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Calcium metabolismCalcium metabolism

Parathyroid hormone Parathyroid hormone -- Vitamin D Vitamin D -- CalcitoninCalcitonin

Overall Ca2+ homeostasis

• Serum [Ca2+] is determined by the interplay of intestinal absorption, renal excretion and bone remodeling (bone resorption and formation). Each component is hormonally regulated.

• To maintain Ca2+ balance, net intestinal absorption must be exactly balanced by urinary excretion:

1. Positive Ca2+ balanceis seen in growing children, where intestinal Ca2+ absorption exceeds urinary excretion and the difference is deposited in the growing bones.

2. Negative Ca2+ balanceis seen in women during pregnancy or lactation, where intestinal Ca2+ absorption is less than urinary excretion and the difference comes from the maternal bones.

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Overview of calcium exchange between different tissue compartments in a person ingesting 1000 mg of calcium per day. Note that most of the ingested calcium is normally eliminated in the feces, although the kidneys have the capacity to excrete large amounts by reducing tubular reabsorption of calcium.

Fecal Ca2+

Calcitriol = 1,25-dihydroxycholecalciferol

Bone formation

Bone resorption

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Parathyroid hormone (PTH)

• the major hormone for regulation of the serum [Ca2+]• synthesized and secreted by the chief cells of the

parathyroid glands.

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Actions of PTH- coordinated to produce an increase in serum [Ca2+] and a decrease in serum [phosphate].- the second messenger for PTH actions on its target tissues is cAMP

1. PTH increases bone resorption/absorbtion, which brings both Ca2+

and phosphate from mineral bone into the ECF. Alone, the effect on bone would not increase the serum [Ca2+] because phosphate complexes Ca2+. Resorption of the organic matrix of bone is reflected in increased hydroxyproline excretion.

2. PTH inhibits renal phosphate reabsorption in the proximal tubule and therefore increases phosphate excretion (phosphaturic effect). As a result, the phosphate resorbed from bone is excreted in the urine, allowing the serum [Ca2+] to increase. cAMP generated as a result of the action of PTH on the proximal tubule is excreted in the urine (nephrogenous cAMP).

3. PTH increases renal Ca2+ reabsorption in the distal tubule, which also increases the serum [Ca2+].

4. PTH increases intestinal Ca2+ absorption indirectly by stimulating the production of 1,25-dihydroxycholecalciferol.

Secretion of PTH

• controlled by the serum [Ca2+] by negative feedback. Decreased serum [Ca2+] increases PTH secretion.

• mild decreases in serum [Mg2+] also stimulate PTH secretion.

• severe decreases in serum [Mg2+] inhibit PTH secretion and produce symptoms of hypoparathyroidism.

• the second messenger for PTH secretion by the parathyroid gland is cyclic AMP.

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Pathophysiology - PTH

Primary hyperparathyroidism

• is most commonly caused by parathyroid adenoma.• is characterized by the following:

↑ serum [Ca2+]↓ serum [phosphate]↑ urinary phosphate excretion (phosphaturic effect of PTH)↓ urinary Ca2+ excretion (caused by ↑ Ca2+ reabsorption)↑ urinary (nephrogenous) cAMP↑ bone resorption

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Hypoparathyroidism• most commonly post thyroid surgery or is congenital• is characterized by the following:

↓ serum [Ca2+] and tetany↑ serum [phosphate]↓ urinary phosphate excretion

Hypocalcemic tetany in the hand, called carpopedal spasm.

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Pseudohypoparathyroidism type Ia –Albright’s hereditary osteodistrophy

• is the result of defective G protein in kidney and bone, which causes end-organ resistance to PTH

• there is hypocalcemia and hyperphosphatemia (like hypoparathyroidism) that is not correctable by administration of exogenous PTH.

• circulating endogenous PTH levels are elevated (stimulated by hypocalcemia).

