Control of Calcium Levels

Question 1

bone consists broadly of what two types of material?

Answer 1

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

Question 2

plasma calcium is present in what forms?

Answer 2

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

Question 3

what is the active form of plasma Ca++?

Answer 3

ionized (unbound)

Question 4

what can occur if plasma Ca++

falls below the normal levels?

is far above normal levels?

Answer 4

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

Question 5

PTH is

• how many aas?
• produced by what cells?

Answer 5

• 84 aas
• produced in the chief cells of the parathyroid gland

Question 6

• outline PTH synthesis
• how does the structure of PTH change throughout synthesis and what is important about its final structure?

Answer 6

• 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 (PTH_1-34) - mostly in aas 25-34

Question 7

PTH has what 3 fates after its synthesis is complete?

Answer 7

1. storage
2. degradation
3. immediate secretion

Question 8

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

Answer 8

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

Question 9

what factors increases synthesis of PTH and how?

Answer 9

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

Question 10

how does low Ca++ induce PTH secretion?

Answer 10

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

Question 11

what is the “set point” for PTH secretions?

Answer 11

1.3 mmol/L

Question 12

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

Answer 12

1.15 mmol/L

Question 13

when is PTH secretion fully suppressed?

Answer 13

PTH secretion is never fully suppressed.

hypercalcemia can persist despite negative feedback because of hyperplasic parathyroid glands

Question 14

what are the t_hree major ways_ PTH restores calcium levels?

which method restores calcium the fastest?

Answer 14

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)

Question 15

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

Answer 15

at the expense of the bones

(could lead to bone weakening in extreme cases)

Question 16

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

what issue does this potentially create?

Answer 16

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)

Question 17

what prevents CaPO4 supersaturation by PTH acting at the bone?

Answer 17

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

Question 18

what is the net effect of PTH on

1. extracellular fluid Ca++
2. extracellular fluid PO4

Answer 18

1. increase ECF Ca
2. decreases ECF PO4

Question 19

hypoparathyroidism

• cause?
• effects?
• clinical presentation

Answer 19

• 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

Question 20

pseudohypoparathyroidism

• cause
• effects
• clinical presentation

Answer 20

• 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

Question 21

hyperparathyoidism

• cause
• effect
• clinical

Answer 21

• 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

Question 22

define primary hyperthyroidism and discuss its pathogenesis

Answer 22

• 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

Question 23

define secondary parathyroidism and describe its pathogenesis.

how does it present clinically?

Answer 23

• 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)

Question 24

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

Answer 24

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

Question 25

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

Answer 25

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

Question 26

what manifestation is seen in secondary but not primary hyperparathyoidism?

Answer 26

**insufficient calcium absorption in the gut** b/c vitamin D is low

Question 27

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

Answer 27

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

Question 28

active vitamin D * binds to what kind of receptor? * induces a intracellular response how?

Answer 28

* 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

Question 29

rickets * is caused by * effects calcium / phosphate how? * how what clinical presentation?

Answer 29

* 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

Question 30

Vitamin D deficiency in adults lead to?

Answer 30

* low calcum & phosphorous (low Ca+ and PO4 absorption in gut) * **osteomalacia** - weak bone structure

Question 31

what does loss of renal parenchyma lead to?

Answer 31

* 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.

Question 32

how is renal osteodystrophy treated?

Question 33

calcitonin * is secreted by what cells? * in response to what state? * and has what effects?

Answer 33

* 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

Question 34

Answer 34