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Cheraghpour M, Hatami B, Singal AG. Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2025; 23:685-694.e6. [PMID: 39800201 DOI: 10.1016/j.cgh.2024.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/19/2024] [Accepted: 09/30/2024] [Indexed: 01/15/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate pharmacologic approach for individuals with MASLD may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.
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Affiliation(s)
- Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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López-Sánchez M, Bautista-Santos A, Milke-García MDP, Allende-López A, Moreno-Alcántar R, Morán S. Nutritional Status and Incidence of Hepatocellular Carcinoma in Patients with Compensated Liver Cirrhosis. Arch Med Res 2025; 56:103127. [PMID: 39591900 DOI: 10.1016/j.arcmed.2024.103127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 10/08/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024]
Abstract
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.
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Affiliation(s)
- Marlene López-Sánchez
- Laboratory of Hepatology Research, Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - Aleida Bautista-Santos
- Gastroenterology Service, Instituto Mexicano del Seguro Social Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - María Del Pilar Milke-García
- Hemato-Oncology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Aldo Allende-López
- Laboratory of Hepatology Research, Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - Rosalba Moreno-Alcántar
- Gastroenterology Service, Instituto Mexicano del Seguro Social Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - Segundo Morán
- Laboratory of Hepatology Research, Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Mexico City, Mexico.
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Bao J, Zhang X, Ye M, Yang Y, Xu L, He L, Guo J, Yao D, Wang S, Zhang J, Tian X. Exploration of Novel Metabolic Mechanisms Underlying Primary Biliary Cholangitis Using Hepatic Metabolomics, Lipidomics, and Proteomics Analysis. J Proteome Res 2025; 24:562-578. [PMID: 39792460 DOI: 10.1021/acs.jproteome.4c00708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.
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Affiliation(s)
- Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xuan Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Mao Ye
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Yiqin Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Leiming Xu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Lulu He
- Department of Biobank, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jixin Guo
- School of Stomatology, Wuhan University, Wuhan 430072, China
| | - Daoke Yao
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Suhua Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Ji Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China
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Zhu Y, Guo C, Fan H, Han X, Li Y, Chen X, Zhang T. Serum Branched-Chain Amino Acids and Long-Term Complications of Liver Cirrhosis: Evidence from a Population-Based Prospective Study. Nutrients 2024; 16:2295. [PMID: 39064737 PMCID: PMC11279618 DOI: 10.3390/nu16142295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
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.
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Affiliation(s)
- Yichen Zhu
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou 176002, China
| | - Chengnan Guo
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
| | - Hong Fan
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou 176002, China
| | - Xinyu Han
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
| | - Yi Li
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
| | - Xingdong Chen
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Fudan University Taizhou Institute of Health Sciences, Taizhou 176002, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China
- Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai 200437, China
| | - Tiejun Zhang
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200437, China; (Y.Z.); (C.G.); (H.F.); (X.H.); (Y.L.); (X.C.)
- Key Laboratory of Public Health Safety, Department of Epidemiology, School of Public Health, Ministry of Education, Fudan University, Shanghai 200437, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou 176002, China
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Zhang Y, Zhan L, Zhang L, Shi Q, Li L. Branched-Chain Amino Acids in Liver Diseases: Complexity and Controversy. Nutrients 2024; 16:1875. [PMID: 38931228 PMCID: PMC11206364 DOI: 10.3390/nu16121875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
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.
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Affiliation(s)
- Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Luqi Zhan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
- Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310024, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China
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Herrera-Martínez AD, León Idougourram S, Muñoz Jiménez C, Rodríguez-Alonso R, Alonso Echague R, Chica Palomino S, Sanz Sanz A, Manzano García G, Gálvez Moreno MÁ, Calañas Continente A, Molina Puertas MJ. Standard Hypercaloric, Hyperproteic vs. Leucine-Enriched Oral Supplements in Patients with Cancer-Induced Sarcopenia, a Randomized Clinical Trial. Nutrients 2023; 15:2726. [PMID: 37375630 DOI: 10.3390/nu15122726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 05/31/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
(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.
