Elsevier

Nutrition

Volume 41, September 2017, Pages 80-85
Nutrition

Review
Branched-chain amino acid supplementation in treatment of liver cirrhosis: Updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation

https://doi.org/10.1016/j.nut.2017.04.003Get rights and content

Highlights

  • The branched-chain amino acids (BCAAs) enhance ammonia detoxification to glutamine (GLN).

  • Adverse side effects may be associated with use of BCAAs in the treatment of cirrhosis.

  • Adverse side effects are cataplerosis, altered neurotransmission, and GLN catabolism to ammonia.

  • Attenuation of adverse effects is needed to enhance therapeutic potential of the BCAA.

Abstract

Branched-chain amino acid (BCAA; valine, leucine, and isoleucine) supplementation is common for patients with liver cirrhosis due to decreased levels of BCAA in the blood plasma of these patients, which plays a role in pathogenesis of hepatic encephalopathy and cachexia. The unique pharmacologic properties of BCAA also are a factor for use as supplementation in this population. In the present article, BCAA is shown to provide nitrogen to alpha-ketoglutarate (α-KG) for synthesis of glutamate, which is a substrate for ammonia detoxification to glutamine (GLN) in the brain and muscles. The article also demonstrates that the favorable effects of BCAA supplementation might be associated with three adverse effects: draining of α-KG from tricarboxylic acid cycle (cataplerosis), increased GLN content and altered glutamatergic neurotransmission in the brain, and activated GLN catabolism to ammonia in the gut and kidneys. Cataplerosis of α-KG can be attenuated by dimethyl-α-ketoglutarate, l-ornithine-l-aspartate, and ornithine salt of α-KG. The pros and cons of GLN elimination from the body using phenylbutyrate (phenylacetate), which may impair liver regeneration and decrease BCAA levels, should be examined. The therapeutic potential of BCAA might be enhanced also by optimizing its supplementation protocol. It is concluded that the search for strategies attenuating adverse and increasing positive effects of the BCAA is needed to include the BCAA among standard medications for patients with cirrhosis of the liver.

Introduction

A hallmark of cirrhosis of the liver is a decrease in branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in blood plasma caused by enhanced consumption of BCAA in ammonia detoxification to glutamine (GLN) in skeletal muscle [1], [2], [3], [4]. Decreased BCAA levels also could be caused by activation of the branched-chain α-ketoacid dehydrogenase by cytokines and cortisol [5], [6] and by impaired reamination of branched-chain keto acids (BCKA) by the cirrhotic liver, which is activated in other catabolic conditions [7], [8]. A decrease in BCAA is not observed in acute liver damage due to a leak of amino acids from the hepatocytes into circulation [9].

Decreased BCAA levels and the hypothesis that correction of the decreased ratio of BCAA to aromatic amino acids (AAA; tyrosine and phenylalanine) may improve symptoms of hepatic encephalopathy (HE) were the main stimuli for investigations of the therapeutic use of BCAA in patients with liver cirrhosis [10]. Potential benefits of BCAA administration include also their positive effects on protein balance, liver regeneration, albumin synthesis, physical and mental fatigue, and immune function [11], [12].

Unfortunately, although there is a good theoretical rationale to administer the BCAA to patients with liver disease, to our knowledge, the results of clinical trials do not provide strong evidence of their therapeutic effectiveness. There are two Cochrane reviews evaluating the results of trials assessing the effects of BCAA supplementation in patients with HE. The authors of the analysis, which was published in 2003, conclude that there is no convincing evidence of the beneficial effects of BCAA on patients with HE [13]. Conclusions of a recent review determined that BCAA had a beneficial effect on HE, but no effect on mortality, quality of life, or nutritional parameters [14].

In recent articles [15], [16], the relationship between BCAA and ammonia metabolism in liver disease have been explained and some strategies to enhance their therapeutic properties suggested. The present review explored why the results of clinical trials indicate poor evidence of the benefits of BCAA supplementation and provided updated views on how to enhance their therapeutic effectiveness in liver cirrhosis.

Section snippets

Effects of BCAA on ammonia levels in the blood

It is scientific consensus that ammonia plays the main role in pathogenesis of HE, thus most strategies for treatment of HE are targeted at decreasing ammonia. A Medline search found only 14 studies [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30] of the effects of BCAA on ammonia and their reports are contradictory. Five studies indicated that administration of BCAA has no effect or decreases ammonia (Table 1 [17], [18], [19], [20], [21]) and nine studies

Increasing ammonia detoxification to GLN and avoiding cataplerosis

Two tips how to enhance ammonia detoxification to GLN and simultaneously attenuate α-KG drain from TCA cycle can be suggested (Fig. 3).

Attenuating ammonia production from GLN

The present possibilities attenuating ammonia production from GLN include decreasing GLN consumption or enhancing GLN elimination from the body by phenylbutyrate/phenylacetate treatment. Because GLN is present in high amounts in most of foodstuffs, its restriction is applicable only in patients fed by artificial diets.

Optimizing BCAA dose

The approximate daily intake of the BCAA (∼180 mg/kg) is much more than what is estimated for a healthy individual (∼84 mg/kg) [65]. Therefore, no matter what the dose is, BCAA supplementation for healthy individuals enhances production of BCKA, alanine, and GLN in muscles and urea in the liver [66]. Assuming that the Fischer's hypothesis of the role of decreased BCAA-to-AAA ratio in pathogenesis of HE is correct, the dose of the BCAA for patients with cirrhosis should be sufficient to

Combining BCAA supplementation with strategies to decrease ammonia levels

Studies are needed to evaluate the effect of combining BCAA with other interventions to decrease ammonia levels, such as nonabsorbable disaccharides, rifaximin, or molecular adsorbent regulating system. Some reports support this suggestion. More improvement in blood ammonia and the Fischer ratio occurred in patients with cirrhosis after administration of BCAA with zinc than after BCAA alone [71]; in patients with cirrhosis and hepatic coma, a significant decrease of ammonia was observed after

Conclusion

Strategies to attenuate adverse effects of BCAA on cataplerosis and ammonia production from GLN and to increase their positive effects are needed in order to include BCAA among standard medications for patients with cirrhosis of the liver.

