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Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event-Free Survival in Patients with Liver Cirrhosis
Abstract
It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis.
We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≥6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis.
The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216-0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336-1.017, p = 0.0575).
Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.
... Information on the characteristics associated with the development of HCC, such as age at baseline and the duration of LC, were recorded ( 24 ). ...
... % of those without SVR developed HCC ( 36 , 37 ). Despite adjusting for clinical characteristics associated with HCC (24)(25)(26)(27), the association between SAT and risk for HCC remained independent. However, after adjustment for etiology and sex, this association was attenuated, suggesting that these factors may act as confounders. ...
... However, only 5.3 % of all compensated patients had muscle wasting, according to MAMC, suggesting that adipose tissue is not an indicator of muscle mass preservation in this case. A previous study demonstrated that supplementation with branched-chain amino acids (BCAA) for at least six months during the compensated phase of the disease decreases the risk of developing HCC ( 24 ). Theoretically, patients with LC experience a decrease in muscle tissue due to an underlying deficiency of BCAAs, which are used as an energy source and for ammonia metabolism in muscle and may improve glucose homeostasis ( 24 , 46 ). ...
Background
Malnutrition in patients with liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC) has been associated with adverse outcomes. However, there is little information on the incidence of HCC during the compensated phase of LC in relation to the nutritional status.
Aim
To evaluate the association between the incidence of HCC in compensated LC and their nutritional status.
Methods
Patients with compensated liver cirrhosis with no previous history of ascites, hepatic encephalopathy, or variceal bleeding attending the Gastroenterology outpatient service at Centro Medico Nacional Siglo XXI were included in a prospective cohort. Clinical and nutritional parameters were collected, including the Royal Free Hospital Subjective Global Assessment (RFH-SGA) as an indicator of protein-calorie malnutrition and the triceps skinfold thickness, which classified patients as having normal subcutaneous adipose tissue (SAT), above average SAT, and below average SAT. Follow-up was censored at the time of HCC diagnosis or LC decompensation.
Results
About 31/187 (16.0 %) and 22/187 (11.8 %) patients were categorized as having above- or below-average SAT at baseline, respectively. 10/187 patients (5.3 %) developed HCC during the compensated phase of LC at a median of 22 months (IQR: 10.0–36.75). A higher risk of HCC was observed in subjects below average SAT (HR: 4.064, CI 95 %: 1.012–16.317, p = 0.048). After adjusting the Cox models for age and α-fetoprotein at baseline, the statistical significance of the association between SAT and HCC was not modified.
Conclusion
These results suggest that decreased SAT may precede the diagnosis of HCC in compensated LC.
... Concerning the liver, the role of BCAAs in HCC development and progression is a controversial topic that still needs further investigation. Available data reveal that BCCAs administrated for more than 6 months significantly decreases the incidence of HCC with a lower trend in liver-related events in patients with Child-Pugh A cirrhosis [151], showing beneficial effect in all stages of HCC [152]. Moreover, Kikuchi et al. reported that BCAAs supplementation reduced HCC recurrence in cirrhotic men with obesity (BMI > 25 Kg/m 2 ) and serum levels of α-fetoprotein levels > 20 ng/mL [153]. ...
... Although available data on alteration of BCAAs metabolism in HCC are, in some cases, contradictory, administration of BCAAs in NAFLD patients results in preventing HCC development [137]. Moreover, evidence-based guidelines suggest a dietary implementation with BCAAs for treating HCC [151,156]. Moreover, NAFLD also mirrors HCC metabolic rewiring in terms of mitochondrial oxidative metabolism, gluconeogenesis, lipolysis and anaplerotic pathways [178][179][180]. ...
Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.
... Research into the association between BCAAs and immunomodulation began in the 1970s and 1980s, when researchers evaluated critically ill patients receiving total parenteral nutrition (TPN) and observed that an increase in the total amount of BCAAs in the formula resulted in elevation of lymphocyte counts in blood and reduced mortality, mainly in the postoperative period and in cases of sepsis (Table 1) 190,191,193,194,198,[202][203][204][206][207][208][209][210]214 Furthermore, when plasma amino-acid concentrations were compared, surviving patients were found to have higher concentrations of BCAAs and lower concentrations of aromatic and sulfur amino acids than those who did not survive sepsis, indicating a preserved liver function and better maintenance of energy metabolism. 189 Considering that hepatic failure is a common cause of death in septic patients, this result demonstrates the beneficial effect of BCAA supplementation on patient survival. ...
... 202 Several studies indicate that supplementation with BCAAs is associated with a lower incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis and may improve nutritional status and quality of life (Table 1). [203][204][205][206][207][208] Moreover, in patients undergoing therapeutic interventions for treatment of HCC, supplementation with BCAAs prevents a Figure 4 Intracellular mechanisms of modulation of the mTOR pathway by branched-chain amino acids (BCAAs). mTOR activation is associated with several pathways, including S6K, IRS-1, NF-jB, SIRT-1, and PPARc. ...
Branched-chain amino acids (BCAA) have been associated with immunomodulation since the mid-1970s and 1980s and have been used in the nutritional therapy of critically ill patients. Evidence shows that BCAA can directly contribute to immune cell function, aiding recovery of an impaired immune system, besides improving the nutritional status in cancer and liver diseases. BCAA may also play a role in patients with sepsis or trauma, contributing to improved clinical outcomes and survival. BCAA, especially leucine, are activators of the mammalian target of rapamycin (mTOR), which in turn, interacts with several signaling pathways involved in biological mechanisms of insulin action, protein synthesis, mitochondrial biogenesis, inflammation and lipid metabolism. Although many studies both in vitro and in human and animal models have provided evidence for the biological activity of BCAA, findings have been conflicting and the mechanisms of action of these amino acids are still poorly understood. This review addresses several aspects related to BCAA, including their transport, oxidation, and mechanisms of action and their role in nutritional therapy and immunomodulation.
... 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 [1,2,76]. BCAA granules (LIVACT, Ajinomoto Pharma, Tokyo, Japan) contain L-valine, L-leucine, and Lisoleucine 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 (mTOR) [1,76,[82][83][84][85][86][87][88]. BCAA granules were originally developed for the treatment of hypoalbuminemia associated with decompensated cirrhosis. ...
... However, later studies found a variety of other pharmacological actions of this drug. BCAA granules therapy not only improves hypoalbuminemia but also inhibits cirrhosis-related complications such as esophageal varices and ascites, reduces insulin resistance and oxidative stress, improves fatty acid metabolism, stimulates the immune system, and inhibits angiogenesis [1,76,[82][83][84][85][86][87][88]. The 2010 guidelines for comprehensive treatment of hepatitis virusrelated cirrhosis in Japanese patients recommend the use of BCAA granules to preserve liver function and inhibit hepatic carcinogenesis [89]. ...
The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes.
... Although previous studies have shown that supplementation with BCAAs may significantly improve prognosis for patients with liver cirrhosis, intervention studies yielded inconsistent results [7,8]. Several randomized controlled trial (RCT) studies conducted in Asian populations showed that oral supplementation with BCAAs could effectively reduce the incidence of serious cirrhotic complications [9,10]. On the basis of a prospective study that enrolled 299 patients from 14 medical institutions in Japan, BCAA supplementation reduced the risk for hepatocellular carcinoma (HCC) and prolonged the survival of patients with cirrhosis [11]. ...
Background and Aims: The role of serum branched-chain amino acids (BCAAs) in long-term liver cirrhosis complication events remains unclear. We aimed to evaluate the associations between serum BCAAs and the risk of liver-related events. Methods: We included a total of 64,005 participants without liver cirrhosis complication events at baseline from the UK Biobank. Cox proportional hazards regression models were utilized to estimate multivariable hazard ratios (HRs) and 95% CIs for the incidence of liver cirrhosis complication events, adjusting for potential confounders, including sociodemographic and lifestyle factors. Relationships between serum BCAAs and liver cirrhosis complications were examined using nonparametrically restricted cubic spline regression. Results: During a median follow-up of 12.7 years, 583 participants developed liver cirrhosis complication events. The multivariable Cox regression model suggested that total BCAAs (HR = 0.88, 95% CI 0.82–0.95), serum leucine (HR = 0.88, 95% CI 0.81–0.95), serum isoleucine (HR = 0.88, 95% CI 0.82–0.96), and serum valine (HR = 0.87, 95% CI 0.82–0.96) were all independent protective factors for liver cirrhosis complications after adjustment for sociodemographic and lifestyle factors. Cox models with restricted cubic splines showed U-shaped associations between serum valine and liver cirrhosis complication incidence. Serum total BCAA and isoleucine concentrations might reduce the risk of liver cirrhosis complications by raising the risk of (type 2 diabetes mellitus) T2DM. Conclusion: Lower serum BCAA levels exacerbate the long-term risk of liver cirrhosis complications. Future studies should confirm these findings and identify the biological pathways of these associations.
... has a promising effect in reducing cachexia, preventing or treating symptoms of HE, and ameliorating liver disease [11][12][13]. However, the use of BCAAs in nutritional supplements remains controversial, and no consensus has been reached. ...
Branched-chain amino acids (BCAAs), as essential amino acids, engage in various physiological processes, such as protein synthesis, energy supply, and cellular signaling. The liver is a crucial site for BCAA metabolism, linking the changes in BCAA homeostasis with the pathogenesis of a variety of liver diseases and their complications. Peripheral circulating BCAA levels show complex trends in different liver diseases. This review delineates the alterations of BCAAs in conditions including non-alcoholic fatty liver disease, hepatocellular carcinoma, cirrhosis, hepatic encephalopathy, hepatitis C virus infection, and acute liver failure, as well as the potential mechanisms underlying these changes. A significant amount of clinical research has utilized BCAA supplements in the treatment of patients with cirrhosis and liver cancer. However, the efficacy of BCAA supplementation in clinical practice remains uncertain and controversial due to the heterogeneity of studies. This review delves into the complicated relationship between BCAAs and liver diseases and tries to untangle what role BCAAs play in the occurrence, development, and outcomes of liver diseases.
... Oral BCAAs supplementation with BCAAs-enriched formulas is often recommended by international guidelines in the management of cirrhosis-related complications [59,60], mainly HE and impaired nutritional status. Some studies on BCAAs supplementation have demonstrated improvements in clinical indicators such as the CP score, MELD score, lower incidence of HCC and better survival rates [61][62][63][64]. Substantial evidence suggests that BCAAs supplementation not only influences cirrhosis-related parameters but also has positive effects on skeletal muscle function parameters, making it a valuable intervention in the management of complications of CLD (Table 2). ...
