Parathyroid hormone by Dr. Amruta Nitin Kumbhar, Asst. Professor Dept. of Physiology, DYPMC,KOP

FUNCTIONAL ANATOMY OF PARATHYROID GLANDS
Histological structure
STRUCTURE, SYNTHESIS AND SECRETION OF PTH
REGULATION OF PTH SECRETION
MECHANISM OF ACTION AND ACTIONS OF PTH
Applied physiology

1. Parathyroid hormone Dr. Amruta Nitin Kumbhar Asst. Professor Dept. of Physiology

2. SLO FUNCTIONAL ANATOMY OF PARATHYROID GLANDS Histological structure STRUCTURE, SYNTHESIS AND SECRETION OF PTH REGULATION OF PTH SECRETION MECHANISM OF ACTION AND ACTIONS OF PTH Applied physiology

3. FUNCTIONAL ANATOMY OF PARATHYROID GLANDS The parathyroid glands are two pairs of small endocrine glands closely ap plied to the back of the thyroid gland gland is about the size of a split pea, measuring 6 × 4 × 2 mm. The total weight of four normal glands is about 140 mg

4. Histological structure The parenchyma of the parathyroid gland is made up of cells that are arranged in cords. The cells of the parathyroid glands are of two main types: chief cells and oxyphil cells. Chief cells, also called as principal cells, are much more numerous. Chief cells secrete the PTH or parathormone . Oxyphil cells. These cells are much larger than the chief cells and first appear at puberty and their function is still not clear.

5. STRUCTURE, SYNTHESIS AND SECRETION OF PTH Structure- PTH is a single chain polypeptide, containing 84 amino acids and having molecular weight 9500. Synthesis- PTH is synthesized from a precursor molecule called prepro -PTH, which contains 115 amino acids. Secretion- PTH is released from the chief cells by exocytosis in response to decrease in plasma-ionized calcium concentration that is sensed by the calcium receptors in the parathyroid cells.

6. REGULATION OF PTH SECRETION 1. Role of plasma-ionized calcium. 2. Role of serum magnesium concentration 3. Role of plasma phosphate concentration 4. Role of vitamin 1,25(OH)2D3.

7. REGULATION OF PTH SECRETION 1. Role of plasma-ionized calcium.

8. 2. Role of serum magnesium concentration Mild decrease in serum Mg2+ concentration stimulates PTH secretion, while Severe decrease in serum Mg2+ concentration inhibits PTH secretion and produces symptoms of hypoparathyroidism (e.g. hypocalcaemia). 3. Role of plasma phosphate concentration- A rise in plasma concentration of phosphate causes an immediate fall in ionized calcium concentration, which in turn stimulates PTH secretion. 4. Role of vitamin 1,25(OH)2D3- It inhibits transcription of the PTH gene and decreases PTH secretion

9. PLASMA LEVELS, HALF-LIFE AND DEGRADATION OF PTH Plasma level of PTH is about l30 pg /mL (approximately 3 × 10−12 M). Half-life of PTH in plasma is 5–8 min. Degradation of PTH occurs rapidly in the peripheral tissues. PTH is predominantly split in the liver.

10. MECHANISM OF ACTION AND ACTIONS OF PTH Mechanism of action of PTH : PTH binds to a membrane receptor proteins on the target cells (in bones, kidney and intestine) activates adenylyl cyclase to liberate cAMP. The cAMP, increases intracellular calcium that promotes the phosphorylation of proteins (by kinases).

11. Actions of PTH 1. Actions on the bone

12. 1. Actions on the bone It stimulates calcium and phosphate resorption from the bones, i.e. causes decalcification or demineralization of bone ( i ) Rapid phase of demineralization: osteocytic osteolysis In this process, the calcium is transferred from the bone canalicular fluid into the osteocytes and then into the ECF. In this process, phosphate is not mobilized along with calcium.

13. (ii) Slow phase of demineralization. This effect requires several days of exposure to PTH. stimulates the formation of new osteoclasts from the osteoprogenitor initiate process of bone resorption in which both calcium and phosphate are released from bone and are transferred to the ECF.

14. 2. Actions on kidney ( i ) Increase in calcium reabsorption . PTH increases the reabsorption of calcium from the ascending limb of loop of Henle and the distal tubules of kidney and helps to prevent hypocalcaemia . (ii) Inhibition of phosphate reabsorption in the proximal tubule is the most dramatic effect of PTH on the kidney. This effect produces phosphaturia and hypophosphataemia .

15. 2. Actions on kidney ( iii) Stimulation of reabsorption of Mg2+ by the renal tubules. (iv) Stimulation of synthesis of 1,25-dihydroxycholecalciferol is a very important action of PTH in the kidney.

