The effect of malnutrition on survival in patients with decompensated liver cirrhosis has not been well defined. Nutritional intervention with branched-chain amino acid (BCAA) can increase serum albumin concentration in patients with decompensated cirrhosis but its effects on survival are unclear. The BCAA to tyrosine ratio (BTR) is a surrogate marker (the normal range of BTR is between 4.41 and 10.05, and a Fischer’s ratio of 1.8 corresponds to a BTR of 3.5) in patients with decompensated liver cirrhosis, and BCAA inhibits hepatic carcinogenesis in patients with compensated cirrhosis. This review discusses data regarding the effect of early administration of BCAA granules based on the ratio of BCAA to BTR on prognosis in patients with cirrhosis.

The liver plays a key role in nutrient metabolism, and patients with cirrhosis may develop various metabolism and nutrition disorders. In fact, many cirrhosis patients suffer from protein-energy malnutrition (PEM)[1], which is particularly pronounced in the decompensated stage. Correction of PEM can improve prognosis in patients with decompensated cirrhosis[2]. Patients with cirrhosis and decreased plasma branched-chain amino acid (BCAA) levels can develop PEM with increased catabolism[3].

PEM is associated with a high morbidity and mortality due to an increased risk of life-threatening complications, resulting in poor survival and poor quality of life (QoL)[4,5].

BCAAs are a group of essential amino acids, including valine, leucine, and isoleucine. A low plasma level ratio of BCAAs to aromatic amino acids suggests the presence of liver cirrhosis, and BCAA supplementation was originally developed in order to normalize the patient’s amino acid profile and nutritional status[6].

This article summarizes the findings of previous studies to determine whether nutritional intervention with a granulated BCAA preparation can contribute to improved prognosis of patients with PEM and cirrhosis.

In Japan, oral BCAA preparations are used in nutritional therapy to correct protein and amino acid abnormalities in patients with cirrhosis. Moreover, enteral nutrition guidelines published by the European Society for Clinical Nutrition and Metabolism list BCAA supplementation as a grade B recommendation in the treatment of advanced cirrhosis[7].

BCAA supplementation effectively increases Fischer’s ratio and improves hypoalbuminemia in patients with liver cirrhosis[8]. In addition, not only does BCAA serve as components of albumin, the activation by L-leucine of mammalian target of rapamycin in hepatocytes and the subsequent activation of albumin mRNA transcription and protein synthesis in ribosomes are thought to constitute the mechanism for albumin increase[9,10]. This increase in albumin has been verified in various clinical trials to be effective for improving hypoalbuminemia[8,11].

Oral BCAA preparations come in two dosage forms: enteral nutrition formulas (or elemental diet products) for liver failure and oral BCAA granules. In 1996, an oral BCAA granule product containing valine, leucine, and isoleucine (Val, Leu, Ile) in a composition ratio of 1:2:1.2 was marketed in Japan (Livact^®, Ajinomoto Pharmaceuticals, Tokyo, Japan). This product is indicated for decompensated cirrhosis patients who have hypoalbuminemia despite adequate dietary intake.

An Italian research group reported a multicenter randomized trial in which a total of 174 patients with advanced liver cirrhosis were given BCAA as a supplement for 1 year and its effects were compared with administration of lactalbumin or maltodextrin[12]. Long-term use of a BCAA granule preparation has been reported to increase serum albumin and to inhibit the incidence of events related to poor prognosis[8,12].

Moreover, Marchesini et al[12] analyzed whether oral BCAA might prevent progressive liver failure and improve nutritional parameters and quality of life.

They conclude that long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve health status ,and recommend that new formulas are needed to increase compliance. An oral BCAA granule (Livact^®, Ajinomoto Pharmaceuticals, Tokyo, Japan) is the form of small uniform granules, which reduces BCAA-induced stimulation of taste buds and contributes to improve compliance.

Kobayashi et al[13] conducted a study of patients with compensated cirrhosis caused by hepatitis C. After a mean follow-up of 3.2 years, the authors reported that the incidence of hepatocellular carcinoma (HCC) among men with a baseline serum albumin level of 3.6 to 4.0 g/dL tended to be lower in the BCAA granule treatment group than in the control group. A large-scale postmarketing clinical study conducted at 89 sites in Japan to determine the effects of BCAA granules on the prognosis of cirrhosis patients [Long-term Survival Study (LOTUS)] demonstrated that the onset of complications associated with poor prognosis (i.e., liver failure, ruptured esophageal varices, HCC, and death) was significantly lower among patients in the BCAA granule treatment group than in the dietary therapy group (hazard ratio: 0.67; 95% CI: 0.49-0.93)[8]. Furthermore, stratified analysis of the LOTUS study for groups at high risk for HCC, specifically, patients with a body mass index ≥ 25 kg/m² or elevated alpha-fetoprotein, showed that BCAA granules had an inhibitory effect on the incidence of HCC[14]. Meanwhile, a study by Tsuchiya et al[15] on radical therapy for HCC patients reported that long-term treatment with BCAA granules reduced the rate of the third and subsequent relapses of HCC and improved the cumulative rate of survival in patients with baseline serum albumin ≤ 3.5 g/dL. Sato et al[16] undertook a comparative study of dietary control protocols and found that a BCAA granule product and an enteral nutrient for liver failure (or an elemental diet product) had similar effects in terms of improving or maintaining serum albumin and preventing the onset of hepatic encephalopathy. The authors reported that, despite control of the total dietary energy intake, an increase in glycosylated hemoglobin and other markers of abnormal glucose tolerance occurred in the enteral nutrient group, whereas these unfavorable changes were not observed in the BCAA granule treatment group[16].

