THE LIVER IS the major organ for the metabolism of protein, fat and carbohydrate.[1, 2] Cirrhosis, which develops over a long period of time, is frequently complicated with protein–energy malnutrition (PEM).[1, 2] Patients with cirrhosis-associated PEM starve even after a short period of fasting because of the increased energy consumption and decreased glycogen-storage capacity of the liver. The body consumes the endogenous fat as an energy substrate instead of carbohydrate. As a result, fasting hypoglycemia and postprandial hyperglycemia typically occur.[1-4] PEM affects the prognosis by increasing the risk of cirrhosis-associated events and deteriorating the patient's quality of life (QoL), so nutritional treatment is absolutely crucial.[1-3]
The treatment of hepatocellular carcinoma (HCC) has improved appreciably in the past 20–30 years. The current treatment for HCC with established efficacy is: (i) hepatectomy/liver transplantation; (ii) transcatheter arterial chemoembolization (TACE); (iii) percutaneous radiofrequency ablation (RFA); (iv) percutaneous ethanol injection; (v) percutaneous microwave coagulation therapy; and (vi) molecular-targeted therapy (e.g. sorafenib).[5-9] The most suitable treatment should be selected for individual patients based on thorough evaluation of HCC stage (tumor factor) and hepatic functional reserve.[5-10] In general, HCC develops after cirrhosis associated with viral hepatitis or alcoholic liver disease, so treatment of the underlying liver diseases is no less important than HCC treatment.[5-9, 11] Preserving adequate hepatic reserves is necessary after HCC recurrence, which is quite frequent no matter how successful the initial radical treatment for HCC.[12-16]
Branched-chain amino acid (BCAA) granules (Livact; Ajinomoto Pharma, Tokyo, Japan) contain L-valine, L-leucine, and L-isoleucine at a ratio of 1.2:2:1. L-Leucine induces albumin synthesis in hepatic cells via transcription factors such as mammalian target of rapamycin.[1-3, 17] BCAA granules were developed originally for the treatment of hypoalbuminemia associated with decompensated cirrhosis. However, subsequent studies found various other pharmacological actions of this drug. Therapy using BCAA granules improves hypoalbuminemia.[16-19] In addition, such therapy also inhibits cirrhosis-related complications such as esophageal varices and ascites,[17, 18, 20] reduces insulin resistance[17, 21, 22] and oxidative stress,[17, 23] improves fatty-acid metabolism,[17, 24] stimulates the immune system,[17, 25, 26] and inhibits angiogenesis.[17, 21, 27] The most noteworthy pharmacological action of BCAA granules, however, is the inhibition of hepatic carcinogenesis (Table 1).[17, 19, 20, 22, 27-29] Based on the significant inhibition of hepatic carcinogenesis observed after therapy using BCAA granules in patients with liver cirrhosis with a body mass index of 25 kg/m2 or more shown in a multicenter, randomized, placebo-controlled study (the Lotus Study), the 2010 guidelines for comprehensive treatment of hepatitis virus-related cirrhosis in Japanese patients recommend the use of BCAA granules to preserve liver function and inhibit hepatic carcinogenesis.[16-19, 28, 30] Conversely, the American Society for Parental and Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and Metabolism recommend that BCAA supplementation be carried out only in cirrhotic patients with chronic hepatic encephalopathy that is refractory to pharmacotherapy.[31, 32]
Here, we review the clinical significance of therapy using BCAA granules in different treatment approaches for cirrhosis and HCC (i.e. hepatectomy, liver transplantation, RFA, TACE and molecular-targeted agents) mainly based on the published work as well as our own data published between 1997 and 2013. We searched the published work in the PubMed database, and the search strategy was based on the following terms: “branched-chain amino acid”, “liver cirrhosis”, “liver function”, “complication”, “clinical outcome”, “carcinogenesis”, “hepatocellular carcinoma”, “recurrence”, “hepatectomy”, “liver transplantation”, “RFA”, “TACE” and “molecular-targeted therapy”.