This comprehensive review focuses on the dynamics of branched-chain amino acids (BCAAs) metabolism and its clinical implications in chronic liver disease, with emphasis on the emerging concept of muscle–liver crosstalk. BCAAs, indispensable for protein synthesis and metabolic pathways, undergo unique tissue-specific processing in skeletal muscle and liver. The liver, responsible for amino acid metabolism, plays a distinctive role in sensing BCAAs catabolism, influencing glucose regulation and contributing to the systemic metabolism of BCAAs. Within the context of chronic liver disease, compromised liver metabolism becomes evident through amino acid abnormalities, particularly in the decrease of the Fischer ratio (BCAAs/aromatic amino acids concentrations in plasma). This reduction becomes important in assessing the severity of liver dysfunction due to its associations with adverse outcomes, including increased mortality and complications related to the liver disease. BCAAs supplementation, as explored in this review, emerges as a promising avenue, displaying positive effects on skeletal muscle mass, strength, and overall nutritional status in cirrhosis management. Understanding this interplay offers insights into therapeutic strategies for chronic liver diseases, exploring the way for precision interventions in clinical practice.
... A recent review of pre-clinical studies found positive implications of leucine supplementation for reducing skeletal muscle loss (since leucin preserves protein synthesis and decreases protein degradation), attenuating cardiac dysfunction, improving immune competence, preserving energy production capacity and decreasing inflammation [4]. Furthermore, oral supplementation with BCAA was associated with a decreased incidence of hepatocellular carcinoma in patients with cirrhosis [42]; in contrast, other studies suggest that this supplementation may increase tumor growth [43]. Despite this, a recent review reports that there is insufficient evidence to establish a cause-effect relationship between leucine supplementation and tumor growth [4]. ...
(1) Background: Malnutrition frequently affects patients with cancer, and it negatively impacts treatment tolerance, clinical outcomes and survival. Thus, appropriate nutritional screening and early nutrition support are extremely recommended. Currently, a significant number of oral supplements (OS) are commercially available; despite this, there is a lack of evidence for recommending specific OS, including leucine-enriched OS, for nutritional support in patients with cancer. (2) Aim: To compare the clinical evolution of patients with cancer (undergoing systemic treatment) that received standard hypercaloric, whey protein-based hyperproteic oral supplements vs. hypercaloric, hyperproteic leucine-enriched OS using a novel morphofunctional nutritional evaluation. (3) Patients and methods: This paper details an open-label, controlled clinical study in which patients were randomly assigned to receive nutritional treatment with whey protein-based hyperproteic oral supplements (control group) vs. hypercaloric, hyperproteic leucine-enriched OS (intervention group) during a twelve-week period. Forty-six patients were included; epidemiological, clinical, anthropometric, ultrasound (muscle echography of the rectus femoris muscle of the quadriceps and abdominal adipose tissue) and biochemical evaluation were performed. All patients received additional supplementation with vitamin D. (4) Results: Nutritional parameters (including bioimpedance, anthropometric, ultrasound and biochemical variables) of all included patients remained stable after the nutritional intervention. Extracellular mass tended to increase in the patients that received the leucine-enriched formula. Functionality (evaluated through the stand-up test) improved in both groups (p < 0.001). Prealbumin, transferrin levels and superficial adipose tissue increased in the control group (p < 0.05), while self-reported quality of life improved in all the evaluated patients (p < 0.001). (5) Conclusions: Nutritional support with hypercaloric, hyperproteic (with whey protein) OS and vitamin D supplementation were associated with the maintenance of body composition and improvements in functionality and in quality of life in the patients with cancer undergoing systemic treatment. No significant benefits were observed when a leucine-enriched formula was used.
... Dietary starvation of a single AA is not a simple task and strategies to limit Gln, Asp, or Ser/Gly intake had a limited positive response due to compensatory metabolic mechanisms [71,72]; clinically speaking, nutritional enrichment of selected AAs is certainly a more accessible objective. Supplementation of branched-chain amino acids (BCAA) is long-known to have favorable effects in patients with hepatocellular carcinoma [73][74][75][76] and is recommended to cirrhotic patients according to the guidelines of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) [70]. Despite its well-known role in fueling cancer proliferation, Gln supplementation, by both increasing its dietary content and supplementation in drinking water, blocked melanoma growth in mice by affecting the epigenetic marks of oncogenic gene expression [77]. ...
Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.
... The beneficial effect of BCAA supplementation was not limited to cirrhotic patients. BCAA supplementation was also found to be useful in preventing the occurrence of HCC in cirrhotic patients [73]. The majority of HCC patients (80-90%) were diagnosed with underlying cirrhotic conditions [74]. ...
Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health.
... BCAAs have been shown to be helpful as a nutritional supplement in liver cirrhosis (19)(20)(21). Several clinical trials reported the efficacy of BCAAs for nutritional status, general status, hepatic encephalopathy, and quality of life (22)(23)(24)(25). Therefore, it is expected that BCAA supplementation may be considered a useful therapeutic modality in treating decreased muscle mass and strength that accompany secondary sarcopenia. ...
Introduction
Sarcopenia is a major element of malnutrition in liver cirrhosis (LC) and is present in 30–70% of this population, being associated with a poor overall prognosis due to related complications such as hepatic encephalopathy, ascites, and portal hypertension. This systematic review and meta-analysis aimed to evaluate the effects of branched-chain amino acids (BCAA) supplementation on several parameters used to assess sarcopenia in LC.
Materials and Methods
A comprehensive systematic electronic search was performed in PubMed, EMBASE, Scopus, Cochrane Library, and ClinicalTrials.gov databases using predefined keywords. We included full articles that satisfied the inclusion and exclusion criteria. Quality assessment of included studies was conducted using Cochrane Collaboration's tool and NHLBI quality assessment tools for interventional and observational studies, respectively. The principal summary outcome was the mean difference (MD) in the evaluated parameters. We performed a pre- and post-intervention analysis and comparison between two intervention groups (BCAA vs. controls) of the evaluated parameters when applicable.
Results
A total of 12 studies involving 1,225 subjects were included in our qualitative synthesis and five in our quantitative synthesis. At baseline vs. post-intervention assessment, subjects receiving BCAA supplementation were found to have a significant improvement in skeletal muscle index (SMI) (−0.347 [95% CI −0.628–0.067; p-value 0.015]) and mid-arm muscle circumference (MAMC) (−1.273 [95% CI (−2.251–0.294; p-value 0.011]). However, no improvements were reported in handgrip (-0.616 [95% CI −2.818–1.586; p-value 0.584]) and triceps subcutaneous fat (1.10 [95% CI −0.814–3.014; p-value 0.263]).
Conclusion
Following BCAA supplementation, several parameters used to evaluate sarcopenia in LC patients were found to be improved, including SMI and MAMC. Nevertheless, no improvements were seen in handgrip and triceps subcutaneous fat. Results should be interpreted with caution due to the limited methodological quality of the included studies.
... We also found that levels of 2-keto-n-caproic acid/2-keto-isocaproic acid increased at 36 weeks after SVR and were inversely correlated with the CTP score. This finding agrees with previous studies, which have shown that branched-chain amino acid (BCAA) supplementation was related to an improved prognosis of cirrhotic patients [37,38]. However, although leucine and other BCAAs have many positive repercussions on metabolism in multiple tissues, elevated levels of leucine and their metabolites, such as the keto-isocaproic acid, have also been associated Statistics: Associations were calculated by Generalized Linear Mixed-effects Model (GLMM) with a gamma distribution (identity-link to variables from LC-MS and log-link to variables from GC-MS); q-values represent p-values corrected for multiple testing using the False Discovery Rate (FDR). ...
Background
A better understanding of the evolution of cirrhosis after hepatitis C virus (HCV) clearance is essential since the reversal of liver injury may not happen. We aimed to assess the evolution of plasma metabolites after direct-acting antivirals (DAAs) therapy and their association with liver disease scores in HIV/HCV-coinfected patients with advanced HCV-related cirrhosis.
Methods
We performed a prospective study in 49 cirrhotic patients who started DAAs therapy. Data and samples were collected at baseline and 36 weeks after SVR. Metabolomics analysis was carried out using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Inflammation-related biomarkers were analyzed using ProcartaPlex Immunoassays.
Results
At 36 weeks after SVR, patients experienced significant decrease in taurocholic acid, 2,3-butanediol, and LPC(18:0); while several phosphatidylcholines (LPC(16:1), LPC(18:1), LPC(20:4), and PC(16:0/9:0(CHO))/PC(16:0/9:0(COH)), 2-keto-n-caproic acid/2-keto-isocaproic acid and N-methyl alanine increased, compared to baseline. The plasma decrease in taurocholic acid was associated with a reduction in Child-Turcotte-Pugh (CTP) (AMR=3.39; q-value=0.006) and liver stiffness measurement (LSM) (AMR=1.06; q-value<0.001), the plasma increase in LPC(20:4) was related to a reduction in LSM (AMR=0.98; q-value=0.027), and the rise of plasma 2-keto-n-caproic acid/2-keto-isocaproic acid was associated with a reduction in CTP (AMR=0.35; q-value=0.004). Finally, plasma changes in taurocholic acid were directly associated with inflammation-related biomarkers, while changes in LPC(20:4) were inversely associated.
Conclusions
Plasma metabolomic profile changed after HCV clearance with all oral-DAAs in HIV/HCV-coinfected with advanced HCV-related cirrhosis. Changes in plasma levels of LPC (20: 4), 2-keto-n-caproic acid/2-keto-isocaproic acid, and taurocholic acid were related to improvements in cirrhosis scores and inflammatory status of patients.
... Similarly, BCAA consumption in patients alleviates the risk of liver-related complications along with encephalopathies, ameliorates the prognosis and improves serum albumin concentrations, restoring the nutritional status. Besides, prospective clinical trials demonstrated that they may reduce the occurrence of HCC in patients with cirrhosis [205,206]. ...
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
... Therefore, further studies are needed to confirm the association of a vegetable rich diet and the risk of HCC development [128,129]. BCAA supplementation has also shown to be protective against HCC but the evidence is limited, and larger randomized controlled trials are needed to evaluate its anti-carcinogenic effects [130][131][132][133]. ...
Hepatic encephalopathy (HE) is a common neurological consequence in patients with cirrhosis and has a healthcare burden of USD 5370 to 50,120 per patient annually. HE significantly hampers the quality of life and is a major cause of morbidity and mortality. Patients with cirrhosis are at a high risk for protein-calorie malnutrition due to altered metabolism. Current evidence has changed the old belief of protein restriction in patients with cirrhosis and now 1.2 to 1.5 g/kg/day protein intake is recommended. Case series and studies with small numbers of participants showed that a vegetarian protein diet decreases the symptoms of HE when compared to a meat-based diet, but the evidence is limited and requires further larger randomized controlled trials. However, vegetable or milk-based protein diets are good substitutes for patients averse to meat intake. Branch chain amino acids (BCAA) (leucine, isoleucine and valine) have also been shown to be effective in alleviating symptoms of HE and are recommended as an alternative therapy in patients with cirrhosis for the treatment of HE. In this review, we provide an overview of current literature evaluating the role of protein intake in the management of HE in cirrhosis.
