PTH & Calcitonin for MBBS, BDS, Lab. Med..pptx

Parathyroid hormone (PTH) is one of three key hormones modulating calcium and phosphate homeostasis; the other two are calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23).

1. Parathormone & Calcitonin Rajendra Dev Bhatt , PhD Scholar Asst. Professor Clinical Biochemistry & Laboratory Medicine Fellow: Translational Research (2018-2022) in CVD in Nepal, NHLBI & NIH, USA

2. Parathyroid hormone (PTH) is one of three key hormones modulating calcium and phosphate homeostasis; the other two are calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23 ). Parathyroid hormone (PTH ) is synthesized in the chief cells of the parathyroid gland . The parathyroids secrete PTH, a 84 AA secreted in 6 to 7 pulses each hour. PTH is governing the calcium homeostasis .

3. It is synthesised as a larger precursor (115 amino acids); the removal of a chain of 25 amino acids produces pro-PTH from which removal of a further six amino acids produces PTH. It is secreted exclusively by the parathyroid glands. The principal stimulus to secretion is a low ionised calcium, which is sensed by a calcium-sensing receptor located on the plasma membrane of parathyroid cells. Secretion is inhibited by an increased ionised calcium

4. The parathyroid glands are located on the posterior, medial aspect of each lobe of the thyroid gland. Anatomically, the glands can be divided into two pairs :

5. Calcium homeostasis is maintained by a highly intricate and complex endocrine system in all vertebrates involving parathyroid hormone (PTH), calcitonin and calcitriol . PTH is a glycoprotein made of 84-amino acids arranged in a linear polypeptide (MW – 9500 Da) a half-life of 2-4 minutes. Along with calcitonin(CT), 1,25 dihydroxy-cholecalciferol { 1,25(OH)2D3}/ calcitriol , PTH maintain the level of calcium and phosphorus in plasma through its action on intestine, kidney, and bone.

6. Maintenance of adequate levels of plasma calcium (8.5 and 10.5 mg/dL) is required for normal neuromuscular function, bone mineralization, and many other physiological processes like cell division, cell adhesion, plasma membrane integrity, protein secretion, glycogen metabolism, and coagulation. 50% to 60% calcium is bound to circulating proteins or complexed with anions such as citrate and phosphate. The remaining ionized (unbound or free) calcium is the portion responsible for controlling the physiologic processes listed above.

7. Structure and Processing of Parathyroid Hormone It is synthesised as a larger precursor (115 amino acids); the removal of a chain of 25 amino acids produces pro-PTH from which removal of a further six amino acids produces PTH Pre sequence is cleaved during the transport of the polypeptide across endoplasmic reticulum (ER) and required as a signal sequence. Pro sequence helps in efficient ER transport of polypeptide and protein folding and cleaved by trypsin-like protease in the golgi apparatus.

8. The mature parathyroid hormone of 84 amino acids is further packed in secretory vesicles and released when required Hypocalcemia stimulates PTH synthesis by increasing PTH gene transcription, stability of its mRNA and by decreasing its degradation. Similarly hypercalcemia leads to increased degradation of pro-PTH leading to decreased PTH secretion.

9. Transport and Degradation PTH is transported in the free form and does not bind to any transport protein. Most of PTH synthesized is degraded within the parathyroid gland. The circulating PTH consist of fully active PTH and also break down fragments (C-terminal fragments) in the ratio of 1:2

10. PTH Secretion PTH secretion is regulated by ambient serum calcium concentration. There is inverse relationship between PTH level and serum calcium concentration. Serum calcium level is sensed by the chief cells of parathyroid gland through a G –protein coupled calcium receptor. Its activation stimulates rise in intracellular calcium level, which stimulates PTH secretion.

11. Mechanism of Action PTH acts through a membrane receptor via the cAMP , intracellular calcium and protein kinase activated cascade leading to activation of specific genes in the target tissue i.e. bones and kidney.