Significance of cirrhosis treatment with BCAA granules
In cirrhotic patients, the plasma level of BCAA is positively correlated with the serum albumin level. Such a correlation is seen only in patients with chronic liver diseases such as cirrhosis. The albumin–BCAA correlation and the inability of cirrhotic patients to maintain an adequate plasma level of BCAA with diet alone serve as the theoretical rationale for the use of BCAA granules for the treatment of cirrhosis. In cirrhotic patients, BCAA uptake in skeletal muscle is increased for ammonia detoxification and energy production and, in turn, the plasma level of BCAA and albumin production decrease.[1-3]
Yatsuhashi et al. conducted a prospective multicenter study in 204 patients with decompensated cirrhosis and reported a mean increase in the serum albumin level of 0.2 g/dL after 6 months of treatment with BCAA granules as well as a significant increase in the serum albumin level in patients with intake of a poor diet (poor intake of energy). Therapy using BCAA granules also significantly decreased the incidence of ascites even in patients with an unchanged serum albumin level because of qualitative improvement of the serum albumin level (specifically, an increase in the level of reduced albumin and decrease in the level of oxidized albumin).[33-35]
The importance of treatment compliance was suggested in a study conducted by Takaguchi et al. That prospective, large-scale, multicenter, observational study in 2894 patients with decompensated cirrhosis reported that the incidence of cirrhosis-associated events was decreased significantly in patients with good adherence to BCAA treatment compared with those with poor adherence. The authors emphasized the importance of thorough instruction regarding medications to patients.
The appropriate timing of the initiation of BCAA treatment is controversial. The approved indication of BCAA granules in Japan is for the treatment of decompensated cirrhosis in patients with a serum albumin level of 3.5 g/dL or less, and the Japanese Nutritional Study Group for Liver Cirrhosis has also recommended that BCAA granules should be administrated in cirrhotic patients with a serum albumin level of 3.5 g/dL or less, Fisher's ratio of 1.8 or less and/or BCAA : tyrosine ratio (BTR) of 3.5 or less. Hence, therapy using BCAA granules is, in general, started when the serum albumin level is 3.5 g/dL or less in clinical settings.[11, 37] However, earlier initiation of BCAA treatment has been attempted in cirrhotic patients with a serum albumin level of 3.6 g/dL or more. Habu et al. classified their patients into four treatment arms based on their serum albumin level and the BTR. The decrease in the serum albumin level was inhibited after therapy using BCAA granules even in patients with a serum albumin level of 3.6 g/dL or more if their BTR was 4 or less, so the authors highlighted the usefulness of early intervention with BCAA granules.[38, 39] A prospective, multicenter study in Japanese patients with hepatitis C virus-related decompensated cirrhosis with a serum albumin level of 3.6 g/dL or more complicated with insulin resistance (BCAA Granules for patients with Hepatitis C virus-related Liver Cirrhosis and Insulin Resistance on the Effect of Reduction of Carcinogenic Risk in the Liver [BLOCK] study, Japan Liver Oncology Group [JLOG] 1004 Trial) is ongoing. If the superiority of therapy using BCAA granules is demonstrated in that study, BCAA granules will become available for a wider range of cirrhotic patients.
As mentioned above, BCAA granules can inhibit hepatic carcinogenesis.[17, 19, 20, 22, 27-29] Several reports have focused on the usefulness of BCAA granules for the inhibition of liver carcinogenesis through improvement of insulin resistance.[17, 21, 22] Insulin and insulin-like growth factor (IGF) can promote the growth of HCC. Kawaguchi et al. reported that BCAA granules suppress liver carcinogenesis through amelioration of insulin resistance via: (i) BCAA activation of the insulin signaling cascade through upregulation of phosphatidylinositol 3-kinase with reduction of serum insulin levels; and (ii) inhibition of the IGF/IGF-1 receptor axis by suppressing the expressions of IGF-1, IGF-2 and IGF-1 receptor mRNA.[17, 41] They also reported that the improvement of insulin resistance by BCAA granules may be related to the migration of HCC, suppression of angiogenesis and epithelial–mesenchymal transition of hepatocytes, and that BCAA granules may inhibit liver carcinogenesis (at least in part) by reduction of oxidative stress and strengthening of immune functions.
