Endocrine regulation of calcium metabolism

Lecture on calcium homeostasis in body

1. Endocrine Regulation of Calcium Metabolism Dr Shamshad College of Medicine Majmaah University KSA

2. Objectives Identify the origin, target organs & physiological effects of parathyroid hormone(PTH)(including effects on vitamin D metabolism) Describe the regulation of PTH secretion & the role of the calcium-sensing receptor. Describe the cell of origin, the target organs, the physiological effects & the regulation of release of calcitonin. Correlate this knowledge to clinical conditions related to hypo & hypersecretion of PTH. Illustrate & discuss the physiological response to hypocalcemia & hypercalcemia.

3. Calcium is most abundant mineral in the body Its main functions include Structural component of bones and teeth Controls excitability and release of NTs. Transmission of nerve impulses Initiates muscle contraction (skeletal, cardiac, and smooth muscles) Coenzyme for coagulation factors-(Factor IV) Acts as intracellular second messenger (signal)

4. Phosphate Nearly 85% of the body’s phosphate is stored in bones. 14 to 15 % is in the cells. Less than 1 % is in the ECF. Phosphate has several important functions along with calcium Controlled by factors that regulate calcium, Kidneys and Effects of PTH Skeleton-90% Intracellular-5% Extracellular-0.03 [50% Free 50% bound]

5. Four parathyroid glands L ocated immediately behind the Thyroid gland One behind each of the upper & each of the lower poles of the thyroid. The parathyroid glands are difficult to locate during Thyroid operations. Even a small quantity of remaining parathyroid tissue is usually capable of hypertrophying to satisfactorily perform the function of all the glands.

6. T he parathyroid gland contains 1:Mainly Chief cells : are believed to secrete most, if not all, of the PTH. and 2:A small to moderate no. of Oxyphil cells. F unction is not certain, but the cells are believed to be modified/ depleted chief cells that no longer secrete hormone. A bsent in young humans.

7. PTH first synthesized on the ribosomes as preprohormone, [polypeptide chain of 110 AA]. The ER & Golgi apparatus first cleave preprohormone to a prohormone [ 90 AA] then to the PTH active hormone [ 84 AA] Then finally packaged in secretory granules in the cytoplasm of the cells. The final hormone has a molecular weight of about about 9500

8. Target organs: Small Intestine,Kidneys,Osteoclasts of bone Principal Effects :PTH secretion in response to low ECF calcium ion. 1) Stimulates bone resorption , cause release of calcium into the ECF. 2)Increases reabsorption of calcium & decreases phosphate reabsorption by the renal tubules , leading to decreased excretion of calcium & increased excretion of phosphate. 3) PTH is necessary for conversion of 25­(OH)cholecalciferol to 1,25­dihydroxycholecalciferol, which help increase calcium absorption by the intestines.

9. PTH mobilizes Calcium & Phosphate from the Bone 1)Rapid phase :Results from activation of the already existing bone cells (osteocytes) to promote calcium & phosphate release. 2)slower phase: R e sults from proliferation of the osteoclasts, followed by greatly increased osteoclastic resorption of the bone itself, not merely release of the calcium phosphate salts from the bone. Activation of the osteoclastic system occurs in two stages: (1) immediate activation of the osteoclasts that are already formed (2) formation of new osteoclasts.

10. • After a few months of excess PTH, osteoclastic resorption of bone can lead to weakened bones & secondary stimulation of the osteoblasts that attempt to correct the weakened state. •Hence the late effect is actually to enhance both osteoblastic and osteoclastic activity. Still, even in the late stages, there is more bone resorption than bone deposition in the presence of continued excess PTH.

11. PTH Decreases Calcium Excretion & Increases Phosphate Excretion by the Kidneys • Administration of PTH causes rapid loss of phosphate in the urine by Diminishing proximal tubular reabsorption of phosphate ions. •The increased calcium reabsorption occurs mainly in the late DCT, collecting tubules, the early collecting ducts, the ascending loop of Henle •It also increases reabsorption of magnesium ions & hydrogen ions •Decreases reabsorption of sodium, potassium ions & AA in similar way that it affects phosphate.

12. PTH Increases Intestinal Absorption of Calcium & Phosphate PTH greatly enhances both calcium & phosphate absorption from the intestines by increasing the formation in the kidneys of 1,25­ dihydroxycholecalciferol from vitamin D.