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Affiliation(s)
- Aura D Herrera-Martínez
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Soraya León Idougourram
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Concepción Muñoz Jiménez
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Rosa Rodríguez-Alonso
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Medical Oncology Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Rosario Alonso Echague
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- General Surgery Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Sonia Chica Palomino
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Ana Sanz Sanz
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Gregorio Manzano García
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - María Ángeles Gálvez Moreno
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - Alfonso Calañas Continente
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
| | - María José Molina Puertas
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
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Foglia B, Beltrà M, Sutti S, Cannito S. Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses. Int J Mol Sci 2023; 24:7463. [PMID: 37108625 PMCID: PMC10138633 DOI: 10.3390/ijms24087463] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
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.
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Affiliation(s)
- Beatrice Foglia
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
| | - Marc Beltrà
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Salvatore Sutti
- Department of Health Sciences, Interdisciplinary Research Center for Autoimmune Diseases, University of East Piedmont, 28100 Novara, Italy
| | - Stefania Cannito
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
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8
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van Dijk AM, Bruins Slot AS, Portincasa P, Siegerink SN, Chargi N, Verstraete CJR, de Bruijne J, Vleggaar FP, van Erpecum KJ. Systematic review with meta-analysis: Branched-chain amino acid supplementation in liver disease. Eur J Clin Invest 2023; 53:e13909. [PMID: 36394355 DOI: 10.1111/eci.13909] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/04/2022] [Accepted: 11/13/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. METHODS We searched MEDLINE and EMBASE for studies with BCAA supplementation with the 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 a 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 = .008; RR .61 95% CI .42-.88) and tended to improve overall survival (p = .05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the 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.
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Affiliation(s)
- Anne M van Dijk
- Department of Internal Medicine and Dermatology, Dietetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Alexandra S Bruins Slot
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Sebastiaan N Siegerink
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Najiba Chargi
- Department of Head and Neck Surgical Oncology, Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Carina J R Verstraete
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Joep de Bruijne
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Frank P Vleggaar
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karel J van Erpecum
- Department Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
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9
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Yu L, Paski SC, Dodge J, Bambha K, Biggins SW, Ioannou GN. Effect of dietary branched chain amino acids on liver related mortality: Results from a large cohort of North American patients with advanced HCV infection. PLoS One 2023; 18:e0284739. [PMID: 37098004 PMCID: PMC10128927 DOI: 10.1371/journal.pone.0284739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 04/06/2023] [Indexed: 04/26/2023] Open
Abstract
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.
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Affiliation(s)
- Lei Yu
- Division of Gastroenterology, University of Washington, Seattle, Washington, United States of America
| | - Shirley C Paski
- Division of Gastroenterology, Cedar Sinai School of Medicine, Los Angeles, California, United States of America
| | - Jennifer Dodge
- Department of Surgery, Division of Transplant Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Kiran Bambha
- Division of Gastroenterology, University of Washington, Seattle, Washington, United States of America
| | - Scott W Biggins
- Division of Gastroenterology, University of Washington, Seattle, Washington, United States of America
| | - George N Ioannou
- Division of Gastroenterology, University of Washington, Seattle, Washington, United States of America
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America
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10
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Ragni M, Fornelli C, Nisoli E, Penna F. Amino Acids in Cancer and Cachexia: An Integrated View. Cancers (Basel) 2022; 14:5691. [PMID: 36428783 PMCID: PMC9688864 DOI: 10.3390/cancers14225691] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
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.
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Affiliation(s)
- Maurizio Ragni
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Claudia Fornelli
- Department of Clinical and Biological Sciences, University of Torino, 10125 Turin, Italy
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Fabio Penna
- Department of Clinical and Biological Sciences, University of Torino, 10125 Turin, Italy
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11
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Lo EKK, Felicianna, Xu JH, Zhan Q, Zeng Z, El-Nezami H. The Emerging Role of Branched-Chain Amino Acids in Liver Diseases. Biomedicines 2022; 10:1444. [PMID: 35740464 PMCID: PMC9220261 DOI: 10.3390/biomedicines10061444] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
| | - Jing-Hang Xu
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland
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12
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An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition. Mol Metab 2022; 60:101478. [PMID: 35367410 PMCID: PMC9014392 DOI: 10.1016/j.molmet.2022.101478] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/10/2022] [Accepted: 03/17/2022] [Indexed: 12/17/2022] Open
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Ismaiel A, Bucsa C, Farcas A, Leucuta DC, Popa SL, Dumitrascu DL. Effects of Branched-Chain Amino Acids on Parameters Evaluating Sarcopenia in Liver Cirrhosis: Systematic Review and Meta-Analysis. Front Nutr 2022; 9:749969. [PMID: 35155535 PMCID: PMC8828569 DOI: 10.3389/fnut.2022.749969] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/03/2022] [Indexed: 12/19/2022] Open
Abstract
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.
