Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives
2003; Elsevier BV; Volume: 124; Issue: 7 Linguagem: Inglês
10.1016/s0016-5085(03)00550-x
ISSN1528-0012
Autores Tópico(s)Liver Disease Diagnosis and Treatment
ResumoFor decades, we have been fed a tantalizing yet unfulfilling diet of small studies on the impact of various formulations and methods of branched-chain amino acid (BCAA) support in chronic liver disease, with equivocal outcomes. An early demonstration of a scientific rationale for BCAA supplementation, an increased molar ratio of BCAAs to aromatic amino acids, in association with an observed clinical benefit,1Ferenci P. Funovics J. Wewalka F. Therapy of hepatic encephalopathy. Modification of the plasma aminogram using amino acid infusions [in German].Chir Forum Exp Klin Forsch. 1978; : 183-189PubMed Google Scholar has been followed by many attempts to define the role of BCAA supplementation in the management of liver disease. The ease with which a beneficial effect of BCAA supplementation has been shown in rats2Kajiwara K. Okuno M. Kobayashi T. Honma N. Maki T. Kato M. Ohnishi H. Muto Y. Moriwaki H. Oral supplementation with branched-chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis.Dig Dis Sci. 1998; 43: 1572-1579Crossref PubMed Scopus (44) Google Scholar, 3Ohashi H. Sukegawa E. Takami T. Yoshida T. Muto Y. Effects of supplementation with branched-chain amino acids on protein-nutritional status in rats treated by carbon tetrachloride [in Japanese].Nippon Shokakibyo Gakkai Zasshi. 1989; 86: 1645-1653PubMed Google Scholar generated optimism that we would see a clear clinical benefit in humans, if only we could design the right study. There have been multiple reports of beneficial effects of BCAA supplementation, including improved metabolic profiles, as measured by protein sparing and/or normalization of respiratory quotients4Nakaya Y. Harada N. Kakui S. Okada K. Takahashi A. Inoi J. Ito S. Severe catabolic state after prolonged fasting in cirrhotic patients effect of oral branched-chain amino-acid-enriched nutrient mixture.J Gastroenterol. 2002; 37: 531-536Crossref PubMed Scopus (59) Google Scholar, 5Watanabe A. Wakabayashi H. Kuwabara Y. Nutrient-induced thermogenesis and protein-sparing effect by rapid infusion of a branched chain-enriched amino acid solution to cirrhotic patients.J Med. 1996; 27: 176-182PubMed Google Scholar, 6Vilstrup H. Gluud C. Hardt F. Kristensen M. Kohler O. Melgaard B. Dejgaard A. Hansen B.A. Krintel J.J. Schutten H.J. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis.J Hepatol. 1990; 10: 291-296Abstract Full Text PDF PubMed Scopus (44) Google Scholar, 7Watanabe A. Shiota T. Okita M. Nagashima H. Effect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis.Acta Medica Okayama. 1983; 37: 321-333PubMed Google Scholar and clinical improvement of hepatic encephalopathy.7Watanabe A. Shiota T. Okita M. Nagashima H. Effect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis.Acta Medica Okayama. 1983; 37: 321-333PubMed Google Scholar, 8Plauth M. Egberts E.H. Hamster W. Torok M. Muller P.H. Brand O. Furst P. Dolle W. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids A double-blind placebo-controlled crossover study.J Hepatol. 1993; 17: 308-314Abstract Full Text PDF PubMed Scopus (106) Google Scholar, 9Bianchi G.P. Marchesini G. Zoli M. Abbiati R. Ferrario E. Fabbri A. Pisi E. Oral BCAA supplementation in cirrhosis with chronic encephalopathy effects on prolactin and estradiol levels.Hepatogastroenterology. 1992; 39: 443-446PubMed Google Scholar, 10Marchesini G. Dioguardi F.S. Bianchi G.P. Zoli M. Bellati G. Roffi L. Martines D. Abbiati R. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group J Hepatol. 1990; 11: 92-101Google Scholar, 11Egberts E.H. Schomerus H. Hamster W. Jurgens P. Branched chain amino acids in the treatment of latent portosystemic encephalopathy A double-blind placebo-controlled crossover study.Gastroenterology. 