Case 2: Chemical Pathology 1 - Coggle Diagram
Case 2: Chemical Pathology 1
Outline the functions of Calcium
Structural: Calcium forms bones and teeth
Calcium is a cofactor for coagulation factors
It is an intracellular second messenger
Calcium plays a role in Hormone secretion
Calcium plays a role in muscle contraction, release of neurotransmitters, control of excitability
List the functions of Phosphate
Phosphate forms bone
Phosphate also plays a role as a Buffer, in acid base reactions
Phosphate form DNA backbone
It takes part in intracellular signaling
And intermediary metabolism
Phosphate is also a energy storage in the form of ATP and Creatine-Phosphate
Outline the Calcium Distribution in the body
Calcium in the Plasma
Total Calcium in the Plasma is 2.2-2.6 mmol/L
Most of the Calcium is Protein-bound to albumin
The TOTAL calcium concentration measured is affected by the amount of Albumin present
And the higher the amount of albumin, the higher the concentration of Calcium
54% of Calcium is NOT protein bound
7% of non protein bound Calcium is complexed with Phosphate or Citrate
The free (ionized) portion of calcium is considered the Biologically Activate form of Calcium
This biologically activate calcium influences the processes that calcium is involved in.
Due to the important functions of Calcium, the body will strictly regulate free (ionized) form of Calcium
Free portion of Calcium is affected by the environment in the Plasma
Therefore, increased availability of cations can displace Calcium off Albumin. (Eg: a patient with a low pH will have a higher Calcium level)
Outline Calcium Regulation of the Free (Ionized) Calcium
Ionized Calcium is tightly regulated by:
Calcitriol ( 1, 25- Hydroxy Vitamin D = Activated Vitamin D)
Calcium Sensing Receptor
These 3 components work together to regulate Free Calcium in Plasma
Function is achieved by:
Movement from Bones Stores
Increased or Decreased reabsorption from the Kidney
Increased or Decreased reabsorption via the GIT
to maintain a tight concentration of ion in plasma
Outline the distribution of Phosphate in the Body
20 000 mmol/L of Phosphate is in the Bone
4000 mmol/L of Phosphate is in the Muscle
36 mmol/L Phosphate is in the GIT taken in through the diet, and 10 mmol/L of Phosphate is lost as faeces
1 mmol/L of phosphate is in the Plasma
Phosphate is also in the Kidney where it is filtered, reabsorbed and a certain percentage is lost in the Urine
Outline the Regulation of Phosphate in the body
Phosphate is mainly regulated by Gastrointestinal Absorption and Renal excretion.
Phosphate is regulated by:
Calcitriol 1,25 (OH)2 Vitamin D
Fibroblast growth factor 23 (FGF23)
The movement of Phosphate is achieved by the:
Bone reabsorption of Phosphate
Increased or Decreased GIT uptake
Increased or Decreased Renal Excretion
**Acute movements such as the rapid exchange of Phosphate between intracellular and extracellular compartments is due to:
Insulin, Glucoses, Catecholamines, Respiratory Alkalosis
Rapid cell breakdown, growth and repair
What is the Function of Vitamin D ?
Vitamin D increases the absorption of Calcium and Phosphate in the GIT
In higher concentrations, Vitamin D can stimulate the increased release of Calcium and Phosphate from the Bone through Bone Resorption
Outline the formation of Vitamin D in the body
In the skin there is 7-Dehydrocholestrol, which is activated by the sun to form Pre-vitamin D3
Pre-Vitamin d is the simulated by heat to become Vitamin D3 (Cholecalciferol)
Cholecalciferol is also obtained from the diet
Cholecalciferol then moves from the skin into the blood.
The Cholecalciferol is catalyzed by the enzyme 25-Hydroxylase to form 25- Hydroxy Vitamin D3 in the liver
The 25-Hydroxy Vitamin D3 then moves into the blood.