There are several reports of the usefulness of BCAA supplementation on the QoL of patients with liver cirrhosis.[42, 43] Kawamura et al. demonstrated that, in 453 patients with chronic liver disease, QoL decreased significantly according to the progression of disease as assessed by the scores from Short Form 36 (P < 0.05) and that the QoL of patients with chronic liver diseases was improved in the BCAA granules administration group (n = 13) compared with the control group (n = 12) after 6 months. Hepatic encephalopathy (HE) is a major complication in patients with liver cirrhosis that is related to a poor prognosis and poor QoL. Sleep disturbance may be associated with minimal HE. Les et al. conducted a randomized study involving 116 patients who had experienced an episode of HE (58 patients in the BCAA group and 58 patients in the maltodextrin group) to examine the effect of BCAA: they reported that supplementation with BCAA improves minimal HE and muscle mass. Tryptophan, which is a precursor of the neurotransmitter 5-hydroxytryptamine (which is related to sleep disturbance), may be regulated by BCAA supplementation.
With the wide range of pharmacological actions, such as increasing the serum albumin level,[16-19] inhibiting cirrhosis complications/angiogenesis/hepatic carcinogenesis,[17-20, 22, 27-29] improving insulin resistance[17, 21, 22] and fatty-acid metabolism,[17, 24] reducing oxidative stress,[17, 23] and increasing stimulation of the immune system,[17, 25, 26] therapy using BCAA granules may be an indispensable treatment for cirrhosis.
Significance of BCAA granules in different approaches to HCC treatment
Along with liver transplantation, hepatectomy is a curative treatment approach for HCC.[6, 8, 9, 47-49] According to guidelines set by the European Association for the Study of the Liver (EASL), hepatectomy is indicated in patients with a single tumor of 2 cm or less in diameter, performance status (PS) 0, Child–Pugh class A and no portal hypertension. In Japan, however, hepatectomy is considered in patients with three or less tumors of less than 3 cm in diameter, no vascular invasion, Child–Pugh class A or B, and expected tolerance to surgery, or even in those with four or more tumors of more than 3 cm in diameter and vascular invasion if they are expected to tolerate surgery and the treatment may improve the prognosis. Hepatectomy is considered the first-line initial treatment for resectable HCC because of generally good surgical outcomes and poor availability of brain-dead liver donors in Japan.[52, 53]
In HCC patients in whom a large volume of liver has been removed and in those with concurrent cirrhosis, the hepatic functional reserve is expected to decrease after resection. In several studies, the serum albumin level has been identified as a contributing factor for the prolonged postoperative survival time in HCC patients.[13, 54-57] Thus, nutritional treatment with BCAA granules would be an essential approach based on this observation as well as the fact that BCAA therapy prevents perioperative complications.
Togo et al. reported, in their study in 43 HCC patients with advanced cirrhosis, that post-hepatectomy treatment with BCAA granules inhibited the progression of cirrhosis and improved the prognosis. The usefulness of oral nutritional supplements to prevent post-hepatectomy hepatic failure and the usefulness of BCAA granules to inhibit postoperative HCC recurrence have also been reported. Ichikawa et al. reported, in their prospective study in 56 HCC patients aged 65 years or more, that post-hepatectomy HCC recurrence was suppressed significantly and that the postoperative clinical course was more favorable in the BCAA treatment group (n = 26) compared with the regular-diet group (n = 30).
Treatment with BCAA granules has appreciable clinical significance in HCC patients (especially those with underlying advanced cirrhosis) in terms of preserving hepatic functional reserve, preventing perioperative complications and inhibiting postoperative recurrence.
