In this letter [Roestel et al., 2004: (http://ajp.psychiatryonline.org/cgi/content/full/161/8/1499-a)(http://www.ncbi.nlm.nih.gov/pubmed/15285984)], Roestel et al. (2004) discuss research showing that serum phosphate correlates negatively with symptoms of anxiety and with physical complaints, etc. Roestel et al. (2004) cite this article [Maddock et al., 1987: (http://www.ncbi.nlm.nih.gov/pubmed/3659218)] as evidence of that, and there's a considerable amount of research showing that hypophosphatemia commonly is associated with various psychiatric disorders (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+psychiatric+OR+psychiatry), especially panic disorder. Some of those articles discuss the capacity of an elevated rate of lactate formation, from various tissues, to contribute to phosphate depletion, and that's been discussed in the context of exercise-induced phosphate depletion (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+lactate+exercise). Adrenaline, by its activation of beta-adrenoreceptors, in particular, is also thought to contribute to phosphate depletion in the long term and to short-term decreases in serum phosphate, given that adrenergic stimulation tends to increase the uptake of phosphate into cells (i.e. skeletal muscle cells, etc.). The same effect could result from chronic psychological stress, given that even anticipated stress can increase the firing rates of noradrenergic neurons in the locus ceruleus, for example. The authors of a lot of articles discuss the fact that hypophosphatemia tends to be associated with irritability, even in people who do not have panic attacks or whatever other symptoms (http://scholar.google.com/scholar?q=hypophosphatemia+irritable+OR+irritability&hl=en). As vague as that may sound, a lot of these articles discuss those types of excessively excitatory states in the context of hypophosphatemia or relative phosphate depletion. It's interesting that Nanji et al. (1985) [Nanji et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/4045178)] suggested that phosphate depletion may have been a cause and not (just) a consequence of liver failure/liver-cell necrosis in one case, and Quirós-Tejeira et al. (2005) [Quirós-Tejeira et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16101727)] found that the normalization of serum phosphate levels paralleled the normalization of liver function in children who had experienced liver damage. Fructose is known to induce ATP depletion by sequestering phosphate, for example, and the point is that hypophosphatemia may actually be, in part, a cause and not just a consequence of some of these conditions that have been associated with hypophosphatemia.
I tend to think that something like ATP disodium might be safer than sodium phosphate for correcting phosphate depletion (in part because some it is likely to be absorbed intact, by paracellular diffusion, and because oral ATP has been shown to elevate adenosine diphosphate and monophosphate levels in the portal venous blood in animals, implying that less of the ATP-derived phosphate might remain in the GI tract and bind calcium and magnesium; there are several other reasons I say that), but it's important to discuss this with one's doctor. Phosphate can inhibit the absorption of calcium, magnesium, iron, and probably other minerals and could, particularly but not exclusively at higher doses, cause life-threatening hypocalcemia in people whose mineral metabolism is already deranged, etc. The kidneys and GI tract and calciotropic hormone system also tend to adapt rapidly to phosphate supplementation, and it seems like it would be more effective, in the long term, in my opinion, to consider some kind of intermittent "challenge" with something like ATP, in combination with resistance exercise, than to try to use sodium phosphate. I actually don't know much about phosphate supplementation, though, and I've never used sodium phosphate and don't intend to. Bremner et al. (2002) [Bremner et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12135811)] found that 4 grams per day of sodium phosphate (Na2HPO4) increased serum phosphate by 30 percent and caused a 25 percent increase in the (intracellular) 2,3-bisphosphoglycerate (BPG) levels in red blood cells (RBC's). BPG alters the affinity of hemoglobin for oxygen and improves the "unloading" of oxygen from hemoglobin, and that's a fairly significant effect. Many other articles have shown similar effects, and Bremner et al. (2002) noted that the steady-state increase in RBC BPG appears to require two or three days to occur at that dosage range (3-4 grams per day). Bremner et al. (2002) also found that the RBC BPG levels didn't correlate with the serum inorganic phosphate concentrations, and that absence of a correlation between serum phosphate and intracellular phosphate levels has been found by many other researchers for many other cell types, such as skeletal muscles, etc. I've discussed that in past postings, and I've also discussed the fact that calcium supplementation tends to bind phosphate in the GI tract and could thereby cause phosphate depletion. Heaney and Nordin (2002) [Heaney and Nordin, 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12074251)] discuss that, and it's interesting that a lot of the assumptions about phosphate metabolism and phosphate intake have ended up being much more complicated than people had previously thought they would be. Hypophosphatemia can cause lactic acidosis, for example, but the correction of the acidosis with bicarbonate has the same effect as BPG depletion from RBC's has on oxygen unloading from hemoglobin and can compound the existing BPG depletion in people who have hypophosphatemia, with disastrous consequences [Jacob, 1975: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1129800&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/1136448)]. But phosphate supplementation can gradually elevate serum bicarbonate and cause compensated metabolic alkalosis. Those types of interactions with acid-base regulation could account for some of the cases in which hypophosphatemia has been associated with idiopathic intracranial hypertension (or, rather, not-idiopathic) (http://scholar.google.com/scholar?hl=en&q=hypophosphatemia+papilledema+OR+%22intracranial+pressure%22+OR+pseudotumor+OR+pseudotumour+OR+%22intracranial+hypertension%22). The rate of CSF formation by the choroid plexuses can be dysregulated by acid-base dysequilibria across the blood-CSF barrier and has been treated by acetazolamide and other carbonic anhydrase inhibitors [see Horovitz et al., 1985: (http://scholar.google.com/scholar?hl=en&q=acid+base+dysequilibrium+papilledema+OR+%22intracranial+pressure%22+OR+pseudotumor+OR+pseudotumor+OR+%22intracranial+hypertension%22)]. It's conceivable that some of the psychiatric symptoms associated with hypophosphatemia are actually, in part, a result of mild elevations [as discussed in this posting, for example: (http://hardcorephysiologyfun.blogspot.com/2009/07/dimming-of-vision-in-depression.html)] in intracranial pressure. There are other paradoxical aspects of phosphate homeostasis, such as the fact that alkaline phosphatase activity is pH-sensitive, to a potentially-important degree, and is inhibited by inorganic phosphate. So phosphate derived from the hydrolysis of pyrophosphate, by smooth-muscle cell alkaline phosphatase, would tend to increase the risk of calcification, by locally diminishing the inhibitory effect of pyrophosphate, but phosphate depletion could conceivably augment alkaline phosphatase activity by causing metabolic acidosis and excessive phosphate turnover, because of adenosine nucleotide deamination in the context of wild swings, up and down, in intracellular free inorganic phosphate concentrations? I don't know, but it's complicated. And the relationship between serum phosphate or extracellular fluid phosphate and calcification risk is "U-shaped," as various authors have noted. In any case, a lot of the research is interesting.
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