Moreover, Hayaishi et al[17] reported that Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis.

Based on these findings, a BCAA granule preparation (Livact^®) has been now recommended in the guidelines for the treatment of liver cirrhosis by the Study Group for the Standardization of Treatment of Viral Hepatitis Including from the Ministry of Health, Labour and Welfare in Japan in order to increase serum albumin in cirrhosis patients with the aim of reducing the onset of cancer[18] (Table 1).

On the other hand, because some patients do not exhibit any increase in serum albumin after taking BCAA granules, further research has been conducted on the dietary intake and baseline characteristics of these patients. Yatsuhashi et al[19] reported that the anti-hypoalbuminemic effect of BCAA granules was not influenced by dietary intake and that continued use of BCAA significantly reduced the incidence of ascites and edema even in patients whose serum albumin did not respond to BCAA granule treatment.

One possible explanation for the significant decline in ascites and edema in the unchanged serum albumin group could be that the BCAA granules improved albumin quality. The sulfhydryl group of the cysteine 34 residue in human serum albumin can exist in a reduced state (reduced albumin) or oxidized state (oxidized albumin). In patients with chronic liver disease, however, the proportion of oxidized albumin increases as the condition progresses[20]; this is associated with body fluid retention, such as ascites and edema. Furthermore, BCAA granules reduce the ratio of oxidized albumin in decompensated cirrhosis patients[21]. These findings suggest that the use of BCAA granules is important in maintaining serum albumin and that its continued use can improve the prognosis of patients with decompensated cirrhosis[22-25].

However, the therapeutic effects of BCAA granules can take longer to appear in patients with advanced decompensated cirrhosis, making it important to determine the optimal timing for administration. After examining the biochemical test results of decompensated cirrhosis patients, Kato et al[26] identified the following four characteristics of uncompensated cirrhosis, and thus, the proper time to begin administration of BCAA granule preparations: (1) serum albumin ≤ 3.5 g/dL; (2) BCAA to tyrosine ratio (BTR) ≤ 3.5; (3) prothrombin activity ≤ 60%; and (4) platelet count of ≤ 100 000/mm³. This in turn led to the search for markers of cirrhosis in order help facilitate determination of the optimal timing to initiate treatment with BCAA granules.

Cirrhosis patients exhibit shifts in their plasma free amino acid concentration, marked declines in BCAA (Val, Leu, Ile), and increases in aromatic amino acids (AAA; tyrosine, phenylalanine) and methionine, whereas their Fischer’s ratio (ratio of molar concentrations of BCAA:AAA) or BTR declines in conjunction with disease severity. Fischer’s ratio has long been used to analyze plasma free amino acids[27], but the BTR is a simpler method. Azuma et al[28] reported that the BTR based on an enzymatic method serves as an alternative to Fischer’s ratio and is a potential indicator of liver disorders as well as subsequent chronic liver disease progression.

In the event of malnutrition, the BTR also declines before the serum albumin declines; therefore, determining the BTR is useful for the early detection of potential hypoalbuminemia. In other words, calculating the BTR enables the prediction of serum albumin level changes[29] and therefore allows determination of the appropriate time to administer BCAA granules. Given this time lag between decreases in serum albumin and BTR, monitoring of BTR needs to be done separately from that of albumin when considering prognostic factors for decompensated cirrhosis. The benefits of administering an oral BCAA preparation in patients with decreased BTR have already been reported in a large-scale clinical study[8]. This also implies that the BTR has considerable potential as a prognostic factor of HCC in decompensated cirrhosis patients. In fact, many reports performed the usefulness of BCAA for the treatment of hepatocellular carcinoma[30-39]. So, BTR may be useful as an indicator of prognosis in patients with HCC[40]. Early administration of BCAA granules based on the ratio of BCAA to tyrosine can improve the prognosis of decompensated cirrhosis.

In conclusion, BCAA supplementation for liver disorders may be expected not only to increase serum albumin, but also to exert other effects, such as prolongation of survival among liver cirrhosis patients, prevention of liver cancer, and enhancement of QoL. However, in cases of severe decompensated liver cirrhosis, determination of the timing of administration is also an important issue because BCAA granules take time to take effect. The decrease in BTR precedes reductions in serum albumin. While early therapeutic intervention with BCAA granules can help improve the prognosis of patients with decompensated cirrhosis and low BTR, more research and analysis are needed to fully explore the novel effects of BCAA granule preparations.