25-Hydrozy Vitamin D3 is then catalyzed by the enzyme 1Alpha-Hydroxylase to form 1Alpha,25-dihydroxy-Vitamin D3 in the Kidney
1Alpha,25(OH)2 Vitamin D3 is called Calcitriol
NOTE: Enzymes involved in Vitamin D formation
If 1Alpha-Hydroxylase is not active, Vitamin D cannot be activated
If 1Alpha-Hydroxylase is over active, it results in increased amount of Activated Vitamin D
Outline the regulation of 1Alpha-Hydroxylase
Parathyroid Hormone (PTH) stimulates the enzyme; 1Alpha-Hydroxylase.
In this way, PTH is able to bring about the uptake of Calcium via the GIT
Fibroblast Growth Factor 23 (FGF 23) inhibits the enzyme: 1Alpha-Hydroxylase
In a Negative feedback fashion the enzyme: 1Alpha-Hydroxylase is also inhibited by
Activated Vitamin D/ 1Alpha,25 (OH)2 Vitamin D
Explain what happens when there is a Deficiency or Excesses in Activated Vitamin D ?
Deficiency of Vitamin D (or failure to activate or resistance) means that there is a:
Low Plasma calcium level
Low Plasma Phosphate Level
High serum PTH
Excessive Vitamin D means that there is a:
High Plasma Calcium level
High Plasms Phosphate level
An appropriately suppressed PTH level
What is the function of the Parathyroid Hormone ?
Increases the calcium absorption in the Renal Tubule
Increases Phosphate excretion from the Renal Tubule
Increases calcium and decreases Phosphate levels in the blood.
Increases Calcium and Phosphate resorption by the Bone
Increases Calcium and Phosphate absorption in the GIT
As the Calcium levels increase, the Calcium-Sensing Receptor is simulated.
Stimulated Calcium-Sensing Receptor inhibits the release of more PTH and further increase in calcium and Loss of Phosphate
Parathyroid Hormone in the Kidney
Explain the action of the Parathyroid Hormone in the Kidney
PTH increases Calcium absorption in the Distal Tubule of the Kidney
PTH causes Phosphaturia, which is the loss of Phosphate renally.
This occurs through the internalization of Sodium/Phosphate Transporter in the Proximal Tubule
PTH will inhibit the Sodium/Phosphate transporter, so that Phosphate is lost in the urine
Parathyroid Hormone increases activation of Vitamin D
This results in an increase in the Calcium levels and an decrease in the Phosphate levels in the Plasma
Explain the action of the Parathyroid Hormone in the Bone
In the Bone, PTH will activate Bone Resorption
PTH binds to Osteoblasts and increases expression of RANK Ligand (RANKL) on the surface of the Osteoblasts
RANK Ligand will then bind to the RANK Receptor on the cell surface of the Osteoclast Precursors
Binding will activate Osteoclasts
Osteoclasts will then perform Bone Resorption, resulting in the increased release of Calcium and Phosphate
The action of the PTH on the bone, increases the Calcium and Phosphate concentration in the Plasma
Explain the action of the Parathyroid Hormone on the GIT
Parathyroid Hormone activates Vitamin D in the Liver by stimulating the enzymes: 1Alpha-Hydrozylase
This leads to increased absorption of Calcium and Phosphate in the GIT
This results in increased Calcium Concentration and Phosphate Concentration in the Blood Plasma
What is the Parathyroid Hormone ?
Parathyroid Hormone is secreted by the Parathyroid Gland in response to decreased ionized plasma Calcium
Action and secretion of PTH is inhibited by a low Magnesium Concentration
If a patient has low Calcium and low PTH levels, ALWAYS check Magnesium levels to see if they are also low.
How is the PTH Regulated
If there is an increase in the ionized Calcium Concentration in the plasma due to increased PTH release
Calcium-Sensing Receptor will be stimulated
The Calcium-Sensing Receptor will then inhibit the PTH production
1,23-(OH)2 Vitamin D (Calcitriol) will inhibit PTH release through negative feedback system
How does PTH Increase Plasma Calcium levels?
PTH stimulates reabsorption of Calcium in the GIT and in the Kidney
PTH stimulate the increased release of Calcium from the bone through Bone Resorption
How does PTH Decrease Plasma Phosphate ?