... Branched chained amino acids also stimulate insulin production and glucose uptake from stem cells and liver [83]. When branched chain amino acids are supplied to men who are suffering with obese cirrhosis, It can resultant to decrease in the development of HCC and also upgrades the survival rate leads to decrease in the development of HCC and upgrades the survival rate [84,85]. ...
Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic evidence of insulin resistance which is the hallmark of type 2 diabetes. NAFLD is considered as the risk factor for developing type 2 diabetes and has a high frequency of occurrence in those with existing type 2 diabetes. Compared with patients with only NAFLD or type 2 diabetes, these patients show a poor metabolic profile and increase mortality. Hence, effective treatment strategies are necessary. Here, we review the role of diet and lifestyle modification in the management of NAFLD and type 2 diabetes. Based on the available studies, it has been shown that the addition of any kind of physical activity or exercise is beneficial for patients with both NAFLD and type 2 diabetes. Proper dietary management leads to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and type 2 diabetes. In conclusion, it is clear that increasing physical activity or exercise is effective in improving metabolic parameters in patients who are suffering with both NAFLD and type 2 diabetes.
... An in vitro study produced evidence that the anticarcinogenic effects of BCAAs are related to down-regulation of insulin-like growth factor-1 receptor and vascular endothelial growth factor [23,24]. However, its efficacy in clinical studies has only been shown in relatively small numbers of participants or limited subgroups, such as obese men with high alpha-fetoprotein [25,26]. ...
Background and aims:
Clinical evidence for the benefits of branched-chain amino acids (BCAAs) is lacking in advanced liver disease. We evaluated the potential benefits of long-term oral BCAA supplementation in patients with advanced liver disease.
Methods:
Liver cirrhosis patients with Child-Pugh (CP) scores from 8 to 10 were prospectively recruited from 13 medical centers. Patients supplemented with 12.45 g of daily BCAA granules over 6 months, and patients consuming a regular diet were assigned to the BCAA and control groups, respectively. The effects of BCAA supplementation were evaluated using the model for end-stage liver disease (MELD) score, CP score, serum albumin, serum bilirubin, incidence of cirrhosis-related events, and event-free survival for 24 months.
Results:
A total of 124 patients was analyzed: 63 in the BCAA group and 61 in the control group. The MELD score (p = 0.009) and CP score (p = 0.011) significantly improved in the BCAA group compared to the control group over time. However, the levels of serum albumin and bilirubin in the BCAA group did not improve during the study period. The cumulative event-free survival was significantly improved in the BCAA group compared to the control group (HR = 0.389, 95% CI = 0.221-0.684, p < 0.001).
Conclusion:
Long-term supplementation with oral BCAAs can potentially improve liver function and reduce major complications of cirrhosis in patients with advanced liver disease.
... In fact, BCAAs stimulates insulin production and glucose uptake from liver and SM cells [135]. Furthermore, BCAAs supplementation in obese cirrhotic men reduces the development of HCC and enhances the survival rate [136,137]. Moreover, it potentiates the antitumor effects of sorafenib in patients with advanced HCC [138]. ...
Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation within the liver affecting 1 in 4 people worldwide. As the new silent killer of the twenty-first century, NAFLD impacts on both the request and the availability of new liver donors. The liver is the first line of defense against endogenous and exogenous metabolites and toxins. It also retains the ability to switch between different metabolic pathways according to food type and availability. This ability becomes a disadvantage in obesogenic societies where most people choose a diet based on fats and carbohydrates while ignoring vitamins and fiber. The chronic exposure to fats and carbohydrates induces dramatic changes in the liver zonation and triggers the development of insulin resistance. Common believes on NAFLD and different diets are based either on epidemiological studies, or meta-analysis, which are not controlled evidences; in most of the cases, they are biased on test-subject type and their lifestyles. The highest success in reverting NAFLD can be attributed to diets based on high protein instead of carbohydrates. In this review, we discuss the impact of NAFLD on body metabolic plasticity. We also present a detailed analysis of the most recent studies that evaluate high-protein diets in NAFLD with a special focus on the liver and the skeletal muscle protein metabolisms.
... 7,8 In addition, BCAA significantly suppressed development of hepatocellular carcinoma in patients with compensated cirrhosis, although not in patients with decompensated cirrhosis. 9 Long-term administration of BCAA for up to 2 years decreased hepatic events in decompensated cirrhosis and suppressed hepatocarcinogenesis. 10 L-carnitine L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid) is an amino acid derivative and an essential nutrient for the beta-oxidation of fatty acid in the mitochondria. Carnitine can be absorbed from food in a normal diet, but it can be synthesized in liver and kidney. ...
... A report from Japan revealed that BCAA supplementation reduced the development of HCC in obese [body mass index (BMI) >25 kg/m 2 ] cirrhotic men and in those with alpha-fetoprotein levels >20 ng/mL (111). Another Japanese study also showed that BCAA supplementation (for longer than 6 months) significantly reduced HCC occurrence while enhancing event-free survival rates in Child-Pugh grade A cirrhotic patients (112). Those results are coincided with the preferential antitumor effects observed in animal models. ...
Branched chain amino acids (BCAAs) are involved in various bioprocess such as protein metabolism, gene expression, insulin resistance and proliferation of hepatocytes. BCAAs have also been reported to suppress the growth of hepatocellular carcinoma (HCC) cells in vitro and to be required for immune cells to perform the function. In advanced cirrhotic patients, it has been clarified that serum concentrations of BCAA are decreased, whereas those of aromatic amino acids (AAAs) are increased. These alterations are thought to be the causes of hepatic encephalopathy (HE), sarcopenia and hepatocarcinogenesis and may be associated with the poor prognosis of patients with these conditions. Administration of BCAA-rich medicines has shown positive results in patients with cirrhosis.
... Previous report indicate that the improvement of malnutrition by the intervention of a nutrition support team and early physical therapy intervention aimed at improving skeletal muscle mass are considered to improve the survival of patients with sarcopenia (17)(18)(19). There are no fasting duration and postoperative activity restrictions in C-ion RT; thus, nutrition and physical therapy interventions could be initiated from the commencement of treatment without any interruption during C-ion RT. ...
Background/aim:
The relationship between sarcopenia and prognosis in carbon ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) has not yet been reported, therefore we analyzed the presence or absence of sarcopenia before C-ion RT as a prognostic factor for patients with HCC.
Patients and methods:
Data were retrospectively collected for patients who had undergone C-ion RT for HCC between September 2010 and December 2016. For defining the presence or absence of sarcopenia, skeletal muscles in the third lumbar vertebrae level were measured. Clinical outcomes were compared in the sarcopenia and non-sarcopenia groups.
Results:
Of the 68 patients who were analyzed, 22 were classified into the sarcopenia and 46 into the non-sarcopenia groups. Median follow-up of patients was 33.5 months. The three-year overall survival (OS) rates in the sarcopenia and non-sarcopenia groups were 66% and 77%, respectively (p=0.51).
Conclusion:
Sarcopenia was not a prognostic factor for patients with HCC treated with C-ion RT, which was effective in HCC patients with sarcopenia without worsening the OS.
... Few studies have evaluated the anticarcinogenic effects of BCAAs in patients with liver cirrhosis. [36][37][38] The anticarcinogenic effect of BCAA supplementation could be due to improvements in insulin resistance, whereas its antiangiogenic effect could be due to the inhibition of the vascular endothelial growth factor. [9,39,40] A Japanese study found that the incidence of HCC decreased in specific populations, such as in patients with chronic hepatitis C (CHC) or in those with a body mass index (BMI) of ≥ 25 kg/m 2 . ...
Evidence of the potential benefits of long-term oral branched-chain amino acid (BCAA) supplementation in reducing the severity of liver disease is limited.
Patients who were diagnosed with liver cirrhosis with a Child–Pugh (CP) score of 8–10 were included. The BCAA group consumed BCAAs daily for at least 6 months, and the control group consumed a diet without BCAA. We analyzed the improvements based on the model for end-stage liver disease (MELD) score, CP score, incidence of cirrhosis-related complications, and event-free survival over 2 years. Among the 867 recruited patients, 307 (166 in the BCAA group and 141 in the control group) were analyzed. The BCAA group was divided into 3 subgroups, whose patients consumed 4.15 g, 8.3 g, or 12.45 g of BCAAs daily for the analysis. There were significant differences in the CP score, albumin, and hepatic encephalopathy between the 2 groups at baseline. After matching the propensity scores, we analyzed patients in the BCAA-12.45 g group (12.45 g of BCAAs daily, n = 41) and matched control group (n = 41). The MELD score significantly improved in the BCCA-12.45 g group compared to the matched control group (P = .004). The changes in the serum bilirubin level (P = .014) and CP score (P = .033) over time also differed significantly between the 2 groups. The incidence rates of cirrhosis-related complications (P = .973) and development of hepatocellular carcinoma (2 cases each) did not differ significantly between the 2 groups.
Long-term oral BCAA supplementation has beneficial effects in patients with advanced liver cirrhosis. A further large-scale prospective study is needed to delineate these beneficial effects.
... Dietary components, including omega-3 fatty acids, may reduce the risk of HCC; recommendation is 4 g/day omega-3, which is found in marine algae, walnut, fish and krill oil (Freidoony and Kong, 2014;Sawada et al., 2012), and BCAA (Hayaishi et al., 2011;Kawaguchi et al., 2008Kawaguchi et al., , 2011Muto et al., 2006) may have protective effects. ...
The liver plays an important role in the absorption, metabolism, synthesis, and storage of nutrients. This organ metabolizes macromolecules such as carbohydrates, lipids, and proteins, which, after intake, are broken into smaller molecules such as glucose, fatty acids, and amino acids. Malnutrition is a common consequence of liver diseases, which is aggravated due to diminished appetite, exacerbated catabolic states, and loss of functions of liver cells. Despite the evidence of malnutrition prevalent in chronic liver diseases, this condition continues to remain under-recognized, underdiagnosed, and undertreated. Dietary elements have long been known to play a critical role in the physiological or pathological response to tissue inflammation and oxidative stress. For this reason, it is necessary to recognize the malnutrition (under/overnutrition) to prevent or reverse hepatic disease and its complications by an adequate dietary intervention and exercise therapy.
... Surveys data was collected by face to face interview tecnique. 58.2% of participants were men and the rest of 41.8% were women. The meanage of the participants was74.98 ± 6.96, the mean BMI was 29.59±6.28. ...
... Marchesini et al. [33] and Muto et al. [19] have reported that BCAA supplementation over a long period increases event-free survival, increases HSA concentration, and improves quality of life in patients with decompensated cirrhosis. Hayaishi et al. [34] also described that oral BCAA supplementation was associated with a reduced incidence of hepatocellular carcinoma in patients with cirrhosis. ...