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Affiliation(s)
- Abdulrahman Ismaiel
- 2nd Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Camelia Bucsa
- Drug Information Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andreea Farcas
- Drug Information Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Daniel-Corneliu Leucuta
- Department of Medical Informatics and Biostatistics, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Stefan-Lucian Popa
- 2nd Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Dan L. Dumitrascu
- 2nd Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Virseda-Berdices A, Rojo D, Martínez I, Berenguer J, González-García J, Brochado-Kith O, Fernández-Rodríguez A, Díez C, Hontañon V, Pérez-Latorre L, Micán R, Barbas C, Resino S, Jiménez-Sousa MA. Metabolomic changes after DAAs therapy are related to the improvement of cirrhosis and inflammation in HIV/HCV-coinfected patients. Pharmacotherapy 2022; 147:112623. [PMID: 35032770 DOI: 10.1016/j.biopha.2022.112623] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/21/2022]
Abstract
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.
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Affiliation(s)
- Ana Virseda-Berdices
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
| | - David Rojo
- Centro de Metabolómica y Bioanálisis (CEMBIO), Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU-San Pablo, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, Spain.
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
| | - Juan Berenguer
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | - Juan González-García
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain.
| | - Oscar Brochado-Kith
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
| | - Cristina Díez
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | - Víctor Hontañon
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain.
| | - Leire Pérez-Latorre
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | - Rafael Micán
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain.
| | - Coral Barbas
- Centro de Metabolómica y Bioanálisis (CEMBIO), Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad CEU-San Pablo, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, Spain.
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
| | - María Angeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
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15
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC. Biomedicines 2021; 9:1524. [PMID: 34829753 PMCID: PMC8614742 DOI: 10.3390/biomedicines9111524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, 20122 Milan, Italy; (M.M.); (M.L.); (S.F.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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16
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Ruiz-Margáin A, Román-Calleja BM, Moreno-Guillén P, González-Regueiro JA, Kúsulas-Delint D, Campos-Murguía A, Flores-García NC, Macías-Rodríguez RU. Nutritional therapy for hepatocellular carcinoma. World J Gastrointest Oncol 2021; 13:1440-1452. [PMID: 34721776 PMCID: PMC8529929 DOI: 10.4251/wjgo.v13.i10.1440] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/23/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Astrid Ruiz-Margáin
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
- Liver Fibrosis and Nutrition Lab, MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases- Research Network), Mexico City 14080, Mexico
| | - Berenice M Román-Calleja
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Paulina Moreno-Guillén
- Liver Nutrition Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - José A González-Regueiro
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Deyanira Kúsulas-Delint
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Alejandro Campos-Murguía
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Nayelli C Flores-García
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
| | - Ricardo Ulises Macías-Rodríguez
- Liver Fibrosis and Nutrition Lab, MICTLÁN-Network (Mechanisms of Liver Injury, Cell Death and Translational Nutrition in Liver Diseases- Research Network), Mexico City 14080, Mexico
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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17
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Bonvini A, Rogero MM, Coqueiro AY, Raizel R, Bella LM, Fock RA, Borelli P, Tirapegui J. Effects of different branched-chain amino acids supplementation protocols on the inflammatory response of LPS-stimulated RAW 264.7 macrophages. Amino Acids 2021; 53:597-607. [PMID: 33715068 DOI: 10.1007/s00726-021-02940-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 01/07/2021] [Indexed: 12/30/2022]
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. The present study aimed to explore the effects of different BCAA supplementation protocols in the inflammatory response of LPS-stimulated RAW 264.7 macrophages. 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. 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. 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.