PTH directly inhibits Tubular Phosphate reabsorption by Phosphaturia
This is done to encounter the anticipated rise in serum Phosphate due to Vitamin D activation
Outline the PTH Negative Feedback Mechanism
A decrease in ionized plasma Calcium Concentration stimulates the release of PTH from Parathyroid Glands
PTH stimulates bone resorption by the activated Osteoclasts resulting in the release of Calcium and Phosphate
PTH activates Vitamin D in the Liver through the stimulation of 1Alpha Hydroxylase
This results in the absorption of calcium and Phosphate in the GIT
PTH also causes the loss of Phosphate via the Kidney (increase Phosphaturia)
What is the NET EFFECT of PTH ?
The net effect of PTH is to:
Increase in Calcium concentration in plasma
Decrease in Phosphate concentration in plasma
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Calcium-Sensing Receptor (CaSR)
What is the Calcium-Sensing Receptor ?
Calcium-Sensing Receptor is found in the Parathyroid Gland and Kidney
Explain the action of the Calcium-Sensing Receptor in the Parathyroid Gland
In the Parathyroid glands, Calcium-Sensing Receptor inhibits PTH Production
Therefore, when calcium binds to Calcium-Sensing Receptor
Calcium-Sensing Receptor inhibits PTH production and release.
Resulting in a decreased Calcium uptake and Calcium Plasma Levels
Explain the action of the Calcium-Sensing Receptor in the Kidney
In the Kidney, Calcium-Sensing Receptor:
Encourages renal calcium and Water loss via the inhibition of ROMK and PTH
Through the stimulation of Calciuria (loss of calcium in urine)
What is ROMK ?
ROMK is a Renal Outer Medullary Potassium Channel
It is an ATP-dependent channel that transports Potassium out of the cells.
When the CaSR is stimulated,
CaSR inhibits the ROMK channel, and Potassium cannot be moved out of the cell.
Which means the Sodium, Potassium 2Cl- channel is not working.
And does not allow Water and Sodium, Chloride to move across into cell.
Inhibition of normal Sodium movement, inhibits paracellular Calcium uptake
Therefore, Calcium is lost in the urine
What is the NET EFFECT of Calcium-Sensing Receptor
The net effect of the Calcium-Sensing Receptor is a decrease in the Calcium level in the Plasma
Explain Over-active and Under active calcium-Sensing Receptor
1.Over-active CaSR causes a:
Rapid decrease in Calcium Levels(Hypocalcaemia)
Increase in amount of Calcium lost in Urine (Hypercalciuria)
Under-active CaSR causes a:
Rapid increase in Calcium Levels(Hypercalcaemia)
Decrease in amount of Calcium lost in Urine (Hypercalciuria)
Fibroblast Growth Factor 23
What is the Fibroblast Growth Factor 23 ?
FGF 23 is produced in the Osteoblasts in response to high phosphate levels
Explain the action of the Fibroblast Growth Factor 23
When there is a high Phosphate Level in the plasma, the FGF 23 decreases the Phosphate Levels in the plasma as follows:
FGF 23 directly inhibits the Phosphate reabsorption in the Kidney (renal tubules)
FGF 23 inhibits 1Alpha-Hydroxlase and prevents the activation of Vitamin D in the liver
A decrease in activated Vitamin D impairs the Phosphate absorption in the GIT
This decreases the overall Phosphate levels in the Plasma
A decrease in Phosphate levels and a decrease in 1,25-(0h)2 Vitamin D in the plasma will decrease the production of FGF 23 from the Osteoblasts.
Outline Excess FGF 23 and Deficient FGF23
Excess FGF 23 results in Hypophosphataemia
Chronic excess of FGF 23 results in Hypocalcaemia
This is because prolonged inactivation of Vitamin D by FGF 23 result in decreased levels of Calcium in the Plasma
Decreased plasma calcium levels result in an increase PTH production and release. Resulting in bone resorption
Deficient FGF 23 results in Hyperphosphataemia.