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Biochem ENDO > Control of Calcium Levels > Flashcards

Control of Calcium Levels Flashcards

1
Q

bone consists broadly of what two types of material?

A
  1. organic (proteins)
  2. inorganic - hydroxyapetite (CaPO4OH)
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2
Q

plasma calcium is present in what forms?

A
  1. protein (albumin) bound
  2. ionized - active form
  3. complexed with citrate, phosphate other anions

a very small fraction of plasma Ca++ is comlexed with ions. the remainder is 1:1 ratio of albumin bound & ionized

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3
Q

what is the active form of plasma Ca++?

A

ionized (unbound)

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4
Q

what can occur if plasma Ca++

falls below the normal levels?

is far above normal levels?

A
  • below normal Ca: “hyperexctitability” - tetany / possible convulsions
  • above normal Ca: muscle paralysis (coma)
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5
Q

PTH is

  • how many aas?
  • produced by what cells?
A
  • 84 aas
  • produced in the chief cells of the parathyroid gland
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6
Q
  • outline PTH synthesis
  • how does the structure of PTH change throughout synthesis and what is important about its final structure?
A
  • PTH synthesized as pre-pro-peptide: PreProPTH
  • “pre” portion is a secretory signal that is cleaved when PTH gets to the ER
  • “pro” portion is cleaved so that PTH can become active
  • PTH released from the golgi in secretory vesicles
    • ​the full biological activity of PTH resides in its N terminal (PTH1-34) - mostly in aas 25-34
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7
Q

PTH has what 3 fates after its synthesis is complete?

A
  1. storage
  2. degradation
  3. immediate secretion
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8
Q

what are VDREs and when are they bound? what does this lead to?

A

Vit D response elements: segments on the PTH gene that, when bound by Vit D (1,25-OH-D3) inhibit transcription of PTH.

  • thus, high Vit D = low PTH synthesis
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9
Q

what factors increases synthesis of PTH and how?

A

low blood Ca+ (hypocalcemia) and Vitamin D deficiency

  • blood Ca+:
    • low plasma Ca++:
      • elevates PTH mRNA synthesis
      • induces chief cell hypertrophy/hyperplasia
  • low Vit D:
    • induces chief cell hypertrophy/hyperplasia
    • VDREs (Vit D reponse elements) on the PTH gene remain unbound, PTH expressed
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10
Q

how does low Ca++ induce PTH secretion?

A

via negative feedback via binding of a unique Ca++ GCRP that has opposite effects on two secondary messenger systems

  • at high [Ca], Ca binds GCPR which:
    • stimulates Gq:
      • stimulating phospholipase C –> IP3 –> Ca++ path
      • Ca production increases
    • stimulates Gi:
      • inhibiting adenylate cyclase –> cAMP –> PKA path
      • which allows for Ca production:
  • if blood calcium low, Ca cant bind GCPR
    • Gq not stimulated
    • Gs not inhibited
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11
Q

what is the “set point” for PTH secretions?

A

1.3 mmol/L

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12
Q

maximal rates of PTH secretion are seen at what blood Ca++ concentration?

A

1.15 mmol/L

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13
Q

when is PTH secretion fully suppressed?

A

PTH secretion is never fully suppressed.

hypercalcemia can persist despite negative feedback because of hyperplasic parathyroid glands

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14
Q

what are the t_hree major ways_ PTH restores calcium levels?

which method restores calcium the fastest?

A
  1. kidney
    • fast
    • inc Ca++ / dec PO4
    • activates a1-phosphorylase –> Vit D
  2. bone
    • slower (but more important)
    • increases the rate of dissolution of bone: inc Ca / inc PO4
  3. inestines
    • indirectly increasses intestinal absorption by promoting synthesis of Vit-D (which acts on intestinal mucosa)
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15
Q

under conditions of prolonged dietary Ca++ deficiency, how does PTH prevent hypocalcemia?

A

at the expense of the bones

(could lead to bone weakening in extreme cases)

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16
Q

in what way does PTH restore calcium at the level of the bone?

what issue does this potentially create?

A

promotes bone dissolution:

  • by: stimulating osteoblasts to produce osteoclast-activating factors (OAFS) that activate osteoclasts
    • activated osteoclasts reabsorp bone, which will:
      • release Ca++
      • release PO4
        • too much PO4 in the blood can lead to CaPO4 mineralization in tissues (supersaturation)
17
Q

what prevents CaPO4 supersaturation by PTH acting at the bone?

