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HORMONES OF PARATHYROID AND REGULATION OF BLOOD CALCIUM LEVEL

BY MOHIT SHARMA ROLL NO. 79 PARA A2

INTRODUCTION
Humans have 4 parathyroid glands: two embedded in the superior poles of the thyroid and two is its inferior poles. They are richly vascularized. They contain two types of cells. The more abundant are the chief cells which secrete the parathyroid hormone (PTH).

Synthesis and Metabolism of PTH


Human PTH contains 84 amino acid residues. It is synthesized as Prepro PTH which on entry into the endoplasmic reticulum gets converted in to pro PTH. The pro PTH is then converted into PTH in the golgi apparatus. The PTH is packaged in secretory granules and released as the main secretory product of the chief cells. The normal plasma level of intact PTH is 10-55 pg/ml. The half life of PTH is approx. 10 min.

ACTIONS
PTH acts directly on bone to increase bone resorption and mobilize Ca2+ . In addition to increasing the plasma Ca2+ and depressing the plasma phosphate, PTH increases phosphate excretion in the urine. This phosphaturic action is due to a decrease in reaboorption of phophate in the proximal tubules. PTH also increases reabsorption of Ca2+ in the distal tubules, although Ca2+ excretion is often increased in hyperparathyroidism because the increase in the amount filtered overwhelms the effect on reabsorption. PTH also increases the formation of 1,2S dihydroxy cholecalciferol, and this increases Ca2+ absorption from the intestine. On a longer timestale, PHT stimulates both osteoblasts and osteoclasts. The net effect varies, but with mildly elevated plasma PTH levels it is usually anabolic.

REGULATION OF SECRETION -

Circulating ionized calcium acts directly on the parathyroid glands in a negative feedback fashion to regulate the secretion of PTH. The key to this regulation is a cell membrane Ca2+ receptor. This serpentine receptor is coupled via a G protein to phosphoinositido turnover and is found is many tissues. In the parathyroid, its activation inhibits PHT secretion. In this way, when the plasma Ca2+ level is high, PHT secretion is inhibited and the Ca2+ is deposited in the bones. When it is low, secretion in increased and Ca2+ is mobilized from the bones.

1,2S dihydroxy cholecalciferol, acts directly on the parathyroid glands to decrease preopro PTH in RNA. Increased plasma phosphate stimulates PTH secretion by lowering plasma Ca2+ and inhibiting the formation of 1,25 dihydroxy cholecalciferol, Magnesium is required to maintain normal parathyroid secretory responses. Impaired PTH release along with diminishied target organ responses to PTH, account for the hypocalcemia that occasionally occur in Mg deficiencies.

EFFECTS OF PARATHYROIDECTOMY
PTH is essential for life. After parathroidectomy, there is a steady decline in the plasma Ca2+ level. Signs of neuromuscular hyperexcitability appear, followed by full-blown hypocalcemic tetany. Plasma phosphate levels usually rise as the plasma calcium level falls after parathyroidectomy, but the rise does not always occur. In humans, tetany is most often due to unintentional parathyroidectomy during thyroid surgery, symptoms usually develop 2-3 days postoperatively but may not appear for several weeks or more.

The signs of tetany in humans include Chvosteks signs, a quick contraction of the ipsilateral facial muscles elicited by tapping over the facial nerve at the angle of the jaw; and Trousseaus sign, a spasm of the muscles of the upper extremity that cause flexion of the wrist and thumb with extension of the fingers. In individuals with mild tetany in whom spasm is not evident, Trousseaus sign can sometimes be produced by occluding the circulation for a few minutes with a blood pressure cuff. EFFECTS OF PARATHYROID HORMONE EXCESSHyperparathyroidism due to infections of parathyoid extract in animals or hypersectetion of a functioning parathyoid tumour in humans is characterized by hypercalcemia and hypo-phosphatemia. Humans with PHT secreting adenomas are usually asymptomatic, with the condition detected when plasma is Ca2+ measured in combination with a routine physical examination. However, there may be minor changes in personality and calcium containing kidney stones occasionally form.

REGULATION OF CALCIUM ION LEVEL


Extracellular calcium ion concentration is determined by the interplay of calcium absorption from the intestine, renal excretion of calcium, and bone uptake and release of calcium. Calcium in the Plasma and Interstitial fluid The calcium in the plasma is present in three forms (i) About 41 per cent of the calcium is combined with the plasma proteins and in this form is nondiffusible through the capillary membrane. (2) About 9% Ca is diffusible through the capillary membranes but is combined with anionic substances of the plasma and interstitial fluids (citrate and phosphate). In such a manner that it is not ionized (3) the remaining 50% of Ca2+ in the plasma is both diffusible through the capillary membrane and ionized.

The plasma and interstitial fluids have a normal calcium ion concentration of about 1.2 mmol/l. (Only one half of total plasma calcium concentration.)

INTESTINAL ABSORPTION AND EXCRETION:

The usual rates of intake are 1000 mg/day for calcium. Divalent calcium ions are poorly absorbed from the intestines. However vitamin D promotes calcium absorption by the intestines and about 35% of ingested calcium is absorbed. The remaining is excreted in the feces. An additional 250 mg/day of calcium enter the intestines via secreted gestrointestinal, juices and sloughed mucosal cells. Thus, about 90 per cent of the daily intake of calcium is excreted is feces.

RENAL EXCRETION OF CALCIUM

Approx 10 per cent of ingested Ca is excreted in the urine. About 41 per cent of the plasma calcium is bound to plasma proteins and is therefore, not filtered by the glomerular capillaries. The rest is combined with anions such as phosphate and is filtered through the glomeruli into the renal tubules. Approx 90% of the calcium in the glomerular filtrate is reabsorbed in the proximal tubules, loop of Henle, and early distal tubules. Then in the late distal tubules and early collecting ducts. Reabsorption of the remaining 10% is very selective, depending on the Ca2+ ion in the blood.

When Ca concentration is low, reabsorption is great. Conversely even a minute increase in blood calcium ion concentration above normal increases Ca excretion. The most important factor controlling the reabsorption of calcium in the distal portion of the nephron and therefore controlling the rate of calcium excretion, is PTH.

MECHANISM OF ACTION OF PTHThere are at least 3 diff. PTH receptors. One also binds parathyroidhormone related protein (PTHVP) and is known as the PHTrP receptor. A second receptor, PTH 2 does not bind PTH and is found in the brain, placenta and pancreas. In addition, there is evidence for a third reception, CPTH, which reacts with the carboxyl terminal rather than the amino terminal of PTH. The first 2 are serpentine receptors coupled to G5 and via this heterotrimic G protein they activate adenylyl cyclase, increases the intracellular cAMP , activates protein kinase C and finally increases intracellular Ca2+.

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