Calcium

[Ref: AV6:chp10; WG21:chp21]

1mol of Calcium = 40g

Normal store and distribution

Normal store in young health human
= 1100g
= 27.5 mol (not mmol)

99% stored in bones.

Input/output and distribution

[WG21:p386]

##20050628(01)

Forms of calcium in blood

Plasma calcium level
= 2.5mmol/L

• Diffusible = 1.34 mmol/L
  * Ionized = 1.18
  * Complexed = 0.16
• Nondiffusible = 1.16 mmol/L
  * Albumin bound = 0.92
  * Globulin bound = 0.24

Or simply,

• 45% of Ca2+ is in free ionized form
• 15% is complexed with anions with relatively low MW, e.g. phosphate and citrate
• 40% is reversibly bound to plasma proteins

Forms of calcium in bone

Calcium in bones are of two types

1. A readily exchangeable reservoir
   * ~0.5 mol of Ca2+/day [WG21:p386]
   * ????~0.5 g of Ca2+/day [AV6:p184]
2. Much larger pool of stable calcium that is only slowly exchangeable
   * ~7.5mmol/day

Free ionized calcium

Free ionized form is the only biologically active form

Ca2+ in ECF:

• Source of calcium entering cells through calcium channels
• Triggers exocytosis
• Signals contraction in smooth and cardiac muscles
• Regulate threshold for excitation in nerve and muscle cells
• Involves in clotting pathways

Factors affecting [Ca2+]

Serum albumin has many anionic sites that reversibly binds protons and calcium

As pH increase, protons dissociate and calcium ions take their place

Thus,

• pH increase
  --> Decreased free ionized Ca2+
• pH decrease
  --> Increased free ionized Ca2+

Alternative way to look at it

When pH increase
--> Plasma protein more ionized
--> More binding sites for Ca2+
--> Less free ionized Ca2+

 

Renal handling of calcium

Filtration

About 60% of plasma Ca2+ is filterable

(Basically all except for the protein-bound Ca2+)

Resorption

Over all, about 98-99% of filtered Ca2+ reabsorbed

• 60% Ca2+ absorption occurs in the proximal tubule
• Rest in loop of Henle and distal segments

Mechanisms of resorption

Ca2+ reabsorption in proximal tubule and LOH

--> Mostly passive and paracellular

Ca2+ reabsorption in the distal segments

--> Active and transcellular

DCT

In DCT,

• Across luminal membrane via calcium-specific channel
• Exit into interstitium via basolateral membrane actively by
  * Ca-ATPase pump
  * Na-Ca antiporter

Endocrinal regulation of Ca2+ resorption occurs in distal segments

--> PTH regulates apical Ca2+ channels

Effects of thiazide

Inhibition of luminal Na-Cl symporter in DCT by thiazide

--> Increase calcium resorption

Possibly due to increased Na-Ca antiporter activity

Because

Decreased Na-Cl symporter

--> Decreased intracellular [Na+]

--> Easier for Na to move in across basolateral membrane via Na-Ca exchange

--> Greater Ca2+ movement into the interstitium

Effects of salt intake

Increased salt intake

--> Decrease Na+ resorption

--> Decreased Ca2+ resorption in proximal tubules and LOH

(Passive Ca2+ resorption depends on sodium reabsorption)

Effects of loop diuretics

Similarly loop diuretics

--> Inhibits Na+ resorption in ascending limb of LOH

--> Decresase Ca2+ resorption in LOH

Effects of acidosis

Acidosis

--> Markedly inhibits Ca2+ reabsorption

--> Increase Ca2+ excretion

 

GIT handling of calcium

Calcium is both absorbed and secreted in the gut

Most of the dietary Ca2+ never get absorbed from GIT

Mechanism of absorption

[WG21:p392]

Calcium binds to calbindin-D proteins
--> Which facilitates the absorption
* Exact mechanism of facilitation is unknown

Active transport by Ca-H ATPase
* Regulated by 1,25-(OH)2D3

Also some absorption by passive diffusion
* [WG21:p386]

