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* Nutrition Department, Pharmacy School, Paris 5 University and Biochem Lab, Hotel-Dieu Hospital, Paris, France and Laboratory of Human Nutrition, Massachusetts Institute of Technology, Cambridge, MA 02139
2 To whom correspondence should be addressed. E-mail: luc.cynober{at}htd.ap-hop-paris.fr.
Cynober: This discussion section deals primarily with this question: which model for which amino acid? To start the discussion, I would like to ask a question to Vicky Baracos. In the figure you showed us about the extraction of amino acids by portal-drain viscera, I noticed that there was no consumption of arginine and no production of citrulline in your piglet model. What is the reason for this? Is it related to enzyme immaturity? Based on Bachier and co-workers' studies, it seems that there is an adaptation with age for amino acids related to proline; this means that this model should be, with regard to this type of amino acid (arginine, proline, glutamate, and so on), nice for the study of amino acid supplementation in infants, but inadequate for adults.
Baracos: Well, that's all it is. It is a model and it is a model of infants, having no particular relevance to adults. You would have to ask the question in "something" that looked like an adult. This is the species-specific stuff, and the developmental stage stuff that you are stuck with. I just find it a compelling data set, because it says a whole lot about the biology of the gut, but how that plays out in different species and developmental stages, we do not yet know.
Millward: We had some outstanding questions for Peter Garlick. One was from Peter Soeters, and I wondered if you would like to deal with that now?
Soeters: I think the message of Peter Garlick was that you can get away with a lot of different intakes of amino acids. But I think there are risk groups that should be considered. Glutamine, for instance, was suggested in anecdotal studies to raise plasma ammonia and to cause hepatic encephalopathy in liver patients. There are also reports, and I think we have seen it in our own patients, that glutamine-enriched formulas in home-parenteral nutrition patients can cause rises in their liver enzymes, reflecting hepatocyte damage. These patients often already have compromised liver function. They often have steatotic livers, or even livers with steato-hepatitis evolving into cirrhosis. So there may be risk factors, or risk populations, where intravenous supplementation of glutamine may cause complications. Maybe this is not the case with oral glutamine supplementation, because there were trials on glutamine oral supplementation in patients with short bowel, which did not report these problems.
Garlick: The raised liver enzymes was something that I did not have time to mention. One of the glutamine studies that was done on healthy volunteers with total parenteral nutrition (TNP) supplemented with glutamine, showed three patients, I think it was, out of 30 who had somewhat raised liver enzymes at the end of the study. The authors did not comment on them further, and said that they resolved the problem quickly. I did not mention it, basically, because I had not seen it in any of the other literature. And I thought, therefore, it must have been something to do with giving them TPN, rather than specifically glutamine. But perhaps you have better information on that.
Soeters: Now this problem is resolved when glutamine treatment was discontinued. We observed it in our TPN patients, but the cause is very difficult to ascribe to one factor, e.g., glutamine supplementation.
Fürst: Another study in which increased liver enzyme concentrations were reported has been published from New York from M. Brennan's group. This study indicates that patients who already suffer from impaired liver function are at risk to receive glutamine [Hornsby-Lewis, L., Shike, M., Brown, P., Klang, M., Pearlstone, D., & Brennan, M. F. (1994) L-glutamine supplementation in home total parenteral nutrition patients: stability, safety, and effects on intestinal absorption. JPEN 18: 268–273]. I think this should be considered. But, I would like to mention another risk group of critically ill patients, like multiorgan failure, sepsis, or systemic inflammatory response syndrome (SIRS) who might be at risk to receive arginine in high doses. Recently, there are data showing immediate risk with immuno-nutrition; thus, one should be careful with this patient population. There are a number of controversial meta-analyses but I would rather look at the separate studies. For instance a current consensus published in Clinical Nutrition shows that out of 18 patients who received immuno-modulating diets with high arginine content, 8 showed increased mortality [Montejo, J. C. et al. (2003) Immunonutrition in the intensive care unit. A systematic review and consensus statement. Clin Nutr 22: 221–233]. Actually, in the most current analyses high-quality studies were distinguished from those of low-quality ones showing increased mortality and morbidity with immuno-modulating diets [Heyland, D. K. (2002) Immunonutrition in the critically ill patient: putting the cart before the horse? Nutr. Clin. Pract. 17: 267–272; Heyland, D. K. & Samis, A. (2003) Does immunonutrition in septic patient do more harm than good? Int. Care Med. 29: 669–671]. Accordingly, the Canadian Clinical Practice Guidelines for Nutrition Support in Mechanically Ventilated, Critically Ill Patients do not recommend arginine supplementation for critically ill patients [Heyland, D. K. et al (2003) JPEN 27:355–73]. In addition, we now have direct experimental data from my former laboratory that arginine is probably the "bad guy" in immuno-diets. It could be shown in a burn model that arginine supplementation together with the produced nitric oxide caused nitrosylation of the aromatic amino acids in the endothelial membrane thereby inducing an impairment of the endothelial barrier function [Frank, J., Pompella, A. & Biesalski, H. K. (2000) Histochemical visualization of oxidant stress. Free Radic. Biol. Med. 29: 1096–1105]. In a clinical context this reaction might be associated with shock.
