CLINICAL CASES
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PTH acts by binding its 7-helix plasma membrane receptor to activate
the adenylate cyclase/protein kinase A signaling system. In some tissues
receptor binding is also coupled to the phosphoinositide signaling system to
activate protein kinase C.
PTH is synthesized as a 115-amino acid preprohormone in the chief cells
of the parathyroid gland, where it is processed by proteolysis to an active 84-
amino acid polypeptide and packaged in secretory vesicles. When blood cal-
cium ion levels fall below normal, the active hormone is secreted by
exocytosis into the blood. The parathyroid cell monitors calcium ion levels by
means of a calcium-sensing receptor in the plasma membrane. Phosphate ion
is a much less significant regulator of PTH secretion and does so by an indi-
rect mechanism. Within seconds of calcium binding its receptor on the chief
cells of the parathyroid gland, PTH secretion is decreased. Within a matter of
hours, transcription of the preprohormone messenger ribonucleic acid
(mRNA) diminishes. If hypocalcemia persists over days and months, the
parathyroid gland enlarges in an effort to increase PTH production.
Bone serves as a vast reservoir of calcium in the body. Approximately
1 percent of calcium in bone can rapidly exchange with extracellular calcium ion.
PTH stimulates demineralization of bone and release of calcium and
phosphate into the blood by stimulating osteoclast formation and activity.
This process is synergistically enhanced by vitamin D.
PTH also acts to increase absorption of calcium ion by the small intes-
tine. It does this indirectly by promoting the formation of active vitamin D in
the kidney. PTH acts on the final, rate-limiting step in vitamin D synthesis, the
formation of 1,25-dihydroxycholecalciferol in the kidney. If PTH is low, for-
mation of the inactive derivative, 24,25-dihydroxycholecalciferol, is stimulated
instead. Vitamin D acts on intracellular receptors in the small intestine to
increase transcription of genes encoding calcium uptake systems, to up-regulate
their expression.
The kidney plays a critical role in calcium homeostasis. PTH acts directly
on the kidney to suppress calcium ion excretion in the urine by maximiz-
ing tubular calcium reabsorption. It increases phosphate ion excretion in the
kidney (phosphaturic effect) to prevent excessive accumulation of this anion
released during bone demineralization.
Hyperparathyroidism results from oversecretion of PTH. This condition
leads to excessive bone turnover and demineralization and must be treated by
removal of the parathyroid gland. The disorder is classified into primary, sec-
ondary, and tertiary hyperparathyroidism. Sporadic primary hyperparathy-
roidism is the third most common endocrine disorder, after diabetes and
hyperthyroidism. It is most common in females older than 55 years of age and
the leading cause is a single adenoma, which secretes the hormone constitu-
tively, without regulation. Symptoms can include osteopenia and bone frac-
tures, renal stones resulting from hypercalciuria, peptic ulcer disease, and
pancreatitis. In milder cases, patients are asymptomatic or suffer only muscle
weakness, fatigue, and/or depression.
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