Background and aimsThe aim of this study was to evaluate structural and functional alterations of human serum albumin (HSA), with a special focus on the oxidized and reduced forms, in patients with chronic liver disease. We also investigated whether oral branched-chain amino acid (BCAA) supplementation could induce structural changes and improve the functions of HSA. Methods
The proportion of reduced and oxidized HSA was determined in 16 healthy controls and in 20 chronic hepatitis and 100 cirrhotic patients with stable conditions. To evaluate the functional properties of HSA, this study focused on the antioxidant and binding functions. The radical scavenging activity and binding ability of purified HSA were measured in 68 participants. After BCAA administration for 6 months, 29 patients were evaluated for HSA structural changes, with 19 out of the 29 patients also analyzed for HSA functional changes. ResultsThere was a significant decrease in the amounts of reduced HSA in conjunction with liver disease progression. Receiver operating characteristic curve analysis demonstrated that the levels of reduced HSA had high accuracy in determining disease progression. Functional alterations were strongly correlated to the levels of reduced HSA. BCAA supplementation led to substantial increases in the amount of reduced HSA. The altered HSA was able to scavenge significantly more radicals and restore the binding ability. Conclusion
This study describes structural alterations and functional disturbances of HSA in patients with chronic liver disease, and indicates that the levels of reduced HSA might reflect disease progression and the functional properties of HSA. Moreover, oral BCAA supplementation increases the amount of reduced HSA, thereby leading to the restoration of HSA function in cirrhotic patients.
... [14]. It is also associated with reduced incidence of HCC in patients with Child-Pugh A cirrhosis [15] and in patients with a BMI of 25 kg/m 2 or higher [16]. [19]. ...
The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.
... [85] However, another randomized controlled trial did not find an improvement in serum albumin levels with BCAA supplementation, possibly due to different patient characteristics (patients were Child-Pugh class B or C). [86] Clinical trials have reported that longterm oral supplementation with BCAAs is associated with decreased frequency of development of HCC in obese patients with cirrhosis and hepatitis C virus infection, [87] significant reduction in HCC incidence rate and improvement of event-free survival rate in patients with cirrhosis, [88] and reduced HCC recurrence after treatment with radiofrequency ablation in patients with cirrhosis. [84,89] Finally, BCAAs have been also shown to improve health-related quality of life [85,86] and sleep disturbances in patients with cirrhosis. ...
Hepatocellular carcinoma (HCC) is a common solid malignancy and a leading cause of cancer-related death worldwide. The mechanisms underlying the pathogenesis and development of HCC are complex and heterogeneous. Although mainly related to hepatitis B and C chronic infection; HCC may also arise from diet-associated conditions such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Furthermore, toxins and nutrients such as mycotoxins and alcohol have an established role in the pathogenesis of chronic liver diseases, whereas specific diet patterns or foods have been associated with a reduction in HCC risk. The aim of this review is to provide a thorough overview of the clinically relevant effects-either beneficial or detrimental-of natural products consumed by humans on HCC risk and management.
... Oral branched-chain amino acid supplementation in patients with decompensated liver cirrhosis improves the nutritional status and prevents liver-related complications. In prospective clinical trials, this therapy was also shown to significantly lower HCC occurrence rates in patients with liver cirrhosis [45,46] . ...
Background:
Hepatocellular carcinoma (HCC) significantly contributes to the global burden of cancer. Liver cancer is the third most frequent cause of cancer-related death with HCC representing more than 90% of primary liver cancers. The majority of patients are not only affected by the malignant disease but do also suffer from chronic liver disease. Therefore, several factors impact on the prognosis of patients with HCC, including tumor-related factors, liver function and patient-related factors such as performance status and other comorbidities. The nutritional status is of high significance for the patients' performance status, the tolerance of tumor-targeting therapy and the prognosis of cancer of any type and is specially referenced in HCC. This overview is on current concepts on the role of nutritional factors in hepatocarcinogenesis and the role of nutrition in patients affected by HCC.
Summary:
Nutritional status and composition of diet are relevant factors related to the risk of HCC. They also have an important role concerning the prognosis of patients with HCC. Besides risk factors, several macro- and micronutrient components have been found to be inversely correlated with the risk of HCC. To prevent disease progression to liver cirrhosis or HCC in patients with nonalcoholic steatohepatitis, it is crucial to optimize the metabolic state.
Key message and practical implication:
Evidence from well-designed prospective interventional trials with the aim to reduce the HCC incidence or to prolong survival in patients with HCC based on nutritional modification is still to be generated.
... It was the limitation that FIB4-index, Child-Pugh class, and tumor stage were factors at the cancer onset. Consumption of coffee, green tea, and branched-chain amino acids, which have antioxidant properties and inhibit the advance of liver fibrosis, are associated with reduced risk of HCC [26][27][28][29]. The evaluation for the presence of these factors and liver biopsy are not investigated. ...
... Significance set at p ≤ 0.05 Newgard et al. 2009;She et al. 2007). In light of recent discoveries demonstrating the clinical effectiveness of BCAA supplementation in liver disease and cancer prevention (Hagiwara et al. 2012;Hayaishi et al. 2011;Miyake et al. 2012), the present study provides important information for NASH researchers and clinicians. Elevated mRNA and protein levels of cytosolic BCAT1 were observed in liver samples diagnosed as NASH in the present study, while no expression of BCAT1 was shown in normal or steatosis samples. ...
Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.
... [35][36][37][38][39][40] Supplementation of BCAAs also seem to result in health benefits in a number of liver diseases. [41][42][43][44][45] As a consequence, supplementation with BCAAs or a BCAA-rich diet is believed to improve metabolic health; an increase in the recommended dietary allowance for protein has been proposed, which would effectively increase dietary levels of BCAAs. 7,13, 20,22,[46][47][48][49][50][51] Nevertheless, the idea that BCAAs or their supplementation might have a positive role in preventing metabolic disease is controversial. ...
Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.
La importancia de los aspectos nutricionales es fundamental en las enfermedades
hepáticas. El hígado tiene múltiples funciones de síntesis, de regulación y de
detoxificación que al encontrarse con una disfunción se puede presentar la malnu�trición en los pacientes con enfermedades hepáticas.
La desnutrición es un fenómeno frecuente y uno de los factores pronósticos más
importantes en la cirrosis hepática debería ser considerada como una complica�ción, así como son consideradas la ascitis, encefalopatía, etc.
La prevalencia de malnutrición en pacientes cirróticos varía de acuerdo con la
gravedad de la enfermedad (reserva funcional hepática) y con la etiología. La des�nutrición en la cirrosis ha sido considerada desde hace muchos años uno de los
factores pronósticos más importantes en la enfermedad.
Independientemente de la etiología de la cirrosis, un pobre estado nutricional
se asocia a un mal pronóstico en cuanto a tasa de complicaciones, calidad de vida
y supervivencia.
Este libro está liderado por la Dra. Sophia E. Martínez Vázquez, nutrióloga exper�ta en enfermedades hepáticas, dos hepatólogas expertas en trasplante hepático y
en enfermedades hepáticas y como coautores un equipo de nutriólogos, gastroen�terólogos – hepatólogos expertos en cada uno de los temas de los capítulos.
El contenido de este maravilloso libro contiene las bases de las funciones y ana�tomía del hígado, las características nutricionales que cada una de las enfermeda�des hepáticas requiere de acuerdo con la etiología, datos claves para los médicos
y al final menús que se sugieren para cada una de las etiologías de la enfermedad
hepática.
Este libro es el primero que se enfoca en la nutrición en las enfermedades he�páticas para que los médicos conozcan a profundidad estos conceptos y puedan
realizar una intervención nutricional precoz con la finalidad de prolongar la espe�ranza de vida, mejorar la calidad de vida, disminuir las complicaciones como es la
sarcopenia y preparar al paciente para un trasplante hepático.
Branched chain amino acids (BCAA) supplementation may reduce the incidence of liver failure and hepatocellular carcinoma in patients with cirrhosis. We aimed to determine whether long-term dietary intake of BCAA is associated with liver-related mortality in a well-characterized cohort of North American patients with advanced fibrosis or compensated cirrhosis. We performed a retrospective cohort study using extended follow-up data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT–C) Trial. The analysis included 656 patients who completed two Food Frequency Questionnaires. The primary exposure was BCAA intake measured in grams (g) per 1000 kilocalories (kcal) of energy intake (range 3.0–34.8 g/1000 kcal). During a median follow-up of 5.0 years, the incidence of liver-related death or transplantation was not significantly different among the four quartiles of BCAA intake before and after adjustment of confounders (AHR 1.02, 95% CI 0.81–1.27, P-value for trend = 0.89). There remains no association when BCAA was modeled as a ratio of BCAA to total protein intake or as absolute BCAA intake. Finally, BCAA intake was not associated with the risk of hepatocellular carcinoma, encephalopathy or clinical hepatic decompensation. We concluded that dietary BCAA intake was not associated with liver-related outcomes in HCV-infected patients with advanced fibrosis or compensated cirrhosis. The precise effect of BCAA in patients with liver disease warrants further study.
Background:
Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore evidence for BCAA supplementation in chronic liver disease.
Methods:
We searched MEDLINE and EMBASE for studies with BCAA supplementation with presence of a disease-control group (placebo or no intervention) using search terms "liver cirrhosis", "hepatocellular carcinoma", "branched chain amino acids" and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with random effects model. Results were reported following EQUATOR guidelines.
Results:
Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p=0.008; RR 0.61 95% CI 0.42-0.88) and tended to improve overall survival (p=0.05; RR 0.58 95% CI 0.34-1.00). Two retrospective studies suggested beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA.
Conclusions:
prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients.
Background:
Oral branched-chain amino acids (BCAAs) might benefit patients with advanced liver disease. We assess its effects on prognosis compared to control from the meta-analysis.
Methods:
Study-endpoints were development of hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), mortality, and overall liver-related events (LREs). Risk ratios (RRs) and hazard ratios (HRs) were calculated using random-effects model and heterogeneity using I2 statistic.
Results:
Twenty-eight studies were included in this meta-analysis; 1578 and 1727 patients in oral BCAAs and control groups, respectively. From studies using RRs as outcome measures, oral BCAAs were better in preventing HE and LRE than controls, with RRs 0.684 (95% confidence interval [CI] 0.497-0.941; P=0.019) and 0.788 (95% CI 0.585-0.810; P<0.001), respectively. Oral BCAAs had marginal effect on preventing HCC compared to control, with RR 0.791 (95% CI 0.619-1.011; P=0.061); no significant difference in mortality was detected. From studies using HRs as outcome measures, oral BCAAs were superior to control in preventing LRE with adjusted HR 0.497 (95% CI 0.321-0.770; P=0.002). In subgroups undergoing HCC resection, oral BCAAs had beneficial effect in preventing HE (RR 0.716, 95% CI 0.514-0.996; P=0.047) and LRE (RR 0.716, 95% CI 0.595-0.860; P<0.001).