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Affiliation(s)
- Andrea Bonvini
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Avenida Professor Lineu Prestes, 580, Butantã, Sao Paulo, 05508-000, Brazil.
| | - Marcelo Macedo Rogero
- Department of Nutrition, Faculty of Public Health, University of Sao Paulo, Sao Paulo, Brazil
| | - Audrey Yule Coqueiro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Avenida Professor Lineu Prestes, 580, Butantã, Sao Paulo, 05508-000, Brazil
| | - Raquel Raizel
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Avenida Professor Lineu Prestes, 580, Butantã, Sao Paulo, 05508-000, Brazil
| | - Leonardo Mendes Bella
- Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Ricardo Ambrosio Fock
- Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Primavera Borelli
- Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Julio Tirapegui
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Avenida Professor Lineu Prestes, 580, Butantã, Sao Paulo, 05508-000, Brazil
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Zhang Y, Yu H, Fu S, Tan L, Liu J, Zhou B, Li L, Liu Y, Wang C, Li P, Liu J. Synthesis and Anti-Hepatocarcinoma Effect of Amino Acid Derivatives of Pyxinol and Ocotillol. Molecules 2021; 26:molecules26040780. [PMID: 33546225 PMCID: PMC7913291 DOI: 10.3390/molecules26040780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/25/2021] [Accepted: 01/30/2021] [Indexed: 11/17/2022] Open
Abstract
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.
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Affiliation(s)
- Ying Zhang
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
- The First Hospital of Jilin University, Changchun 130021, China
| | - Hui Yu
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Shuzheng Fu
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Luying Tan
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Junli Liu
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Baisong Zhou
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Le Li
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Yunhe Liu
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Caixia Wang
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Pingya Li
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
| | - Jinping Liu
- School of Pharmaceutical Sciences, Jilin University, Fujin Road 1266, Changchun 130021, China; (Y.Z.); (H.Y.); (S.F.); (L.T.); (J.L.); (B.Z.); (L.L.); (Y.L.); (C.W.); (P.L.)
- Research Center of Natural Drug, Jilin University, Changchun 130021, China
- Correspondence:
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Iqbal U, Jadeja RN, Khara HS, Khurana S. A Comprehensive Review Evaluating the Impact of Protein Source (Vegetarian vs. Meat Based) in Hepatic Encephalopathy. Nutrients 2021; 13:370. [PMID: 33530344 PMCID: PMC7911290 DOI: 10.3390/nu13020370] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
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.
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Affiliation(s)
- Umair Iqbal
- Geisinger Medical Center, Department of Gastroenterology and Hepatology, Danville, PA 17822, USA; (U.I.); (H.S.K.)
| | - Ravirajsinh N. Jadeja
- Department of Biochemistry and Molecular Biology, The Medical College of Georgia at Augusta University, Augusta, GA 30912, USA;
| | - Harshit S. Khara
- Geisinger Medical Center, Department of Gastroenterology and Hepatology, Danville, PA 17822, USA; (U.I.); (H.S.K.)
| | - Sandeep Khurana
- Geisinger Medical Center, Department of Gastroenterology and Hepatology, Danville, PA 17822, USA; (U.I.); (H.S.K.)
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20
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Prabhakar O, Bhuvaneswari M. Role of diet and lifestyle modification in the management of nonalcoholic fatty liver disease and type 2 diabetes. Tzu Chi Med J 2020; 33:135-145. [PMID: 33912410 PMCID: PMC8059462 DOI: 10.4103/tcmj.tcmj_86_20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/11/2020] [Accepted: 06/08/2020] [Indexed: 12/15/2022] Open
Abstract
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.
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Affiliation(s)
- Orsu Prabhakar
- Department of Pharmacology, GITAM Institute of Pharmacy, Visakhapatnam, Andhra Pradesh, India
| | - Mylipilli Bhuvaneswari
- Department of Pharmacology, GITAM Institute of Pharmacy, Visakhapatnam, Andhra Pradesh, India
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21
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Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene 2020; 39:6747-6756. [PMID: 32978521 PMCID: PMC7606751 DOI: 10.1038/s41388-020-01480-z] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- Hui Peng
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Yingfei Wang
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. .,Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
| | - Weibo Luo
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. .,Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
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22
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Park JG, Tak WY, Park SY, Kweon YO, Chung WJ, Jang BK, Bae SH, Lee HJ, Jang JY, Suk KT, Oh MJ, Heo J, Woo HY, Jang SY, Lee YR, Lee JS, Kim DY, Kim SH, Suh JI, Kim IH, Kang MK, Lee WK. Effects of Branched-Chain Amino Acid (BCAA) Supplementation on the Progression of Advanced Liver Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort Study. Nutrients 2020; 12:1429. [PMID: 32429077 PMCID: PMC7284598 DOI: 10.3390/nu12051429] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/09/2020] [Accepted: 05/13/2020] [Indexed: 01/01/2023] Open
Abstract
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.
