Effects of Oral Branched-Chain Amino Acid Granules on Event-Free Survival in Patients With Liver Cirrhosis
2005; Elsevier BV; Volume: 3; Issue: 7 Linguagem: Inglês
10.1016/s1542-3565(05)00017-0
ISSN1542-7714
AutoresYasutoshi Muto, Shunichi Sato, Akiharu Watanabe, Hisataka Moriwaki, Kazuyuki Suzuki, Akinobu Kato, Masahiko Kato, Teiji Nakamura, Kiyohiro Higuchi, Shuhei Nishiguchi, Hiromitsu Kumada,
Tópico(s)Biochemical effects in animals
ResumoBackground & Aims: Nutritional intervention with branched-chain amino acid (BCAA) is reported to increase serum albumin concentration in patients with decompensated cirrhosis. However, a definite conclusion on whether it can improve patients’ survival has not yet been reached. The present study aimed to test possibilities of improving survival of patients with decompensated cirrhosis by using a BCAA preparation that is suitable for long-term oral administration. Methods: A multicenter, randomized, and nutrient intake-controlled trial on the comparative effects of BCAA orally administered at 12 g/day for 2 years versus diet therapy with defined daily food intake (1.0–1.4 g protein kg−1 day−1 including BCAA preparation and 25–35 kcal kg−1 day−1) was conducted in 646 patients with decompensated cirrhosis. The primary end point was a composite of death by any cause, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival). The secondary end points were serum albumin concentration and health-related quality of life (QOL) measured by Short Form-36 questionnaire. Results: The incidence of events comprising the primary end point significantly decreased in the BCAA group as compared with the diet group (hazard ratio, 0.67; 95% confidence interval, 0.49–0.93; P = .015; median observation period, 445 days). Serum albumin concentration increased significantly in the BCAA group as compared with the diet group (P = .018). The “general health perception” domain in Short Form-36 measures was also improved (P = .003). Patients’ adherence to the prescription was favorable. Conclusions: Oral supplementation with a BCAA preparation that can be administered for a long period improves event-free survival, serum albumin concentration, and QOL in patients with decompensated cirrhosis with an adequate daily food intake. Background & Aims: Nutritional intervention with branched-chain amino acid (BCAA) is reported to increase serum albumin concentration in patients with decompensated cirrhosis. However, a definite conclusion on whether it can improve patients’ survival has not yet been reached. The present study aimed to test possibilities of improving survival of patients with decompensated cirrhosis by using a BCAA preparation that is suitable for long-term oral administration. Methods: A multicenter, randomized, and nutrient intake-controlled trial on the comparative effects of BCAA orally administered at 12 g/day for 2 years versus diet therapy with defined daily food intake (1.0–1.4 g protein kg−1 day−1 including BCAA preparation and 25–35 kcal kg−1 day−1) was conducted in 646 patients with decompensated cirrhosis. The primary end point was a composite of death by any cause, development of liver cancer, rupture of esophageal varices, or progress of hepatic failure (event-free survival). The secondary end points were serum albumin concentration and health-related quality of life (QOL) measured by Short Form-36 questionnaire. Results: The incidence of events comprising the primary end point significantly decreased in the BCAA group as compared with the diet group (hazard ratio, 0.67; 95% confidence interval, 0.49–0.93; P = .015; median observation period, 445 days). Serum albumin concentration increased significantly in the BCAA group as compared with the diet group (P = .018). The “general health perception” domain in Short Form-36 measures was also improved (P = .003). Patients’ adherence to the prescription was favorable. Conclusions: Oral supplementation with a BCAA preparation that can be administered for a long period improves event-free survival, serum albumin concentration, and QOL in patients with decompensated cirrhosis with an adequate daily food intake. It has been reported that nutritional state influences survival in patients with decompensated cirrhosis.1Alberino F. Gatta A. Amodio P. