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The relationship between intake of nutrients and Hepatic Encephalopathy (HE) dates back to the historical roots of experimental hepatology. Branched-Chain Amino Acids (BCAA; Isoleucine, leucine and valine) have attracted particular interest and in 1956 Müting described the amino acid pattern in patients with cirrhosis. The abnormal plasma pattern has been characterized by the ratio between BCAA and aromatic amino acids in plasma, the so called 'Fischer´s ratio'. This ratio has been associated with the grade of HE. Under normal conditions, ammonia detoxification predominantly takes place in the liver. When the liver fails, the homeostasis is altered and muscle tissue becomes the main alternative organ for at least temporary detoxification of ammonia. BCAA are believed to support this muscle ammonia detoxification and the ammonia lowering effect of BCAA has been intensely investigated. In this review the effect of BCAA on muscle ammonia metabolism and the protein sparing and anabolic effects of BCAA are discussed. A Cochrane metaanalysis showed that BCAA had beneficial effects on HE with a number needed to treat of 5 patients (RR 0.73, 95% CI 0.61 to 0.88). The combined evidence suggests that although the pathophysiology is poorly understood, there is evidence to support clinical benefits of BCAA. BCAAs enhance muscle mass and exert anabolic effects via stimulation of protein synthesis. The beneficial long-term effects of BCAA on HE could be related to these effects and not only related to Branched-Chain Amino Acid increased ammonia metabolism.
The relationship between intake of nutrients and Hepatic Encephalopathy (HE) dates back to the historical roots of experimental hepatology. In Saint Petersburg in 1893, behavioral scientists Pavlov and colleagues described how dogs with a portacaval shunt (Eck’s fistula) developed ataxia and coma when being fed with meat.
They found that the behavioral changes reversed when the dogs were switched to dairy products, which we now know contain a high level of the Branched-Chain Amino Acids (BCAA) valine, isoleucine and leucine. In 1956 Müting found that cirrhosis was associated with low BCAA levels in plasma.
The decreased BCAA concentrations combined with elevated concentrations of the aromatic amino acids (AAA) tyrosine and phenylalanine) were later confirmed in several other publications. The abnormal plasma amino acid pattern has been characterized by the ratio between BCAA and AAA in plasma, the so called ‘Fischer´s ratio’. This ratio has been associated with the grade of HE.
Both groups of amino acids compete for entry across the blood–brain barrier by the same transporter leading to an increased concentration of aromatic neurotransmitter precursors. These precursors were believed to cause an inefficient (‘false’) dopaminergic neurotransmission and inhibition of dopamine synthesis resulting in the neuro-depression seen in HE.
Although subsequent studies were unable to confirm this theory, BCAAs were continuously used as a pharmacological nutrient for patients with chronic liver disease. However, increasing evidence now suggests that BCAA is beneficial in HE but the mechanism of action seems to be different than primarily assumed. It is now believed that the beneficial effect of BCAA is associated with ammonia detoxification outside the liver, predominantly in muscles.
Under normal physiological conditions the key part of ammonia detoxification takes place in the liver. The urea cycle runs in periportal hepatocytes and glutamine synthesis in the perivenous hepatocytes. In patients with advanced liver disease, ammonia reaches the systemic circulation due to diminished urea synthesis
This is in contrast to the majority of amino acids which are metabolized mainly in the liver.
The muscle arterial-venous uptake of BCAA increases with the arterial ammonia concentration in patients with decompensated cirrhosis, indicating that muscle BCAA metabolism plays a role for ammonia removal.
This suggests that hyperammonemia lowers the plasma levels of BCAA by increased muscle BCAA uptake and increased glutamine synthesis in muscle. In vitro experiments of muscle metabolism under control of effects of glucose, insulin and pH found that high levels of ammonia increase the oxidation of leucine and the release of glutamine.
Thus, ammonia may lower the plasma levels of BCAA by increasing the intramuscular metabolism by diverting their carbon skeletons and amino-N towards glutamate synthesis and coupling with ammonia for carbamate N in glutamine (Figure 1). In this way, muscular metabolism of BCAA results in muscular export of twice the amount of N and hence removal of ammonia.
BCAA enhance ammonia detoxification in skeletal muscle and thereby reduce plasma ammonia concentration. This leads to the assumption that external replenishment of BCAA further enhances the detoxification of ammonia in muscle.
In 2011 we studied ammonia and amino acid metabolism in muscle before and after ingestion of BCAA in patients with cirrhosis and healthy subjects.
