These [Siddiqui and Bertorini, 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9572247); Gravelyn et al., 1988: (http://deepblue.lib.umich.edu/bitstream/2027.42/27325/1/0000348.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3364446); Steckman et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16642427); Heames and Cope, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/17090245)] are some interesting articles that show some of the variegated manifestations of hypophosphatemia. A crucial fact that I've taken from the research on phosphate homeostasis (it's arguably the most crucial point) is that neither the steady-state nor the between-dosage (in the context of phosphate infusions in animals or phosphate supplementation in humans) intracellular phosphate levels, in either muscle cells or red blood cells, correlates with the serum phosphate levels. For example, Chobanian et al. (1995) [Chobanian et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7900836)] found that the intracellular ATP concentrations in cells in the proximal tubules correlated positively with the intracellular inorganic phosphate (Pi) concentrations, and artificially-induced changes in extracellular Pi concentrations produced changes in the intracellular Pi concentrations. But in human studies, the intracellular Pi values generally do not correlate with serum Pi values, and the intracellular Pi concentrations can be significantly depleted in a person who has a normal serum Pi level.
That usual absence of a correlation between intracellular and serum Pi concentrations means, in my opinion, that intracellular phosphate depletion, in "normophosphatemic" people, should be considered as a possible factor contributing to some of these conditions that have been associated with hypophosphatemia. Siddiqui and Bertorini (1998) cited research showing that phosphate depletion can produce neuropathy that mimics Guillain-Barre syndrome, and the authors described the symptoms of a patient who developed neurological symptoms after she had been given parenteral nutrition without phosphate. The manifestations of neuropathy were suggestive of demyelinating polyneuropathy but were rapidly reversed by phosphate supplementation, meaning that there wasn't demyelination. The authors also discussed the fact that an increase in hexokinase activity, in response to insulin that has been released after the intake of carbohydrates, is thought to be an important factor that mediates the carbohydrate-induced increase in the transport of phosphate into cells and the decrease in serum phosphate that can result from that transport (Siddiqui and Bertorini, 1998). The authors also cited research showing cognitive dysfunction and encephalopathy in hypophosphatemic or (merely) intracellular-phosphate-depleted people (Siddiqui and Bertorini, 1998). One interpretation of the article by Steckman et al. (2006), in which gallstone-induced pancreatitis occurred in conjunction with hypophosphatemia and improved in response to phosphate administration, is that the phosphate depletion was causing neuropathy and interfering with gallbladder contractions. Neuropathy is known to be associated with gallbladder disease, and the normal functioning and contraction of the gallbladder is regulated by its autonomic (and sensory) innervation [(http://scholar.google.com/scholar?q=neuropathy+gallbladder+gallstone&hl=en);
the visceral sensory innervation can influence mast cell degranulation in the gallbladder, via the efferent-action-potential-mediated release of neuropeptides, and changes in mast cell degranulation and neuropeptide release can influence the autonomic regulation of gallbladder functioning, etc.: (http://scholar.google.com/scholar?hl=en&q=%22mast+cell%22+gallbladder+CGRP+OR+%22substance+P%22+OR+%22vasoactive+intestinal+peptide%22)]. Another interpretation would be to say that the phosphate depletion caused ATP depletion in the liver and led to cholestasis, etc. Similarly, the respiratory muscle weakness found in association with hypophosphatemia or low serum phosphate levels (Gravelyn et al., 1988, cited above) could be a result of autonomic dysfunction, particularly given that hypophosphatemia can cause reversible quadriparesis (paralysis, meaning the people are transiently quadripalegics) (http://scholar.google.com/scholar?hl=en&q=quadriparesis+hypophosphatemia). The hypoventilation that can accompany hypophosphatemia could also be due to autonomic neuropathy and ATP depletion in parts of the brain (http://scholar.google.com/scholar?hl=en&q=hypoventilation+hypophosphatemia). Hypophosphatemia has also shown up in association with extrapontine myelinolysis (which is central "pontine" myelinolysis that doesn't occur in the pons, essentially), one of the forms of osmotic demyelination that can result from the excessively-rapid correction of hyponatremia with intravenous, hypertonic saline [Qadir et al., 2005: (http://www.jpma.org.pk//PdfDownload/759.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/16045098)]. The authors suggested that ATP depletion in glial cells in parts of the brain might have contributed to the case, but I'm not sure that the authors actually said that the phosphate might have contributed to or caused the ATP depletion. The intracellular phosphate may well have been depleted in parts of the brain, and that depletion may have impaired volume regulation and predisposed to the osmotic demyelination.