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 2Pugh R.N. Murray-Lyon I.M. Dawson J.L. et al.Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649Crossref PubMed Scopus (6664) Google Scholar, 3Christensen E. Schlichting P. Fauerholdt L. et al.Prognostic value of Child-Turcotte criteria in medically treated cirrhosis.Hepatology. 1984; 4: 430-435Crossref PubMed Scopus (281) Google Scholar, 4Merkel C. Bolognesi M. Finucci G.F. et al.Indocyanine green intrinsic hepatic clearance as a prognostic index of survival in patients with cirrhosis.J Hepatol. 1989; 9: 16-22Abstract Full Text PDF PubMed Scopus (62) Google Scholar Two studies have shown a reduction in mortality of such patients with enteral feeding.5Cabre E. Gonzalez-Huix F. Abad-LaCruz A. et al.Effects of total enteral nutrition on short-term outcome of severely malnourished cirrhosis.Gastroenterology. 1990; 98: 715-720PubMed Google Scholar, 6Mendenhall C.L. Tosch T. Weesner R.E. et al.VA cooperative study on alcoholic hepatitis II prognostic significance of protein-calorie malnutrition.Am J Clin Nutr. 1986; 43: 213PubMed Google Scholar Nevertheless, current guidelines state that no nutritional intervention is required for patients with a sufficient food intake.7Plauth M. Merli M. Kondrup J. et al.ESPEN guidelines for nutrition in liver disease and transplantation.Clin Nutr. 1997; 16: 43-55Abstract Full Text PDF PubMed Scopus (331) Google Scholar Thus, further studies are required to draw definite conclusions as to whether nutritional intervention can improve the prognosis of patients with decompensated cirrhosis.Protein malnutrition, as manifest for example by reduced skeletal muscle mass and hypoalbuminemia, might exist in patients with cirrhosis despite apparent adequate food consumption.1Alberino F. Gatta A. Amodio P. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 8Marchesini G. Bianchi G. Merli M. et al.Nutritional supplementation with branched-chain amino acids in advanced cirrhosis a double-blind, randomized trial.Gastroenterology. 2003; 124: 1792-1801Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, 9Tajika M. Kato M. Mohri H. et al.Prognostic value of energy metabolism in patients with liver cirrhosis.Nutrition. 2002; 18: 229-234Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 10Moriwaki H. Miwa Y. Tajika M. et al.Branched-chain amino acids as a protein- and energy-source in liver cirrhosis.Biochem Biophys Res Commun. 2004; 313: 405-409Crossref PubMed Scopus (155) Google Scholar When used as a treatment for protein malnutrition, long-term supplementation with BCAA has been reported to raise or maintain nutritional status and to improve the survival of patients with decompensated cirrhosis.11Yoshida T. Muto Y. Moriwaki H. et al.Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis.J Gastroenterol. 1989; 24: 692-698Google Scholar, 12Muto Y. Yoshida T. Effect of oral supplementation with branched-chain amino acid granules on improvement of protein nutrition in decompensated liver cirrhosis a cross-over controlled study.in: Ogoshi S. Okada A. Parenteral and enteral hyperalimentation. Excerpta Medica, Amsterdam1984: 280-292Google Scholar, 13Muto Y. Yoshida T. Sato S. et al.Effect of oral supplementation with BCAA-G on the prognosis of liver cirrhosis.JJPEN. 1992; 14: 765-775Google Scholar However, these results have not been confirmed in more extensive studies, partly because of the lack of a BCAA preparation suitable for long-term administration. A recent study from Italy8Marchesini G. Bianchi G. Merli M. et al.Nutritional supplementation with branched-chain amino acids in advanced cirrhosis a double-blind, randomized trial.Gastroenterology. 