A
  • preventing by PTH’s effect of PO4 on the kidney - PTH inreases renal phosphate clearance
18
Q

what is the net effect of PTH on

  1. extracellular fluid Ca++
  2. extracellular fluid PO4
A
  1. increase ECF Ca
  2. decreases ECF PO4
19
Q

hypoparathyroidism

  • cause?
  • effects?
  • clinical presentation
A
  • insufficient circulating PTH, usually due to
    • autoimmune destruction of the gland (primary)
    • removal/damage of parathyroid during neck surgery
  • marked by:
    • decreased serum calcium
    • elevated serum phosphate
  • clinical:
    • mild condition: cramps / tetany
    • severe, acute condition: paralysis of respiratory muscles / convulsions / death
20
Q

pseudohypoparathyroidism

  • cause
  • effects
  • clinical presentation
A
  • cause: end-organ resistance (including bone) resistance to PTH in the contex of normal, active circulating PTH.
  • effects:
    • low calcium
    • high phosphate
  • clinical:
    • short stature
    • short metacarpals & metatarsals
    • mental retardation
21
Q

hyperparathyoidism

  • cause
  • effect
  • clinical
A
  • cause: high circulating PTH
    • primary hyperparathyroidism (m/c = adenonoma)
    • secondary hyperparathyroidism (hyperplasia due to renal failure)
  • effect:
    • high calcium
    • low phosphate
  • clinical:
    • severe hypocalcemia leads to extensive bone reabsorption, which can lead to lead to kidney depositions & related problems:
      • kidney stones
      • nephrolithiasis
      • UTIs
22
Q

define primary hyperthyroidism and discuss its pathogenesis

A
  • dx = serum [Ca] > 10.5 mg/dL with continued PTH secretion
  • m/c due to a parathyroid adenoma
  • like all hyperparathyroidism: bone reabsorption & kidney deposition defects
23
Q

define secondary parathyroidism and describe its pathogenesis.

how does it present clinically?

A
  • defined has high PTH secretion resulting from hyperplasia as a compensatory response to the inability of the kidney to convert Vit D to its active form - i.e., renal failure.
    • ​there is low plasma Vit D, so:
      • VRDE segments are unbound –> high PTH transcription
      • insufficient Ca reabsorption in gut
  • clinical:
    • excess bone reabsorption / kidney defects (stones/UTIs/nephrolithiasis)
24
Q

outline the synthesis of of active Vitamin D: 1,25(OH)2-D3

A
  1. in the skin: 7-dehydrocholesterol –> D3 by photolysis
  2. vitamin-D binding protein binds D3 and transfers it to intestines
  3. D3 travels thru the GI tract to the liver
  4. in the liver: D3 –> 25(OH)-D3 by 25-hydroxylase + NADPH
  5. 25(OH)-D3 enters circulation
  6. vitamin-D binding protein binds 25(OH)-D3 and takes it to the kidney
  7. in the PCT of the kidney: 25(OH)-D23 –> 1,25 (OH)2-D3 by 1-alpha hydroxylase + NADPH
25
Q

what are the two key enzymes involved in synthesis of active Vit D and where do they act?

A
  1. 25-hydroxylase in the liver: converts D3 to 25(OH)-D3
  2. 1-alpha hydroxylase in the kidney: converts 1,25(OH)2-D3
26
Q

what manifestation is seen in secondary but not primary hyperparathyoidism?

A

insufficient calcium absorption in the gut

b/c vitamin D is low

27
Q

how is 1,25(OH)2 D3 synthesis regulated?

A
  1. by feedback regulation at the of 1a-hydroxylase
    • ​inhibited by high levels of 1,25(OH)2-D3
      • via an increase in synthesis of the inactive Vit D analog: 24,25(OH)2-D3
    • increased by hypocalcemia / PTH / low PO4
28
Q

active vitamin D

  • binds to what kind of receptor?
  • induces a intracellular response how?
A
  • to a steroid receptor
    • _​_specifically, to a nuclear (Sublcass II) intracellular receptor: a DNA-binding protein with a zinc finger domain
      • ​induces a cellular response by stimulating gene transcription –> formation of specific mRNAs
29
Q

rickets

  • is caused by
  • effects calcium / phosphate how?
  • how what clinical presentation?
A
  • pathogenesis:
    • two types - both autosomal recessive
      • Type I: defect in conversion from 25(OH)-D3 to 1,25(OH)2-D3
      • Type II: nonfunctional steroid receptor - due to DNA-binding domain
  • low calcium & low phosphorous
  • clinical: high bone demineralization –> skeletal deformities
30
Q

Vitamin D deficiency in adults lead to?

A
  • low calcum & phosphorous (low Ca+ and PO4 absorption in gut)
  • osteomalacia - weak bone structure
31
Q

what does loss of renal parenchyma lead to?

A
  • reduced production of active Vitamin D (Vitamin D defiency) by the kidney –> which will stimulate production of PTH –> which will stimulate bone reabsorption –> increased plasma Ca++
    • = renal osteodystrophy.
32
Q

how is renal osteodystrophy treated?

A
33
Q

calcitonin

  • is secreted by what cells?
  • in response to what state?
  • and has what effects?
A
  • by parafollicular cells in the thyroid gland
  • in response to high blood Ca++ (hypercalcemia_)_
  • calctonin then: lowers both plasma Ca++ and PO4
    • at bone: suppresses osteoclasts, inhibiting bone reabsorption, lowering Ca
    • at kidney:
      • suppresses phosphate reabsorption, lowering PO4
      • increase calcium excretion/lowers Ca+ reabsorption, lowering Ca
34
Q
A

Biochem ENDO (13 decks)

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