1985; 88: 887-895PubMed Scopus (131) Google Scholar, 12Cerra F.B. McMillen M. Angelico R. Cline B. Lyons J. Faulkenbach L. Paysinger J. Cirrhosis, encephalopathy, and improved results with metabolic support.Surgery. 1983; 94: 612-619PubMed Google Scholar Other studies have failed to show a clinical benefit of BCAA supplementation.6Vilstrup H. Gluud C. Hardt F. Kristensen M. Kohler O. Melgaard B. Dejgaard A. Hansen B.A. Krintel J.J. Schutten H.J. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis.J Hepatol. 1990; 10: 291-296Abstract Full Text PDF PubMed Scopus (44) Google Scholar, 13Sieg A. Walker S. Czygan P. Gartner U. Lanzinger-Rossnagel G. Stiehl A. Kommerell B. Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver A double blind crossover trial.Z Gastroenterol. 1983; 21: 644-650PubMed Google Scholar, 14McGhee A. Henderson J.M. Millikan Jr, W.J. Bleier J.C. Vogel R. Kassouny M. Rudman D. Comparison of the effects of hepatic-aid and a casein modular diet on encephalopathy, plasma amino acids, and nitrogen balance in cirrhotic patients.Ann Surg. 1983; 197: 288-293Crossref PubMed Scopus (85) Google Scholar, 15Michel H. Bories P. Aubin J.P. Pomier-Layrargues G. Bauret P. Bellet-Herman H. Treatment of acute hepatic encephalopathy in cirrhotics with a branched-chain amino acids enriched versus a conventional amino acids mixture A controlled study of 70 patients.Liver. 1985; 5: 282-289Crossref PubMed Scopus (61) Google Scholar Fabbri et al.16Fabbri A. Magrini N. Bianchi G. Zoli M. Marchesini G. Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy.J Parenter Enteral Nutr. 1996; 20: 159-164Crossref PubMed Scopus (67) Google Scholar bravely tried to bring clarity to the role of BCAA supplementation in the treatment of chronic hepatic encephalopathy through a meta-analysis of the randomized controlled trials published in the field. Unfortunately, authors of only 2 (of 9) studies submitted data for the meta-analysis. Fabbri et al.16Fabbri A. Magrini N. Bianchi G. Zoli M. Marchesini G. Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy.J Parenter Enteral Nutr. 1996; 20: 159-164Crossref PubMed Scopus (67) Google Scholar lamented, as had the authors of a meta-analysis of intravenous BCAA therapies of hepatic encephalopathy,17Naylor C.D. O'Rourke K. Detsky A.S. Baker J.P. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy A meta-analysis.Gastroenterology. 1989; 97: 1033-1042Abstract PubMed Google Scholar that large multicenter, long-term studies incorporating important clinical outcomes were needed. And now we have one. In this issue of Gastroenterology, Marchesini et al.18Marchesini G. Bianchi G. Merli M. Amodio P. Panella C. Loguerico C. Rossi Fanelli F. Abbiati R. Italian BCCA Study GroupNutritional supplementation with branched-chain amino acids in advanced cirrhosis A double-blind, randomized trial.Gastroenterology. 2003; 127: 1792-1801Abstract Full Text Full Text PDF Scopus (464) Google Scholar report the results of a large multicenter, randomized controlled trial comparing outcomes after 1-year of nutritional support with BCAA-enriched dietary supplements versus lactoalbumin (L-ALB) or maltodextrin (M-DXT) dietary supplementation. The principal finding was that the primary outcome (a composite of death, frequency of hospital admission, and duration of hospital stay) was significantly lower in the BCAA arm of the study than in the L-ALB arm (odds ratio, 0.51; 95% confidence interval, 0.19–0.96; P = 0.039). There was a trend for superiority of BCAA over M-DXT (P = 0.108). In terms of scale, duration, and design, this was, to draw from the global zeitgeist, the mother of all BCAA supplement studies. One hundred seventy-four patients were enrolled into 1 of 3 treatment arms at 15 centers. Data completeness was remarkable. Only 1 patient was lost to follow-up—a feat that will catch the eye of parole officers the world