2003; 124: 1792-1801Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar suggested a benefit to BCAA-enriched nutritional supplements in patients with cirrhosis, but the interpretability of the study was limited by a short observation period and poor adherence to the BCAA prescription. In the present study, we investigated the effects of long-term supplementation with BCAA on the event-free survival in patients with cirrhosis who had hypoalbuminemia despite an apparently adequate food intake. We conducted a multicenter, randomized, and nutrient intake-controlled study in 89 institutions in Japan by using a preparation consisting entirely of BCAA in a palatable formulation.Patients and MethodsStudy DesignThe present study was designed in 1997 by the steering committee as a multicenter, randomized, and nutrient intake-controlled trial. The study recruited patients with decompensated cirrhosis from 89 medical institutions in Japan.Eligibility criteria were as follows: (1) serum albumin concentration of 3.5 g/dL or less; (2) presence of ascites, peripheral edema, or hepatic encephalopathy, or a history of any one of these conditions; and (3) aged 20–75 years.Exclusion criteria were as follows: serum albumin concentration continuously lower than 2.5 g/dL, requirement of albumin infusion at least once a week for 1 month or more, a history of receiving BCAA granules for 5 months or more, serum total bilirubin of 3.0 mg/dL or higher, dietary protein restriction, complicated liver cancer, complicated esophageal varices that require sclerosing or ligation therapy, and complicated hepatic encephalopathy graded III or higher.Primary end point was time to the earliest of the following events: (1)Aggravation of hepatic failure (ascites, peripheral edema, hepatic encephalopathy, and jaundice). Ascites, peripheral edema, and jaundice were graded as none, mild, moderate, and severe. Grade of ascites was estimated by ultrasonography, according to the presence or absence of ascites in the liver-kidney interspace and the depth of ascites on the liver surface. Peripheral edema was graded according to the depth of pitting edema on the tibia. Aggravation of ascites and peripheral edema was defined when the severity progressed to severe grade. Aggravation of jaundice was defined when the severity progressed to severe grade (serum bilirubin, 10.0 mg/dL or higher). Aggravation of hepatic encephalopathy was defined when advanced to grade III or higher.(2)Rupture of esophageal or gastric varices.(3)Development of liver cancer assessed by diagnostic imaging. Patients were screened by ultrasonography every 3 months. Lesions suspicious for possible hepatocellular carcinoma were further examined by computed tomography, magnetic resonance imaging, and celiac angiography to confirm or exclude the development of liver cancer.(4)Death from any cause.Patients were instructed to visit their outpatient clinic every 3 months and were checked by the study physician for any subjective changes during the course of the given therapy. They also received routine physical examinations, blood biochemical tests, and ultrasonography at each visit. The physicians participating in this study were instructed to record and grade each event, but they were not informed of the end point criteria as defined above to exclude any bias in evaluation. For each patient, the occurrence and timing of any primary end point were judged by the independent evaluation committee under blinded conditions.Discontinuation, dropout, or trial termination as a result of reasons other than the above 4 events was classified as censoring.Secondary end points were changes in serum albumin concentration and health-related quality of life (QOL) measured by Short Form-36 questionnaire.Intervention ProtocolBaseline evaluation included physical examination and routine laboratory tests. Daily food intake was estimated by self-administered questionnaire. Screening information and prognostic factors of possibly eligible patients were transmitted to the registration center by phone or fax, after written informed consent was obtained. After confirmation of eligibility, the patients were randomly assigned by the center to either supplementation with BCAA granules consisting of BCAA alone (Livact Granules; AJINOMOTO Co, Inc, Tokyo, Japan; 1 sachet contains 4 g of BCAA; L-isoleucine 952 mg, L-leucine 1904 mg, and