Calcium Calcitonin
Clinical background
Medullary thyroid cancer (MTC)
is a rare malignancy arising from the parafollicular thyroid C cells that
secrete calcitonin. It usually presents as a lump in the thyroid gland or as
lymph node metastases in the neck. Diagnosis is made by a biopsy and the
treatment is surgical, possibly with adjunctive chemother- apy. MTC may be
sporadic or familial and in both types may be associated with phaeochromocytoma
or other features of the Multiple Endocrine Neoplasia Type 2 (MEN 2) syndrome
(Table 50.1). It is important to distinguish the truly sporadic cases from the
first presentation of familial disease as screening can allow early detection
and treatment in family members.
Calcitonin
Calcitonin is a hypocalcaemic
polypeptide hormone. In mammals, it is synthesized and secreted in
parafollicular (C) cells in the thyroid gland. C cells have been found in much
lower density in the parathyroid glands and in the thymus. In fish and birds,
calcitonin is synthesized within a specific organ, the ultimobranchial body.
The ultimobranchial bodies do develop in mammals during fetal life, but
eventually disappear. It is thought that the C cells evolved before the
parathyroids, to help sea-dwelling animals to cope with the relatively high
concentrations of calcium in sea water.
Biosynthesis and secretion.
The calcitonin gene
occurs on the short arm of chromosome 11. Calcitonin (CT) is synthesized in C
(clear) cells from a larger 136 amino acid precursor, called calcitonin
precursor, from which CT is cleaved, together with two other peptides of
unknown function (Fig. 50a). The gene which encodes CT has been characterized,
and is expressed not only in the C cells of the thyroid but also in the brain.
In neural tissue, however, the gene expresses not CT but another peptide, the
calcitonin gene-related peptide (CGRP). This is therefore an example of
tissue-determining expression of a common gene.
At normal plasma calcium
levels, CT release is low but a rise in calcium causes a rapid (threefold) rise
in CT concentrations.
Even if a small amount of
calcium, which is insufficient to raise plasma concentrations of the ion in
plasma, reaches the gastrointestinal tract (GIT), CT is released. It is
therefore thought that other GIT factors, for example gastrin and/or
cholecystokinin (CCK), may trigger CT secretion. The sensitivity of the
CT-release mechanism is sexually differentiated, being greater in males, and
the responsiveness of the CT release mechanism declines with ageing. The
half-life of CT in plasma is less than 15 minutes, and it may be degraded and
excreted principally by the kidney.
Physiological actions of
calcitonin (Fig. 50b). In
humans, calcitonin is not as important as is PTH in the regulation of calcium
metabolism. The two main target organs for CT are bone and kidney.
In bone, CT is a potent inhibitor of resorption, both in vivo and in
vitro, although CT has no effects on bone formation. There is an inhibition
of calcium resorption by the osteoclasts within 20 minutes of administration of
a dose of CT. CT may be particularly important during periods of threatened
increased calcium loss, such as occurs during pregnancy and lactation.
In the kidney, CT is
concentrated in the renal cortex. Membranes of the tubule cells possess
specific CT receptors, and the second messenger may be adenylate cyclase,
although administration of CT does not appear to alter cellular levels of cAMP.
In the kidney, CT increases the excretion of calcium, sodium and potassium and
reduces excretion of magnesium.
CT may be important in the
regulation of postprandial feeding, to prevent food-induced hypercalcaemia. CT
may also be a satiety hormone. In humans, injection of CT is followed by a
significant fall in body weight within 36 hours, and CT inhibits feeding
behaviour in rhesus monkeys and rats. The hormone is particularly potent when
administered directly to the brain, suggesting that it may have a central role.
CT affects vitamin D metabolism
by lowering plasma calcium, resulting in the release of PTH, which in turn
promotes the production and secretion of vitamin D metabolites in the kidney.
