These articles [Heidland et al., 1978: (http://www.ajcn.org/cgi/reprint/31/10/1784.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/707333); Lamiell et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2108005)] show that supplementation with free-form amino acids, particularly in conjunction with a low- or "no-phosphate" diet (Lamiell et al., 1990), can fairly drastically reduce serum phosphate and also increase serum calcium. I've discussed some of these articles in past postings (http://hardcorephysiologyfun.blogspot.com/2009/02/potential-for-hypophosphatemia-or.html). Heidland et al. (1978) found that the serum calcium levels varied inversely with the serum phosphorus levels, in the people who had been given supplemental essential amino acids, and the authors suggested that that inverse relationship might have resulted from the increases in serum 1alpha,25-dihydroxyvitamin D3 (calcitriol, hormonal vitamin D, HVD) and the resorptive effect of an increase in serum HVD (?). These are really good articles, and I've never seen anyone mention that increase in "calcium mobilization from bone" (Heidland et al., 1978, p. 1791) in response to an increase in serum HVD. It's not widely-recognized, but there is a lot of research showing that increases in serum HVD can produce effects that are basically opposite to those of increases in autocrine or paracrine HVD (HVD that is formed in response to increases in extracellular 25-hydroxyvitamin D and that acts on nearby cells or in the same cell in which it is formed), and those paradoxical effects seem to show up more in relation to the calcemic or calcium-transport-modifying effects of HVD. For example, increases in HVD are known to be somewhat permissive with respect to soft-tissue calcification in animals, but increases in 25-hydroxyvitamin D, in the absence of concomitant increases in serum calcium (effects that are potentially more likely to occur in response to UV-induced increases in vitamin D than in response to oral vitamin D, in my opinion, given that oral vitamin D is likely to be more calcemic, etc.), have generally not increased soft tissue calcification and may have the potential to decrease soft-tissue calcification by, in theory, helping to prevent the osteoblastic differentiation of smooth muscle cells, etc. But combining high-dose vitamin D3 with high-dose calcium supplements has the potential to cause problems, and Heidland et al. (1978) suggested that the association of the amino acid supplementation with hypercalcemia, in some people, had been a result of the extra calcium supplementation (coupled with the relative absence of dietary phosphate).
A lot of these articles on these strategies for managing hyperparathyroidism and hyperphosphatemia in people who have kidney failure only look at serum phosphate or serum parathyroid hormone (PTH) levels and don't consider the levels of intracellular phosphate or the context in which the increases in PTH levels are occurring, and these are problematic aspects of a lot of these articles (I'm not talking about the ones I cited above). Lamiell et al. (1990) found, for example, that, after the second administration of the zero-phosphate parenteral nutrition formula was given to a person (they gave it and discontinued it a few times before they determined that hypophosphatemia or intracellular phosphate depletion, in addition to hyperammonemia, was causing the encephalopathy, and this is understandable), the encephalopathy occurred when the serum phosphate was normal. Lamiell et al. (1990) attributed that encephalopathic episode to hyperammonemia, and that's plausible, but it's important to remember that the intracellular inorganic and organic (i.e. ATP and ADP, phosphocreatine, etc.) phosphate levels can be significantly depleted in a person whose steady-state serum inorganic phosphate levels are normal [for example, Ambuhl et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10561144)]. Many most articles whose authors have measured the intracellular 2,3-diphosphoglycerate (2,3-DPG) concentrations in red blood cells have shown that have shown that those concentrations don't correlate at all with serum phosphate levels. I also think there's a danger in thinking that these derangements in calcium and phosphate homeostasis will only occur in people who have renal failure, but supplemental phosphate decreased urinary calcium excretion in normal people who had evidently not been exhibiting hypercalciuria [Heaney and Recker, 1987: (http://www.ncbi.nlm.nih.gov/pubmed/2851341)]. So some of these unspoken assumptions, such as the assumption that massive doses of calcium are going to not cause hypercalcemia or pathological effects in people who do not have kidney disease, in short-term trials with calcium supplements have the potential to be invalid.
