Journal of Nutrition Animal Diets/Enrichment Products...

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marchesini, G.
Right arrow Articles by Bianchi, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchesini, G.
Right arrow Articles by Bianchi, G.
© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1596S-1601S, June 2005

4th Amino Acid Assessment Workshop

Branched-Chain Amino Acid Supplementation in Patients with Liver Diseases1

Giulio Marchesini2, Rebecca Marzocchi, Marianna Noia and Giampaolo Bianchi

Department of Internal Medicine, "Alma Mater Studiorum," University of Bologna, Italy

2To whom correspondence should be addressed. E-mail: giulio.marchesini{at}unibo.it.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Because of their peculiar role in whole-body nitrogen metabolism and the competitive action on amino acid transport across the blood–brain barrier, branched-chain amino acids (BCAAs) have been extensively used in subjects with liver disease to preserve or to restore muscle mass and to improve hepatic encephalopathy. There are no data regarding safe limits of BCAA administration; the results appear to be better when BCAA-enriched formulas or BCAA-supplemented diets are preferred to pure BCAA formulas. Improved nitrogen retention might ameliorate the nutritional status, a prognostic index of long-term survival in cirrhosis and of short-term survival in patients undergoing surgical procedures. The effects on nutrition and ultimately on prognosis of patients with advanced cirrhosis were confirmed in a large multicenter, long-term trial where oral BCAA supplements were compared with equicaloric or equinitrogenous–equicaloric supplements (maltodextrin or lactoalbumin). Similarly, BCAA treatment improved the prognosis of patients with hepatocellular carcinoma, treated by surgical resection or chemoembolization, and of liver transplant patients. The mechanism(s) for the beneficial effects of BCAAs might be mediated by their stimulating activity on hepatocyte growth factor, favoring liver regeneration. The debate regarding the potential effectiveness of BCAAs dates back to the early 1980s. The number of patients who cannot tolerate dietary proteins in amounts sufficient to meet the higher catabolism of advanced liver disease is probably low, but BCAAs remain the sole treatment of proved efficacy in this specific setting.

KEY WORDS: • nutrition • cirrhosis • nitrogen balance • encephalopathy • survival • hepatocyte growth factor

Advanced liver diseases probably represent the area in which the clinical usefulness of branched-chain amino acids (BCAAs) has most extensively been tested. There are several potential reasons for beneficial effects of BCAAs in liver diseases, in addition to the regulatory activity of BCAAs (in particular, leucine) on whole-body protein and general metabolism. First, cirrhotic patients are generally hypermetabolic (1), and the higher-than-normal protein–amino-acid requirement may be easily met by an increased BCAA supply (2). The prevalence of protein–energy malnutrition (PEM)3 in cirrhosis is as high as 65–90%, depending on the etiology of disease (alcoholic–nonalcoholic) and the severity of liver failure. The high prevalence of PEM reported in old studies, which included a high proportion of patients with alcoholic cirrhosis, will probably decline in the future, because of a progressive increase in the prevalence of patients with "metabolic" liver diseases (3), i.e., those associated with obesity and diabetes (4). When present, PEM is characterized by a low serum albumin level (visceral protein) and by a decreased skeletal-muscle volume (muscular protein) (5,6) and carries a high risk of morbidity and mortality by increasing the risk of life-threatening complications, which in turn reduce survival and quality of life (7). Long-term prognosis after liver transplantation also depends on the patient’s nutritional status (8). Several studies have shown that BCAA supplementation is effective in downregulating protein metabolism in cirrhosis, improving nitrogen balance, and finally resulting in better clinical outcomes.

Second, BCAAs escape liver metabolism and are available in the general circulation for protein synthesis. The handling of BCAAs, also in the presence of liver disease, is probably mediated by circulating insulin concentrations, and their defective use in the presence of insulin resistance is likely to be overcome by systemic administration.