Conclusion:
Oral BCAAs could afford clinical benefits in reducing HE and LRE risks, especially among patients undergoing HCC resection.
Abstract
Objective
Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy.
Methods
We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids (EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixture designed on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells.
Results
The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells.
Conclusion
Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells’ death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers.
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and presents together with cirrhosis in most cases. In addition to commonly recognized risk factors for HCC development, such as hepatitis B virus/hepatitis C virus infection, age and alcohol/tobacco consumption, there are nutritional risk factors also related to HCC development including high intake of saturated fats derived from red meat, type of cooking (generation of heterocyclic amines) and contamination of foods with aflatoxins. On the contrary, protective nutritional factors include diets rich in fiber, fruits and vegetables, n-3 polyunsaturated fatty acids and coffee. While the patient is being evaluated for staging and treatment of HCC, special attention should be paid to nutritional support, including proper nutritional assessment and therapy by a multidisciplinary team. It must be considered that these patients usually develop HCC on top of long-lasting cirrhosis, and therefore they could present with severe malnutrition. Cirrhosis-related complications should be properly addressed and considered for nutritional care. In addition to traditional methods, functional testing, phase angle and computed tomography scan derived skeletal muscle index-L3 are among the most useful tools for nutritional assessment. Nutritional therapy should be centered on providing enough energy and protein to manage the increased requirements of both cirrhosis and cancer. Supplementation with branched-chain amino acids is also recommended as it improves response to treatment, nutritional status and survival, and finally physical exercise must be encouraged and adapted to individual needs.
Abstract: Although branched-chain amino acids (BCAA) are commonly used as a strategy to recover nutritional status of critically ill patients, recent findings on their role as immunonutrients have been associated with unfavorable outcomes, especially in obese patients. Objective: The present study aimed to explore the effects of different BCAA supplementation protocols in the inflammatory response of LPS-stimulated RAW 264.7 macrophages. Material and Methods: Cell cultures were divided into five groups, with and without BCAA supplementation, (2 mmol/L of each amino acid). Then, cell cultures followed three different treatment protocols, consisting of a pretreatment (PT), an acute treatment (AT), and a chronic treatment (CT) with BCAA and LPS stimulation (1 µg/mL). Cell viability was analyzed by MTT assay, NO production was assessed by the Griess reaction and IL-6, IL-10, TNF-α and PGE2 synthesis, was evaluated by ELISA. Results: BCAA significantly increased cell viability in AT and CT protocols, and NO and IL-10 synthesis in all treatment protocols. IL-6 synthesis was only increased in PT and CT protocols. TNF-α and PGE2 synthesis were not altered in any of the protocols and groups. Conclusion: BCAA supplementation was able to increase both pro and anti-inflammatory mediators synthesis by RAW 264.7 macrophages, which was influenced by the protocol applied. Moreover, these parameters were significantly increased by isoleucine supplementation, highlighting a potential research field for future studies.
Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound 2e displayed the most excellent activity with an IC50 value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound 2e. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound 2e or compound 2e combined with cyclophosphamide (CTX) (p < 0.05, p < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound 2e caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound 2e was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound 2e is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.
Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.
Patients with chronic liver disease have a very high lifetime risk of malnourishment. It has been increasingly identified in literature that the severity of liver disease affects severity of malnutrition and vice versa. The objective of this review article is to recognize the severity of complications associated with malnutrition in patients with cirrhosis and ways to overcome these obstacles.
Nutritional/metabolic disorders such as protein–energy malnutrition are frequently observed with liver cirrhosis. Nutritional therapy prevents complications of liver cirrhosis and improves prognoses as well as quality of life. Branched chain amino acids are key drugs of nutritional therapy for liver cirrhosis, improve hypoalbuminemia, and are useful as a late evening snack for energy malnutrition. Appropriate nutritional therapy must be conducted for liver cirrhosis patients associated with sarcopenia or obesity.
Introduction and objectives
The potential benefits of branched-chain amino acids (BCAAs) in cirrhosis extend beyond just the improvement of nutritional status. Their effects include improvement of glucose tolerance, oxidative stress, and inflammatory markers, as has been shown in several studies. A dual nutritional approach of a high-protein, high-fiber diet plus BCAAs in cirrhosis could have additional benefits, compared with BCAAs alone. Such an approach has not been explored and therefore the aim of the present study was to evaluate the effect of a combination of a high-protein, high-fiber diet plus BCAA supplementation over a 6-month period of time on the nutritional status of patients with cirrhosis, as well as its safety and tolerability for those same patients.
Methods
An open, randomized clinical trial was conducted. Patients were randomized to one of two groups: the BCAAs + HPHF diet intervention group: a high-protein, high-fiber diet with 1.2 g/kg protein and 30 g of fiber plus supplementation with oral branched-chain amino acids 110 g daily and the HPHF diet control group: a high-protein, high-fiber diet with 1.2 g/kg protein and 30 g of fiber. The differences between the treatment groups were compared using the unpaired T test and the differences at the end of treatment were compared using the paired T test.
Results
A total of 72 patients were included, 37 in the intervention group and 35 in the control group. At the end of the study period, ammonia and glucose levels showed no significant increase in either group, reflecting the safety of the BCAA supplement. Furthermore, muscle and fat mass were evaluated through triceps skinfold thickness and mid-arm muscle circumference measurements. There was an increase in muscle mass and a decrease in fat mass in the BCAA group, but not in the control group. After the intervention, there were no significant changes in the Psychometric Hepatic Encephalopathy Score or the Critical Flicker Frequency score results in either group, and no episodes of hepatic encephalopathy were observed during the treatment period.
Conclusion
Supplementation with branched-chain amino acids plus a high-fiber, high-protein diet is a safe intervention in patients with cirrhosis. It helps increase muscle mass and does not raise the levels of ammonia or glucose, nor is it associated with the development of hepatic encephalopathy.
Introduction and objectives:
The potential benefits of branched-chain amino acids (BCAAs) in cirrhosis extend beyond just the improvement of nutritional status. Their effects include improvement of glucose tolerance, oxidative stress, and inflammatory markers, as has been shown in several studies. A dual nutritional approach of a high-protein, high-fiber diet plus BCAAs in cirrhosis could have additional benefits, compared with BCAAs alone. Such an approach has not been explored and therefore the aim of the present study was to evaluate the effect of a combination of a high-protein, high-fiber diet plus BCAA supplementation over a 6-month period of time on the nutritional status of patients with cirrhosis, as well as its safety and tolerability for those same patients.
Methods:
An open, randomized clinical trial was conducted. Patients were randomized to one of two groups: the BCAAs+HPHF diet intervention group: a high-protein, high-fiber diet with 1.2g/kg protein and 30g of fiber plus supplementation with oral branched-chain amino acids 110g daily and the HPHF diet control group: a high-protein, high-fiber diet with 1.2g/kg protein and 30g of fiber. The differences between the treatment groups were compared using the unpaired T test and the differences at the end of treatment were compared using the paired T test.
Results:
A total of 72 patients were included, 37 in the intervention group and 35 in the control group. At the end of the study period, ammonia and glucose levels showed no significant increase in either group, reflecting the safety of the BCAA supplement. Furthermore, muscle and fat mass were evaluated through triceps skinfold thickness and mid-arm muscle circumference measurements. There was an increase in muscle mass and a decrease in fat mass in the BCAA group, but not in the control group. After the intervention, there were no significant changes in the Psychometric Hepatic Encephalopathy Score or the Critical Flicker Frequency score results in either group, and no episodes of hepatic encephalopathy were observed during the treatment period.
Conclusion:
Supplementation with branched-chain amino acids plus a high-fiber, high-protein diet is a safe intervention in patients with cirrhosis. It helps increase muscle mass and does not raise the levels of ammonia or glucose, nor is it associated with the development of hepatic encephalopathy.
Oral administration of branched-chain amino acids (BCAA) is important in improving the prognosis of patients with chronic liver disease. BCAA can improve albumin synthesis, hepatic encephalopathy, insulin resistance, and suppress hepatocarcinoma, leading to higher event-free survival rate and better quality of life. We addressed the effects of BCAA dietary supplementation on global gene expression in liver and skeletal muscle and the molecular mechanisms underlying the improvement in liver cirrhosis using DNA microarray analysis combined with RNase protection assay. We established, for the first time, the regulatory gene pathways of processes involved in hepatic fibrosis and energy metabolism (hypoalbuminemia, hyperammonemia, and carbohydrate catabolism, and their relationships) under BCAA supplementation.
As acute or chronic liver diseases progress, liver failure and related hepatic encephalopathy may develop. The latter occurs in more than 70% of patients with hepatic cirrhosis. Because of declining cognitive functions, sleep disturbances, memory problems and impaired motion coordination, this condition can - even in mild form - limit the patient's self-sufficiency and activity and can lead to a decreased quality of life and ability to work. Its most advanced stage, hepatic coma is one of the leading causes of liver-related mortality. These conditions generate a substantial healthcare costs. Treatment of hepatic encephalopathy involves dietary restrictions, prevention and treatment of precipitating factors, inhibition of the production and absorption of toxic substances (especially ammonia) and restoration of the amino acid balance. In addition to the traditionally used treatment with disaccharids (lactulose, lactitol), evidence has been accumulating regarding the efficacy and safety of a nonabsorbable antibiotic compound, rifaximin, which targets enteral pathogen bacteria, both in treatment and in prevention of hepatic encephalopathy. Artificial liver support therapies have been also introduced in Hungary. This review summarises the experience regarding treatment of hepatic encephalography for physicians involved in the management of patients with hepatic diseases.
Management of nutrition in cancer patients plays an important role in supporting anti-cancer treatment. Parenteral nutrition is considered to assist with nutrition in cancer patients. Central venous catheters(CVC)are useful for intravenous infusion of not only nutrients with high osmotic pressure but also chemotherapeutic drugs and other substances. Central venous access through CV ports reduces patient's burden and complications, and it contributes to maintaining a patient's quality of life(QOL).
Purpose:
The aim of this retrospective cohort study was to clarify the effect of a branched-chain amino acids (BCAA) on the liver function and the prognosis of Child-Pugh class (C-P) A and B liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) undergoing hepatic arterial infusion chemotherapy (HAIC).
Methods:
Ninety-two adult Japanese patients with LC and aHCC underwent HAIC. They were in C-P A or B, and they showed multiple partial responses or stable disease. We excluded 11 patients classified as C-P C and 47 patients who showed no response. The patients were divided into an HAIC group receiving HAIC alone (n = 43) and a BCAA group treated with HAIC plus BCAA (n = 49). HAIC was delivered via the proper hepatic artery. The BCAA group also received oral administration of BCAA.
