Corrected Calcium: Add 0.1 mmol/L to the measured calcium for every 4 g/L albumin is below normal.
- Calcium is an important extracellular cation in the body.
- 99% of calcium and phosphate in the body is stored within the bone
- It is stored as hydroxyapatite
- A small amount of total calcium circulates free in the plasma
- It is however metabolically active
- Osteoblasts store calcium in bone
- Osteoclasts breaks down bone and release calcium
Calcium in the plasma exists in several forms
- 45% exists as the free and physiologically active, ionised form.
- 40% circulates bound to albumin and is metabolically inactive
- 15% is complexed with moieties such as citrate, phosphate, oxalate or sulphate, which although diffusible are not active.
The total calcium that is measured on blood testing includes all of these forms, and may be subject to error in cases where there is low albumin.
Corrected calcium (mmol/L) = measured calcium (mmol/L) + 0.02(40 - serum albumin in g/L)
Albumin Binds to Calcium
- The calcium levels can be changed depending on the albumin levels
- An alkalosis leaves more of the negatively charged COO- sites to bind to calcium, thus lowering the levels of the ionised calcium.
- The normal range for total plasma calcium is 2.25-2.65 mmol/L.
- Secondary messenger intracellularly
- Muscle contraction
- Membrane excitation
- Hormone secretion
- Structural support (cellularly as well as in bone)
- As noted, intracellular calcium levels are usually kept very low.
Indeed, calcium entry into cells is part of the apoptosis pathway.
- This low level is maintained by active transport of calcium out of the cells, through calcium pumps and sodium-calcium exchanger pumps.
- The intracellular calcium that is present is primarily stored within the different organelles e.g. endoplasmic reticulum.
- This allows some control of the calcium levels for specific tasks e.g. release for muscular contraction.
- Phosphorus is found in the plasma in both inorganic and organic forms.
- Inorganic phosphate in plasma is completely ionised as either HPO4-- (80%) or H2PO4- (20%).
- Body calcium is absorbed from dietary sources via the GI tract. This occurs via two mechanisms:
- Paracellular transport through the length of the gut
- An active transcellular pathway
- These two mechanisms do not lead to complete absorption, in contrast to some other ingested products.
Partly this is because of the combination with other moieties in the gut to form insoluble salts, but the absorption mechanism is also vitamin D dependent.
The TRPV6 (transient receptor potential vanilloid 6) is the channel found in the duodenum and proximal jejunum where the active transcellular movement occurs.
- As noted, as certain amount is simply lost from the gut through a failure to absorb - about 18 mmol of the total of 20 mmol ingested.
- This amount can be regulated to some degree through the action of PTH.
- The kidneys remain the main site of regulated excretion.
- Much of the filtered ionised calcium is reabsorbed passively in the PCT or loop of Henle.
- However, about 10-15% is under active reabsorption control in the more distal part of the nephron (DCT through the TRVPV5 channel) and can be adjusted to regulate calcium levels.
Homeostasis: There are 3 key hormones involved:
- Parathyroid hormone (PTH)
- Vitamin D
- Calcitonin (less important)
These have their actions through a number of tissues
- Parathyroid gland
- Thyroid gland
- GI tract
- This is produced by the chief cells of the parathyroid glands in response to a drop in plasma calcium levels, sensed by the calcium-sensing receptor on the cells.
- This has a number of direct and indirect actions on calcium and phosphate, raising plasma calcium levels and lowering phosphate levels. It results in:
- Release of calcium and phosphate from bone
- Increased renal reabsorption of calcium
- Decreased renal reabsorption of phosphate
- Activation of vitamin D
- This can be seen as another very important part of the homeostasis of calcium, but there are a few different molecules in the pathway to be aware of.
- Vitamin D3 (cholecalciferol) is initially synthesised in the skin by the action of UV light from the sun on 7-dehydrocholesterol.
- It is fairly common that there is inadequate sunlight for this synthesis, and so may also need to be ingested orally.
- The next step of metabolism occurs in the liver, where it is hydroxylated by the enzyme 25-hydroxylase to form 25-hydroxyvitamin D (the 25 because the hydroxylation occurs at the 25th position) which is also called calcidiol. This is the most common form of vitamin D in circulation.
- The final step occurs in the kidney, where it is initially filtered at the glomerulus, reabsorbed at the PCT and then activated, stimulated by PTH, to form calcitriol (1,25-dihydroxy vitamin D).
- There is also a pathway in the kidney where vitamin D is inactivated (24,25-dihydroxy vitamin D).
The calcitriol is the form that has the most activity.
The actions include:
- Releasing calcium and phosphate from bone
- Increasing GI absorption of calcium and phosphate
- Increasing renal reabsorption of calcium
- Inhibiting PTH release (as part of a negative feedback loop)
- An additional source of calcitriol may arise from activated macrophages and thymic derived lymphocytes, which may play a role in the pathophysiology of some conditions e.g. sarcoidosis.
- Released from the parafollicular C-cells of the thyroid gland in response to a rise in plasma calcium levels.
- The effects are essentially the opposite of PTH.
- It partly acts by reducing osteoclast activity leading to less bone breakdown.
- These effects are not fully understood, and it seems that much of the homeostatic response to high calcium is through a reduction in the activity of the other mechanism (PTH and Vitamin D).