Third, the plasma concentration of BCAAs is lower than normal in cirrhosis, suggesting a relative dearth of these substrates. This has not been confirmed by measurements of intracellular amino acid concentration, which showed normal levels of BCAAs in the muscle tissue of subjects with end-stage liver disease. However, in the presence of muscle wasting, total body BCAA mass is likely to be lower than normal in these patients.

Fourth, the supplementation of the diet with BCAAs does not produce hepatic encephalopathy, contrary to what may be seen by increasing nitrogen supply by means of dietary proteins. This issue is controversial. BCAAs have been proposed for cirrhotic patients, based on the "false neurotransmitters" hypothesis (9) and their competitive action on amino acid transport across the blood–brain barrier and, ultimately, on the brain synthesis of neurotransmitters. A few controlled studies have demonstrated beneficial effects of i.v. administration of BCAAs, further supported by a meta-analysis (10), whereas no consensus has been reached for oral BCAAs (2,11). These conclusions have been challenged over the years, and a recent Cochrane review has reassessed the pros and cons of BCAA treatment (12).

Finally, BCAAs, namely leucine as the most potent agent, activate the synthesis of hepatocyte growth factor (HGF), a pleiotropic substance with mitogenic activity (13), by hepatic stellate cells (14). Accordingly, the beneficial effects observed in patients with advanced cirrhosis during BCAA supplementation might stem from increased liver regeneration, compensating for progressive liver-cell death.

The present report is specifically aimed at reviewing the results of BCAA supplementation in liver disease in relation to the amount of amino acid supply, with special emphasis on the data reported in a recently published, controlled clinical trial.

BCAA supplementation in cirrhosis

BCAAs constitute a large part of dietary amino acids. The percentage of BCAAs in food categories varies between 20 and 25% of total protein content, with few exceptions. It is higher in dairy products and in vegetables, which might explain the favorable effects of a milk-and-cheese or a vegetable–protein diet on hepatic encephalopathy and nitrogen balance (15,16). In subjects consuming a diet containing 1 g protein/kg body weight, the total amount of dietary BCAAs is estimated to be 10–15 g/d. This amount may be easily doubled by oral BCAA supplements and more than doubled by means of BCAA-enriched i.v. amino acid solutions (Table 1). However, the difference in comparison to standard treatment (either standard amino acid solution or dietary proteins or casein–lactoalbumin) is definitely lower, because of the presence of BCAAs in control treatments.


View this table:
[in this window]
[in a new window]
  		TABLE 1 Randomized controlled trials of BCAA treatment in cirrhosis1

 
In a few studies, patients were given pure BCAA solutions for days, at doses 3–4 times their habitual oral intake. Although no "toxic" effects were demonstrated, most of these studies were negative. BCAA-enriched formulas via i.v. are probably superior to pure BCAA infusions. In PEM, pure BCAAs might fail to provide nonessential nutrients, which become essential in the presence of cirrhosis. This concept has been extensively demonstrated for choline (36) but might apply to several compounds that are lacking in nonbalanced formula diets (37).

In conclusion, the optimum amount of BCAA supplements for liver disease has not been determined, nor has their definitive role in patients with advanced disease. International guidelines on nutrition in liver disease, published a few years ago (2), concluded that oral BCAA supplementation may be useful to provide the patients with the desired amount of proteins, while permitting the continuation of an oral diet. This treatment should be limited to patients intolerant of a daily intake of 1 g protein/kg body weight, to avoid the necessary reduction of dietary proteins. In these rare patients, a positive nitrogen balance and an improvement of nitrogen intake can indeed be achieved by oral supplementation of BCAAs at 0.25 g · kg body weight–1 · d–1, without increasing the risk of encephalopathy.