Results:
In the BCAA group, serum albumin increased significantly after HAIC, while there were no significant changes in serum total bilirubin, serum aminotransferases, prothrombin time, ascites, and hepatic encephalopathy. The C-P score decreased significantly after HAIC compared with before HAIC in C-P B patients, although there was no significant change in C-P A patients. Survival of the BCAA group was significantly longer than that of the HAIC group, with the median survival time being 426 versus 272 days for C-P B patients, although there was no significant difference for C-P A patients.
Conclusions:
Branched-chain amino acids might improve the survival and C-P score by increasing serum albumin in C-P B patients with aHCC receiving HAIC.
Background
& Aims: Branched-chain amino acid supplementation in porto-systemic encephalopathy remains controversial. Here, we examined the systematic review evidence for their effect on encephalopathy, hepatic decompensation, survival, infection, hospital stay and quality of life, and review data on adherence, side-effects and cost/ economic evaluation.
Methods
Four electronic databases were searched from 1980 to June 2011, with an update search in two databases in July 2013. Hand-searching was performed of references lists from included trials and six conference proceedings from 2005-2010. We included randomised controlled trials of branched chain amino acids versus other nutritional supplements in adults with cirrhosis and porto-systemic encephalopathy. Data extraction and quality assessment were performed by two independent assessors. Meta-analysis was performed if data were sufficient.
Results
The search identified nine randomised controlled trials (436 patients in total) of branched-chain amino acid therapy for > 2 weeks’ duration. The overall quality of trials was poor. At meta-analysis, a significant improvement in the grade of encephalopathy was demonstrated in favour of branched-chain amino acids compared to other nutritional supplements (Risk Ratio 2.6, 95% Confidence Interval 1.7-3.9, p<0.001, 2 trials, n 122) but no significant difference was found for either resolution or worsening of encephalopathy, gastrointestinal bleeding, survival or infection. Limited data suggested no difference in health-related quality of life, ascites or admission to hospital. Studies did not include cost data or economic evaluations. Side-effects appeared mild and gastrointestinal in nature.
Conclusions
Branched-chain amino acids might improve porto-systemic encephalopathy but more robust trials are needed to determine their role.
Primary liver cancer, 95% of which is hepatocellular carcinoma (HCC), is ranked third in men and fifth in women as a cause of death from malignant neoplasms in Japan. The number of deaths and death rate of HCC began to increase sharply in 1975. These numbers peaked at 34,510 and 27.4/100,000, respectively, in 2004, but decreased to 33,662 annual deaths and a 26.7/100,000 death rate in 2006. Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are both major causes of HCC, HCV-related HCC represents 70% of all cases. The incidence of HCC without hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV) accounts for 8%-15% of HCC patients nationwide. Geographically, HCC is more frequent in western than eastern Japan, and death rates of HCC in each prefecture correlate with anti-HCV, but not HBsAg, prevalence. Interferon therapy for chronic hepatitis C reduces the risk of development of HCC, especially among patients with sustained virological response. Further research should focus on the mechanisms of carcinogenesis by HCV and HBV, development of more effective treatments, and establishment of early detection and preventative approaches. Better understanding of HCC unrelated to HCV and HBV, possibly caused by steatohepatitis and diabetes, should also be a major concern in future studies.
Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia.
Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content-matched control diet, for 7 weeks.
Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and beta-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet-fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3beta, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA.
BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.
Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors.
Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression.
1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC.
We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.
Resection of hepatocellular carcinoma is associated with high rates of morbidity and mortality. Since intensive nutritional support can reduce the catabolic response and improve protein synthesis and liver regeneration, we performed a prospective study to investigate whether perioperative nutritional support could improve outcome in patients undergoing hepatectomy for hepatocellular carcinoma.
We studied 124 patients undergoing resection of hepatocellular carcinoma. Sixty-four patients (39 with cirrhosis, 18 with chronic active hepatitis, and 7 with no associated liver disease) were randomly assigned to receive perioperative intravenous nutritional support in addition to their oral diet, and 60 patients (33 with cirrhosis, 12 with chronic active hepatitis, and 15 with no associated liver disease) were randomly assigned to a control group. The perioperative nutritional therapy consisted of a solution enriched with 35 percent branched-chain amino acids, dextrose, and lipid emulsion (50 percent medium-chain triglycerides) given intravenously for 14 days perioperatively.
There was a reduction in the overall postoperative morbidity rate in the perioperative-nutrition group as compared with the control group (34 percent vs. 55 percent; relative risk, 0.66; 95 percent confidence interval, 0.45 to 0.96), predominantly because of fewer septic complications (17 percent vs. 37 percent; relative risk, 0.57; 95 percent confidence interval, 0.34 to 0.96). There were also a reduction in the requirement for diuretic agents to control ascites (25 percent vs. 50 percent; relative risk, 0.57; 95 percent confidence interval, 0.37 to 0.87), less weight loss after hepatectomy (median loss, 0 kg vs. 1.4 kg, P = 0.01), and less deterioration of liver function as measured by the change in the rate of clearance of indocyanine green (-2.8 percent vs. -4.8 percent at 20 minutes, P = 0.05). These benefits were seen predominantly in the patients with underlying cirrhosis who underwent major hepatectomy. There were five deaths during hospitalization in the perioperative-nutrition group, and nine in the control group (P not significant).
Perioperative nutritional support can reduce complications after major hepatectomy for hepatocellular carcinoma associated with cirrhosis.
Amino acids are nutrients responsible for mammalian target of rapamycin (mTOR) regulation in mammalian cells. The mTOR protein is mainly known for its role in regulating cell growth, notably via protein synthesis. In addition to amino acids, mTOR is regulated by insulin via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. mTOR mediates crosstalk between amino acids and insulin signaling. We show that in freshly isolated rat adipocytes, insulin stimulates the phosphorylation of mTOR on serine 2448, a protein kinase B (PKB) consensus phosphorylation site. This site is also phosphorylated by amino acids, which in contrast to insulin do not activate PKB. Moreover, insulin and amino acids have an additive effect on mTOR phosphorylation, indicating that they act via two independent pathways. Importantly, amino acids, notably leucine, permit insulin to stimulate PKB when PI 3-kinase is inhibited. They also rescue glucose transport and the mTOR pathway. Further, leucine alone can improve insulin activation of PKB in db/db mice. Our results define the importance of amino acids in insulin signaling and reveal leucine as a key amino acid in disease situations associated with insulin-resistance in adipocytes.
It is well established that impaired glucose metabolism is a frequent complication in patients with hepatic cirrhosis. We previously showed that leucine, one of the branched-chain amino acids (BCAA), promotes glucose uptake under insulin-free conditions in isolated skeletal muscle from normal rats. The aim of the present study was to evaluate the effects of BCAA on glucose metabolism in a rat model of CCl(4)-induced cirrhosis (CCl(4) rats). Oral glucose tolerance tests were performed on BCAA-treated CCl(4) rats. In the CCl(4) rats, treatment with leucine or isoleucine, but not valine, improved glucose tolerance significantly, with the effect of isoleucine being greater than the effect of leucine. Glucose uptake experiments using isolated soleus muscle from the CCl(4) rats revealed that leucine and isoleucine, but not valine, promoted glucose uptake under insulin-free conditions. To clarify the mechanism of the blood glucose-lowering effects of BCAA, we collected soleus muscles from BCAA-treated CCl(4) rats with or without a glucose load. These samples were used to determine the subcellular location of glucose transporter proteins and glycogen synthase (GS) activity. Oral administration of leucine or isoleucine without a glucose load induced GLUT4 and GLUT1 translocation to the plasma membrane. GS activity was augmented only in leucine-treated rats and was completely inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. In summary, we found that leucine and isoleucine improved glucose metabolism in CCl(4) rats by promoting glucose uptake in skeletal muscle. This effect occurred as a result of upregulation of GLUT4 and GLUT1 and also by mammalian target of rapamycin-dependent activation of GS in skeletal muscle. From these results, we consider that BCAA treatment may have beneficial effects on glucose metabolism in cirrhotic patients.
Background: The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined. Objective: To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C. Design: Retrospective cohort study. Setting: One university hospital and seven university-affiliated hospitals. Patients: 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). Intervention: Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-α2a, or recombinant interferon-α2b for 6 months. Measurements: The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns. Results: Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P = 0.041), older age (P = 0.003), greater histologic activity (P= 0.029), and higher histologic stage (P = 0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% Cl, 0.01 to 0.46), 0.51 (Cl, 0.20 to 1.27), and 0.95 (Cl, 0.48 to 1.84), respectively, compared with controls. Conclusions: The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.
Background: Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma. Objective: To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis. Design: Retrospective cohort study. Setting: Seven university hospitals and one regional core hospital in Japan. Patients: 2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490 were untreated. Measurements: The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional hazards regression. Results: Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis (P = 0.0128) and for those with stage F3 fibrosis (P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% Cl, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [Cl, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [Cl, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [Cl, 0.206 to 0.622]). Conclusions: Interferon therapy significantly reduces the risk for hepatocellular carcinoma, especially among virologic or biochemical responders.
BACKGROUND
Hepatocellular carcinoma (HCC) occurs more frequently in patients with hepatitis C virus (HCV)-related chronic liver disease than those with hepatitis B virus-related disease. It is important to assess the factors affecting the development of HCC.METHODSA long term follow-up study involving patients with chronic HCV was performed retrospectively. A total of 153 patients diagnosed between June 1981 and November 1990 with chronic HCV with or without cirrhosis by liver biopsy were enrolled in a long term follow-up study (average, 99.4 months) and the cumulative incidence rate of HCC and factors affecting the appearance of HCC were examined.RESULTSThe 5-year cumulative incidence rate was 9%, the 10-year cumulative incidence rate was 23%, and the 15-year cumulative incidence rate was 42%. The annual rate of incidence increased as the follow-up period progressed. The authors selected ten variables and investigated their effect on the incidence rate of HCC, including age, gender, habitual heavy drinking, positivity of antibody against hepatitis B virus surface antigen, treatment with interferon (IFN) during the follow-up period, maximum and minimum serum alanine aminotransferase levels during the follow-up period, histologic staging, grading, and irregular regeneration of hepatocytes. Of the 10 variables, age (> 50 years), habitual heavy drinking, and histologic staging were determined to be independent risk factors according to multivariate Cox proportional hazards regression analysis. IFN therapy by itself was not found to be an independent factor affecting the appearance of HCC.CONCLUSIONS
In patients with chronic HCV, the annual incidence rate of HCC appeared to increase as the follow-up period progressed. According to the results of the current study, the factors that independently affected the development of HCC were age, habitual heavy drinking, and histologic staging. Cancer 2000;89:53–9. © 2000 American Cancer Society.