CHVOSTEK’S SIGNElicitation: Tapping on the face at a point just anterior to the ear and just below the zygomatic bonePostitive response: Twitching of the ipsilateral facial muscles, suggestive of neuromuscular excitability caused by hypocalcemia

TROUSSEAU’S SIGNElicitation: Inflating a sphygmomanometer cuff above systolic blood pressure for several minutesPostitive response: Muscular contraction including flexion of the wrist and metacarpophalangeal joints, hyperextension of the fingers, and flexion of the thumb on the palm, suggestive of neuromuscular excitability caused by hypocalcemia

Clinical signs of Clinical signs of hypocalcemiahypocalcemia

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Vitamin D (Cholecalciferol)

• Vitamin D is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone.

• in children, vitamin D deficiency causes rickets; in adults, vitamin D deficiency causes osteomalacia.

Vitamin D metabolism• the active form of vitamin D is 1,25-dihydroxycholecalciferol.

Its production in the kidney is catalyzed by 1α-hydroxylase.

• 1α-hydroxylase activity is increased by the following:↓ serum [Ca2+]↑ PTH levels (secondary to ↓ Ca2+ )↓ serum [phosphate] (secondary to ↑ PTH)

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Actions of 1,25-dihydroxycholecalciferol

• coordinated to increase both Ca2+ and phosphate concentrations in ECF in order to mineralize new bone:

1. Increases intestinal Ca2+ absorption. The protein induced by 1,25-dihydroxycholecalciferol is vitamin D-dependent Ca2+ -binding protein. The action of PTH to increase intestinal Ca2+

absorption is indirect, via its stimulation of the 1α-hydroxylase and increased production of the active form of vitamin D.

2. Increases intestinal phosphate absorption

3. Increases renal reabsorption of Ca2+ and phosphate, analogous to its actions on intestine.

4. Increases resorption of bone, which provides Ca2+ and phosphate from ‘old’ bone to mineralize ‘new’ bone.

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Calcitonin• is synthesized and secreted by the parafollicular

cells of the thyroid.• Secretion is stimulated by an increase in serum [Ca2+].• Calcitonin’s major action is to inhibit bone resorption.

Summary of the Hormones Regulating Ca2+

PTH Vitamin D Calcitonin Stimulus for secretion

↓ serum [Ca2+] ↓ serum [Ca2+] ↑ PTH ↓ serum phosphate

↑ serum [Ca2+]

Actions on: Bone Kidney Intestine

↑ resorption ↓ P reabsorption (↑ urinary cyclic AMP) ↑ Ca2+ reabsorption ↑ Ca2+ absorption (via vitamin D)

↑ resorption ↑ P reabsorption ↑ Ca2+ reabsorption ↑ Ca2+ absorption (vitamin D-dependent Ca2+ -binding protein) ↑ P absorption

↓ resorption

Overall effect on: Serum [Ca2+] Serum [phosphate]

↑ ↓

↑ ↑

↓

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Low intestinal absorption and enhanced renal excretion guard against development of hypercalcemia.

Typically see near normal serum concentrations of calcium and phosphate due to compensatory mechanisms. Long term deprivation leads to bone thining (osteopenia).

General Response

Decreased due to hypoparathyroidism

Strongly stimulated by parathyroid hormone; this phosphaturic activity prevents adverse effects of elevated phosphate from bone resorption

Renal excretion of phosphate

Elevated due to decreased parathyroid hormone-stimulated reabsorption.

Decreased due to enhanced tubular reabsorption stimulated by elevated parathyroid hormone and vitamin D; hypocalcemia also activates calcium sensors in loop of Henle to directly facilitate calcium reabsorption

Renal excretion of calcium

Decreased due to low parathyroid hormone and vitamin D

Stimulated by increased parathyroid hormone and vitamin D

Release of calcium and phosphate from bone

Low basal uptakeEnhanced due to activity of vitamin D on intestinal epithelial cellsIntestinal absorption of calcium

Secretion stimulated high blood calciumVery low level secretionCalcitonin

Synthesis suppressed due to low parathyroid hormone secretion

Production stimulated by increased parathyroid hormone secretionVitamin D

Secretion inhibitedSecretion stimulatedParathyroid hormone

Calcium LoadingCalcium Deprivation

Calcium LoadingCalcium Deprivation