Application of Branched-Chain Amino Acids in Human Pathological States: Discussion of Session 4 ,

Dr. Fernstrom started the discussion by asking Dr. Charlton, with regard to the Marchesini study he discussed, if this new study included measures beyond the simple outcome measures followed in the earlier study? If so, did the new measures provide some indication of the underlying biochemical or metabolic actions of the BCAA that might begin to explain some of the positive results? Dr. Charlton responded that they had tracked the components of the Child-Pugh-Turcotte score, which included albumin, bilirubin, and prothrombin time. These variables improved, and probably reflected increased liver hepatocyte mass, which was most likely the primary basis for the observed improvement. He added that after liver, muscle is the most important ammonia-producing organ and that at present an effect on muscle could not be excluded. Dr. Fernstrom then asked if the current view regarding the development of encephalopathy is that ammonia buildup is more important than elevated tryptophan uptake into brain. Dr. Charlton commented that he thought ammonia is important, though clearly not the whole story. Other transmitters, such as endogenous benzodiazepines and glutamate, appear to play a role; the etiology of encephalopathy is a multifactorial process. Nevertheless, fluctuations in ammonia are reasonably predictive, and thus useful. A question was then raised to Dr. Layman if, in his studies, all the symptoms of the metabolic syndrome could be reversed by the consumption of the high-protein diet. For example, what were the effects on high-density lipoproteins and triglycerides? Dr. Layman responded that all symptoms were reversed. He noted that when he compared the higher protein-lower carbohydrate and the lower protein–higher carbohydrate diets, the former produced a 25–30% drop in triglycerides compared with the latter diet, and always produced a small increase in the high-density lipoproteins. The higher carbohydrate–lower protein diet always reduced high-density lipoproteins; this diet also produced a slight reduction in the LDL/total cholesterol ratio, compared with the higher protein–lower carbohydrate diet, but the effect was transient. He added that his group had recently completed a 16-mo study with 130 subjects, and found that by 12 mo, the 2 diets produce about the same effects on total cholesterol and LDL, along with parallel weight loss. But, the positive effects of the high-protein diet on serum triglycerides and HDL were still present. On consideration of the question as to whether the effects of the higher protein diet were related to branched-chain amino acids, he thought that probably they were not. Dr. Baracos then asked the session speakers, in relation to their study populations, to identify the single feature of a patient most predictive of a positive outcome to branched-chain amino acid supplementation. The responses were 1) a preexisting low protein intake or poor nutritional status; 2) the degree of emaciation, or the biggest reduction in body mass; 3) poor tolerance to standard dietary proteins. Dr. Cynober noted that most trauma patients had high muscle levels of the branched-chain amino acids. He thus wondered what the rationale might be for expecting a positive response to further elevations of plasma branched-chain amino acid levels in such subjects in response to amino acid supplements. Dr. Rennie responded that he did not think this issue had been carefully examined, a position with which Dr. De Bandt agreed. Another participant suggested that perhaps supplemental amino acids had a sparing effect on endogenous amino acid and protein pools, for example, by providing an alternative source of the amino acids needed for the proliferative response to an immune challenge. Dr. Volpi shifted focus to another topic, asking about the leucine effect on muscle protein synthesis after 8 h of leucine infusion. She noted that Dr. Rennie had shown data indicating that the infusion of a mixture of amino acids induced muscle protein synthesis for 2–3 h, after which, despite continued infusion, protein synthesis returned to baseline. She therefore wondered if measuring protein synthesis only at 8 h, and observing no treatment effect, would allow one to conclude that none had occurred at an earlier timepoint. Dr. Nair added that the effects in muscle of administering insulin and amino acids on transcriptional and translation events, and probably for particular transcripts and proteins as well, are likely to have unique time profiles. He noted that at present, relatively little 1 Published in a supplement to The Journal of Nutrition. Presented at the conference ‘‘Symposium on Branched-Chain Amino Acids,’’ held May 23–24, 2005 in Versailles, France. The conference was sponsored by Ajinomoto USA, Inc. The organizing committee for the symposium and guest editors for the supplement were Luc Cynober, Robert A. Harris, Dennis M. Bier, John O. Holloszy, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest editor disclosure: L. Cynober, R. A. Harris, D. M. Bier, J. O. Holloszy, S. M. Morris, Y. Shimomura: expenses for travel to BCAA meeting paid by Ajinomoto USA; D. M. Bier: consults for Ajinomoto USA; S. M. Morris: received compensation from Ajinomoto USA for organizing BCAA conference. 2 Author Disclosure: No relationships to disclose. 3 To whom correspondence should be addressed. fernstromjd@upmc.edu.