Aim: In chronic hepatitis C virus (HCV) infection, it is thought that both chronic persistent inflammation and oxidative stress contribute to the development of hepatocellular carcinoma (HCC), and it has been reported that long-term oral supplementation with branched-chain amino acid (BCAA) granules could inhibit liver carcinogenesis. However, the extent of the involvement of these factors remains obscure.
Methods: To clarify the involvement of inflammation and oxidative stress in the inhibition of liver carcinogenesis, we evaluated the effect of oral administration of BCAA granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis.
Results: Twenty-seven patients were enrolled in the study: 18 of the patients were treated with BCAA granules (administered group) and nine were observed without BCAA granules (non-administered group). In the non-administered group, the production of oxidative stress, as indicated by urine 8-hydroxydeoxyguanosine (8-OHdG) and 15-F2t-Isoprostane (8-IsoPs), significantly increased with time, while in the administered group the levels of ferritin and 8-OHdG decreased significantly. Comparison of the two groups demonstrated that highly sensitive CRP, ferritin, 8-OHdG and 8-IsoPs were significantly reduced by taking BCAA granules. The time-course analysis showed that ferritin and highly sensitive CRP seemed to decrease first, followed by a decrease of 8-OHdG and 8-IsoPs.
Conclusion: These findings indicated that the administration of BCAA granules influenced microinflammation and the metabolism of iron in HCV-positive patients with liver cirrhosis, and subsequently seemed to reduce the production of oxidative stress, possibly leading to a decrease in the occurrence of HCC.
In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted.
Branched-chain amino acids (BCAAs) have a potential to improve glucose metabolism in cirrhotic patients; however, the contribution of liver in this process has not been clarified. To estimate the effect of BCAA on glucose metabolism in liver, we evaluated the mRNA expression levels of glucose-sensing apparatus genes in HepG2 cells and in rat liver after oral administration of BCAA. HepG2 cells were cultured in low glucose (100 mg/dl) or high glucose (400 mg/dl) in the absence or presence of BCAA. The mRNA expression levels and protein levels of GLUT2 and liver-type glucokinase (L-GK) were estimated using RT-PCR and immunoblotting. The expression levels of transcriptional factors, including SREBP-1c, ChREBP, PPAR-γm and LXRα, were estimated. The mRNA expression levels of transcriptional factors, glycogen synthase, and genes involved in gluconeogenesis were evaluated in rat liver at 3 h after the administration of BCAA. BCAA accelerated the expression of GLUT2 and L-GK in HepG2 cells in high glucose. Expression levels of ChREBP, SREBP-1c, and LXRα were also increased in this condition. BCAA administration enhanced the mRNA expression levels of L-GK, SREBP-1c, and LXRα and suppressed the expression levels of G-6-Pase in rat liver, without affecting the expression levels of glycogen synthase or serum glucose concentrations. BCAA administration enhanced the bioactivity of the glucose-sensing apparatus, probably via the activation of a transcriptional mechanism, suggesting that these amino acids may improve glucose metabolism through the accelerated utility of glucose and glucose-6-phosphate in the liver.
Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.
Unlabelled:
An imbalance of plasma amino acids is observed in patients with advanced cirrhosis. The aim of this study was to investigate the influence of the extracellular amino acid imbalance on the function of myeloid dendritic cells (DCs) in patients with advanced cirrhosis. We made a serum-free culture medium consistent with the average concentration of plasma amino acids from healthy controls (HC, n = 25) or patients with advanced cirrhosis (LC, n = 43) to reflect more closely the actual environment of the living body. We compared the phenotypical and biological functions of blood dendritic cells antigen-positive dendritic cells (BDCA+ DCs) and monocyte-derived dendritic cells (MoDCs) from LC and HC with these media. After adding stimulants, the CD83 and CD86 expressions of DCs from LC were lower than those from HC. In both HC and LC, both CD83 and CD86 expressions of DCs stimulated under the cirrhotic medium were lower than under the control medium. This phenomenon was accompanied by a suppression of the mammalian target of rapamycin (mTOR)/S6K-signaling pathways. The interleukin 12 (IL-12) production in the cirrhotic medium was significantly lower than in the control medium and increased when valine or leucine was added to the medium. In patients with advanced cirrhosis, peripheral blood mononuclear cells stimulated in the autologous plasma after oral administration of branched-chain amino acid (BCAA) granules had significantly increased interferon gamma production.
Conclusion:
In advanced cirrhosis, there is impairment of the function and maturation of DCs, which has been shown to be related to an imbalance in the extracellular amino acid profile. Elevating the extracellular concentration of BCAAs ex vivo in patients with advanced cirrhosis improved the function of DCs.
Asia has a disproportionately large share of the world's hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.
The effects of antiviral therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis are unclear. We performed a systematic review and meta-analysis to assess HCC risk reduction in patients with HCV-related cirrhosis who have received antiviral therapy.
Twenty studies (4700 patients) were analyzed that compared untreated patients with those given interferon (IFN) alone or ribavirin. Risk ratios (RRs) determined effect size using a random effects model.
Pooled data showed reduced HCC risk in the treatment group (RR, 0.43; 95% confidence interval [CI], 0.33-0.56), although the data were heterogenous (chi(2) = 59.10). Meta-regression analysis showed that studies with follow-up durations of more than 5 years contributed to heterogeneity. Analysis of 14 studies (n = 3310) reporting sustained virologic response (SVR) rates with antiviral treatment showed reduced HCC risk in patients with an SVR, compared with nonresponders (RR, 0.35; 95% CI, 0.26-0.46); the maximum benefits were observed in patients treated with ribavirin-based regimens (RR, 0.25; 95% CI, 0.14-0.46). Meta-analysis of 4 studies assessing the role of maintenance IFN in nonresponders did not show HCC risk reduction (RR, 0.58; 95% CI, 0.33-1.03). No publication bias was detected by the Egger test analysis (P > 0.1).
The risk of HCC is reduced among patients with HCV who achieve an SVR with antiviral therapy. Maintenance therapy with IFN does not reduce HCC risk among patients who do not respond to initial therapy. View this article's video abstract atwww.cghjournal.org.
Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Although many risk factors for HCC are well defined, including hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol, most series have indicated that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer. The majority of "cryptogenic" HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome. The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer with respect to both increased risk of disease and worsened outcome. In this review, the authors focused on the relation between metabolic syndrome and HCC. They investigated the increased risks of HCC among individuals with features of metabolic syndrome, potentially worsened cancer outcomes in these patients, possible pathogenic mechanisms to explain these relations, and treatment options for those with NAFLD and its progressive counterpart, nonalcoholic steatohepatitis. It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC.
At least five groups have evaluated treatment for patients with decompensated cirrhosis preliminary to liver transplantation.330–334 In the earliest reported study, 32 patients awaiting liver transplantation were considered for antiviral treatment, but over one-half were found ineligible because of cytopenias.330 Among those treated with standard or low doses of interferon alfa-2b or low doses of both interferon alfa-2b and ribavirin, 33% became HCV RNA negative. Almost all developed adverse effects, most of which was graded as severe. In a second study, 30 patients with HCV-related cirrhosis destined for liver transplantation (half graded as CTP class A) were treated with interferon alfa-2b, 3 mU daily and ribavirin, 800 mg/day if their presumed time to liver transplantion was less than 4 months.331 After a median treatment duration of 12 weeks, 30% responded to treatment and then underwent liver transplantation, 2/3 of whom remained HCV RNA negative over a median follow-up period of 46 weeks. Sixty percent developed neutropenia. Reported in the same year was a study of 20 patients, most with genotype 1 infection, who were treated before transplantation for a mean of 14 months with interferon alfa-2b in a dose of 5 mU daily.332 At transplantation, 60% were HCV RNA negative, but only 20% remained negative after transplantation. A fourth study involved 124 patients with advanced cirrhosis (CTP classes A, B and C) treated mainly with interferon alfa-2b plus ribavirin, and less frequently, with pegylated interferon plus ribavirin.333 Treatment began with half doses that were increased incrementally as tolerated at 2 week intervals (referred to as a low accelerating dose regimen), and growth factors were used as needed. An SVR developed in 13% of patients with genotype 1 and in 50% with non-genotype 1 infections. Adverse events were frequent, requiring dose reductions or treatment termination, but among those who did become HCV RNA negative before transplantation, 80% remained negative 6 or more months after transplantation. The most recent study is the only one to include non-treated controls but these consisted of patients unwilling to participate in the study.334 The treatment administered was peginterferon alfa-2b, 1.0 μg/kg body weight given weekly and ribavirin, 800 to 1000 mg daily for 24 weeks. An SVR developed in 44% of the patients with HCV genotypes 2 or 3, and in 7% of those with genotypes 1 or 4. Treatment had to be discontinued in 20%, was reduced in 39%, and was tolerated in 41%. Over a 30-month follow-up period, decompensated events occurred in 83% of the controls, 62% of the non-responders, and in 23% of the patients who had developed an SVR. The conclusion of this study was that antiviral therapy can be life-saving, improves hepatic function, and that treatment seems appropriate for persons with genotype 2 and 3 infections particularly in those with cirrhosis, CTP classes A and B.
Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). However, the possible mechanism is still obscure. The aim of the present study was to examine the effect of BCAAs, especially in conjunction with angiogenesis, on hepatocarcinogenesis under the condition of IR.
The effect of BCAAs on the development of liver enzyme-altered preneoplastic lesions and angiogenesis was examined in obese diabetic Otsuka Long-Evans Tokushima Fatty rats. We also performed an in vitro study to elucidate the possible mechanisms involved.
Treatment with BCAAs markedly inhibited glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of neovascularization in the liver. The hepatic expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, was also attenuated. BCAA treatment significantly suppressed glucose- and insulin-induced in vitro angiogenesis in the presence of VEGF.
In obese diabetic rats BCAAs exerted a chemopreventive effect against HCC, associated with the suppression of VEGF expression and hepatic neovascularization. Since BCAA preparations are widely used in clinical practice for patients with chronic liver diseases, this agent may represent a new strategy for chemoprevention against HCC in the future.
Most patients with hepatocellular carcinoma (HCC) have underlying liver cirrhosis that is frequently associated with a state of protein energy malnutrition. The aim of this study was to evaluate the clinical benefit of perioperative supplementation of a branched-chain amino acid-enriched nutrient-mixture for patients undergoing liver resection for HCC.
A total of 112 patients with HCC who underwent hepatic resection were enrolled in this study. These patients were divided into two groups: 40 patients received perioperative supplementation of branched-chain amino acid-enriched nutrient-mixture (AEN group) and 72 patients did not (control group). Laboratory data, postoperative complications, duration of hospitalization, and survival were assessed for each group and compared.
The overall incidence of postoperative complications was lower in the AEN group (17.5%) than in the control group (44.4%) (P = 0.01). Among the postoperative complications, surgical site infection and bile leakage was observed in 5% of patients in the AEN group and in 15.3% and 12.5% of patients in the control group, respectively. Ascites appeared after the surgery in 7.5% of patients in the AEN group and in 16.7% of patients in the control group. The duration of hospitalization was significantly shorter in the AEN group was than in the control group (P < 0.05).
