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,3
* 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.
Hebuterne: Now it is the time for our general discussion. We will discuss the amino acid requirements in pathologic states. To introduce this debate I would like to tell you that for a clinician it is really a very important problem. As Peter Fürst said in the first lecture, there are very few data on amino acid requirements in wasting diseases and many other pathologic states.
Why there are very few data is probably because the issue is very complicated. Many factors can influence amino acid requirements during different diseases. First of all, anorexia is worth noting. It is really a major factor and we know that >60–70% of patients hospitalized for >1 wk have low-protein intakes in terms of energy.
The second factor to consider is immobility. The importance of physical activity in branched-chain amino acid (BCAA) metabolism has been nicely demonstrated. Therefore, immobility has a very quick impact on amino acid metabolism during various pathological states.
The third factor is inflammation. It is important to consider amino acid requirements separately in chronic disease and inflammation, especially when considering the requirements of a patient with inflammatory bowel disease or chronic rheumatic disease.
Age is probably another important factor, because many hospitalized patients are aged. Absorption rate is another factor because in many diseases, patients have malabsorption or malutilization of nutrients. We also have to consider the route of administration. Another point probably is organ failure. Probably one of the most important problems to consider is the amino acid needs of the cirrhotic patient with liver failure.
And finally, I think we have also to consider the effect of the treatment on metabolism, including chronic treatment with steroids or immunosuppressive drugs. As you can see many factors influence amino acid requirements during disease.
Young: I would like to make a few comments. The purpose of this session was not only to review the approaches to amino acid assessment adequacy and the physiological or pathophysiological factors that affect requirements, but also on the basis of those considerations, the extent to which those factors may influence the upper safe range of amino acid intake.
What had we in mind when we were putting this workshop together? What is the effect of developmental state? What is the effect of progressive adult age? What is the effect of dietary energy? And, what is the effect of energy source?
Let me ask Paul Pencharz because he was asked to address the issue of amino acid requirements for early growth and development. Let's go to your nice work on BCAA requirements in which you have compared the young and the adult. They were not very different. Are the responses to high intakes of branched-chain amino acids different—more sensitive, less sensitive, equal in the young versus the adult?
Pencharz: Vernon (Young), those are very good questions and the truth of the matter is we have not studied it yet. It was only the group with liver disease that we were able to show actually had higher requirements. We have not gone toward the upper limit at all. Our only study that really looked at upper limits was the piglet study with phenylalanine. An additional issue is the ability of neonates being fed formulas to handle excess amino acids given as intact proteins; for example casein dominant protein giving more phenylalanine and tyrosine and whey dominant protein giving more threonine. So the upper limits are remarkably understudied, and that really is a problem. There is a glaring lack of data at the moment.
Young: Another issue that we're interested in in terms of the road map that we are developing is what amino acids should we really focus our attentions on, with respect to generating more extensive data that relate to an understanding of the consequences of high intakes. Can I ask Naomi Fukagawa? You gave a very nice talk, Naomi, on the sulfur amino acid side of the amino acid world. Are the sulfur amino acids the amino acids that we should be concerned with, when we are concerned particularly with the progression through adult years?
Secondly, your presentation raised in my mind a question: Are we really concerned with acute intakes or the consequences of chronic intakes? How do you think we distinguish and develop the paradigms to look at these different situations?
Fukagawa: As you may guess from my presentation, I do think that sulfur amino acids (SAA) are extremely important, not necessarily because of their role as precursors in protein synthesis and products of breakdown, but more because of the other pathways that they feed into, and the fact that they are extremely important in redox signaling within cells. Therefore, acute or chronic intakes may not necessarily be problematic, although we were always taught that excess SAAs create problems. Perhaps with advancing age, or with certain diseases, SAA requirements, or intake, could potentially be higher. Our bodies can achieve balance because of the various metabolic pathways utilizing or catabolizing SAA. The utilization of these single amino acids as signal transducers would help the cell modulate growth, apoptosis, etc. There is also a role in the post-translational modification of specific proteins. Unfortunately, Dr. Kimura is not here, but much of the work that he has done with respect to cystine, for example, is very reminiscent of results I obtained with high glucose and its effects on injury of mitochondrial DNA in the specific loci he mentioned. I have come to the conclusion that much of the injury was the result of oxidative stress. Perhaps some of that injury is the result of cystine, itself, not capable of being released and thereby creating a further imbalance of the redox state and antioxidant availability. Therefore, this might have led to the injury that he saw in pulmonary as well as cardiac systems. Acute intake of excess SAA may influence the regulation of amino acid metabolism and signaling pathways. However, it is important to remember that other amino acids are key to SAA metabolism (e.g., serine and glycine) and cofactors such as vitamins B-6 and B-12 and folate also influence the outcome. Medullary metabolism of SAA and serine as discussed by Dr. Fürst is of great interest and in need of further study.
Young: Various categories of amino acids have been proposed. Among them, serine was named in the totally dispensable group, and glycine in the conditionally indispensable group. You mentioned our friend Alan Jackson's hypotheses, studies, and so on. If serine is totally dispensable, and is a source of glycine, why should glycine be categorized as conditionally indispensable?