In any case, I found this article showing "sinusoidal" seasonal changes in the incidence of sudden infant death syndrome (SIDS) (the seasonal change in the incidence shows up in the Southern and Northern hemispheres, and SIDS was found to peak in the winter in both hemispheres) [Douglas et al., 1996: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2351134)(http://www.ncbi.nlm.nih.gov/pubmed/8646093)], and there's old research suggesting an association of SIDS with vitamin D depletion or differences in vitamin D metabolism or rickets, etc. [Schluter, 1996: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2352183&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/8842097); (http://scholar.google.com/scholar?hl=en&q=%22sudden+infant+death%22+%22vitamin+D%22)] (or with other light-associated changes, such as involving changes in melatonin levels induced by sleeping on the back as opposed to the side, etc.) (Douglas et al., 1996). There's also research showing that infants who were experiencing apnea were more likely to be hypercalcemic than infants not experiencing apnea [Kooh and Binet, 1990: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1452283&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2207905)]. I couldn't get results to show up on a quick search, but hypercalcemia has been found to occur in hypophosphatemic people. Although Kooh and Binet (1990) didn't find that serum phosphate levels were associated with apnea in any way, the serum Pi levels wouldn't have to. Given that intracellular Pi levels do not reliably correlate with serum Pi levels and that phosphate depletion is known to be capable of causing respiratory paralysis/hypoventilation and hypoxia and neuropathy [see this and many others, some of which I discussed above: Weber et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10663486)] [and given that vitamin D depletion is known to be a cause of phosphate depletion (and that vitamin D supplementation, even in the absence of any genetic defect specifically involving vitamin D receptor signalling)], one possibility is that intracellular phosphate depletion in parts of the brain (and in the red blood cells, causing low-level hypoxia that might gradually have more severe consequences) could contribute to some cases of SIDS. Although there was one small study showing no apparent depletion of 25-hydroxyvitamin D levels in the context of SIDS, there could very easily be different degrees of intracellular phosphate depletion among infants with the same 25(OH)D levels. And looking at the serum phosphate levels wouldn't necessarily show anything, given the lack of correlation of intracellular and serum Pi levels. Someone would have to use MRS scans or look at the intracellular 2,3-DPG or Pi levels in red blood cells in infants, instead of just looking at the serum Pi. It's interesting that Heames and Cope (2006) (cited above) found that they could reduce the rate of infusion of noradrenaline in a manner that was proportional to the increase in serum phosphate, in a person who had developed transient heart failure from postsurgical phosphate depletion. The phosphate depletion basically caused hypotension, and the interactions with noradrenaline are really interesting (the usual thing people discuss is the fact that adrenergic drugs decrease serum phosphate by promoting phosphate uptake into cells). Given the changes in the autonomic regulation of blood pressure that occur in response to changes in the orientation of the body, such as in a baby sleeping prone vs. supine (http://scholar.google.com/scholar?q=autonomic+orthostatic+prone+supine&hl=en), it's possible that there's a kind of feed-forward depletion of intracellular phosphate in parts of the brain that can lead to apnea and then increased ventilation to compensate (and then phosphate depletion because of that and because of the noradrenaline released in response to that, as in the stress response to hypoxia, and to the potential vitamin D-depletion-induced renal phosphate wasting, etc.).
Arguably, the most well-established cause of hypophosphatemia is alkalosis induced by hyperventilation (http://scholar.google.com/scholar?q=hyperventilation+alkalosis+hypophosphatemia&hl=en), and apnea commonly occurs in response to post-hyperventilation alkalosis (http://scholar.google.com/scholar?q=hyperventilation+apnea&hl=en). So the alkalosis, in response to hyperventilation (as in response to autonomic dysfunction during sleep, resulting from changes in the sleep position and from phosphate depletion in neurons or smooth muscle cells or muscle cells in the diaphragm), could drive phosphate into cells outside the brain, thereby reducing phosphate availability to the brain, and then that could gradually set the stage for more severe episodes of hypoxia, more autonomic dysfunction due to the phosphate depletion in the brain, etc. There's evidence of repeated episodes of hypoxia in some research on SIDS [see Takashima et al. (1978) and Rognum et al. (1991): (http://scholar.google.com/scholar?hl=en&q=%22sudden+infant+death%22+hypoxia)]. A decrease in the responsiveness of smooth muscle cells (or other cell types, as in neurons in the brainstem, in the context of phosphate depletion) to noradrenaline occurs in people who have orthostatic hypotension and other derangements of baroreceptor functioning, and L-threo-3,4-dihydroxyphenylserine (DOPS) has been researched as a treatment for orthostatic hypotension and orthostatic tachycardia (DOPS is a precursor of noradrenaline) (http://scholar.google.com/scholar?hl=en&q=orthostatic+DOPS). Hypophosphatemia has been associated with instability in blood pressure, in association with postural hypotension and other problems with the sensitivity and functioning of the baroreceptor reflexes (http://scholar.google.com/scholar?hl=en&q=orthostatic+hypophosphatemia). Anyway, I just put those types of crude thoughts up on this blog.
No comments:
Post a Comment