After this guideline was published (2), the comprehensive Cochrane review by Als-Nielsen et al. (12) confirmed that BCAAs significantly increase the number of patients improving from hepatic encephalopathy, compared with control treatments (59% vs. 41%; risk ratio, 1.31; 95% CI, 1.04–1.66), without any convincing evidence for an effect of BCAAs on survival or adverse events. The review was based on 11 randomized trials (556 patients in total), where BCAAs, either parenterally or orally administered, were compared with carbohydrates, neomycin–lactulose, and isonitrogenous regimes. The median amount of BCAAs was 28 g/d (range 11–57 g), and the median duration of treatment was 7 d (range 4–90 d). The authors remarked that most trials were small, with a short follow-up, and were of low methodological quality (12). In general, BCAAs were more effective when given enterally to subjects with chronic encephalopathy, than when given i.v. to patients with acute encephalopathy, in keeping with a possible action through improved nutrition.

This issue has been specifically addressed in a recent multicenter, randomized study comparing long-term BCAA supplementation with equicaloric (maltodextrin) or equicaloric–equinitrogenous supplements (lactoalbumin) for 1 y (35). The study enrolled 174 patients with advanced cirrhosis and a Child-Pugh score between 7 and 12 (Table 2). Additional exclusion criteria were active alcohol consumption, overt hepatic encephalopathy, refractory ascites, impaired renal function, suspected hepatocellular carcinoma, and being considered for liver transplantation, to avoid attrition biases. Prevention of liver-cell failure (death or deterioration to exclusion criteria) and hospital admission were the primary outcomes, with nutritional parameters, laboratory data, anorexia, and health-related quality of life as secondary outcomes. BCAA administration significantly lowered the combined event rates (death or progression to liver failure) compared with lactoalbumin (odds ratio, 0.43; 95% CI, 0.19–0.96; P = 0.039) and nonsignificantly compared with maltodextrin (odds ratio, 0.51; 95% CI, 0.23–1.17; P = 0.108). Also, the average hospital admission rate was lower in the BCAA arm, and in the patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during BCAA treatment. Also, anorexia and health-related quality of life (Short Form-36 questionnaire) improved.


View this table:
[in this window]
[in a new window]
  		TABLE 2 Study profile (events and withdrawal from regular follow-up) of the BCAA trial (35)

 
In summary, this large study indicates that BCAA supplements are better than equicaloric–equinitrogenous supplements with regard to prevention of liver failure and death in patients with advanced cirrhosis. The number of patients recruited for the study nearly equals the number enrolled in the previous 11 studies on oral BCAA treatment, where sample size was a critical factor. The BCAA-related improvement in anorexia and in the perceived health status deserves special attention. Anorexia is a common finding in cirrhosis (38) and may worsen malnutrition (39). Although more patients in the BCAA group withdrew from the study because of noncompliance with poorly palatable supplements, the improved health status might stem from an increased dietary intake adding to the anticatabolic effects of BCAAs. Finally, the improved health status is perceived by patients as an improvement in their poor health-related quality of life (7), measured by validated questionnaires. This outcome is particularly relevant in chronic diseases and is considered by regulatory agencies in the assessment of the utility of new drugs.

BCAA treatment in liver patients undergoing hepatectomy and invasive procedures

A high proportion of cirrhotic patients undergo invasive procedures during the last period of their lives. It has been estimated that 10% of cirrhotic patients undergo at least 1 operative procedure during the final 2 y (40). Patients with hepatocellular carcinoma (HCC) are particularly at risk.

Their nutritional status may be further compromised by tumor-induced increased protein catabolism, adding to the malnutrition of cirrhosis. To our knowledge, 2 studies have tested the effects of BCAAs in subjects undergoing major hepatic resections (Table 3). Fan et al. (41) carried out a randomized, controlled study comparing perioperative (7 d before and 7 d after surgery) nutritional support with BCAAs (0.5 g · kg–1 · d–1), dextrose, and lipid emulsion added to oral diet vs. diet alone. The experimental treatment resulted in lower morbidity rates, mainly by preventing septic complications, favoring weight maintenance, and slowing the decline in liver-cell function. A 1-y supplementation with a BCAA-enriched formula [100 g Aminoleban EN (Otsuka) per day; total BCAAs, 11 g], started 2 to 3 wk after curative resection of HCC, was tested in a randomized, controlled trial, using multiple outcome measures (42). Body weight and performance status were better than in the control group, and albumin levels were higher, both in subjects undergoing major resections and in patients with more advanced liver disease. The cumulative tumor recurrence rate was not increased by amino acid treatment, but overall survival was not different.


