Download - HORMONES THAT REGULATE CALCIUM METABOLISM
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HORMONES THAT REGULATE CALCIUM METABOLISM
Prof.Dr.Arzu SEVEN
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• In calcium homeostasis, bones serve as the reservior
• There is ~ 1 kg of calcium in the human body• The skeleton contains 99% of calcium as
hydroxyapatite crystals, the remainder is distributed in the soft tissues, teeth and ECF
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• Bone is a dynamic tissue, it undergoes constant remodeling
• In the steady state condition, there is a balance between new bone formation and bone resorption
• About 1% of skeletal Ca+2 is in a freely exchangeable pool
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• Yenı kıtap p 68 fıg 1
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• Total serum calcium is maintained between 8.8-10.4 mg/dl
• Calcium exists in the circulation in 3 forms
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• Mb p339 fıg 25.2
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• Yeni katap p 69 fıg 3
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• If serum protein concentrations (dehydration, after prolonged venous stasis)
protein_bound calcium and total serum calcium
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• In conditions of reduced serum proteins (liver disease, nephrotic syndrome, malnutrition)
protein _bound calcium is reduced, decreasing total calcium
(ionized calcium is within the reference range)
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• In clinical situations, it is important to calculate the adjusted calcium(total serum calcium, adjusted for the patient’s prevailing albumin concentration)
• Adjusted Ca =measured Ca (mmol/L) + 0.02 (40_ albumin g/L)
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• Ionızed calcium is maintained within a narrow range through an extracellular calciım sensing receptor(Ca SR) that is a cell surface G_protein coupled receptor present in the chief cells of parathyroid gland, thyroidal_C cells and along kidney tubules
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• Minute changes in ionized calcium modulate cellular function to maintain normocalcemia
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Hormonal control of calcium homesotasis
• PTH• PTH is an 84_amino acid single chain peptide
hormone, secreted by the chief cells of parathyroid glads
• preproPTH: 115 amino acid with hydrophobic amino terminal extension of 25_amino acids
(leader/signal sequence)• proPTH: 90 amino acid, having highly basic
dexapeptide extension
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• P341 fıg 25 4 MB
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• No biologic function for the carboxy terminal segment of PTH has been defined
• Cathepsin B cleaves PTH into 2 fragments : PTH1-34 and PTH35-84
( biological active ( inactive carboxy terminal )
amino terminal )
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• Pro_PTH has never been found in circulation • The liver(Kupffer cells) and kidney are involved
in peripheral metabolism of secreted PTH• secretion is inversely related to ambient
concentrations of ionized calcium
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• A decrease in extracellular ionized calcium or an increase in serum phosphate concentration stimulates PTH secretion
• Chronic severe Mg deficiency can inhibit its release from secretory vasicles
• Low concentrations of 1,25(OH)2 cholecalciferol interfere with its synthesis
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• P340 MB fıg 25 3
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• PTH acts via a membrane receptor • The hormone_receptor interaction initiates a
typical cascade
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• Activation of adenylyl cyclase
intracellular cAMP
intracellular Ca
phosphorylation of specific intracellular proteins by kinases
Activation of specific genes and intracellular enzymes that mediate the biologic actions of PTH
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• The PTH response system is subject to DOWN_REGULATION of receptor number and to DESENSITIZATION, which may involve a post_cAMP mechanism
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• PTH restores normal extracellular fluid calcium concentration by acting DIRECTLY on kidney and bone and by acting INDIRECTLY on the intestinal mucosa(through stimulation of 1,25(OH)2 cholecalciferol synthesis)
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• The most rapid changes occur through the action on the kidney but the largest effect is from bone
• Phosphate is released with calcium from bone whenever PTH increases dissolution of mineral matrix
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• PTH increases renal phosphate clearance, thus, net effect of PTH on bone and kidney is to increase the ECF calcium concentration and decrease ECF phosphate concentration
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• Yeni kit68 fıg 2
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Pathophysiology
• Insufficient amounts of PTH result in hypoparathyroidism
• The biochemical hallmarks: serum ionized Ca and serum phosphate
• Symptoms: neuromuscular irritability, which, when mild, causes muscle cramps and tetany
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• Severe acute hypocalcemia results in tetanic paralyses of the respiratory muscles,laryngospasm,severe convulsions and death
• Long_standing hypocalcemia results in cutaneous changes, cataract and calcification of the basal ganglia of the brain
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• The most common cause of hypoparatyhroidism is accidental removal or damage of the glands during neck surgery (pharyngeal or laryngeal tm, thyroid or parathyroid disease)secondary hypoprathyroidsm
• Autoimmune destruction of the glands results inprimary hypoparathyroidsim
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Pseudohypoparathyroidism(PHP)
• An inherited disorder,characterized by hypocalcemia, hyperphosphatemia, increased PTH concentrations
• The classic type of PHP is due to end_organ resistance to PTH, caused by a genetic defect resulting in an abnormal regulatory subunıt of G_protein of adenylate cyclase complex
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• Development anomalies such as short stature, short metacarpal or metatarsal bones and mental retardation