The mechanisms by which free-form amino acids can decrease serum phosphate are not well-understood, but Heidland et al. (1978) noted that the persistence of the decreases in serum phosphate over the long term, in some people who are given supplemental amino acids, argues against the idea that the hypophosphatemic effect is a result of the "refeeding syndrome" or even something akin to it. I think it's caused by changes in the interactions of renal ammoniagenesis with the mechanisms governing phosphate reabsorption in the proximal tubules, and those interactions basically boil down to changes in acid-base homeostasis. For example, the acute, supplemental-glutamine-induced increases in serum bicarbonate that can occur in humans could be expected to favor an increase in phosphate transport into cells. There probably is an increase in phosphate uptake into cells, in response to some amino acids, but it's noteworthy that excessive or high doses of some mixtures of free-form amino acids seem to be more likely to produce hyperammonemia than protein does. Lamiell et al. (1990) attributed that to the absence of arginine in some mixtures, and that's conceivable. But it might be a result of the kinetics of the absorption of free-form amino acids. Their absorption is going to be much more rapid than the absorption of protein-derived amino acids, and that could overwhelm the liver's capacity for ureagenesis. It's also possible that increases in phosphate utilization (or loss of phosphate in the urine, induced by the amino acids) decreases the availability of intracellular inorganic and organic phosphate in a way that impairs the activities of hepatic urea cycle enzymes. But one possibility that seems plausible to me is that amino acids increase urinary phosphate loss and that the loss of phosphate increases renal ammoniagenesis to a degree that is significant enough to disturb the systemic acid-base homeostatic mechanisms and actually contribute to hyperammonemia. Under some circumstances, the overall urea cycle activity is thought to be an important factor in influencing systemic acid-base homeostasis, and Haussinger et al. (1990) [cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/02/urea-cycle-renal-glutaminase-activity.html); Haussinger et al., 1990: ([Haussinger et al., 1990: (http://www.springerlink.com/content/l2vx314521367706/)] basically found that even mild liver dysfunction was associated with a failure of renal ammoniagenesis to downregulate in response to systemic metabolic alkalosis. So, in a normal person, glutamine supplementation might acutely increase serum bicarbonate or only increase it on some days, such as on a day of intense exercise (in response to acidosis), but massive doses of glutamine or other essential amino acids that increase renal glutamine availability (glutaminase and the glutamine cycle are important in the regulation of renal ammoniagenesis, in response to metabolic acidosis) could contribute to the persistently-alkalotic state that can occur even in compensated liver disease, as discussed by Haussinger et al. (1990).
It's worth noting that alkalosis doesn't just increase phosphate uptake into cells (it tends to decrease intracellular phosphate availability in the long-term or even short term, because the uptake into cells provides phosphate to some cells at the expense of others, given the usual, alkalosis-induced reduction in serum phosphate) but impairs the unloading of oxygen from hemoglobin in a "2,3-DPG-depletion-independent" manner. That's one reason why bicarbonate administration can be so disastrous in a person who is hypophosphatemic, as discussed in past postings. One would think that the alkalosis-induced uptake (it's thought to partially be a result of the alkalosis-induced activation of glycolytic enzymes) of phosphate would increase 2,3-DPG levels, but it tends to not be the case in hypophosphatemia. It might be that more 2,3-DPG is driven into skeletal muscle myocytes or other cells that are not red blood cells, or it might be that the 2,3-DPG-independent "impairment" in the unloading of oxygen from hemoglobin tends to offset any potential for an increase in 2,3-DPG formation to occur in response to the alkalosis-induced increase in phosphate uptake by red blood cells. In any case, an inappropriate and persistent increase in renal ammoniagenesis could cause an ammonia-mediated impairment of TCA cycle activity in proximal tubule cells, given that ammonia excesses are known to inhibit TCA cycle enzymes and other mitochondrial enzymes and to interfere with energy metabolism by all sorts of mechanisms. That metabolic toxicity could reduce phosphate reabsorption by proximal tubule cells and exacerbate phosphaturia. Some of these articles by Ambuhl and colleagues (http://scholar.google.com/scholar?hl=en&q=ambuhl+phosphate) look promising as sources of information on those types of mechanisms.
No comments:
Post a Comment