This study strongly suggests that perioperative supplementation of a branched-chain amino acid-enriched nutrient-mixture is clinically beneficial in reducing the morbidity associated with postoperative complications and in shortening the duration of hospitalization of patients with chronic liver disease who undergo liver resection for HCC.
Hepatocyte proliferative activity is elevated in cirrhotic patients who develop hepatocellular carcinoma (HCC) and decreased in alcohol-induced hepatitis patients with poor outcome. Hepatocyte proliferative activity has not been evaluated in an unselected population of cirrhotic patients regarding the severity of the disease. Forty-six cirrhotic patients (21 alcoholic, 20 viral, and 5 other) were prospectively analyzed by proliferating cell nuclear antigen (PCNA) immunostaining on methanol-fixed, paraffin-embedded liver biopsy specimens. In these conditions, the PCNA-labeling index (PCNA-LI) measures the number of cells in the S-phase and assesses tissue proliferation. The median value of the PCNA-LI for all samples was 4.3% (range, 0%-20.2%). It declined with worsening Child-Pugh score: 9.15% (range, 3.3%-20.2%), 5.3% (range, 1.2%-18%), and 2.4% (range, 0%-4.4%) in Child classes A, B, and C, respectively (P < .05). Using the best cutoff PCNA-LI value to divide cirrhosis into slowly and rapidly proliferating tissue subsets, the PCNA index was independently associated with serum albumin. The probability of survival in patients with a high PCNA-LI ( > 4.4%) was significantly higher than in those with a lower PCNA-LI (0.93 vs. 0.53, at a median follow-up of 153 days; P = .01). In all 6 patients undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS), the PCNA-LI decreased after the procedure. This early impairment of hepatocyte proliferative activity after TIPS placement might reflect the functional alterations induced by this treatment. In conclusion, hepatocyte proliferative activity assessed by PCNA-LI is increased in cirrhotic patients and decreases with worsening of the disease.
The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined.
To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C.
Retrospective cohort study.
One university hospital and seven university-affiliated hospitals.
419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls).
Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-alpha2a, or recombinant interferon-alpha2b for 6 months.
The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns.
Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls.
The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.
Little is known about the influence of amino acid imbalance by supplementation of branched-chain amino acids (BCAAs) on human hepatocellular carcinoma (HCC). We investigated the effect of various BCAA concentrations in culture medium on the growth and metabolism of two human HCC cell lines: Hep G2 and KYN-1. DNA and protein syntheses were studied by radiolabeled thymidine and leucine uptake, Amino acid concentrations in cell and medium were measured with an amino acid analyzer. Expression and excretion of transforming growth factor (TGF)-alpha and TGF-beta1 were studied by immunostaining and enzyme linked immunosorbent assay methods. The cell growth was suppressed in media with higher and lower BCAA concentrations than Dulbecco's modified Eagle's medium, and this was grossly correlated with the incorporation of [3H]thymidine into DNA and incorporation of [3H]leucine into intracellular protein. Pretreatment with 10,000 nmol/ml of BCAA did not suppress the cell growth in subsequent culture in the standard Dulbecco's modified Eagle's medium, indicating that the effect of BCAAs was not cytocidal but cytostatic and reversible. BCAA and aromatic amino acid concentrations in cells increased in parallel as the BCAA level in medium was increased, despite the fixed aromatic amino acid level. Intracellular expression and extracellular excretion of TGF-alpha were higher at BCAA concentrations of 100 and 1,000 nmol/ml than at 10 or 1,000 nmol/ml. The present finding that the in vitro growth of HCC can be suppressed by enriched BCAA levels in medium may indicate that amino acid-imbalanced therapy with enriched BCAAs is useful in the treatment of HCC.
Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma.
To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis.
Retrospective cohort study.
Seven university hospitals and one regional core hospital in Japan.
2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490 were untreated.
The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional hazards regression.
Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis (P = 0.0128) and for those with stage F3 fibrosis (P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% CI, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [CI, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [CI, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [CI, 0.206 to 0.622]).
Interferon therapy significantly reducesthe risk for hepatocellular carcinoma, especially among virologic or biochemical responders.
Hepatocellular carcinoma (HCC) occurs more frequently in patients with hepatitis C virus (HCV)-related chronic liver disease than those with hepatitis B virus-related disease. It is important to assess the factors affecting the development of HCC.
A long term follow-up study involving patients with chronic HCV was performed retrospectively. A total of 153 patients diagnosed between June 1981 and November 1990 with chronic HCV with or without cirrhosis by liver biopsy were enrolled in a long term follow-up study (average, 99.4 months) and the cumulative incidence rate of HCC and factors affecting the appearance of HCC were examined.
The 5-year cumulative incidence rate was 9%, the 10-year cumulative incidence rate was 23%, and the 15-year cumulative incidence rate was 42%. The annual rate of incidence increased as the follow-up period progressed. The authors selected ten variables and investigated their effect on the incidence rate of HCC, including age, gender, habitual heavy drinking, positivity of antibody against hepatitis B virus surface antigen, treatment with interferon (IFN) during the follow-up period, maximum and minimum serum alanine aminotransferase levels during the follow-up period, histologic staging, grading, and irregular regeneration of hepatocytes. Of the 10 variables, age (> 50 years), habitual heavy drinking, and histologic staging were determined to be independent risk factors according to multivariate Cox proportional hazards regression analysis. IFN therapy by itself was not found to be an independent factor affecting the appearance of HCC.
In patients with chronic HCV, the annual incidence rate of HCC appeared to increase as the follow-up period progressed. According to the results of the current study, the factors that independently affected the development of HCC were age, habitual heavy drinking, and histologic staging.
Recently, several epidemiologic observations have suggested that obesity might be an independent risk factor for certain malignancies such as breast cancer, colon cancer, renal cell carcinoma, and esophageal adenocarcinoma. However, there are no studies examining the risk of hepatocellular carcinoma (HCC) in obesity. The aim of the present study was to determine whether obesity is an independent risk factor for HCC in patients with cirrhosis. Explanted liver specimens from a national database on patients undergoing liver transplantation were examined for HCC, and the incidence was compared among patients with varying body mass indices according to the etiology of cirrhosis. A multivariate analysis was used for controlling other potentially confounding variables such as age and sex. Among 19,271 evaluable patients, the overall incidence of HCC was 3.4% (n = 659) with a slightly higher prevalence among obese patients compared with lean patients. Obesity was an independent predictor for HCC in patients with alcoholic cirrhosis (odds ratio [OR], 3.2; 95% CI, 1.5-6.6; P =.002) and cryptogenic cirrhosis (OR, 11.1; 95% CI, 1.5-87.4; P =.02). Obesity was not an independent predictor in patients with hepatitis C, hepatitis B, primary biliary cirrhosis, and autoimmune hepatitis. The higher risk of HCC in obese patients is confined to alcoholic liver disease and cryptogenic cirrhosis. In conclusion, more frequent surveillance for HCC may be warranted in obese patients with alcoholic and cryptogenic cirrhosis. However, as this study is based on patients with advanced cirrhosis, our findings need to be confirmed in a broader population of individuals with cirrhosis.
The role of oral supplementation with branched-chain amino acids (BCAA) in advanced cirrhosis is far from settled. A nutritional approach might prevent progressive liver failure and improve nutritional parameters and quality of life.
A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis. Primary outcomes were the prevention of a combined end point (death and deterioration to exclusion criteria), the need for hospital admission, and the duration of hospital stay. Secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy.
Treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43; 95% confidence interval, 0.19-0.96; P = 0.039) and nonsignificantly compared with maltodextrins (odds ratio, 0.51; 95% confidence interval, 0.23-1.17; P = 0.108). The average hospital admission rate was lower in the BCAA arm compared with control treatments (P = 0.006 and P = 0.003, respectively). In patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during treatment with BCAA and the Child-Pugh score decreased (P = 0.013). Also, anorexia and health-related quality of life (SF-36 questionnaire) improved. Long-term compliance with BCAA was poor.
In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status. New formulas are needed to increase compliance.
An association between diabetes and chronic liver disease has been reported. However, the temporal relationship between these conditions remains unknown.
We identified all patients with a hospital discharge diagnosis of diabetes between 1985 and 1990 using the computerized records of the Department of Veterans Affairs. We randomly assigned 3 patients without diabetes for every patient with diabetes. We excluded patients with concomitant liver disease. The remaining cohort was followed through 2000 for the occurrence of chronic nonalcoholic liver disease (CNLD) and hepatocellular carcinoma (HCC). Hazard rate ratios (HRR) were determined in Cox proportional hazard survival analysis.
The study cohort comprised 173,643 patients with diabetes and 650,620 patients without diabetes. Most were men (98%). Patients with diabetes were older (62 vs. 54 years) than patients without diabetes. The incidence of chronic nonalcoholic liver disease was significantly higher among patients with diabetes (incidence rate: 18.13 vs. 9.55 per 10,000 person-years, respectively, P < 0.0001). Similar results were obtained for HCC (incidence rate: 2.39 vs. 0.87 per 10,000 person-years, respectively, P < 0.0001). Diabetes was associated with an HRR of 1.98 (95% CI: 1.88 to 2.09, P < 0.0001) of CNLD and an HRR of 2.16 (1.86 to 2.52, P < 0.0001) of hepatocellular carcinoma. Diabetes carried the highest risk among patients with longer than 10 years of follow-up.
Among men with diabetes, the risk of CNLD and HCC is doubled. This increase in risk is independent of alcoholic liver disease, viral hepatitis, or demographic features.
Patients undergoing transarterial chemoembolization for hepatocellular carcinoma have advanced tumour or severe cirrhosis and frequently have associated protein-calorie malnutrition. The role of nutritional supplements for such patients is unclear.
To investigate, in a randomized controlled trial, any benefit of the long-term administration of branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma.
Forty-one patients received oral branched chain amino acids for up to four courses of chemoembolization and 43 patients did not receive any nutritional supplement. Morbidity, liver function, nutritional status, quality of life and long-term survival were compared between the two groups.
The administration of branched chain amino acids resulted in a lower morbidity rate compared with the control group (17.1% vs. 37.2%, P = 0.039). In particular, the group given branched chain amino acids showed a significantly lower rate of ascites (7.3% vs. 23.2%, P = 0.043) and peripheral oedema (9.8% vs. 27.9%, P = 0.034). Significantly higher serum albumin, lower bilirubin and a better quality of life were observed after chemoembolization in the group given branched chain amino acids. However, there was no significant difference in survival between the two groups.
Nutritional supplementation with oral branched chain amino acids is beneficial in increasing the serum albumin level, reducing t