View this table:
[in this window]
[in a new window]
  		TABLE 3 Randomized controlled trials of BCAA treatment in liver patients undergoing surgical or invasive procedures1

 
Besides surgical procedures, HCC patients frequently undergo chemoembolization or radiofrequency ablation, and their final survival may change according to the presence and the severity of malnutrition. In patients with inoperable HCC, chemoembolization is widely used to prolong survival, and nutritional support might play an important role during this phase of disease. In subjects randomized to treatment with a BCAA-enriched formula for 1 y (43), morbidity rate was lower than in controls (17.1% vs. 37.2%, P = 0.039) (Table 3). In particular, the BCAA group had lower rates of ascites (7.3% vs. 23.2%, P = 0.043) and peripheral edema (9.8% vs. 27.9%, P = 0.034) and a better quality of life, but no significant differences in survival were observed in these high-risk patients.

BCAAs in liver transplantation

The detrimental effect of malnutrition on the outcome of patients undergoing liver transplantation has recently been confirmed (46). These patients constitute a specific group in which to test the efficacy of nutritional supplementation with BCAAs, both before transplantation, to prevent progressive malnutrition, and after surgery, to increase the rate of recovery. The altered amino acid turnover of cirrhosis seems to normalize after liver transplantation (47), but BCAA levels fail to normalize >6 mo after transplantation (48). In children awaiting liver transplantation, a BCAA-enriched formula (BCAA, 31% of total protein intake) improved growth and the overall nutritional status, but the incidence of postoperative complications was not different (44).

In adults, 7-d postoperative total parenteral nutrition with either a standard or a BCAA-enriched formula (1.5 g protein · kg body weight–1 · d–1; BCAAs, 0.60 g/kg) was better than nutrition with glucose alone (45). The rapid achievement of nitrogen balance was accompanied by improved respiratory muscle function and more rapid recovery, with a shorter period of intensive care treatment. No specific effects of BCAA supplementation were demonstrated, but the limited sample size carries a high risk of type 2 error.

In summary, cirrhotic patients undergoing liver transplantation remain a select group who might take great advantage of the theoretical beneficial effects of BCAA supplementation, and new studies are needed.

Mechanism for BCAA effectiveness in advanced cirrhosis

The beneficial effects of BCAAs in a variety of liver diseases raise questions as to the mechanism of improved liver function. In experimental animals and humans, liver resection stimulates a regenerative response, mediated by circulating factors, including HGF, a pleiotropic substance with mitogenic activity (13), which also prevents hepatotoxin-mediated liver damage. HGF is secreted by hepatic stellate cells, and BCAAs, specifically leucine, are potent stimulators of HGF production (14). Accordingly, BCAAs not only provide substrates for protein synthesis but also accelerate the biochemical machinery, which facilitates liver regeneration, compensating for progressive liver-cell death. The simultaneous activation of mammalian target of rapamycin signaling in the liver, a well-demonstrated effect of BCAAs, promotes albumin synthesis in the liver (49) and protein and glycogen synthesis in the muscle tissue. All these effects will ultimately be beneficial in poor-risk patients with advanced cirrhosis.

