This article [Yamazawa et al., 2006: (http://pediatrics.aappublications.org/cgi/reprint/118/6/2557)(http://www.ncbi.nlm.nih.gov/pubmed/17142545)] is really interesting, and Yamazawa et al. (2006) found that dysfunction of the renal proximal tubules caused hypouricemia, hypophosphatemia, and hyponatremia. Some interesting things in the article are that, as shown in figure 1, the serum uric acid (UA) correlated with the serum phosphate (Pi) for a period of time and that, as mentioned by the authors, past research has shown that elevations in pro-inflammatory cytokines (or the administration of exogenous, recombinant cytokines) have been shown to induce either hypouricemia or hypophosphatemia. One explanation for those associations of pro-inflammatory disease states with hypouricemia and hypophosphatemia is, as discussed by Yamazawa et al. (2006), that nitric oxide (NO), produced in excess by activated macrophages and monocytes (cytokine-activated monocytes or resident macrophages, etc.), along wiht TNF-alpha and other pro-inflammatory cytokines, can inhibit the proximal tubule Na+/K+-ATPase activity that's essential for UA and Pi reabsorption from the tubular fluid. NO and TNF-alpha inhibit mitochondrial activity, and it's known that the proximal tubule epithelial cells display an exceptionally high tissue-specific metabolic rate. The proximal tubules have enormous energy requirements and are strongly affected in people with a variety of different mitochondrial disorders.
Yamazawa et al. (2006) also mention that increases in the levels or actions of atrial natriuretic peptide (ANP) are thought to contribute to the hypervolemic hyponatremia that is characteristic of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and it's conceivable that vitamin D deficiency could contribute to hypouricemia and hypophosphatemia by derepressing ANP formation. There's a vitamin D response element in the promoter of the ANP gene, and vitamin D repletion suppresses ANP formation (http://scholar.google.com/scholar?q=%22vitamin+D%22+%22atrial+natriuretic+peptide%22&hl=en). Increases in ANP formation are thought to contribute to the heart problems that occur in vitamin D receptor knockout mice (see search results), and 25-hydroxyvitamin D levels were found to be inversely associated with serum TNF-alpha and N-terminal pro-ANP peptide levels (a propeptide of ANP that's cleaved into ANP) in people with congestive heart failure [Zittermann et al., 2003: (http://content.onlinejacc.org/cgi/reprint/41/1/105)(http://www.ncbi.nlm.nih.gov/pubmed/12570952?dopt=Abstract)], but increases in ANP levels, in vitamin D deficiency, could also contribute to hyponatremia, in people who have various neurological disorders, and, secondarily, to hypophosphatemia, conceivably. Liamis et al. (2007) [Liamis et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17541217)] found that hypophosphatemia was the most commonly-seen electrolyte disorder in people with hyponatremia resulting from SIADH. These are some of the articles whose authors discuss the association of SIADH, a hyponatremic state, with hypouricemia and with brain injuries or brain diseases in general (cerebral salt wasting or SIADH or another hyonatremic osmoregulatory pathology very commonly are accompanied by hypouricemia and seem to just be a common end point of many neurological disorders, such as Parkinson's disease, Alzheimer's, etc.) [Palmer, 2003: (http://utenti.unife.it/giampaolo.garani/salt%20wasting/SIADH%20versus%20CSW.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12714279); Nelson et al., 1981: (http://www.ncbi.nlm.nih.gov/pubmed/7299468); Coenraad et al., 2001 and others: (http://scholar.google.com/scholar?q=hyponatremia+SIADH&hl=en)]. Haglin (2001) [Haglin, 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11399116)] suggested that hypophosphatemia could cause elevations in serum UA, given that, as discussed by the author in the context of reference 35, cited on page 661, hyperphosphatemia can increase ATP levels in some cells, such as red blood cells, and slow ATP degradation. I actually think both concepts may be valid. I mean that low intracellular phosphate could produce short-term elevations in serum UA [as in response to fructose ingestion, as discussed by Haglin (2001)] or augment the exercise-induced elevations in serum UA and depletion of purines from the skeletal muscles, even if the long-term effect of hypophosphatemia or phosphate depletion is hypouricemia. The research that Haglin (2001) discussed, about purine salvage being more efficient in hyperphosphatemic states or in phosphate-replete states, does have validity, in my opinion, and there are other, similar articles. That article by Haglin (2001) is a great article, and research, since the article was published, has lended credence to a lot of the ideas in that article. Serum phosphate and magnesium levels were found to be lower in people who displayed markers consistent with insulin resistance [Kalaitzidis et al., 2005: (http://www.nephrology.uoi.gr/uliko/Dimosievseis_engl_pdf/176.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15861350); ]. Schwille et al. (1997) [Schwille et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9079746)] found that the urinary phosphate loss that occurred after a meal, among people with calcium urolithiasis (kidney stones consisting of insoluble precipitates of calcium salts of organic anions) who had been treated with vitamin C, correlated inversely with the vitamin C-induced increases in insulin sensitivity (so the higher the subjects' insulin sensitivity, the lower their postprandial urinary phosphate losses were). There are lots of other articles showing that phosphate depletion has been associated with a worsening of insulin resistance (with a decrease in insulin sensitivity), but I'm not finding them easily or on my computer right now. It's worth noting, however, that serum phosphate doesn't correlate reliably with intracellular phosphate levels, and serum phosphate is arguably going to be a more valid marker of phosphate depletion among people who display significant degrees of intracellular phosphate depletion. But I still think there's validity to that type of research on phosphate metabolism, especially when one looks at the research in the context of other pieces of information (such as data on serum magnesium or serum insulin levels or measures of insulin sensitivity, etc.).
No comments:
Post a Comment