The net metabolism of ammonia across the leg was studied directly by arterial-venous differences and blood flow measurements. Such measurements reflect the combined metabolism of blood-borne (exogenous) ammonia and any contribution to ammonia metabolism from the leg itself (endogenous). To distinguish these effects, the uptake of blood borne ammonia was measured by dynamic 13N-ammonia-PET. We found that the ingestion of BCAA increased the uptake of ammonia by skeletal muscle in all persons, but also increased the blood ammonia concentration. This may reflect that BCAA exert their primary effect on ammonia by stimulation of the intramuscular ammonia metabolism rather than by increasing the metabolism of blood-supplied ammonia.
The baseline muscle uptake of BCAA was similar in cirrhosis patients and healthy subjects. However, cirrhosis patients usually suffer from muscle wasting and the muscle BCAA uptake per kilo muscle was likely higher in the cirrhosis compared to healthy subject who did not have sarcopenia.
All in all, these studies on BCAA supplementation in cirrhosis show effects on blood concentrations of amino acids and ammonia indicating that muscles metabolize more ammonia when BCAA are supplied. The mechanism on the molecular signaling level is not clarified. Skeletal muscle hyperammonemia contributes to the sarcopenia observed in cirrhosis. One possibility is that ammonia affects the mTOR signaling system. Ammonia impairs mTOR signaling that decreases protein synthesis and increases autophagy. Thus, reactivation of mTOR is a potential target to reverse impaired muscle protein synthesis. Leucine in itself is a powerful activator of mTOR and may alleviate the detrimental effects of mTOR inhibition, possibly potentiated by the leucine induced fall in ammonia. This was confirmed by a muscle biopsy study of healthy controls and patients with cirrhosis given an oral leucine supplement. The study found that both the impaired mTOR signaling and the increased autophagy in the skeletal muscle of patients with alcoholic cirrhosis were reversed by Leucin.
Thirty-seven hospitalized patients with protein intolerance were fed weekly with increasing amounts of 20 g of either dietary protein or BCAA until they attained an intake of 80 g/protein per day or until they developed grade 2 HE. The study found that BCAA decreased the occurrence of HE and that both groups improved their nitrogen balance.
An Italian multicenter double-blinded, placebo-controlled and randomized trial with 15 centers was published in 2005.
The study caompared: BCAA, lactoalbumin (isonitrogenous) and maltodextrin (isocaloric) administered to 174 patients. The duration of follow up was one year. The combined risk of HE, ascites formation and death, was significantly lower in the group who received BCAA.
A Japanese multicenter, randomized, and calorie intake–controlled trial was published by Muto in 2005.
The effects of orally administered BCAA 12 g/day for 2 years was compared to diet therapy with defined daily food intake (1.0–1.4 g protein/kg/day and 25–35 kcal/kg/day) in 646 patients with decompensated cirrhosis. 89 centers included patients. BCAA decreased the risk of HE, but the control arm was not isonitrogenous.
Based on these trials, the European Society for Nutrition (ESPEN) recommended BCAA for the improvement of clinical outcome in advanced cirrhosis. The International Society for HE and Nitrogen metabolism (ISHEN) recommends that BCAA supplements may be of value in the occasional patient intolerant of dietary protein.
We evaluated the beneficial and harmful effects of BCAA supplements versus no intervention, placebo or control diets on HE, mortality, nutritional status and adverse events for patients with HE. We found 16 randomized clinical trials comprising 827 participants with HE classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials), lactulose (two trials), or neomycin (two trials). In 15 trials, all participants had cirrhosis.
BCAA had a beneficial effect on hepatic encephalopathy with a number needed to treat of 5 patients (RR 0.73, 95% CI 0.61 to 0.88; 827 participants; 16 trials). We confirmed the beneficial effect of BCAA in a sensitivity analysis that only included trials with a low risk of bias (RR 0.71, 95% CI 0.52 to 0.96). We found no effect on mortality, quality of life, or nutritional measures. Unfortunately, we have no head-to-head trials to compare the effect of BCAAs with the effects of non-absorbable disaccharides (lactulose), rifaximin, or other antibiotics.
The combined evidence suggests that although the pathophysiology is poorly understood, there is evidence to support the clinical benefits of BCAA. BCAAs enhance muscle mass and exert anabolic effects via stimulation of protein synthesis. Furthermore, BCAAs are precursors for protein synthesis, but also stimulate insulin secretion and hepatocyte growth factor which may support both protein synthesis and the liver function. The beneficial long-term effects of BCAA on HE could therefore be related to these effects and not only related to an increase in ammonia metabolism. In our institution we use BCAA as an “add on” to correct lactulose treatment and nutrition if the patients nonetheless have minimal/covert HE, if they are protein intolerant or if they have recurrent HE.
Conflicts of interest
The authors have none to declare.
Die Eck’sche Fistel zwischen der unteren Hohlvene und er pfortader und ihre Folgen fur den Organismus.