Side-effects of BCAA treatment

In general, BCAA treatment is regarded as safe. Very few studies report evidence of side effects with either i.v. or oral BCAA treatment. Symptoms vary from vomiting and bloating to abdominal distension and diarrhea. The prevalence is difficult to estimate but does not exceed 10–15% in reports where figures are reported (28,30,42,44). The side effects tend to disappear in the course of treatment, but, although rare, they are associated with a higher drop-out rate (35). Any effort should be taken to increase palatability and solubility of oral solutions, to decrease the large amounts of water needed to dissolve BCAA powder.

Conclusion

The potential benefits of BCAA treatment in advanced cirrhosis have received further support from the recent publication of the Italian study in 2003 (35). However, even this study, nicknamed "the mother of all BCAA supplement studies" in a Gastroenterology editorial (50) because of the very large number of randomized patients, failed to settle the issue, and has been criticized on the basis of economic considerations. New studies are awaited to identify those patients at higher risk where BCAA administration is probably the only way to prevent catabolic losses and improve prognosis.

Finally, the amount of BCAAs supplied in the various studies is extremely variable (Fig. 1), and dose-finding studies are needed to detect the optimum dosage, safe limits of administration, and whether higher doses will produce better results. As previously reported, studies published so far limited oral BCAA supplementation to amounts doubling the usual dietary intake. In view of reported side effects, this policy seems largely acceptable. More importantly, studies are needed to define whether all 3 BCAAs need to be supplied. Considering the specific effects of leucine on protein turnover and HGF secretion, supplements of only leucine might achieve similar beneficial results at lower total doses.



View larger version (29K):
[in this window]
[in a new window]
  		FIGURE 1 Amount of BCAAs supplied in the various randomized, controlled studies in patients with liver disease. Black columns are i.v. BCAAs, open columns are oral BCAAs. The amount of dietary BCAAs is not included. Data are in g · kg body weight–1 · d–1, referred to a 70-kg patient.

 


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the conference "The Fourth Workshop on the Assessment of Adequate Intake of Dietary Amino Acids" held October 28–29, 2004, Kobe, Japan. The conference was sponsored by the International Council on Amino Acid Science. The Workshop Organizing Committee included Dennis M. Bier, Luc Cynober, David H. Baker, Yuzo Hayashi, Motoni Kadowaki, and Andrew G. Renwick. Guest editors for the supplement publication were David H. Baker, Dennis M. Bier, Luc Cynober, John D. Fernstrom, Yuzo Hayashi, Motoni Kadowaki, and Dwight E. Matthews. Back

3 Abbreviations used: HCC: hepatocellular carcinoma; HGF: hepatocyte growth factor: PEM: protein-energy malnutrition. Back


   LITERATURE CITED
TOP
 ABSTRACT
 LITERATURE CITED
 

1. Müller, M. J., Selberg, O. & Böker, K. (1994) Are patients with liver cirrhosis hypermetabolic?. Clin. Nutr. 13:131-144.

2. for the ESPEN Consensus GroupPlauth, M., Merli, M., Kondrup, J., Weimann, A., Ferenci, P. & Muller, M. J. (1997) ESPEN guidelines for nutrition in liver disease and transplantation. Clin. Nutr. 16:43-55.

3. Neuschwander-Tetri, B. A. & Caldwell, S. H. (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37:1202-1219.[Medline]

4. Falck-Ytter, Y., Younossi, Z. M., Marchesini, G. & McCullough, A. J. (2001) Clinical features and natural history of nonalcoholic steatosis syndromes. Semin. Liver Dis. 21:17-26.[Medline]

5. Italian Multicentre Cooperative Project on nutrition in liver cirrhosis (1994) Nutritional status in cirrhosis. J. Hepatol. 21:317-325.[Medline]

6. Tajika, M., Kato, M., Mohri, H., Miwa, Y., Kato, T., Ohnishi, H. & Moriwaki, H. (2002) Prognostic value of energy metabolism in patients with viral liver cirrhosis. Nutrition 18:229-234.[Medline]