Fürst: Actually, I was not mentioning glycine. I do not believe that glycine is an indispensable amino acid, although it is very important, as is any other amino acid. It is presumably a limiting amino acid for glutathione synthesis. This function is probably the only factor concerning its indispensability. There are some theories in the literature claiming that glycine is indispensable because of its specific protecting effects against ischemia and also due to cytoprotection affecting calcium and chloride channels. Nevertheless, looking at available data, appropriate controls are always lacking. Indeed, the great enthusiasm about these hypotheses related to the channels is currently slowly disappearing. I believe that during the in vivo condition, there are no situations in which glycine might be deficient. Therapeutically, we have no difficulties in providing a sufficient amount of glycine in the routine clinical setting.
Millward: Can I just comment on that? I think it is a very important question; it has always puzzled me, but I think the rat data on the importance of glycine in pregnancy is very powerful. We know that the effect of a low-protein diet fed to the mother results in offspring, which are small and become hypertensive. This is the animal model for the Barker hypothesis. Alan Jackson has shown that glycine alone, given with a low-protein diet, will relieve all of those symptoms. And there is evidence that one of the possible mechanisms, which relates to closure of the neural cleft, where a N-methyl-D-aspartate (NMDA) receptor is involved, may well have a glycine component. Thus, I think there is emerging literature on normal and abnormal fetal development where there seems to be a specific role for glycine. If glycine is never limiting, then it is difficult to see how such a role could be played.
Pencharz: Just to add to what Joe was saying, Alan's studies were with 15N-glycine, and he found that the tracer in 15N-urea disappeared from the urine. These studies were in human milk–fed neonates and were interpreted as evidence that glycine was so limiting for protein synthesis that none of the label was being released for urea synthesis.
Tontisirin: There has been no mention about the study of the tryptophan requirement. Can the study of the tryptophan requirement be considered as a model to study requirements from infancy to the aged? Why are there currently only a few studies on tryptophan? Is it viewed to be technically too difficult to study, in particular the safe range of intakes of tryptophan including lower and upper levels of intakes.
Young: Well, maybe we ought to pass the microphone to Paul Pencharz, who, other than you, Kraisid (Tontisirin), probably is the only one who has studied tryptophan requirements of people, both adults and infants.
Pencharz: We actually determined tryptophan requirements in women using indicator amino acid oxidation, and the results are surprisingly similar to those determined by nitrogen balance. We have other work that at the moment is accepted by Pediatric Research, in which we studied the enteral and parenteral requirement of tryptophan in piglets. Interestingly, the gut appears to play a very small role in tryptophan metabolism; the tryptophan requirement estimates are identical, whether the piglets were fed enterally or parenterally.
Millward: In relation to the question of potential problems of high intakes, in the context of developmental changes in requirements, that I have discussed, if you ask the question, "What age group is exposed to the largest amount of intake in relation to their requirements?" Then you could identify the weaning period. This is because the weaning period is the transition from a diet, which is really very low in protein, to a diet that reflects the diet of the adult population. The adult diet is suited for individuals with generally low energy levels so that a high protein density is needed.
Now, at the point of weaning, children actually do go through a transition where their protein intake often more than doubles, it may well even triple. And at that time, their energy level is still very high, so they will be consuming a lot of it. If you think about their livers and the experience of their livers in terms of responding to dietary amino acid intake then it is probably the age group that gets the biggest challenge in intake compared with any other period of life. I wonder whether we should think about that age group as a group where the problems associated with high intakes might be most apparent.
Bier: I would just like to follow up on the consideration of the weaning period. I think the first issue about the magnitude of the protein intake depends upon whether the child is getting human milk or formula, because the marginality or not of that intake is going to heavily depend on the source of the protein. And secondly, at least during some part of the weaning period, those protein foods are replaced by nonprotein foods, fruits, vegetables, and cereals. And there is a period of time when intake goes down.
Young: Well, I think Joe Millward has a nice point. I think it is one that is worth looking into in further detail. Now there are good protein-intake data, and there are reasonable protein-requirement data for this entire developmental period, so we ought to see whether or not your point is actually correct. It has some significance, that is for sure.
Mr. Chairman, maybe there are many additional questions.
Hebuterne: Yes, I want to ask the audience: What do you think about the problem of amino acid requirements in sarcopenia? Sarcopenia is mainly related to decreased physical activity. But perhaps there is also some issue in amino acid requirements in the elderly and hospitalized people. Do you think there is a specific amino acid requirement in the elderly to prevent the progressive decrease of muscle mass with age?
Millward: My understanding of the literature is that it is still an open question. Bill Evans has published very nice data that the elderly exposed to resistance exercise are able to gain strength, and replete muscle mass, on an intake of only 0.8 g/kg/d, which is lower than their usual intake. In other words, if you take elderly people and you give them a protein intake that is less than their usual intake, but equal to the supposed safe allowance at the moment, they are able to gain strength and replete muscle mass on that intake. I think the studies that have looked at simple measures of muscle mass are equivocal about whether or not you can get a better repletion of wasted muscle with higher intake. Whereas the studies that have looked at protein synthesis, per se, rather than repletion of muscle mass generally point to extra benefit of higher protein intakes. I think it is still an open question.
Young: Well, the organizers think this bell means we are about out of time. We will entertain one more question.
Shimomura: The amount of protein intake is important, but the timing of the protein intake is also very important. One article suggests that protein ingestion just after exercise promotes exercise-induced increase in muscle mass and muscle strength compared to protein ingestion 2 h after exercise. Maybe, it is important to think about the timing of protein intake or amino acid intake, too.
Hebuterne: I would like to thank all the speakers and all the participants. Thank you very much.
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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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