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SOE 617: Calcium Physiology

Introduction

Regarding calcium…

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Question No. 2

Q: What are the functions of calcium in the body?

Answer No. 2

  • Bone formation and metabolism:
    • Contributes to strength and structure
  • Role as a strong cation in acid-base balance
  • Coagulation of blood (cofactor in coagulation pathway)
  • Cellular functions:
    • Excitation–contraction coupling in cardiac, skeletal and smooth muscle
    • Cardiac action potentials and pacemaker activity
    • Regulation of cell growth and apoptosis
    • Cofactor for many enzymes (e.g. lipase) and proteins
    • Membrane integrity & permeability
    • Ciliary motility
  • Cellular communication:
    • Intracellular secondary messenger systems
    • Secretory processes:
      • Release of neurotransmitters
      • Hormone release
    • Catecholamine responsiveness

Question No. 3

Q: Which enzymes need calcium to function?

Answer No. 3

  • The protein calmodulin activates many enzymes in the presence of calcium:
    • Calcium-calmodulin complexes bind to enzymes acting as a co-factor
    • Known as a 'calcium-binding regulatory protein'
  • Enzymes activated by calmodulin include:
    • Glycogen synthase
    • Adenyl cyclase
    • Pancreatic lipase
    • Pyruvate carboxylase
    • Phospholipase A2

Question No. 4

Q: Why it is needed for clotting?

Answer No. 4

  • Ionized calcium is essential for many stages of both coagulation and platelet plug formation
  • Multiple roles in coagulation pathway (Calcium is known as Factor IV):
    • Required for the activation of factors VII, IX and X
    • Acts as a co-factor in the conversion of prothrombin (II) to thrombin (IIa) - binds to the tenase enzyme where it acts as a catalyst speeding up the reaction
  • Important in platelet activation and aggregation:
    • Increase in intracellular calcium upon stimulation activates a number of calcium-dependent enzymes and regulated release of active substances
  • Standard anticoagulant solutions contain citrate which chelates calcium ions and efficiently prevents clotting

Question No. 5

Q: How is calcium present in the body?

Answer No. 5

Calcium distribution and stores in the body

Question No. 6

Q: What is the normal daily turnover of calcium?

Answer No. 6

Daily turnover of calcium in the body

Question No. 7

Q: What is the normal concentration of calcium in the blood and what forms is it found in?

Answer No. 7

Forms of calcium in the blood (ionized, protein and anion bound)
  • Biological effect is determined by the amount of ionised calcium which is under tight homeostatic control and usually remains constant

Question No. 8

Q: How are calcium levels affected by changes in albumin concentration?

Answer No. 8

  • Total calcium levels are generally dependent on the level of plasma albumin
  • With reduced serum albumin proportionally less calcium is bound
  • This results in a lower measured total plasma calcium

Question No. 9

Q: How can the affect of albumin levels be accounted for?

Answer No. 9

  • Total calcium levels are generally dependent on the level of plasma albumin
  • With reduced serum albumin proportionally less calcium is bound
  • This results in a lower measured total plasma calcium
  • A corrective formula (Payne's formula) is commonly applied to account for albumin concentrations when considering the measured total calcium levels
  • A correction factor of 0.02 mmol/L is added to the measured calcium level for every 1 g/L of albumin below a value of 40 g/L)
  • Results in the formula:

Corrected Ca2+ = measured Ca2+ + 0.02 x (40 – serum albumin)

  • For example, if the measured total plasma calcium is 1.876 mmol/L and plasma albumin is 26 g/L:
Corrected Ca2+ = 1.83 + 0.02 x (40 – 26) = 1.83 + 0.28 = 2.11 mmol/L

Worked Example

Question No. 10

Q: What role does calcium play in cell excitability?

Answer No. 10

  • Ca2+ ions competes for binding sites on albumin with H+ ions
    • As pH changes the proportion of calcium bound to albumin and freely ionised in the plasma varies
    • For every 0.1 unit reduction in plasma pH, the albumin bound calcium decreases by 0.07 mmol/L and ionised calcium increases by 0.07 mmol/L
  • Hyperventilation can lead to alkalosis, and thus reduced plasma ionised calcium:
    • As ionised calcium determines clinical effects tetany may be precipitated

Question No. 11

Q: How does the ionised calcium alter with changes in pH?

Answer No. 11

  • Ca2+ ions compete for binding sites on albumin with H+ ions
    • As pH changes the proportion of calcium bound to albumin and freely ionised in the plasma varies
    • For every 0.1 unit reduction in plasma pH, the albumin bound calcium decreases by 0.07 mmol/L and ionised calcium increases by 0.07 mmol/L

Question No. 12

Q: Why does tetany occur if you hyperventilate?

Answer No. 12

  • Hyperventilation can lead to alkalosis, and thus reduced plasma ionised calcium:
    • As ionised calcium determines clinical effects tetany may be precipitated

Question No. 13

Q: How is calcium homeostasis achieved? Which organs and which hormones are important and what are their effect?

Answer No. 13

  • Calcium homeostasis can be considered through the action of:
    • Three organs: bone, kidney, small intestine
    • Three hormones: parathyroid hormones, calcitonin, vitamin D metabolites
Calcium homeostasis - regulation of normal levels

Question No. 14

Q: What is parathyroid hormone? Where is it produced, what are its effects?

Answer No. 14

Hormone
Hormone
Hormone
Parathyroid Hormone
  • Protein hormone produced by chief cells of the parathyroid gland
  • Secretion stimulated by a decrease in serum calcium levels
  • Normal levels are 1.3 – 6.8 pmol/L
  • Acts to increase serum calcium and decrease serum phosphate levels through a number of mechanisms:
  • Kidney: Increases calcium reabsorption
  • Bone: Mobilises calcium from bone stores by stimulating osteoclast activity and inhibiting osteoblast activity
  • GI Tract: Increases GI absorption of calcium and phosphate indirectly by production active vitamin D metabolites

Question No. 15

Q: How is vitamin D synthesised and activated?

Answer No. 15

Vitamin D synthesis and activation in the skin, kidneys and liver

Question No. 16

Q: What are the effects of vitamin D?

Answer No. 16

Hormone
Hormone
Hormone
Vitamin D3
(cholecalciferol)
  • Originates from:
    • Dietary intake
    • Synthesis in the skin through effects of UV light on 7-dehydrocholesterol
  • Modified by liver and kidney to form active 1-25-hydroxycholecalciferol - under the influence of parathyroid hormone
  • Levels also increase in response to low phosphate levels
  • Acts to increase serum calcium levels
  • GI Tract: Increases GI absorption by upregulating number and activity of transport proteins
  • Kidneys: Weak effect to increase calcium and phosphate reabsorption
  • Plays a minimal role in calcium homeostasis, secreted only when levels rise above normal limits

Question No. 17

Q: What is calcitonin? Where is it produced, what are its effects?

Answer No. 17

Hormone
Hormone
Hormone
Calcitonin
(minimal role)
  • Peptide hormone produced by parafollicular cells of the thyroid gland
  • Secretion stimulated by an increase in serum calcium levels
  • Acts to decrease serum calcium levels when elevated (physiological antagonist to PTH)
  • Bone: Prevents resorption by inhibiting osteoclast activity and stimulating osteoblast activity
  • Kidneys: Weak action to decrease calcium reabsorption

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