7. Marchesini, G., Bianchi, G., Amodio, P., Salerno, F., Merli, M., Panella, C., Loguercio, C., Apolone, G., Niero, M. & Abbiati, R. (2001) Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 120:170-178.[Medline]

8. Selberg, O., Bottcher, J., Tusch, G., Pichlmayr, R., Henkel, E. & Muller, M. J. (1997) Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 25:652-657.[Medline]

9. James, J. H., Ziparo, V., Jeppsson, B. & Fischer, J. E. (1979) Hyperammonaemia, plasma amino acid imbalance, and blood-brain amino acid transport: a unified theory of portal-systemic encephalopathy. Lancet 2:772-775.[Medline]

10. Naylor, C. D., O’Rourke, K., Detsky, A. S. & Baker, J. P. (1989) Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology 97:1033-1042.

11. Fabbri, A., Magrini, N., Bianchi, G., Zoli, M. & Marchesini, G. (1996) Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy. J. Parenter. Enteral Nutr. 20:159-164.[Abstract]

12. Als-Nielsen, B., Koretz, R. L., Kjaergard, L. L. & Gluud, C. (2004) Branched-chain amino acids for hepatic encephalopathy (Cochrane review). The Cochrane Library, Issue 2 2004 John Wiley and Sons Chichester, UK .

13. Ishiki, Y., Ohnishi, H., Muto, Y., Matsumoto, K. & Nakamura, T. (1992) Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 16:1227-1235.[Medline]

14. Tomiya, T., Inoue, Y., Yanase, M., Arai, M., Ikeda, H., Tejima, K., Nagashima, K., Nishikawa, T. & Fujiwara, K. (2002) Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem. Biophys. Res. Commun. 297:1108-1111.[Medline]

15. Fenton, J. C., Knight, E. J. & Humpherson, P. L. (1966) Milk-and-cheese diet in portal-systemic encephalopathy. Lancet 1:164-166.[Medline]

16. Bianchi, G. P., Marchesini, G., Fabbri, A., Rondelli, A., Bugianesi, E., Zoli, M. & Pisi, E. (1993) Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J. Intern. Med. 233:385-392.[Medline]

17. Rossi-Fanelli, F., Riggio, O., Cangiano, C., Cascino, A., De Conciliis, D., Merli, M., Stortoni, M., Giunchi, G. & Capocaccia, L. (1982) Branched-chain amino acids vs. lactulose in the treatment of hepatic coma. A controlled study. Dig. Dis. Sci. 27:929-935.[Medline]

18. Wahren, J., Denis, J., Desurmont, P., Eriksson, L. S., Escoffier, J. M., Gauthier, A. P., Hagenfeldt, L., Michel, H. & Opolon, P., et al (1983) Is intravenous administration of branched chain amino acids effective in the treatment of hepatic encephalopathy?. A multicenter study. Hepatology 3:475-480.

19. Michel, H., Bories, P., Aubin, J. P., Pomier-Layrargues, G., Bauret, P. & Bellet-Herman, H. (1985) 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 5:282-289.[Medline]

20. Cerra, F. B., Chung, N. K., Fischer, J. E., Kaplowitz, N., Schiff, E. R., Dienstag, J. L., Bower, R. H., Mabry, C. D., Leevy, C. M. & Kiernan, T. (1985) Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind controlled trial. J. Parenter. Enteral Nutr. 9:288-295.[Abstract]

21. Fiaccadori, F., Ghinelli, F., Pedretti, G., Pelosi, G., Sacchini, D., Zeneroli, M. L., Rocchi, E., Gibertini, P. & Ventura, E. (1985) Branched-chain enriched amino acid solutions in the treatment of hepatic encephalopathy: a controlled trial. Ital. J. Gastroenterol. 17:5-10.

22. Strauss, E., dos Santos, W. R., da Silva, E. C., Lacet, C. M., Capacci, M.L.L. & Bernardini, A. P. (1986) Treatment of hepatic encephalopathy: a randomized clinical trial comparing branched chain enriched amino acid solution to oral neomycin. Nutr. Supp. Services 6:18-21.