13. cAMP Mediates the Effects of PTH Effect on target organs •Within a few minutes after PTH administration, the concentration of cAMP increases in the osteocytes, osteoclasts, & other target cells. •cAMP may be responsible for functions as osteoclastic secretion of enzymes & acids to cause bone resorption & formation of 1,25(OH)2 cholecalciferol in the kidneys. •Other direct effects of PTH probably function independently of the second messenger mechanism.

14. PTH related protein (PTHrP) 140 AA encoded in gene on chromosome 12

15. Calcium Sensing receptor (CASR) Changes in ECF calcium ion concentration are detected by a CASR in parathyroid cell membranes. The CASR is a G protein–coupled receptor when stimulated by calcium ions, activates phospholipase C,increases intracellular inositol 1,4,5­triphosphate(IP3) and diacylglycerol (DAG) formation. This activity stimulates release of bone calcium from intracellular stores, which, then, decreases PTH secretion. While decreased ECF calcium ion concentration inhibits these pathways and stimulates PTH secretion.

16. Origin in thyroid gland : C cells Target organ Bone : Osteoblasts cells: Functions: Stimulates calcium deposition and ossification. Reduces calcium concentration in blood

17. Calcitonin, is a 32 AA peptide hormone secreted by the thyroid gland. molecular weight 3400. It decreases plasma calcium concentration. Has effects opposite of PTH. Synthesis & secretion of calcitonin occur in the parafollicular cells(C cells), lying in the interstitial fluid between the follicles of the thyroid gland. These cells constitute only about 0.1 % of the human thyroid gland

18. Increased Plasma Calcium Concentration Stimulates Calcitonin Secretion The primary stimulus for calcitonin secretion is increased ECF calcium ion concentration by two ways . First:the immediate effect is to decrease the absorptive activities of the osteoclasts & possibly the osteolytic effect of the osteocytic membrane throughout the bone, thus shifting the balance in favor of deposition of calcium in the exchangeable bone calcium salts.

19. Second & more prolonged effect of calcitonin is to decrease the formation of new osteoclasts. •Also, because osteoclastic resorption of bone leads secondarily to osteoblastic activity, decreased numbers of osteoclasts are followed by decreased numbers of osteoblasts. T he net result :Reduced osteoclastic & osteoblastic activity • Minor effects on calcium handling in the kidney tubules & the intestines. Thus effects are opposite those of PTH.

20. Action of Vitamin D ON GUT: To help calcium absorption. Stimulate trans epithelial transport of Calcium & Phosphate in the Small intestine (duodenum) Induce synthesis of calcium binding proteins,calbinding,&calcium dependant ATPase. On BONE : Stimulate terminal differentiation ,Stimulate osteoblasts to stimulate to stimulate osteoclasts to mobilize calcium = BONE RESORPTION

21. KIDNEYS: Increase renal reabsorption of calcium and Phosphates PARATHYROID HORMONE Inhibit transcription of the PTH gene =Feedback regulation.

22. Hypoparathyroidism: Inadvertent removal of parathyroid glands •Hypocalcemia & Hyperphosphatemia •Increased NM excitability, Tingling & pins and needle sensation •Muscle cramps twitches,Irritability and paranoia Hyperparathyroidism •Prolonged break down of bone causes brittlle bones •High level of calcium collect in blood • forms renal calculi •Cardiac arrhythmias ,Muscle & bone weakness.

23. Hypocalcemia Decreased plasma calcium <4-8mg% & ionised calcium<3mg%. Leads clinical condition : TETANY 1. Latent tetany: (Sub clinical) –Assessed by –Trausseau’s sign & Chvostek’s sign. 2. Manifest Tetany:Carpal & pedal(rare)spasm,Laryngeal stridor-asphyxia,Visceral features-bronchospasm,etc

24. HYPERCALCEMIA: SIGNS AND SYMPTOMS CNS : Altered Mental state, including lethargy, depression, decreased alertness, confusion and coma GI : Anorexia, Constipation, Nausea, and Vomiting RENAL : Diuresis,Impaired concentrating ability, Dehydration. Hypercalciuria is a risk for kidney stones. SKELETAL : most causes of hypercalcemia are associated with increased bone resorption, and thus, fracture risk CARDIOVASCULAR : cause/exacerbate Hypertension, shortened QT interval