Factors influencing GIT absorption of Ca2+

Increased protein intake increase Ca2+ absorption from GIT

When substances that form insoluble salt with Ca2+ is taken (e.g. phosphates and oxalates)
--> Decreased Ca2+ absorption from GIT

Alkaline environment
--> Favour formation of insoluble calcium soaps
--> Decreased Ca2+ absorption

Calcium intake

Ca2+ absorption from GIT undergoes adaptation

• High absorption when calcium intake is low
• Low absorption when calcium intake is high
• Ca2+ absorption is also facilitated by protein
  * [WG21:p481]
• Ca2+ absorption is inhibited by phosphate and oxalates
  * Due to formation of insoluble salts with Ca2+

NB:

[WG21:p481]

• 30% to 80% of ingested Ca2+ is absorbed
• Magnesium absorption is also facilitated by protein

 

Regulation

Regulation is more focused on intake from GIT than output

Factors that increase [Ca2+]

• Vitamin D
• PTH
• Thiazide diuretic
  * Increase Ca2+ resportion in DCT
• Hyperthyroidism
  * Decrease 1,25-(OH)2D3
  * Increase [Ca2+]
  * Increase urinary Ca2+ excretion
  * Osteoporosis

See vitamin D  and PTH

Factors that decrease [Ca2+]

• Increased salt intake
• Calcitonin
• Salt
  * Decrease Ca2+ resorption in proximal tubule and LOH
• Glucocorticoids
  * By inhibiting osteoclast formation and activity
  * In long term cause osteoporosis by decreasing bone formation
  * Decrease GIT aborption of Ca2+ and PO4
  * Increase urinary excretion of Ca2+ and PO4

See Calcitonin

Factors that affect Ca2+ metabolism but may not change [Ca2+]

• Acidosis
  * Decrease Ca2+ resorption in kidney
  * But increase free ionized [Ca2+] because of decreased albumin dissociation
• Growth hormone
  * Increase urinary Ca2+ excretion and GIT absorption
  * Overall may cause positive Ca2+ balance
• IGF-I
  * Stimulated by growth hormone
  * May increase protein synthesis in bone
• Insulin
  * Increase bone formation
  * In DM, increased risk of osteoporosis
• Oestrogen
  * Inhibiting osteoclasts

Calcium absorption in GIT

[AV6:p187]

Ca2+ enters intestinal cells by calcium channel

--> Binds to intracellular calcium-binding proteins (calbindins)

--> Free intracellular [Ca2+] not elevated (thus more diffusion

--> Actively transported out of basolateral side via Ca-ATPase

 

Other notes

Hypocalcemic tetany

Low levels of ECF calcium can influence electric field sense by all voltage-gated channels (including sodium channels)

--> lead to increased spontaneous firing of motor neurons

--> hypocalcemic tetany
* Extensive spasms
* Laryngospasm

Coagulopathy occurs at much lower level
--> Hypocalcemia tetany would be fatal before [Ca2+] drops that low

Chvostek's sign

Quick contraction of ipsilateral facial muscles by tapping over the facial nerve at the angle of jaw

Trousseau's sign

Spasm of muscles of forearm that causes flexion of wrists and thumb with extension of fingers

Hypercalcemia of malignancy

• 20% = due to tumour erosion of bone
  * Local osteolytic hypercalcemia
• 80% = due to increased level of PTHrP
  * Humoral hypercalcemia of malignancy

Others

• Sodium diuresis promotes calcium excretion

[WG21:p40]

• Ca-H ATPase pump
  = Ca2+ out of cell, in exchange for 2H+ into the cell (in addition to Na-Ca antiport)
• Na-Ca exchanger
  = Ca2+ out of cell, in exchange for 3 Na+ into cell (driven by Na+ gradient)
• IP3 is the major secondary messenger that causes Ca2+ release from the endoplasmic reticulum
• Of all the intracellular electrolytes, calcium is the lowest in concentration