23. Vilstrup, H., Gluud, C., Hardt, F., Kristensen, M., Køler, O., Melgaard, B., Dejgaard, A., Hansen, B. E. & Krintel, J. J., et al (1990) Branched chain enriched amino acids versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. J. Hepatol. 10:291-296.[Medline]

24. Eriksson, L. S., Persson, A. & Wahren, J. (1982) Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut 23:801-806.[Abstract/Free Full Text]

25. Sieg, A., Walker, S., Czygan, P., Gärtner, U., Lanzinger-Rossnagel, G., A., S. & Kommerell, B. (1983) Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. Z. Gastroenterol. 21:644-650.[Medline]

26. Simko, V. (1983) Long-term tolerance of a special amino acid oral formula in patients with advanced liver disease. Nutr. Rep. Int. 27:765-773.

27. McGhee, A., Henderson, M., Millikan, W. J., Bleier, J. C., Vogel, R., Kassouny, M. & Rudman, D. (1983) 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. 197:288-293.[Medline]

28. Horst, D., Grace, N. D., Conn, H. O., Schiff, E., Schencker, S., Viteri, A., Law, D. & Atterbury, C. E. (1984) Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy. Hepatology 4:279-287.[Medline]

29. Guarnieri, G. F., Toigo, R., Situlin, R., Pozzato, G., Faccini, L., Marini, R., Giuntini, D., Parco, S. & Lucchesi, A., et al (1984) Muscle biopsy study on malnutrition in patients with liver cirrhosis. Capocaccia, L. Fischer, J. E. Rossi-Fanelli, F. eds. Hepatic Encephalopathy in Chronic Liver Failure 1984:193-209 Plenum Press New York, NY. .

30. Christie, M. L., Sack, D. M., Pomposelli, J. & Horst, H. (1985) Enriched branched-chain amino acid formula vs. a casein-based supplement in the treatment of cirrhosis. J. Parenter. Enteral Nutr. 9:671-678.[Abstract]

31. Egberts, E. H., Schomerus, H., Hamster, W. & Jürgens, P. (1985) Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled cross-over study. Gastroenterology 88:887-895.[Medline]

32. Fiaccadori, F., Elia, G. F., Lehndorff, H., Merli, M., Pedretti, G., Riggio, O. & Capocaccia, L. (1988) The effect of dietary supplementation with branched-chain amino acids vs. casein in patients with chronic recurrent portal systemic encephalopathy: a controlled trial. Soeters, P. B. Wilson, J.H.P. Meijer, A. J. Holm, E. eds. Advances in Ammonia Metabolism and Hepatic Encephalopathy 1988:489-497 Excerpta Medica Amsterdam, The Netherlands. .

33. Swart, G. R., van den Berg, W. O., van Vuure, J. K., Rietveld, D., Wattimena, D. L. & Frenkel, M. (1989) Minimum protein requirements in liver cirrhosis determined by nitrogen balance measurements at three levels of protein intake. Clin. Nutr. 8:329-336.[Medline]

34. Marchesini, G., Dioguardi, F. S., Bianchi, G. P., Zoli, M., Bellati, G., Roffi, L., Martines, D. & Abbiati, R. & the Italian Multicenter Study Group (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. J. Hepatol. 11:92-101.[Medline]

35. Marchesini, G., Bianchi, G., Merli, M., Amodio, P., Panella, C., Loguercio, C., Rossi Fanelli, F. & Abbiati, R. (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792-1801.[Medline]

36. Chawla, R. K., Wolf, D. C., Kutner, M. H. & Bonkovsky, H. L. (1989) Choline may be an essential nutrient in malnourished patients with cirrhosis. Gastroenterology 97:1514-1520.[Medline]

37. Lieber, C. S. (2000) Alcoholic liver disease: new insights in pathogenesis lead to new treatments. J. Hepatol. 32:113-128.[Medline]

