ReviewBranched-chain amino acid supplementation in treatment of liver cirrhosis: Updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation
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.
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The present work was supported by the program PROGRES Q40/02 of the Charles University, Faculty of Medicine in Hradec Kralove.