Calcium Metabolism Flashcards
Calcium is a metal iron that is wide-spread in the body, what are the normal serum levels and where is the calcium?
Normal serum levels are 2.2-2.6M (biologically active, free ionised calcium is regulated at about 1-1.3M, with the rest bound to plasma proteins or complexed with citrate - most is stored in the skeleton.
It is very important to regulate serum calcium as it has so many important functions, name a few.
Regulates heart rhythm, assists normal blood clotting (it is factor IV), intracellular signalling pathways etc.
An adult human contains ~1000g of calcium, how much is in the bone, in what form and how does this change physiologically?
99% is sequestered in the form of hydroxyapatite crystals (Ca2+ + Pi) in bone. ~300-600mg of calcium are exchanged between the bone and extracellular fluid each day.
The daily dietary requirement for calcium intake is 1000mg, how are regular levels maintained (briefly)?
Each day there is urinary loss of 175mg and a GI loss of 825mg. The skeleton helps to buffer the serum levels by releasing calcium phosphate into the interstitum / the uptake of these.
Regulation of calcium levels is controlled by 3 hormones, what are they and how?
Parathyroid hormone stimulates bone reabsorption (release of Ca2+ into blood), reabsorption in kidney (and phosphate excretion) and hydroxylation of D3 to active vitamin D.
Active vitamin D increases interstitial absorption of dietary calcium, renal reabsorption and bone resorption.
Calcitonin (from C cells in thyroid), counteract effects of PTH.
What is active vitamin D called?
Calcitriol.
How are changes in the plasma concentration of calcium regulated?
Feedback - first with PTH.
What are parathyroid glands made up of and where are they?
Parathyroid glands are usually found 2 per lobe on the back of the thyroid gland (functionally separate). It is made up of chief cells, which produce PTH, oxyphil cells (with more cytoplasm) and some adipose.
PTH is a ___________ chained polypeptide hormone (prepro hormone cleaved twice, to form one that’s _____ amino acids long). There is no serum __________ protein and ___________ is regulated at a transcription and post-transcriptional level.
Straight
84
Binding
Synthesis
PTH synthesis and secretion is regulated. What happens with low and high serum concentrations of calcium
Low serum calcium upregulates transcription and prolongs mRNA survival. The half life of PTH is only 4 minutes and it’s continually synthesised with little stored (chief cells degrade as well as synthesise. High serum levels of calcium down regulate transcription, and accelerates the cleavage of PTH. Ca2+ binds to a GPCR (q) to slow transcription and release.
Parathyroid hormone may sometimes be cleaved in the chief cells, before release. Once it has been released, where is the PTH cleaved?
The liver.
What are the target organs and physiological effects at them of parathyroid hormone?
Bone - increases resorption of calcium into the blood, Gut - activates vitamin D and hence increases trans cellular uptake of calcium, Kidney - decrease calcium loss in urine (and increase phosphate loss).
What are the two primary functions of bone and which is more important?
Structural support and maintaining serum calcium concentrations, the latter of which is a priority. Disease of the bone affecting structural integrity can have consequences for serum calcium concentration and vice versa.
Calcium phosphate crystals are found within collagen fibrils in the extracellular matrix of bone. Which cells are involved in the lay down/removal and how?
Osteoblasts are involved in deposition, making the collagen matrix which is mineralised by hydroxyapatite.
Osteoclasts are involved in resorption, producing an acid micro-environment, so the hydroxyapatite dissolves.
Bone is dynamic. In 1-2 hours parathyroid can stimulate osteolysis, how specifically?
PTH induces osteoblastic cells to synthesise and secrete cytokines on their cell surface, which stimulates differentiation and activity in osteoclasts, protecting them from apoptosis and decreasing the osteoblasts activity (calcium and phosphate go into the extra cellular fluid).
Where specifically does parathyroid hormone work in the kidney and how?
PTH increases calcium reabsorption in the thick ascending limb and distal convoluted tube, phosphate is removed from the circulation by inhibition of kidney reabsorption (preventative to calcium stone formation). There is also an impact on magnesium.
The calcium receptor in chief cells of the parathyroid gland is also present and important elsewhere in the body, where?
In the TAL of the kidney, regulating calcium reabsorption.
How and why does parathyroid hormone exert its effect on the gut?
Only 30% of the 1000mg/d is absorbed by paracellular uptake effective when the calcium concentration is not limited. This is significantly increased by vitamin D transcellular uptake - PTH stimulates the conversion to the active form, increasing calcium gut uptake.
Calcitriol is the active form of vitamin D used by the body, where does the body get vitamin D from?
It can be made from cholesterol in the skin when exposed to sunlight (UV) or from dietary dairy (D2). Alternatively from foods that are fortified with D3 made by fungi and yeast. Both are equipotent in forming active vitamin D, calcitriol.
How does the body go from vitamin D 2/3 to the active calcitriol?
2 step hydroxylation.
First at the liver into 25-hydroxyvitamin D (25 hydroxylase), which is a major circulating hormone. Then in the kidney, triggered by PTH, active 1,25-dihydroxyvitamin D / calcitriol is formed (1 alpha hydroxylase).
Vitamin D3 is is lipid soluble so how must it travel in the blood and what are the consequences of its short half life?
It is bound to transcalciferin with only a small fraction free form. It doesn’t exist as it is for too long, but once converted into 25-hydroxyvitamin D, it can stay in the liver for around 2 weeks.
The previtamin 25-hydroxyvitamin D is bound to a carrier small enough to be filtered by the glomerulus and enter the PCT, where it is converted by 1 alpha hydroxylase. After this, what is the half life of calcitriol?
A quarter of a day.
Feedback is important in the production of calcitriol as it affects the very influential calcium concentration, how is it regulated?
Elevated serum calcium prevents C-1 hydroxylation and elevated PTH stimulates it.
Calcitriol works on the bone, gut and kidney - decreases urinary loss by stimulating kidney reabsorption.
Where is calcitonin secreted?
From the thyroid, calcitonin is secreted by parafollicular cells / C cells.