38. Marsano, L. & McClain, C. J. (1991) Nutrition and alcoholic liver disease. J. Parenter. Enteral Nutr. 15:337-344.[Abstract]

39. Marchesini, G., Bianchi, G., Lucidi, P., Villanova, N., Zoli, M. & De Feo, P. (2004) Plasma ghrelin concentrations, food intake, and anorexia in liver failure. J. Clin. Endocrinol. Metab. 89:2136-2141.[Abstract/Free Full Text]

40. Merli, M., Nicolini, G., Angeloni, S. & Riggio, O. (2002) Malnutrition is a risk factor in cirrhotic patients undergoing surgery. Nutrition 18:978-986.[Medline]

41. Fan, S. T., Lo, C. M., Lai, E. C., Chu, K. M., Liu, C. L. & Wong, J. (1994) Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N. Engl. J. Med. 331:1547-1552.[Abstract/Free Full Text]

42. The San-in Group of Liver Surgery (1997) Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. Br. J. Surg. 84:1525-1531.[Medline]

43. Poon, R. T., Yu, W. C., Fan, S. T. & Wong, J. (2004) Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment. Pharmacol. Ther. 19:779-788.[Medline]

44. Chin, S. E., Shepherd, R. W., Thomas, B. J., Cleghorn, G. J., Patrick, M. K., Wilcox, J. A., Ong, T. H., Lynch, S. V. & Strong, R. (1992) Nutritional support in children with end-stage liver disease: a randomized crossover trial of a branched-chain amino acid supplement. Am. J. Clin. Nutr. 56:158-163.[Abstract/Free Full Text]

45. Reilly, J., Mehta, R., Teperman, L., Cemaj, S., Tzakis, A., Yanaga, K., Ritter, P., Rezak, A. & Makowka, L. (1990) Nutritional support after liver transplantation: a randomized prospective study. J. Parenter. Enter Nutr. 14:386-391.[Abstract]

46. Bilbao, I., Armadans, L., Lazaro, J. L., Hidalgo, E., Castells, L. & Margarit, C. (2003) Predictive factors for early mortality following liver transplantation. Clin. Transplant. 17:401-411.[Medline]

47. Luzi, L., Perseghin, G., Regalia, E., Sereni, L. P., Battezzati, A., Baratti, D., Bianchi, E., Terruzzi, I. & Hilden, H., et al (1997) Metabolic effects of liver transplantation in cirrhotic patients. J. Clin. Invest. 99:692-700.[Medline]

48. Tietge, U. J., Bahr, M. J., Manns, M. P. & Boker, K. H. (2003) Hepatic amino-acid metabolism in liver cirrhosis and in the long-term course after liver transplantation. Transpl. Int. 16:1-8.[Medline]

49. Ijichi, C., Matsumura, T., Tsuji, T. & Eto, Y. (2003) Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system. Biochem. Biophys. Res. Commun. 303:59-64.[Medline]

50. Charlton, M. (2003) Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives. Gastroenterology 124:1980-1982.[Medline]




This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
M. P. Engelen, E. P. Rutten, C. L. De Castro, E. F. Wouters, A. M. Schols, and N. E. Deutz
Supplementation of soy protein with branched-chain amino acids alters protein metabolism in healthy elderly and even more in patients with chronic obstructive pulmonary disease
Am. J. Clinical Nutrition, February 1, 2007; 85(2): 431 - 439.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
D. R. Mager, L. J. Wykes, E. A. Roberts, R. O. Ball, and P. B. Pencharz
Branched-Chain Amino Acid Needs in Children with Mild-to-Moderate Chronic Cholestatic Liver Disease
J. Nutr., January 1, 2006; 136(1): 133 - 139.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marchesini, G.
Right arrow Articles by Bianchi, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchesini, G.
Right arrow Articles by Bianchi, G.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]