HORMONES THAT REGULATE CALCIUM METABOLISM

Prof.Dr.Arzu SEVEN

• 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

• 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

• Yenı kıtap p 68 fıg 1

• Total serum calcium is maintained between 8.8-10.4 mg/dl

• Calcium exists in the circulation in 3 forms

• Mb p339 fıg 25.2

• Yeni katap p 69 fıg 3

• If serum protein concentrations (dehydration, after prolonged venous stasis)

protein_bound calcium and total serum calcium

• 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)

• 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)

• 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

• Minute changes in ionized calcium modulate cellular function to maintain normocalcemia

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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• 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 )

• 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

• 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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• PTH acts via a membrane receptor • The hormone_receptor interaction initiates a

typical cascade

• 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

• The PTH response system is subject to DOWN_REGULATION of receptor number and to DESENSITIZATION, which may involve a post_cAMP mechanism

• 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)

• 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

• 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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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

• 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

• 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

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

• 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

Hyperparathyroidism

• The excessive production of PTH, may be due to

Parathyroid adenomaParathyroid hyperplasiaEctopic production of PTH or PTHrP

• 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)

Secondary hyperparathyroidism

• Characterized by hyperplasia of the glands and PTH hypersecretion, may be seen in patients with progressive renal failure

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

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

• İmportant in regulating fetal calcium homeostasis and skeletal development

• Has an important role in the hypercalcemia associated with malignancy(HCM)

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)

• Vitamin D3 and its metabolites are transported in the plasma, bound to a specific globulin, vitamin D_binding protein(DBP)

• 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)

• 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

• 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

• 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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• 1 α hydroxylase activity is stimulated by PTH, low serum concentrations of phosphate or calcium, vitamin D deficiency, calcitonin, growth hormone, prolactin and estrogen

• Herper p 573 table 47,1

• 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

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

• 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

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

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

• 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

• Vitamin D deficiency in the adult result in OSTEOMALACIA

• Ca and phosphorus absorption are

• Extracellular Ca and posphorus levels are decreased

mineralization of osteoid to form bone is impaired

weak and fragile bone

Calcitonin

• 32 amino acid peptide• Synthesized and secreted primarily by the

parafollicular cells of the thyroid gland (C_cells)

• Secretion is regulated acutely by serum calcium through calcium_sensing receptor(Ca_SR)

• Serum Ca calcitonin• Serum Ca calcitonin

• 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