Calcium and Phosphate Metabolism

this is Eric strong from Stanford University and the Palo Alto Veterans Hospital this is the first video in a series on disorders of calcium and phosphate metabolism I'll provide an overview of the normal physiology of calcium and phosphate and in each subsequent video I'll cover hypercalcemia hypocalcemia hyper phosphate anemia and hypophosphatemia understanding the regulation of calcium and phosphate in the human body is a fascinating exercise in synthesizing knowledge from various domains in both physiology and biochemistry calcium and phosphate balance exists at the intersection of four separate yet intertwined physiologic systems the gastrointestinal system the endocrine system the renal system and our musculoskeletal system or our bones calcium and phosphate enter the system through the GI tract some is lost in the feces while some is absorbed into the bloodstream both electrolytes undergo continuous exchange with mineral in our bones as our bones are in a constant balance between resorption and formation a process sometimes referred to as bone turnover both are freely filtered in the glomeruli of the kidney where some is reabsorbed in the renal tubules while that which is not reabsorbed is excreted in the urine the endocrine system uses hormones to mediate the processes of GI reabsorption bone turnover and tubular reabsorption in order to keep serum levels of both calcium and phosphate normal despite fluctuations in intake and physiologic need pictured here in the dark pink are the four parathyroid glands in the neck which play a critical role in this for patients in net zero calcium phosphate balance the amount of calcium and phosphate taken into the GI tract via food must be equal to the sum of that lost in feces and that excreted in urine within the body there are different forms of calcium at any given time the vast majority of calcium is stored in the bones as a mineral called hydroxyapatite which has the chemical formula to the right the small minority of calcium in the plasma exists in three forms approximately 45% is in the free ionized form another 45% is bound to proteins predominantly albumin the remaining 10% is complexed with circulating anions such as citrate sulfate and phosphate when measuring serum calcium levels it's important to remember that only the free ionized form is physiologically active yet routine blood tests measure the total circulating calcium while it's possible to measure ionized calcium directly there are technical limitations and samples require special handling which decreases precision and increases costs as compared to total serum calcium due to the fact that a large fraction of serum calcium is bound to albumin the serum calcium level should be corrected in states of hypoalbuminemia the most commonly cited correction formula states that the corrected calcium equals the measured calcium plus 0.8 times 4 minus the serum albumin thus whenever a patient with low albumin initially appears to have low calcium in practice it usually corrects into the normal range corresponding with that patient having a normal eye on iced calcium level as with calcium there are also different forms of phosphate in the body most is also stored in the bones as hydroxyapatite of the remainder most is intracellular as a component of phospholipids and cell membranes DNA and RNA and the energy storing compounds of ATP and ADP the small fraction of phosphate that is in the serum exists as circulating phospholipids and inorganic phosphate inorganic phosphate consists of hpo4 and h2 po4 in a four to one ratio at a pH of seven point four zero the sum of hpo4 and h2 po4 is both what is physiologically active and what is typically measured in routine blood tests a few minutes ago I mentioned that the endocrine system mediates the processes calcium phosphate balance using hormones there are two major relevant hormones the first is parathyroid hormone usually abbreviated PTH this is an 84 amino acid polypeptide which is produced by the parathyroid glands its net effect is to increase your calcium and decrease serum phosphate the other major hormone is calcitriol also known as the active form of vitamin d this is derived from diet or from a cholesterol derived precursor with help from ultraviolet light formation of calcitriol also requires enzymatic steps in the liver and kidney its net effect is to increase both serum calcium and the serum phosphate let me talk a little bit more in depth about each one PTH is synthesized and secreted by the cheap cells of the parathyroid gland it's secretion is primarily regulated by serum calcium elevated calcium inhibits PTH synthesis and release decreased calcium stimulates it the curve of how PTH secretion relates to serum calcium is important over the range of normal total calcium levels of about