L-valine 1144 mg, 1 sachet orally after each meal) or a diet therapy. Patients were then kept on their assigned therapy for 2 years or more.Daily food intake was mandated by the study dieticians as 25–35 kcal · kg−1 · day−1 and 1.0–1.4 g protein · kg−1 · day−1 according to the European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines.7Plauth M. Merli M. Kondrup J. et al.ESPEN guidelines for nutrition in liver disease and transplantation.Clin Nutr. 1997; 16: 43-55Abstract Full Text PDF PubMed Scopus (331) Google Scholar Patients completed a questionnaire on their diet every 3 months in the first year and every 6 months thereafter. Dietary education was given to those with excess or deficiency in their daily energy and protein intake. The dietitians provided written instructions for dietary guidance to the patients via the study physician at each institution.Determination of Sample Size and Methods for RandomizationReduction of the hazard ratio by supplementation with BCAA was assumed to be 1/3 according to Muto et al.14Muto Y. Yoshida T. Kato M. et al.Serum albumin level and prognosis in patients with liver cirrhosis result of branched-chain amino acids granules (BCAA-G) supplement trial.JJPEN. 1995; 17: 1135-1143Google Scholar When the significance level was set at 5% (two-tailed) for α error and 80% for β error, the required number of events was 98 for each group. Taking the pursuit period of this study as 2 years on average, and assuming the appearance rate of events in the diet group in 2 years as 27% according to Muto et al,13Muto Y. Yoshida T. Sato S. et al.Effect of oral supplementation with BCAA-G on the prognosis of liver cirrhosis.JJPEN. 1992; 14: 765-775Google Scholar the required number of patients was calculated as 313 in each group. Sample size was finally determined as 323 patients each in consideration of withdrawal from the study before the implementation of assigned therapies.The patients were randomly assigned to treatment group by using a minimization method that incorporates a measure of imbalance between 2 groups in the composition of the following strata: existence of hepatic encephalopathy and ascites, serum albumin concentration (3.0 g/dL or less vs 3.1–3.5 g/dL), supplementation of nutrients, hospitalization, and study institutions.PatientsWritten informed consent to participate in the trial was obtained from all patients. The study protocol was approved by the ethical committee of each medical institution and conducted in accordance with the Good Clinical Practice guidelines.Composition of patients is shown in Figure 1. A total of 646 patients were initially enrolled and randomized. Assigned therapy was initiated in 625 patients (314 in the BCAA group and 311 in the diet group, respectively) excluding 21 patients who opted for other therapeutic interventions before the start of the assigned therapy. Three of these 625 patients (all in the diet group) were excluded from statistical analysis because of noncompliance with assignment. Thus, data from a total of 622 patients (314 and 308 patients in the BCAA and the diet groups, respectively) were subjected to statistical analysis.The baseline characteristics of patients are summarized in Table 1. No significant difference was noted between the BCAA and the diet groups in age, sex, incidence of complicated esophageal varices, serum albumin concentration, total bilirubin, platelet count, cause of cirrhosis, or the Child-Pugh Classification. The incidences of complications attributable to hepatic failure within the last 2 months before the initiation of the therapy in BCAA group and diet group, respectively, were as follows: hepatic encephalopathy, 8.6% and 3.9%; ascites, 23.6% and 21.4%; peripheral edema, 50.0% and 52.3%; and jaundice, 8.3% and 6.8%. Of these background factors, the incidence of hepatic encephalopathy was significantly higher in the BCAA group than in the diet group (P = .015).Table 1Demographic and Clinical Characteristics of the Patients at Entry Into the StudyCharacteristicBCAA groupDiet groupP valueaStatistical analysis was performed by Fisher exact