Calcium Parathyroid Hormone
Clinical scenario
A 55-year-old woman, Mrs CB, had a
routine blood test at her general practitioners and was found to have a serum calcium
level of 2.88 mmol/L. She was referred to the local endocrine clinic. She was
completely asymptomatic, having none of the classical symptoms associated with
hypercalcaemia such as bone pain, abdominal pains, renal colic, thirst,
polyuria or tiredness. Further investigations confirmed a high serum calcium in
association with a low serum phosphate, normal Vitamin D concentrations, a
raised 24-hour urine calcium excretion and an elevated serum parathyroid
hormone concentration. Sestamibi radioisotope scanning revealed a single
abnormality in the upper right parathyroid gland and subsequent surgery confirmed
the presence of a single parathyroid adenoma.
Role of calcium
Calcium is essential for: bone growth,
blood clotting, maintenance of the transmembrane potential, cell replication,
stimulus contraction and stimulus secretion coupling, and the second messenger
process.
Circulating and extracellular
calcium, in adult humans, is kept
at 2.2–2.6 mmol/L. This equilibrium is achieved mainly in the kidney and the
digestive tract, and by an exchange between bone and extracellular fluid. About
half the circulating ion is free and the rest is bound to plasma albumin.
Circulating calcium equilibrium is upset by protein abnormalities, acidbase
disturbances, and by changes in the concentrations of plasma albumin. Bone
provides the largest pool of calcium, a smaller pool is provided by the soft
tissues and an even smaller pool by the extracellular fluid. Children are in a
positive calcium balance, and over the first 18 years postnatally they will
retain about 1 kg of calcium.
Regulation of calcium metabolism
This is principally through three
hormones: parathyroid hormone (PTH), from the parathyroid gland (Fig. 49a),
which raises circulating calcium concentrations; calcitonin from the
parafollicular cells of the thyroid, which lowers calcium; and
1,25-dihydroxy-vitamin D3, a metabolite of vitamin D, which increases
circulating calcium ions.
The parathyroid glands are present in all terrestrial vertebrates. In
humans, there are four parathyroid glands embedded one at each pole of the
thyroid gland and consisting of adipocytes and chief cells, which synthesize
the hormone. There are other cells, called oxyphil cells, which increase in
number after puberty, and whose function is unknown. Parathyroid hormone is
also called parathormone and is abbreviated to PTH.
Synthesis and secretion of PTH
The PTH gene is localized to the short
arm of chromosome 11. Mature PTH is a polypeptide of 84 amino acids, cleaved
from a pro-PTH of 90 amino acids, which in turn is cleaved from a prepro-PTH of
115 amino acids (Fig. 49b). Cleavage of pro- PTH to PTH occurs about 15 minutes
after arrival at the Golgi apparatus of pro-PTH, which is packaged in vesicles
and released by exocytosis.
Secretion is controlled by plasma
calcium such that there is an inverse relationship between plasma calcium and
PTH (Fig. 49c). The parathyroid chief cells have recognition sites for calcium
and the second messenger appears to be cAMP. PTH is cleaved in the circulation,
the liver and the kidney, and one of the circulating fragments (1–34) retains
biological activity.
Physiological actions of PTH
Bone. PTH acts on bone to liberate calcium,
orthophosphate, magnesium, citrate, hydroxyproline and osteocalcin, which forms
1–28% of all bone protein and has a high affinity for calcium. PTH therefore
has a resorptive effect on bone, which is probably directly on the osteoblasts,
which then stimulate osteoclast activity. Osteoblasts synthesize collagen, on
which calcium phosphate precipitates as hydroxyapatite crystals. Bone is
demineralized by the osteoclast cells, which release hyaluronic acid and acid
phosphatase, which solubilize calcium phosphate.
Gastrointestinal tract. PTH stimulates the uptake of calcium from the
GIT by an indirect action on vitamin D metabolism.
Kidney. PTH enhances the urinary excretion of phosphate
through a direct action on the proximal tubules of the kidney (Fig. 49a). This
stimulates calcium resorption of bone because it promotes calcium ionization
through the reduction in the [Ca2+] × [PO3-4]
solubility product. In addition, PTH inhibits bicarbonate reabsorption,
stimulating a metabolic acidosis which favours calcium ionization, resorption
of calcium from bone, and dissociation of calcium from plasma protein binding
sites.
Pathophysiology of PTH
Hypercalcaemia is a common endocrine
disorder. The vast majority (97%) are either due to primary hyperparathyroidism
or the hypercalcaemia associated with malignancy (Table 49.1). Rarely,
hypercalcaemia is caused by sarcoidosis, untreated renal failure, thyrotoxicosis,
ingestion of excess milk, alkali or vitamin D or by prolonged immobilization.
The symptoms of hypercalcaemia include polyuria, polydipsia, bone pain,
abdominal pain due to renal stones and depression. There may be radiological
evidence of bone resorption, particularly in the terminal phalanges.
Hyperparathyroidism. Most patients with primary hyperparathyroidism are
found to have a benign parathyroid adenoma. More rarely, four gland parathyroid
hyperplasia or (very rarely) a parathyroid carcinoma may be found. In patients
with a single parathyroid adenoma, occasionally conservative management with
monitoring of the calcium is appropriate, particularly in the elderly. However,
in general, surgical removal is advised to prevent the onset of bone disease in
the long term. Secondary hyperparathyroidism occurs after prolonged hypocalcaemia,
usually seen in chronic renal failure.
Hypoparathyroidism or PTH deficiency leads to hypocalcaemia. Primary
hypoparathyroidism is a rare condition of autoimmune origin; more commonly
hypoparathyroidism occurs following thyroid surgery and inadvertent damage to
the parathyroid glands.