eight to ten point five milligrams per deciliter the relationship is relatively linear however when serum calcium is below normal serum PTH secretion is maximized at around 100 micrograms per milliliter no matter how low the calcium gets a normal set of parathyroid glands will not secrete anymore PTH than that likewise no matter how elevated above normal your serum calcium Rises PTH secretion will never be fully suppressed the role of magnesium in PTH regulation is complicated and not completely understood in normal physiologic conditions magnesium impacts PTH secretion in a way parallel to calcium such that small increases in serum magnesium lead to small decreases in PTH secretion and small decreases in magnesium lead to small increases in PTH however in states of significant magnesium depletion there's an impairment in PTH secretion and resistance to PT action from which hypocalcemia can develop the details of the synthesis and regulation of calcitriol is significantly more complex than that of PTH the biggest source of this complexity stems from the fact that each compound and each enzyme has at least two and sometimes three different names which can be used interchangeably and which sounds remarkably similar to one another for this diagram I'll use my standard notation for physiology diagrams in which physiologic effects will be in green boxes enzymes in blue and hormone and pre hormones in tan let's first consider the pre hormone 25 hydroxy cholecalciferol also known as kalsa dial there are two possible sources of this compound the first is cholecalciferol also known as vitamin d3 the second is our goal Calcifer all also known as vitamin d2 there are a few dietary sources of these precursors to active vitamin d in the u.s. the major dietary source is supplementation of dairy products and to a lesser extent cereals and grain products for some reason probably historical most US food companies supplement with vitamin D to the minor dietary source in the u.s. is naturally occurring vitamin d3 found predominantly in salmon tuna and swordfish and most prominently in cod liver oil I've heard that d3 may be used more for supplementation in Europe but I don't know this for a fact the most prominent source of these vitamin d precursors however is not our diet but rather a steroid derived compound called 7 d hydro cholesterol which is converted to vitamin d3 by UV light that's right Sun striking our skin helps to produce a vitamin as an interestingly historical footnote in London during the industrial revolution the combination of fog and thick industrial smog led to an extraordinarily high incidence of rickets a childhood bone disease caused by vitamin D deficiency possibly the first widespread disease caused by environmental pollution I'll mention also the conversion of vitamins d2 and d3 two kalsa dial occurs in the liver with the assistance of an enzyme usually called vitamin D 25 hydroxylase but occasionally also known as cytochrome p450 to our one the final step in this pathway is the most important and the one that's actively regulated this is when kalsa dial is converted to 125 dihydroxy cholecalciferol also known as calcitriol or active vitamin d this occurs in the kidneys and requires vitamin d 1 alpha hydroxylase also known as cytochrome p450 27 b1 1 alpha hydroxylase is inhibited by counter trial itself a form of negative feedback that prevents overproduction of the reactions product and an important link between calcio trial and PTH is that PTH increases the activity of one alpha hydroxylase in addition low serum phosphate also stimulates this enzyme and it's inhibited by high serum phosphate finally there is a protein called fibroblast growth factor 23 or fgf 23 for short its role in calcium phosphate homeostasis was just discovered about 10 years ago and the complicated details are still being sorted out what is known so far is that it's released by osteocytes and osteoblasts in response to PTH and hyper phosphate emia and one of its primary functions is to inhibit the activity of vitamin D 1 alpha hydroxylase I know all of these names are frustrating and I wish medicine would just pick one name for each molecule and forget the others but unfortunately all these are in common use and despite this diagrams relative complexity all these details are necessary to understanding the diagnosis and treatment of calcium and phosphate disorders so how does all of this come together in regulating calcium phosphate homeostasis it starts in the GI tract with absorption of calcium and phosphate into the blood this absorption is stimulated by calcitriol from the blood calcium and phosphate undergo newest exchange with bone PTH inhibits bone formation and stimulates bone resorption while calcitriol only directly stimulates resorption there's another hormone to mention here called