test, χ2 test, Wilcoxon test, or Student t test.Number of patients314308—Sex (M/F)147/167147/161NSAge (y)62 ± 861 ± 9NSBody weight (kg)58 ± 1058 ± 11NSEtiology (HCV/HBV/alcoholic/others)227/39/20/28204/33/32/39NSSerum albumin (g/dL)3.3 ± 0.33.3 ± 0.3NSTotal bilirubin (mg/dL)1.3 ± 0.81.3 ± 0.7NSPlatelet count (×104/mm3)9 ± 69 ± 5NSChild-Pugh grade (A/B/C)118/138/5105/125/7NSPresence of varices170 (54%)187 (61%)NSHepatic coma (grade 0/1/2/3/4)287/15/11/1/0295/9/3/0/0.015Ascites (absent/slight/moderate/severe)240/61/9/4241/51/12/3NSPeripheral edema (absent/slight/moderate/severe)157/138/18/1146/136/22/3NSNOTE. Data are expressed as number of patients or mean ± standard deviation.a Statistical analysis was performed by Fisher exact test, χ2 test, Wilcoxon test, or Student t test. Open table in a new tab Statistical AnalysisData were analyzed by using SAS (Release 6.12 or Release 8.1; SAS Institute Inc, Cary, NC). Cumulative survival function of each treatment group was estimated by using the Kaplan-Meier method, and differences between the 2 groups were analyzed by log rank test. Hazard ratio between the groups was also estimated by the Cox proportional hazards model by using the following parameters as independent variables: treatment assignment, serum albumin concentration at entry (3.0 g/dL or less vs 3.1–3.5 g/dL), cause of cirrhosis, plasma concentration of BCAA/L-tyrosine molar ratio at entry (BTR; more than 4.0 vs 4.0 or lower). Changes in serum albumin concentration and health-related QOL during the study period were analyzed by repeated measures analysis of variance.ResultsClinical CourseThe observation period ranged from 1–1058 days (median, 445 days) in 622 patients analyzed. A total of 154 events were recorded (Table 2). Twelve patients died during the course of the study (6 patients each in the BCAA group and in the diet group). A total of 89 patients developed liver cancer (40 and 49 patients in the BCAA and the diet groups, respectively) and discontinued the study at the time of diagnosis. Furthermore, 17 patients (8 and 9 in the BCAA and the diet groups, respectively) had rupture of esophageal varices, and 36 patients had advanced hepatic failure (12 and 24 in the BCAA and the diet groups, respectively). Incidences of total events and aggravation of hepatic failure were significantly lower in the BCAA group than in the diet group (P = .03 and P = .04, respectively) (Table 2).Table 2Incidence of Recorded Events for Primary End PointEventBCAA groupDiet groupP valueaStatistical analysis was performed by χ2 test.Number of patients314308—Total events66 (21%)88 (29%).03Death6 (2%)6 (2%)NSRupture of varices8 (3%)9 (3%)NSLiver cancer40 (13%)49 (16%)NSHepatic failure12 (4%)24 (8%).04NOTE. Data are expressed as number (%) of patients.a Statistical analysis was performed by χ2 test. Open table in a new tab The drug compliance of patients in the BCAA group is shown in Table 3. For all time points during the course of the trial, 85% or more of the patients consumed “nearly all” of the prescribed amount of the BCAA preparation.Table 3Adherence of Patients to Prescribed BCAA GranuleStudy period (mo)Number of patientsConsumedAllThree quarters or moreHalf or moreHalf or less328586%8%4%2%625986%7%4%2%921589%6%2%3%1219091%4%2%2%1815490%3%3%1%249990%3%3%1%302095%5%0%0%NOTE. Data are expressed as % of patients who consumed the indicated amount of BCAA preparation. Open table in a new tab No difference was noted between the BCAA and the diet groups in total energy and protein intake during the trial (including BCAA granule-derived energy and protein in the former group). In particular, 48 patients (26 and 22 in the BCAA and the diet groups, respectively) were closely surveyed for 3–24 months for precise food consumption analysis. Their energy and protein intakes during the trial were 30 ± 7 kcal · kg−1 · day−1 (mean ± standard deviation) (median, 1660 kcal · body−1 · day−1) and 1.3 ± 0.3 g · kg−1 · day−1, respectively, in the BCAA group and 31 ± 7 kcal · kg−1 · day−1 (median, 1592 kcal · body−1 · day−1) and 1.3 ± 0.3 g · kg−1 · day−1 in the diet group (analysis of