References (72)

  • M. Holecek et al.

    Leucine metabolism in rats with cirrhosis

    J Hepatol

    (1996)
  • A. Watanabe et al.

    Ammonia detoxification by accelerated oxidation of branched chain amino acids in brains of acute hepatic failure rats

    Biochem Med Metab Biol

    (1986)
  • R.M. Salloum et al.

    Dietary modulation of small intestinal glutamine transport in intestinal brush border membrane vesicles of rats

    J Surg Res

    (1990)
  • M. Romero-Gomez et al.

    Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy

    J Hepatol

    (2004)
  • U. Staedt et al.

    Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

    J Hepatol

    (1993)
  • S. Dadsetan et al.

    Interorgan metabolism of ornithine phenylacetate (OP)—a novel strategy for treatment of hyperammonemia

    Biochem Pharmacol

    (2013)
  • A.V. Kurpad et al.

    Branched-chain amino acid requirements in healthy adult human subjects

    J Nutr

    (2006)
  • Y. Nakaya et al.

    Hepatic Nutritional Therapy (HNT) study group. BCAA-enriched snack improves nutritional state of cirrhosis

    Nutrition

    (2007)
  • M. Holecek et al.

    Plasma amino acids in four models of experimental liver injury in rats

    Amino Acids

    (1996)
  • M. Holecek et al.

    Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle

    Amino Acids

    (2011)
  • M.D. Nawabi et al.

    Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase

    J Clin Invest

    (1990)
  • M. Holecek et al.

    Metabolism of branched-chain amino acids in starved rats: The role of hepatic tissue

    Physiol Res

    (2001)
  • M. Holecek et al.

    Plasma amino acid levels after carbon tetrachloride induced acute liver damage. A dose-response and time-response study in rats

    Amino Acids

    (1999)
  • J.M. Davis et al.

    Serotonin and central nervous system fatigue: nutritional considerations

    Am J Clin Nutr

    (2000)
  • B. Als-Nielsen et al.

    Branched-chain amino acids for hepatic encephalopathy

    Cochrane Database Syst Rev

    (2003)
  • L.L. Gluud et al.

    Branched-chain amino acids for people with hepatic encephalopathy

    Cochrane Database Syst Rev

    (2015)
  • D. Horst et al.

    Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial

    Hepatology

    (1984)
  • F.L. Weber et al.

    Effects of branched-chain amino acids on nitrogen metabolism in patients with cirrhosis

    Hepatology

    (1990)
  • P. Rigotti et al.

    Infusion of branched-chain amino acids and ammonium salts in rats with portacaval shunts

    Arch Surg

    (1985)
  • A. Watanabe et al.

    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 Med Okayama

    (1983)
  • Y. Nishikawa et al.

    Administration of a branched-chain amino acid preparation during hepatic failure: a study emphasizing ammonia metabolism

    Acta Med Okayama

    (1994)
  • G. Dam et al.

    Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects

    Am J Physiol

    (2011)
  • P. Watson et al.

    The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment

    Eur J Appl Physiol

    (2004)
  • E.F. De Palo et al.

    Branched-chainα-amino acid chronic treatment: Responses of plasma α-keto-related compounds and ammonia when used in physical exercise performance

    Amino Acids

    (1996)
  • K. Madsen et al.

    Effects of glucose, glucose plus branched-chain amino acids, or placebo on bike performance over 100 km

    J Appl Physiol

    (1996)
  • D.A. MacLean et al.

    Stimulation of muscle ammonia production during exercise following branched-chain amino acid supplementation in humans

    J Physiol

    (1996)
  • Cited by (65)

    • Hepatic effects of rumen-protected branched-chain amino acids with or without propylene glycol supplementation in dairy cows during early lactation

      2021, Journal of Dairy Science
      Citation Excerpt :

      Previous studies have showed that supplementation with BCAA alone reduced hepatic TG in rodents and humans with nonalcoholic fatty liver (Muto et al., 2006; Arakawa et al., 2011; Honda et al., 2017). Suppression of gene and protein expression of fatty-acid synthase (Holeček, 2017), or upregulation of the hepatic sterol regulatory element-binding protein/liver x receptor pathway (Nishimura et al., 2010) could explain this effect. Oral administration of PG during 3 d postpartum did not produce a significant reduction in hepatic TG accumulation (Pickett et al., 2003; Mann et al., 2018).

    • Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis

      2021, Gastroenterology
      Citation Excerpt :

      Firm conclusions regarding the role of these metabolites in PSC in humans would require an interventional trial with, for example, supplementation,41 while the potential clinical value of vitamin B6 or BCAAs as predictive biomarkers in PSC would require independent validation studies. Notably, because deficiencies of vitamin B6 and BCAAs have been observed in liver diseases of several etiologies, similar gut microbiome–related modifier effects may be seen also in other liver diseases.37,42 For other measured metabolites, the relationship between the gut microbiome and plasma levels was less obvious.

    View all citing articles on Scopus

    The present work was supported by the program PROGRES Q40/02 of the Charles University, Faculty of Medicine in Hradec Kralove.

    View full text