• Confirmation of diagnosis : lack of increase in plasma/urinary cAMP in
response to PTH infusion
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Hyperparathyroidism
• The excessive production of PTH, may be due to
Parathyroid adenomaParathyroid hyperplasiaEctopic production of PTH or PTHrP
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• The biochemical hallmarks:• Elevated serum ionized Ca and PTH and
depressed serum phosphate levels • In long_standing hyperparathyrodism ; extensive resorption of bone and renal effects
( kidneystones, nephrocalcinosis, frequent urinary tract infections, in severe cases decreased renal function)
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Secondary hyperparathyroidism
• Characterized by hyperplasia of the glands and PTH hypersecretion, may be seen in patients with progressive renal failure
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Hyperparathyroidism is
due todecreased conversion
of 25(OH)D3 to1,25(OH)2
D3 in diseased
renal paranchyma
İnefficient Ca
absorption in the gut
Secondary PTH release
as a compensation to maintai
n normal calcium levels
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Parathyroid_hormone related protein(PTHrP)
• Synthesized as 3 isoforms containing 139, 141 and 173 amino acids, as a result of alternative differential splicing of RNA
• Structurally and functionally similiar to PTH, especially in amino terminal region
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• İmportant in regulating fetal calcium homeostasis and skeletal development
• Has an important role in the hypercalcemia associated with malignancy(HCM)
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Vitamin D
• Is synthesized in the skin by UV radiation• Vitamin D2(ergocalciferol) is synthesized in the
skin by UV radiation of ergesterol• Vitmain D3 (cholecalciferol) is derived also by
UV radiation from 7_hydro_cholesterol in the skin of animals (nonenzymatic photolysis reaction)
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• Vitamin D3 and its metabolites are transported in the plasma, bound to a specific globulin, vitamin D_binding protein(DBP)
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• 25-hydroxylation occurs in the endoplasmic reticulum of liver
• It requires Mg, NADPH, molecular oxygen and an uncharacterised cytoplasmic factor
• NADPH_dependent cytocrome P450 reductase and cytocrome P450 are involved (hepatic microsomal enzyme)
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• Rate limiting step in the conversion of vitamin D3 to its active metabolite
• 25(OH)D3 is the main liver storage form of vitamin D
• Its levels in the circulation reflect hepatic stores
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• A significant proportion of 25(OH)D3 is subject to enterohepatic circulation bilereabsorbed in the small bowel
• Second hydroxylation at position C1 occurs at the renal tubules by a mitochondrial enzyme, requiring
• NADPH, Mg and molecular oxygen
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• 3 component monooxygenase reaction requires : renal ferredoxin reductase, cytocrome P450 and renal ferrodoxin(iron sulfur protein)
• The product 1,25 (OH)2D3 = calcitriol is the most potent naturally occuring metabolite of vitamin D3
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• Mb p342 fıg 25.5
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• 1 α hydroxylase activity is stimulated by PTH, low serum concentrations of phosphate or calcium, vitamin D deficiency, calcitonin, growth hormone, prolactin and estrogen
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• Herper p 573 table 47,1
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• The renal tubules, cartilage, intestine and plasenta contain 24_hydroxylase, producing the inactive 24,25(OH)2D3
• The 24,25(OH)2D3 in circulation is reciprocally related to 1,25(OH)2D3
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1,25(OH)2D3 is an important regulator of its
own production
High levels of 1,25(OH)2D3 inhibit renal
1 α hydroxylase and stimulate 24 hydroxylase
activity
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• Vitamin D may be described as a hormone • In the intestinal epithelial cells, it binds to a
cytoplasmic receptor like other steroid hormones
• This ligand_protein complex is transported to the nucleus 1,25(OH)2D3 induces gene expression affecting Ca metabolism
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Calcitriol
• Increases calcium and phosphate absorption from the gut via active transport by calcium binding proteins
• Together with PTH, it stimulates bone resorption by osteoclasts
• These effects increase serum calcium and phosphate concentrations
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Pathophysiology
• Rickets: a childhood disorder characterized by low plasma calcium and phosphorus levels and by poorly mineralized bone with associated skeletal deformites
• Most comonly due to vitamin D deficiency
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• 2 types of vitamin D_dependent rickets:Type 1 inherited autosomal recessive trait,
characterized by a defect in the conversion 25(OH)D3 to 1,25(OH)2D3
Type 2 autosomal recessive disorder in which there is a single amino acid change in one of the zinc fingers of DNA_binding domain nonfunctional receptor
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• Vitamin D deficiency in the adult result in OSTEOMALACIA
• Ca and phosphorus absorption are
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• Extracellular Ca and posphorus levels are decreased
mineralization of osteoid to form bone is impaired
weak and fragile bone
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Calcitonin
• 32 amino acid peptide• Synthesized and secreted primarily by the
parafollicular cells of the thyroid gland (C_cells)
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• Secretion is regulated acutely by serum calcium through calcium_sensing receptor(Ca_SR)
• Serum Ca calcitonin• Serum Ca calcitonin
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• Chronic stimulation results in axhaustion of the secretory reserve of the C_cells
• Main effect is inhibition of osteo clastic bone resorption
• The most potent naturally ocurring CT is isolated from salmon
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