16. 3. Actions on intestines Parathormone greatly enhances both calcium and phosphate absorption from intestine indirectly by increasing synthesis of 1,25-dihydroxycholecalciferol in the kidney

17. APPLIED ASPECTS Hyperparathyroidism and hypercalcaemia, Hypoparathyroidism and hypocalcaemia Metabolic bone diseases

18. HYPERPARATHYROIDISM Primary hyperparathyroidism Aetiology: Primary hyperparathyroidism occurs due to excessive secretion of PTH by single autonomous parathyroid adenoma (most common). Clinicobiochemical features - Typical manifestations are hypercalcaemia, hypophosphataemia , hypercalciuria and renal calculi (kidney stones) Hypercalcaemia may produce muscle weakness, lethargy and constipation. Since calcium can stimulate release of gastrin there may occur hyperchlorhydria and peptic ulceration. Hypercalcaemia may also cause hypertension, cardiac arrhythmias and ECG changes

19. Secondary hyperparathyroidism Excessive PTH secretion occur secondary to persistent hypocalcaemia , which causes continued stimulation of parathyroid gland. Aetiology: typically seen in slowly developing renal failure. Clinicobiochemical features: involvement of bones. Bone pains, fractures and deformity may result. Alkaline phosphatase and osteocalcin levels are elevated .

20. HYPERCALCAEMIA Causes depending on the levels of PTH can be divided into two groups: 1. Conditions associated with hypercalcaemia and raised PTH levels 2. Conditions associated with hypercalcaemia and low or undetectable PTH levels are: Hypercalcaemia of malignancy, Multiple myeloma, Familial hypercalcaemia, Hyperthyroidism ,

21. Local osteolytic hypercalcaemia is seen in 20% of the patients which have bone metastasis. Humoral hypercalcaemia of malignancy is seen in 80% of the patients who do not have bone metastasis. Familial hypercalcaemia occurs due to mutations in the gene for Ca2+ receptor.

22. HYPOPARATHYROIDISM AND HYPOCALCAEMIA Hypoparathyroidism refers to a clinical condition characterized by low level of plasma calcium either due to deficient production of PTH or its unresponsiveness. Hypoparathyroidism can be classified into two main groups: True hypoparathyroidism and Pseudohypoparathyroidism .

23. A. True hypoparathyroidism In true hypoparathyroidism there is deficient production of PTH due to heritable or acquired causes. Post-ablative or post-operative hypoparathyroidism . most common cause of hypoparathyroidism is either damage to glands or their blood supply or their inadvertent removal during thyroidectomy operation. The incidence is 1% of all the thyroidectomies .

24. B. Pseudohypoparathyroidism This is a congenital condition , in which PTH production is normal but the target tissues are resistant to its effects. The defect may lie in parathyroid receptors or there may be post-receptor defect. The clinical and biochemical features are similar to hypoparathyroidism, but PTH levels are elevated (since hypocalcaemia produces more production of PTH).

25. Characteristic features of hypoparathyroidism Hypocalcaemia . Total serum calcium may be decreased to 4–8 mg/dL and the ionized calcium to 3 mg/dL. A 50% fall in the levels of ionized calcium leads to a clinical condition called tetany (described below). Hyperphosphataemia , i.e. an increase in serum inorganic phosphate levels to 6–16 mg/dL.

26. TETANY Tetany refers to a clinical condition resulting from increased neuromuscular excitability . Causes of tetany include: 1. Hypocalcaemia . Extracellular calcium plays an important role in membrane integrity and excitability. Thus when concentration of ionic calcium is reduced to < 50% of normal in ECF, cell membrane of neurons becomes more permeable resulting in a series of action potentials. Thus hypocalcaemia is the most common cause of increased neuromuscular irritability leading to tetany. 2. Hypomagnesaemia also causes tetany, because magnesium ions are also associated with neuromuscular irritability. 3. Alkalosis , which reduces ionic calcium, can also produce tetany.

27. Clinical features Carpopedal spasm: The hands in carpopedal spasm adapt a peculiar posture in which there occurs flexion at metacarpophalangeal joints, extension at interphalangeal and there is apposition of thumb (This peculiar posture of hand is called obstetric hand . Pedal spasm is less frequent. In it the toes are plantarflexed and feet are drawn up.

28. Laryngeal stridor (loud sound) results from spasm of laryngeal muscles. It may produce asphyxia. Paraesthesias , i.e. tingling sensations in the peripheral parts of limbs or around the mouth is common feature. Trousseau’s sign : (pronounced as ‘ Troosoz’s sign’). Occluding the blood supply to a limb for about 3 min by inflation of a sphygmomanometer cuff (above the systolic blood pressure level) produces characteristic carpal spasm. Chvostek’s sign : the twitching of facial muscles produced by tapping the facial nerve at the angle of jaw. This occurs due to increased excitability of nerves to mechanical stimulation.

29. Latent tetany: In latent or subclinical tetany, the typical symptoms and signs of tetany are absent, but can be unmasked by following provocative tests: Trousseau’s sign and Chvostek’s sign

30. Management an intravenous injection of 20 mL of 10% calcium gluconate is given to correct hypocalcaemia and relieve tetany.

31. References 1. Text book of medical physiology Indu Khurana 2. Text book of Physiology, Gyuton 2 nd south Asian Edition 3. Text book of Physiology, Ganong 4. Comprehensive Text book of Physiology, G.K.Pal vol.I 5. Internet source