12. Metabolic effects Effect on Bone: Rapid phase (1-3hrs) leads to osteocystic osteolysis or activation of osteocytes for the transfer of calcium from bone fluid to extracellular fluid via activity of osteocytes without any decrease in the bone mass. Low calcium level in the extracellular fluid activates parathyroid gland to release PTH. The association of PTH to its receptors present on the osteocytic membrane system increases the activity of calcium pump resulting in diffusion of calcium phosphate salts from bone fluid to the osteocytic membrane. Then the calcium pump on the other side of the cell membrane transfers the calcium ions to the extracellular fluid.

13. Slower phase (12-24hrs) – osteoclastic osteolysis leads to proliferation of osteoclasts to promote reabsorption of the bone. Increased level of PTH as stimulated by continued hypocalcemia causes hypertrophy and hyperplasia of osteoclasts. The increases activity of osteoclast thus enhances bone resorption to mobilize calcium, magnesium and inorganic phosphate from mineralized bone into the plasma.

14. Effect on Kidney Parathyroid hormone acts on the distal convoluted tubules and collecting ducts to increase calcium and magnesium reabsorption. Also it increases the excretion of phosphate, sodium and bicarbonate by its action on proximal convoluted tubule (PCT). PTH by increasing the activity of 1α- hydroxylase facilitates the production of 1, 25-(OH)2-Vit D in PCT. The increased calcitriol further acts on small intestine to increase calcium and phosphate ion absorption ..

15. Effect of on Intestine PTH indirectly affects the function of intestine through calcitriol . Kidneys under PTH influence form the hormone calcitriol , resulting in increased calcium and phosphate absorption from the gastrointestinal tract into bloodstream . The increased absorption is achieved by increase in activity of sodium-calcium antiporter activity and synthesis of calcium binding proteins called calbindins .

16. Hyperparathyroidism Hyperparathyroidism is the  over-activity  of the parathyroid glands and can be classed as primary, secondary, tertiary or malignant depending on the underlying cause . Primary  hyperparathyroidism is a result of direct alterations to the parathyroid gland such as a benign tumour , hyperplasia or very rarely parathyroid cancer. The excess secretion of PTH leads to  elevated calcium  in the blood which can cause signs of hypercalcaemia , osteoporosis, osteitis fibrosa cystica and hypertension.

17. Secondary  hyperparathyroidism is a physiologically elevated PTH due to reduced calcium levels. This could be caused by  chronic renal failure  or  decreased vitamin D intake . Tertiary  hyperparathyroidism occurs after prolonged secondary hyperparathyroidism. This is due to structural changes seen within the gland. To distinguish between secondary and tertiary hyperparathyroidism, a blood test will be carried out.  Elevated calcium levels  indicate tertiary hyperparathyroidism.

18. Malignant  hyperparathyroidism can be caused by some tumours , such as bronchial squamous cell carcinomas, as they produce a protein called parathyroid hormone related protein  ( PTHrP ) . PTHrP can mimic PTH due to the similarity in their structure which ultimately results in elevated calcium in the blood. However, PTH will be reduced due to negative feedback to the parathyroid gland itself.

19. Hypoparathyroidism Hypoparathyroidism is the  underactivity  of the parathyroid gland and can be classed as primary or secondary depending on the cause . Primary  hypoparathyroidism is a result of decreased PTH secretion due to gland failure. This results in symptoms of hypocalcaemia and patients will often need calcium supplementation .

20. Secondary  hypoparathyroidism is commonly caused by surgical removal of the parathyroid glands. This is often accidental due to the fact that the inferior parathyroid glands are difficult to locate . Pseudo- hypoparathyroidism: In this condition parathyroid gland is normal with sufficient biologically active PTH secretion but there is defect in target end organ receptors such as deficiency of receptor associated Gs dependent adenyl cyclase or post cAMP production defect.