calcitonin which blocks bone resorption calcitonin is a polypeptide secreted by the para follicular cells or c cells of the thyroid gland in response to hypercalcemia the reason it's in parentheses in the diagram and the reason i haven't yet mentioned it is because it's physiologic role is suspected to be very minimal neither thyroidectomy nor thyroid tumors have an appreciable impact on calcium homeostasis the only reason to even be aware of the existence of calcitonin is due to its potential use as treatment for severe hypercalcemia which we discussed in the next video besides the process of bone turnover the other path for calcium and phosphate to take is glomerular filtration in the kidneys after filtration PTH stimulates reabsorption of calcium but blocks reabsorption of phosphate while calcitriol stimulates reabsorption of both calcium and the phosphate the reason that it's critical for PTH to cause phosphate excretion in the urine is because otherwise if calcium and phosphate were reabsorbed in equal amounts they would just complex with one another leading to no net increase in the free ionized and physiologically active form of calcium in addition fgf 23 inhibits phosphate reabsorption in the renal tubules which is probably its most important function as its expression is stimulated by a hyper phosphate amia this function in the kidney acts as negative feedback to regulate serum phosphate so in summary as I mentioned near the beginning the net effect of PTH is to increase your calcium and a decrease serum phosphate while the net effect of calcitriol is to increase both serum calcium and phosphate an empiric feature of this complex homeostatic system is that both PTH in calcitriol but particularly PTH have a greater clinically relevant impact on calcium levels than on phosphate in other words it's common for a patient presenting with manifestations of an abnormal calcium level to be ultimately diagnosed with a primary problem of either PTH or calcitriol however it's rare for a patient presenting with manifestations of an abnormal phosphate level to be ultimately diagnosed with one of the same there is one final physiologic mechanism to mention which further links the endocrine and renal systems this is the effect of pH on calcium phosphate metabolism in addition to its regulation by calcium PTH is also regulated by acid-base status decreased serum pH that is a state of acidemia leads to increased PTH secretion PTH acts on the renal tubules to increase urinary excretion of phosphate which then increases the buffering capacity of hydrogen ions excreted in the late distal tubule with more hydrogen ions buffered more hydrogen ions can be excreted and thus serum pH is increased closer to normal the last issue I'll discuss here has to do with measuring vitamin D levels while measuring PTH is very straightforward vitamin D is not when measuring vitamin D one can test for either 25 hydroxy vitamin D or kalsa dial or 125 dihydroxy vitamin D or calcitriol sometimes both are ordered potential problems with measuring vitamin D levels include lack of standardization of different assays lack of consensus on what constitutes a normal vitamin D level lack of consensus on treatment implications after a low level is detected confusion among providers regarding the clinical relevance of the different forms of vitamin D for example some providers think they're they are smart in recognizing that it's calcitriol that is the active form of the vitamin and thus that's the one that should be measured however in the absence of renal failure the presence of which would be obvious the council dial level is actually more sensitive to the arrangements in vitamin D tambul ism as a regulatory mechanisms acting on one Alfa hydroxylase can partially compensate for situations such as vitamin D deficiency this is ironic as the less useful test which is over-ordered is also the more expensive of the two which brings us to the last potential problem the possible lack of cost-effectiveness based on currently available information vitamin D levels should only be measured as part of the diagnostic workup of disorders of calcium phosphate homeostasis they should not be routinely checked in patients with normal levels of calcium and phosphates that's it for this video on the normal physiology of calcium and phosphate metabolism as I mentioned at the beginning the next four videos will cover hypercalcemia hypocalcemia hyper phosphate emia and hypophosphatemia respectively you you you

Channel: Strong Medicine

Views: 434,676

Keywords: calcium, phosphate, metabolism, homeostasis, pth, parathyroid, parathyoid hormone, fgf23, fibroblast growth factor 23, calcitonin, physiology, vitamin d, calcitriol, calcidiol, cholecalciferol, ergocalciferol

Id: SWv-aY4RH3c

Length: 17min 45sec (1065 seconds)

Published: Tue Jul 16 2013