variance, not significant).Adverse effects appeared in 38 of 317 patients in the BCAA group (12.0%). The majority of the effects were gastrointestinal problems, such as abdominal distention, diarrhea, and constipation. Serious adverse events were increases in serum ALT and AST in a single patient.Primary End PointEvent-free survival curves are shown in Figure 2. The survival rate was significantly higher in the BCAA group than in the diet group (P = .015). Hazard ratio obtained by the Cox proportional hazards model was 0.67 with 95% confidence interval ranging from 0.49–0.93 (Table 4). Among individual events of primary end point, a significant difference in the rate of hepatic failure was noted between the 2 groups (Figure 3, P = .016), giving a hazard ratio of 0.45 with 95% confidence interval ranging from 0.23–0.88 (Table 4).Figure 2Kaplan-Meier estimates of event-free survival in the 2 study groups. Events for the primary end point were aggravation of hepatic failure (ascites, peripheral edema, hepatic encephalopathy, and jaundice), rupture of esophageal or gastric varices, development of liver cancer, and death due to any cause.View Large Image Figure ViewerDownload (PPT)Table 4Hazard Ratios of BCAA Supplementation to Diet Therapy for Events of Primary End PointEventHazard ratio95% confidence intervalP valueaP values obtained by log rank test.Overall0.670.49–0.93.015Hepatic failure0.450.23–0.88.016Liver cancer0.760.50–1.15.197Rupture of varices0.830.32–2.15.696Death1.180.41–3.41.760a P values obtained by log rank test. Open table in a new tab Figure 3Kaplan-Meier estimates of the proportion of patients without aggravation of hepatic failure (ascites, peripheral edema, hepatic encephalopathy, and jaundice) in the 2 study groups.View Large Image Figure ViewerDownload (PPT)Within the baseline characteristics of sex, age, etiology of cirrhosis, serum albumin concentration, and BTR (Table 5), the 95% confidence interval of hazard ratio of less than 1 was witnessed among female patients, patients younger than 65 years of age, those with HCV-related cirrhosis (Figure 4), and those with a BTR of less than 4.0 (Figure 5). With regard to hepatic failure, the hazard ratio was less than 1 in female patients, patients with HCV-related cirrhosis, and those with a BTR of less than 4.0 (Table 5).Table 5Hazard Ratios of BCAA Supplementation to Diet Therapy for Overall Events, Liver Cancer, and Aggravation of Hepatic Failure in Subgroups of PatientsCategoryOverall eventsLiver cancerHepatic failureSexMale0.72 (0.48–1.10)0.69 (0.41–1.17)0.98 (0.40–2.41)Female0.59 (0.35–0.98)aP < .05 by Cox proportional hazards model analysis.0.89 (0.45–1.73)0.16 (0.05–0.56)aP < .05 by Cox proportional hazards model analysis.Age (y)<650.57 (0.36–0.88)aP < .05 by Cox proportional hazards model analysis.0.71 (0.40–1.27)0.43 (0.17–1.05)≥650.82 (0.52–1.31)0.81 (0.45–1.47)0.50 (0.19–1.35)Etiology of cirrhosisHCV0.61 (0.42–0.89)aP < .05 by Cox proportional hazards model analysis.0.66 (0.42–1.06)0.37 (0.14–0.95)aP < .05 by Cox proportional hazards model analysis.Serum albumin (g/dL)≤3.00.59 (0.37–1.01)0.66 (0.31–1.41)0.41 (0.15–1.11)>3.10.69 (0.46–1.02)0.79 (0.48–1.30)0.45 (0.18–1.11)BTR≤4.00.62 (0.43–0.91)aP < .05 by Cox proportional hazards model analysis.0.84 (0.52–1.34)0.31 (0.13–0.74)aP < .05 by Cox proportional hazards model analysis.>4.00.95 (0.40–2.25)0.55 (0.18–1.68)1.27 (0.21–7.62)NOTE. Data are expressed as hazard ratio (95% confidence interval).a P < .05 by Cox proportional hazards model analysis. Open table in a new tab Figure 4Kaplan-Meier estimates of event-free survival in the 2 study groups with HCV-positive liver cirrhosis.View Large Image Figure ViewerDownload (PPT)Figure 5Kaplan-Meier estimates of event-free survival in the 2 study groups with serum BTR less than 4.0 at entry.View Large Image Figure ViewerDownload (PPT)Secondary End PointSerum albumin concentration increased significantly in the BCAA group as compared with the diet group (P = .018, Figure 6). Supplementation with BCAA had a significant favorable effect on general health perception scores in the Short Form-36 