Parathyroid Hormone

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Parathyroid Hormone Calcium MetabolismGretchen
Perilli, M.D.Lehigh Valley HospitalMay 2, 2003
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Total Body Calcium

• 99 of calcium of body calcium is in bone
• 99 of that calcium is in the mineral phase
• Remaining calcium (1) is exchangeable
• 40 protein bound
• 10 complexed with anions (phosphate)
• 50 ionized in the biologically active form
• Ionized calcium is tightly regulated by hormonal
  mechanisms
• Calcium plays a major role in many body functions

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Total Body Phosphate

• 85 phosphate is in mineral phase of bone
• 15 extra/intracellular compartments
• 12 is protein bound
• some loosely complexed with Ca, Mag
• extra/Intracellular equilibrium
• Phosphate is key component of genetic and
  physiologic activity

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Intro to Parathyroid Gland

• 4 separate glands
• 40 mg/gland
• Adjacent to thyroid gland
• superior glands near posterior aspect of capsule
• inferior glands near inferior margin
• Originates from 3rd 4th branchial pouches

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Intro to Parathyroid Gland

• Parathyroid gland epithelial cells and stromal
  fat
• Chief cell is the predominant epithelial cell
• Chief cell properties
• rapidly secrete stored hormone
• synthesize, process and store large amounts of
  PTH
• replicate when chronically stimulated

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Parathyroid Hormone

• 84 amin0 acid polypeptide
• Gene located chromosome 11
• PTH is synthesized in prepro form
• 23 AA pre signaling sequence
• 6 AA pro sequence
• guides peptide through cell with serial cleavage
  of pre and pro
• Result is storage of the 84 AA PTH in
  neuroendocrine granules
• some granules have proteases that cleave PTH and
  secrete inactive carboxy-end

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PTH Secretion

• Responds to calcium levels with sigmoidal
  response
• Minimal secretion is low but not zero
• Steady state is at the low end of the curve
• Maximum secretory rate represents the large
  reserve of the gland

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PTH Secretion

• Parathyroid calcium receptor member of G
  protein coupled family
• Receptor spans the membrane seven times
• Large extracellular domain binds calcium

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G-Protein Coupled Cascade

• Complicated cascade initiated by calcium binding
  to the outer domain
• Triggers phospholipase C to hydrolyze PIP2 into
  IP3 and diacylglycerol
• IP3 binds to ER releasing stored calcium
  triggering the influx of calcium
• Increased intracellular calcium blocks the
  release of PTH containing granules
• Diacylglycerol regulates transcription of PTH
• Overall result decreased PTH release

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PTH Response to Low Calcium

• Most cells contain a low constant level of
  calcium despite extracellular fluctuations
• Parathyroid gland is unique
• Small extracellular changes leads to dramatic
  intracellular changes via the super sensitive
  calcium receptor
• Drops in extracellular calcium lead to a decrease
  in inhibition of release of PTH

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PTH at the Gene Level

• Serves as second line, delayed response to
  changes in calcium
• Calcium regulates PTH formation at the gene level
  by an unknown mechanism
• Studies show prolonged hypocalcemia causes
  changes at the level of gene transcription, mRNA
  expression, and stability
• Hypercalcemia has little effect
• 1,25(OH)2D3 suppresses PTH release

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Regulation of Cell Replication

• Parathyroid cells undergo little replication in
  adulthood
• Can grow dramatically in the setting of ongoing
  hypocalcemia
• Calcium acts on calcium receptor via unknown
  mechanism restraining cell proliferation
• Neonates who lack two copies of the calcium
  receptor gene have severe primary
  hyperparathyroidism and large, diffusely
  hyperplastic glands

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Other PTH Regulators

• Hypermagnesemia inhibits PTH secretion
• Hypomagnesemia stimulates secretion
• Catecholamines (acting on b adrenergic receptors)
  stimulate PTH secretion

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PTH at the Kidney

• Almost all initial filtered calcium is resorbed
  by the renal tubules
• 65 is resorbed in the proximal convoluted tubule
  and straight tubule by a passive, paracellular
  route
• Changes in rate of sodium resorption (hence
  changing transepithelial voltage gradient)
  controls the rate of calcium resorption
• PTH has little effect _at_ proximal convoluted
  tubule

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PTH and the Kidney

• Remainder of calcium is absorbed more distally
• 20 resorbed at the cortical thick ascending limb
  of Henle
• Passive, paracellular
• Driven by lumen positive voltage gradient and
  concentration gradient
• 10 resorbed within distal convoluted and
  connecting tubule
• PTH regulation

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Regulation at the Distal Nephron

• Unique transcellular active transport mechanism
• Calcium moves down concentration gradient from
  filtrate into cell (voltage sensitive calcium
  channel)
• PTH plays active role
• Moves chloride out of cell (hyperpolarizes)
• Requires calcium to move to extracellular space
  to balance charge in exchange for sodium (PTH
  dependent)

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PTH, Phosphate, the Kidney

• 80 phosphate reabsorption occurs mainly in the
  proximal renal tubules
• 8-10 reabsorbed in distal tubule
• 10-12 excreted in urine
• Phosphate reabsorption in both proximal and
  distal tubule is strongly inhibited by PTH
• PTH causes sequestration of Na-Phos transporters
  into lysosomes for proteolysis
• Blocks phosphate reabsorption

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PTH and Bone
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