As an important choice of HCC treatment in western countries,[8, 60, 61] liver transplantation is considered even in patients with decompensated cirrhosis of various causes. Assuming that the Milan criteria are satisfied, living donor partial liver transplantation for the treatment of decompensated cirrhosis complicated by HCC has been covered by the national health insurance system in Japan since 2004. As described above, living donor liver transplantation is the major choice of treatment because of the shortage of brain-dead donors in Japan.[8, 60, 61, 63, 64]
The usefulness of BCAA granules in patients who have undergone liver transplantation has been reported in two studies.[65, 66] In a prospective randomized study in 56 Child–Pugh class A cirrhotic patients without major complications, Kawamura et al. reported that early intervention with BCAA granules significantly decreased cirrhosis-related complications and prolonged the time to liver transplantation. In a retrospective study in 236 patients who underwent living donor liver transplantation, Shirabe et al. reported a significant decrease in post-transplantation septic complications in patients pretreated with BCAA granules. Considering the global shortage of liver donors,[6-9] BCAA granules could be a promising treatment for subjects undergoing liver transplantation.
Since its introduction in Japan in 1999, RFA has rapidly gained popularity because of its excellent antitumor effect and low extent of invasiveness. Percutaneous RFA is the first-line percutaneous treatment for HCC.[5-9, 11, 14, 67-72] EASL guidelines recommend percutaneous RFA for HCC of PS 0–2, Child–Pugh class A or B, and three or less unresectable tumors of 3 cm or less in diameter. In Japan, percutaneous RFA is, in general, indicated for patients of Child–Pugh class A or B and three or less unresectable tumors of 3 cm or less in diameter. Even in patients with unresectable tumors of 3 cm or more in diameter, percutaneous RFA in combination with TACE is recommended to expand the ablated area.[50, 51, 73]
Percutaneous RFA is less invasive than hepatectomy, but hepatic functional reserve may decrease after RFA in some patients.[74-76] The possible causes of a postoperative decrease in the serum albumin level include: (i) decreased albumin synthesis secondary to hepatocyte decrease; (ii) inhibition of albumin synthesis by inflammatory cytokines; and (iii) loss of protein due to inflammation at the ablation site.[74-76] We reported the association between the serum albumin level and survival of HCC patients treated with percutaneous RFA, so therapy using BCAA granules may be a useful treatment for RFA-treated HCC frequently complicated by cirrhosis.[11, 67]
One of the disadvantages of percutaneous RFA is the high prevalence of recurrence of HCC.[6, 8, 9, 15, 48, 67] We found the prevalence of HCC 5 years after RFA to be approximately 80% even in patients with a single HCC. The regimen to prevent HCC after RFA includes antiviral therapy (interferon therapy for hepatitis C and nucleoside analog therapy for hepatitis B) and liver-support therapy to keep the hepatic enzymes at a low level.[67, 77-83] BCAA granules with potential anticarcinogenic effects may also be useful for preventing HCC recurrence post-RFA.[11, 27]
Yoshiji et al. focused on the inhibitory action of BCAA granules and an angiotensin-converting enzyme inhibitor (ACE-I) against angiogenesis, and evaluated the effect of these agents in preventing post-RFA recurrence of HCC in a prospective randomized study. The post-RFA prevalence of HCC and levels of vascular endothelial growth factor were decreased significantly in the combined BCAA granules and ACE-I treatment group compared with the control group, suggesting a possible synergistic effect of the two drugs to inhibit HCC recurrence after RFA. Our retrospective controlled study in 256 HCC patients with a serum albumin level of 3.5 g/dL or less treated with percutaneous RFA showed significantly higher overall and recurrence-free survival in patients treated with BCAA granules (n = 115) compared with those receiving a regular diet (n = 141). The use of BCAA granules was identified as a contributing factor to prolonged survival in a multivariate analysis. The mechanism of the inhibitory effect of BCAA granules against HCC recurrence after RFA needs to be verified in a large-scale prospective study. BCAA granules may inhibit HCC recurrence in patients who have undergone percutaneous RFA as well as in those who have undergone hepatectomy.[11, 29]
Transcatheter arterial chemoembolization is a combination of local chemotherapy through feeding blood vessels and the use of embolizing material.[16, 84-87] TACE is most frequently used for the treatment of HCC in Japan, where it was originally developed.[84, 87-90] EASL guidelines recommend TACE for unresectable, Child–Pugh class A or B multiple HCC with no vascular invasion, whereas in Japan the therapy is recommended even for HCC with vascular invasion if it is Vp1 or Vp2.[50, 51]
The factors affecting the survival of HCC patients treated with TACE are: (i) tumor stage; (ii) tumor markers; and (iii) hepatic functional reserve. Preserving hepatic functional reserve is a critical issue in HCC patients who, in general, are treated repeatedly with TACE.[16, 88-92] However, in some patients, hepatic functional reserve decreases after TACE because of complications such as post-TACE syndrome.