questionnaire as compared with diet therapy (P = .003, Figure 7).Figure 6Serum albumin concentration in BCAA group (closed circles) and diet group (closed squares). Data are represented as means and standard errors. The P value of repeated measures analysis of variance is reported.View Large Image Figure ViewerDownload (PPT)Figure 7General health perception scores of the Short Form-36 questionnaire for health-related QOL in BCAA group (closed columns) and diet group (open columns). Data are represented as means and standard errors. The P value of repeated measures analysis of variance is reported.View Large Image Figure ViewerDownload (PPT)DiscussionIt is well accepted that protein and energy malnutrition is common in patients with liver cirrhosis.1Alberino F. Gatta A. Amodio P. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 9Tajika M. Kato M. Mohri H. et al.Prognostic value of energy metabolism in patients with liver cirrhosis.Nutrition. 2002; 18: 229-234Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 10Moriwaki H. Miwa Y. Tajika M. et al.Branched-chain amino acids as a protein- and energy-source in liver cirrhosis.Biochem Biophys Res Commun. 2004; 313: 405-409Crossref PubMed Scopus (155) Google Scholar, 15Muller M.J. Malnutrition in cirrhosis.J Hepatol. 1995; 23: 31-35PubMed Google Scholar Protein and energy malnutrition is also a significant predictor of survival in these patients1Alberino F. Gatta A. Amodio P. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 9Tajika M. Kato M. Mohri H. et al.Prognostic value of energy metabolism in patients with liver cirrhosis.Nutrition. 2002; 18: 229-234Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 10Moriwaki H. Miwa Y. Tajika M. et al.Branched-chain amino acids as a protein- and energy-source in liver cirrhosis.Biochem Biophys Res Commun. 2004; 313: 405-409Crossref PubMed Scopus (155) Google Scholar and is a putative predictor for outcomes after liver transplantation in patients with cirrhosis.16Selberg O. Bottcher J. Tusch G. et al.Identification of high- or low-risk patients before liver transplantation a prospective cohort study of nutritional and metabolic parameters in 150 patients.Hepatology. 1997; 25: 652-657Crossref PubMed Scopus (317) Google Scholar Because BCAA exerts a protein-sparing effect, increases serum albumin concentration, and improves other protein nutritional parameters in patients with cirrhosis,11Yoshida T. Muto Y. Moriwaki H. et al.Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis.J Gastroenterol. 1989; 24: 692-698Google Scholar, 12Muto Y. Yoshida T. Effect of oral supplementation with branched-chain amino acid granules on improvement of protein nutrition in decompensated liver cirrhosis a cross-over controlled study.in: Ogoshi S. Okada A. Parenteral and enteral hyperalimentation. Excerpta Medica, Amsterdam1984: 280-292Google Scholar, 13Muto Y. Yoshida T. Sato S. et al.Effect of oral supplementation with BCAA-G on the prognosis of liver cirrhosis.JJPEN. 1992; 14: 765-775Google Scholar supplementation with BCAA has been suggested as a candidate intervention to improve protein malnutrition in patients with cirrhosis. BCAA supplementation has been reported to improve QOL and increase survival rates in patients with decompensated cirrhosis.8Marchesini G. Bianchi G. Merli M. et al.Nutritional supplementation with branched-chain amino acids in advanced cirrhosis a double-blind, randomized trial.Gastroenterology. 2003; 124: 1792-1801Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, 11Yoshida T. Muto Y. Moriwaki H. et al.Effect of long-term oral supplementation with branched-chain amino acid granules on the prognosis of liver cirrhosis.J Gastroenterol. 1989; 24: 692-698Google Scholar However, the utility and applicability of BCAA supplementation have been questioned,17Christie M.L. Sack D.M. Pomposelli J. et al.Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis.JPEN. 1985; 9: 671-678Crossref PubMed Scopus (62) Google Scholar, 18McGhee A. Henderson J.M. Millikan Jr, W.J. et al.Comparison of the effects of Hep
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