over. We ought to collectively stand up and applaud the authors for designing, conducting, and reporting such an epic undertaking. Before we whip out our drug-company-logo-embossed pens and start writing year-long prescriptions for BCAA supplements, however, we should more closely examine the results of this study and consider their implications. The first observation that emerges on closer inspection is that only 115 of 174 patients had regular follow-up to the end of the study. This had the important effect of reducing the power of the study. Perhaps because of this, in intention-to-treat analysis (a prerequisite for many Food and Drug Administration registration studies), the time course of events was not different among groups. A benefit of BCAA supplementation could only be seen when non-liver-related deaths were excluded from the analysis. Participants in the BCAA arm may have had lower mortality, but they were the focus of a similar number of funerals as were participants in the other 2 groups. The higher-than-expected number of participants withdrawing from the study was most commonly caused by noncompliance and/or side effects of therapy (principally withdrawal of consent because of poor palatability and intolerance of required water intake). As might be expected by anyone who has sampled BCAA supplements, this occurred 3 times more frequently in the BCAA arm (15%) than in the L-ALB and M-DXT arms (5% combined). Participants in the BCAA arm who withdrew may have surmised that, whether or not BCAA supplements had a life-prolonging effect, life was certainly going to feel longer. As the authors point out, a higher frequency of noncompliance and side effects in the BCAA group may have led to an ascertainment bias for event rates. Data concerning hospital admissions seem clearer: the mean admission rate was lower for participants receiving BCAAs (0.6 per year) than for participants receiving L-ALB (2.1 per year, P = 0.006) and M-DXT (1.9 per year, P = 0.003). Although no cost-effectiveness analysis was performed during this study, these results are likely to prompt one. Mean hospital stays were similar in all 3 groups. Unfortunately, no data are provided about the reasons for hospital admission. How might these benefits have been achieved? A good part of the rationale for administering BCAA supplements to patients with chronic liver disease is the efficacy of BCAA in decreasing ammonia/genesis and ameliorating protein calorie malnutrition. Altered amino acid metabolism is a hallmark of liver disease, characterized by low levels of circulating BCAA (leucine, isoleucine, and valine) and elevated levels of circulating aromatic amino acids (phenylalanine and tyrosine), tryptophan, and methionine. The authors included a rigorous analysis of portosystemic encephalopathy and nutritional status in their study. Surprisingly, no significant differences in encephalopathy test scores, including Reitan testing, were seen among treatment groups. Participants in the BCAA arm did, however, experience significant improvement in nutritional status, which decreased in the M-DXT and L-ALB groups. An improvement in nutritional status is likely to have contributed to the observed differences in hospitalization as severity of malnutrition has been shown to correlate with progression of cirrhosis and the development of complications.19Abad-Lacruz A. Cabre E. Gonzalez-Huix F. Fernandez-Banares F. Esteve M. Planas R. Llovet J.M. Quer J.C. Gassull M.A. Routine tests of renal function, alcoholism, and nutrition improve the prognostic accuracy of Child-Pugh score in nonbleeding advanced cirrhotics.Am J Gastroenterol. 1993; 88: 382-387PubMed Google Scholar, 20Chedid A. Mendenhall C.L. Gartside P. French S.W. Chen T. Rabin L. Prognostic factors in alcoholic liver disease. VA Cooperative Study Group. Am J Gastroenterol. 