The usefulness of BCAA granules or BCAA-enriched “snacks” for patients with unresectable HCC treated with TACE has been suggested in several studies.[16, 91, 92] In a randomized controlled trial (RCT) in 56 HCC patients treated with TACE, Takeshita et al. found that the post-TACE decrease in liver function was suppressed significantly in patients who received an enteral nutritional formula for hepatic failure given as a late-evening snack (LES) compared with the control group.[91, 94] Our retrospective controlled study in 99 HCC patients treated with TACE showed that therapy using BCAA granules significantly inhibited the decrease in hepatic functional reserve at 3 months and 6 months compared with the regular diet group. According to EASL guidelines, if HCC with Child–Pugh class B treated with TACE recurs as Child–Pugh class C, TACE is not indicated for the recurred HCC. The significance of therapy using BCAA granules is considerable in terms of permitting repeated TACE.
Molecular-targeted drugs (sorafenib)
There had long been a lack of evidence to support systemic chemotherapy for unresectable advanced HCC. However, after the efficacy of a molecular-targeted drug, sorafenib, for unresectable advanced HCC was demonstrated in two RCT (SHARP trial and Asia–Pacific trial), the drug was approved for the treatment of unresectable advanced HCC in Japan in 2009.[96, 97]
The action of sorafenib against tumor growth and angiogenesis is based on the inhibition of the activities of intracellular kinase and receptor tyrosine kinase.[96-106] The new era of systemic chemotherapy for unresectable advanced HCC was started with the introduction of sorafenib.[96-103, 106] EASL guidelines recommend sorafenib for unresectable, advanced, Child–Pugh class A or B HCC with PS 0–2 and vascular invasion or distant metastasis. According to Japanese guidelines, sorafenib is recommended for unresectable, advanced, Child–Pugh class A HCC with vascular invasion or distant metastasis as well as for patients intolerant to TACE or in whom the procedure is anatomically unsuitable.[51, 104, 105]
Several cases of adverse events associated with the use of sorafenib have been reported.[96-106] Patients should be monitored carefully for hepatic dysfunction during sorafenib therapy because decreased hepatic reserve caused by sorafenib may result in irreversible hepatic failure. Even if hepatic failure is avoided, sorafenib treatment may have to be discontinued or the dose reduced. Many HCC patients treated with sorafenib have concurrent cirrhosis.[96-106] Hence, intervention with BCAA granules has appreciable importance in terms of preserving hepatic functional reserve and ensuring continued sorafenib treatment. Our previous study revealed that therapy using BCAA granules significantly inhibited the decrease in serum albumin level and prolonged the duration of sorafenib treatment and survival in patients with a serum albumin level of 3.5 g/dL or less compared with the regular diet group. The synergistic effect of sorafenib and therapy using BCAA granules to inhibit angiogenesis may have contributed to the better prognosis.
There remains a lack of evidence to support the effect of nutritional intervention in patients with unresectable advanced HCC treated with sorafenib. However, therapy using BCAA granules should be considered as a treatment option.