21. Review Select the incorrect match with respect to hormone and respective deficiency disease PTH-Diabetes insipidus Growth hormone-Dwarfism Thyroid hormone-cretinism Adrenal cortex-Addison’s disease PTH-Diabetes insipidus

22. Calcitonin Calcitonin is a peptide hormone primarily synthesized and secreted by the parafollicular or clear or C cells of the thyroid gland . It is a 32-amino acid polypeptide hormone. It acts opposite to the parathyroid hormone by reducing the blood calcium levels . It also lowers the concentration of  phosphorus  in the blood when levels exceed normal .

23. Chemistry and Synthesis Calcitonin is a single chain polypeptide hormone with a 1–7 disulfide bridge at the  amino terminus and a carboxy -terminal  proline  amide . This hormone was first discovered in 1962 and so named because of its ability to lower plasma calcium levels .

24. Calcitonin is biosynthesised by the proteolytic cleavage of prepropeptide that is released from the CALC1 gene. It functions antagonistically to vitamin D3 and parathyroid hormone. The synthesis or secretion of calcitonin is triggered by high levels of calcium in blood.

25. The gene encoding calcitonin, called the CALC1 gene, is transcribed into messenger RNA (mRNA) in the nucleus of the C cells. This mRNA is then translated by ribosomes in the cytoplasm to produce a preprohormone called preprocalcitonin . Preprocalcitonin undergoes post-translational modifications in the rough endoplasmic reticulum (ER) and Golgi apparatus. Signal peptides are cleaved off to form procalcitonin, which is then further processed into the active form, calcitonin, by removal of additional amino acids.

26. Once processed, calcitonin is stored in secretory granules within the C cells. Upon stimulation, these granules fuse with the cell membrane, releasing calcitonin into the bloodstream .

27. Mechanism of Action Calcitonin binds to calcitonin receptors present on osteoclasts, which are cells responsible for breaking down bone tissue (a process called bone resorption ). When calcitonin binds to its receptor, it inhibits osteoclast activity, reducing bone resorption and promoting bone formation. This action helps to maintain calcium homeostasis in the blood by decreasing the release of calcium from bone into the bloodstream.

28. Calcitonin also acts on the kidneys to enhance urinary excretion of calcium and phosphate ions. It does this by inhibiting tubular reabsorption of these ions, leading to increased excretion in the urine. This further helps to lower blood calcium levels.

29. Metabolic Effects Decreased Bone Resorption : By inhibiting osteoclast activity, calcitonin reduces the breakdown of bone tissue, leading to decreased bone resorption . This effect helps to maintain bone density and strength . Lowered Blood Calcium Levels : Calcitonin promotes the deposition of calcium into bone and inhibits its release from bone into the bloodstream. Additionally, by enhancing urinary excretion of calcium, calcitonin helps to decrease blood calcium levels.

30. Phosphate Regulation : Calcitonin also affects phosphate metabolism by promoting its excretion in the urine, although its role in phosphate regulation is less significant compared to its effects on calcium . Overall , calcitonin plays a crucial role in calcium homeostasis by opposing the actions of parathyroid hormone (PTH), another hormone involved in calcium regulation. While PTH acts to increase blood calcium levels, calcitonin works to lower them, thereby helping to maintain the delicate balance of calcium in the body.

31. Procalcitonin (PCT) PCT is a 116-amino acid peptide with a molecular weight of 14.5 kDa . PCT , the precursor of the hormone calcitonin, has been used as a biomarker to aid in diagnosis of bacterial infection or sepsis. Procalcitonin (PCT), regarded as a biomarker specific for bacterial infections, is used in a variety of clinical settings including primary care, emergency department and intensive care . PCT measurement aids in the diagnosis of sepsis and to guide and monitor antibiotic therapy.

32. PCT starts to rise earlier and returns to normal concentration more rapidly than CRP, allowing for an earlier diagnosis and better monitoring of disease progression .

33. Interpretation of PCT concentration

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