Millward: Can I just make a final comment on that, before we go back to models, under the instruction of my co-chairman? I thought with arginine, we had one mechanistic approach, in terms of potential problems in the gut, in relation to nitric oxide production. If we have a patient group in which inhibitors of nitric oxide production improve the condition of those patients, then that is a group where arginine supplementation is likely to be deleterious. Whereas, if inhibitors of nitric oxide production worsen the condition of the patients, then one finds that arginine is likely to be effective.
Fürst: In other words, you would like to use nitric oxide as a biomarker. We know that burn patients produce a considerable amount of nitric oxide. However, the literature is very confusing concerning other diseases. I think Peter Soeters' group was investigating septic patients without significant increase.
Soeters: Yes. Nitric oxide (NO) production in septic patients is identical to production in less ill patients in intensive care. That is what I demonstrated yesterday. And appearance of arginine in those two groups was similar. But that is NO production at the whole-body level, which is a gross simplification of the situation. If you really want to study this well, you should go for the different synthetases, and go at the organ level. It will take some time before we can do that.
Pencharz: I thought I would share some data that we had on giving glutamine intravenously, because the name of this session is "Risk Assessment of Amino Acid Intake." We published a study in neonatal piglets, in which the first author is Jim House, a few years ago in The Journal of Nutrition. Our purpose was to define whether glutamine is a dietary, conditionally indispensable amino acid, in an intravenously fed piglet. We matched the treatment and control group, for nitrogen intake. Stepwise increases of glutamine made no difference; there was no improvement in nitrogen balance. A lot of literature reports that glutamine improves nitrogen balance, however, in our view this is because they do not have a proper (nitrogen) control group. To our surprise, we actually saw a marked increase in body weight in the piglets. When we examined their body composition, we found that extracellular fluid volume was greatly expanded. In terms of being toxic, parenteral glutamine significantly expands extracellular fluid volume, and does this pose a health risk to a parenterally fed subject?
Baker: I just wanted to make the point that there is a significant population group that could be studied, with regard to lysine. If you talk to pharmacists and proprietors of health food stores, they will tell you there is a certain group of people that come in routinely and buy lysine pills. The reason these people are buying lysine is because they have chronic problems with cold sores. If one could locate that population, I believe they would say they are generally taking 800–1600 mg/d of lysine for prevention of cold sores. But some may be taking a lot more. If you could locate this population and ask them their experience in terms of any adverse effects, etc., it seems to me that would be valuable.
Fernstrom: Peter Garlick nicely summarized a large body of information, but did not convey what I suspect was the pain associated with collecting that information. Having looked at one or two amino acids in the past, the variability and quality of published data are enormous. So, one message you don't see is just how bad the existing databases are. This means that one cannot use them with confidence for assessing adverse effects or toxicities. You might wish to make a comment about the quality of the database for any given amino acid.
Garlick: My conclusions, ultimately, were that there are no data for amino acids that would enable us to define an upper level, which would be of any use at all. There are some data for some amino acids in humans, but it is still no good. It is only good enough to say that there may be an effect from very high intakes. But to actually select a level that would be safe, there is nothing there at all. Perhaps there was a study where one showed that 5 g did not seem to really have any effect and 20 g had an effect, but the study was not good enough to select a dose we could have as an upper level. Even the animal studies do not help at all either, because they are not proper dose responses in almost all cases. So I think basically we are completely lacking in human data, and we are almost completely lacking in the necessary animal data, as well.
Cynober: I would like to comment about the lecture on biomarkers in cancer. Just to mention that amino acids, themselves, can be considered as biomarkers in cancer. There were studies by Michael Meguid's group and by Rossi Fanelli in Italy. And we also have an article in press in Cancer Investigation concerning this issue, which indicates that there is a specific profile of amino acids, which depends on the type of tumor. And it is very easy to demonstrate that they are tumor-related specific biomarkers because the tumor-related pattern disappears after resection of the tumor.
Young: Just on that point of amino acids, I want to go back to Dr. Endo's question of Peter Garlick. Is there an opportunity from the literature you surveyed, Peter, to relate the levels of intake of specific amino acids to plasma amino acid levels?
Garlick: In principle there ought to be, but I do not know in most cases that the studies were necessarily done or that the measurements were made. I am sure they were in some cases but not uniformly. But the problem is I am sure that after you take an amino acid supplement, the amino acid in the blood will rise quite considerably. But very soon it will come back to a more normal sort of level. So, you have to relate intake and blood sampling. I do not think you could take a spot sample of blood and expect to get an answer.
Millward: Can I make a comment on that? From the combination of the animal data that we have seen and the review of the human data, I get the impression that it is a difficult issue to generalize about. For those amino acids with a fairly high Km for their oxidative pathways, like threonine and lysine, we see very large postprandial increases, which do not seem to be associated with any problems. With other amino acids like leucine, we can consume large quantities without inducing particularly excessive plasma levels. We are able to deal with those very effectively because, presumably, if they were to increase to very high levels there would be severe problems. So we have developed catabolic pathways that are very good at dealing with those amino acids that are likely to cause the most problems, and pathways that are less effective for those where accumulations in the tissues, like threonine and lysine, do not seem to be associated with adverse responses. So, there is not even a mechanistic framework or paradigm within which you can predict whether you could have a general approach.
Endo: It is an interesting notion, but at present I am not able to give any comments on it. We need to review the possible relationships among the toxicity, the normal variations of blood levels, and metabolic capacities. Thank you.
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FOOTNOTES |
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3 The 3rd Amino Acid Assessment Workshop is dedicated to Vernon R. Young who recently passed away.
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