1991; 86: 210-216Google Scholar BCAAs have recently been shown to stimulate hepatic regeneration, perhaps further contributing to the benefits seen in the study by Marchesini at al.,18Marchesini G. Bianchi G. Merli M. Amodio P. Panella C. Loguerico C. Rossi Fanelli F. Abbiati R. Italian BCCA Study GroupNutritional supplementation with branched-chain amino acids in advanced cirrhosis A double-blind, randomized trial.Gastroenterology. 2003; 127: 1792-1801Abstract Full Text Full Text PDF Scopus (464) Google Scholar such as improved biochemical profiles and Child-Pugh scores.21Saito Y. Saito H. Nakamura M. Wakabayashi K. Takagi T. Ebinuma H. Ishii H. Effect of the molar ratio of branched-chain to aromatic amino acids on growth and albumin mRNA expression of human liver cancer cell lines in a serum-free medium.Nutr Cancer. 2001; 39: 126-131Crossref PubMed Scopus (14) Google Scholar So, how should we incorporate this landmark study into our practices? The previously published negative studies had left BCAA-based therapy in a moribund state. Both the American and the European Societies of Parenteral and Enteral Nutrition have recently recommended that BCAA be used only in the few patients with liver disease who are intolerant of standard protein intake. A failure of the study by Marchesini et al.18Marchesini G. Bianchi G. Merli M. Amodio P. Panella C. Loguerico C. Rossi Fanelli F. Abbiati R. Italian BCCA Study GroupNutritional supplementation with branched-chain amino acids in advanced cirrhosis A double-blind, randomized trial.Gastroenterology. 2003; 127: 1792-1801Abstract Full Text Full Text PDF Scopus (464) Google Scholar to show a benefit of BCAA supplementation would certainly have dealt a mortal blow to this treatment concept. The results of the study by Marchesini et al.18Marchesini G. Bianchi G. Merli M. Amodio P. Panella C. Loguerico C. Rossi Fanelli F. Abbiati R. Italian BCCA Study GroupNutritional supplementation with branched-chain amino acids in advanced cirrhosis A double-blind, randomized trial.Gastroenterology. 2003; 127: 1792-1801Abstract Full Text Full Text PDF Scopus (464) Google Scholar do not, however, provide a compelling reason to expand current recommendations for BCAA use. There are other means to ameliorate muscle wasting and negative nitrogen balance in patients with cirrhosis. A late-evening meal has been shown to have a positive effect on nitrogen balance in patients with cirrhosis when compared with equicaloric diets without a late-evening meal.22Swart G.R. Zillikens M.C. van Vuure J.K. van den Berg J.W. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver.BMJ. 1989; 299: 1202-1203Crossref PubMed Scopus (152) Google Scholar Uptake of BCAA therapy will also be limited by the fact that lactulose is cheap and effective for the treatment of acute and chronic encephalopathy, presumably a common cause of hospital admissions in the study by Marchesini et al.18Marchesini G. Bianchi G. Merli M. Amodio P. Panella C. Loguerico C. Rossi Fanelli F. Abbiati R. Italian BCCA Study GroupNutritional supplementation with branched-chain amino acids in advanced cirrhosis A double-blind, randomized trial.Gastroenterology. 2003; 127: 1792-1801Abstract Full Text Full Text PDF Scopus (464) Google Scholar Prophylaxis of spontaneous bacterial peritonitis and variceal hemorrhage, other likely causes of hospital admissions, have also evolved during the course of this study. Practicing physicians are likely to require clearer evidence of benefits to this expensive and bad-tasting therapy before BCAA supplementation becomes a standard of care. Unfortunately, we still need a large(r) multicenter, randomized, controlled trial. The most obvious impact of the limited beneficial effects of BCAA observed in this study is that the concept of BCAA supplementation for the prevention of progression and complications of cirrhosis has new life—Rasputin lives, albeit close to the Neva River.
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