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Affiliation(s)
- Jung Gil Park
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea; (J.G.P.); (H.J.L.); (M.K.K.)
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (S.Y.P.); (Y.O.K.); (S.Y.J.); (Y.R.L.)
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (S.Y.P.); (Y.O.K.); (S.Y.J.); (Y.R.L.)
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (S.Y.P.); (Y.O.K.); (S.Y.J.); (Y.R.L.)
| | - Woo Jin Chung
- Department of Internal Medicine, School of Medicine, Keimyung University, Daegu 42601, Korea; (W.J.C.); (B.K.J.)
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Keimyung University, Daegu 42601, Korea; (W.J.C.); (B.K.J.)
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Heon Ju Lee
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea; (J.G.P.); (H.J.L.); (M.K.K.)
| | - Jae Young Jang
- Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul 04401, Korea;
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon 24252, Korea;
| | - Myung Jin Oh
- Department of Internal Medicine, CHA Gumi Medical Center, CHA University School of Medicine, Gumi 39295, Korea;
| | - Jeong Heo
- Department of Internal Medicine, School of Medicine, Pusan National University, Pusan 49241, Korea; (J.H.); (H.Y.W.)
| | - Hyun Young Woo
- Department of Internal Medicine, School of Medicine, Pusan National University, Pusan 49241, Korea; (J.H.); (H.Y.W.)
| | - Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (S.Y.P.); (Y.O.K.); (S.Y.J.); (Y.R.L.)
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea; (S.Y.P.); (Y.O.K.); (S.Y.J.); (Y.R.L.)
| | - June Sung Lee
- Department of Internal Medicine, Ilsan Paik Hospital, College of Medicine, Inje University College of Medicine, Goyang 10380, Korea;
| | - Do Young Kim
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul 03722, Korea;
| | - Seok Hyun Kim
- Department of Internal Medicine, School of Medicine, Choungnam National University, Daejeon 61469, Korea;
| | - Jeong Ill Suh
- Department of Internal Medicine, College of Medicine, Dongguk University, Gyeongju 39067, Korea;
| | - In Hee Kim
- Department of Internal Medicine, School of Medicine, Chonbuk National University, Chungju 54907, Korea;
| | - Min Kyu Kang
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea; (J.G.P.); (H.J.L.); (M.K.K.)
| | - Won Kee Lee
- Medical Research Collabration Center in KNUH and School of Medicine, Kyungpook National University, Daegu 41944, Korea;
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Abstract
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.
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Affiliation(s)
- Aiman Ghufran
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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24
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High Protein Diet and Metabolic Plasticity in Non-Alcoholic Fatty Liver Disease: Myths and Truths. Nutrients 2019; 11:nu11122985. [PMID: 31817648 PMCID: PMC6950466 DOI: 10.3390/nu11122985] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/27/2019] [Accepted: 11/30/2019] [Indexed: 02/07/2023] Open
Abstract
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.
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25
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Sakamoto N, Suda G, Morikawa K, Ogawa K. Nutrition is often ignored in management of chronic liver diseases. J Gastroenterol Hepatol 2019; 34:1127-1128. [PMID: 31317602 DOI: 10.1111/jgh.14776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Naoya Sakamoto
- Department of Gastroenterology and Hepatology Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Kennichi Morikawa
- Department of Gastroenterology and Hepatology Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology Faculty of Medicine, Hokkaido University, Sapporo, Japan
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26
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Bonvini A, Coqueiro AY, Tirapegui J, Calder PC, Rogero MM. Immunomodulatory role of branched-chain amino acids. Nutr Rev 2018; 76:840-856. [PMID: 30124936 DOI: 10.1093/nutrit/nuy037] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Branched-chain amino acids (BCAAs) 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 BCAAs can directly contribute to immune cell function, aiding recovery of an impaired immune system, as well as improving the nutritional status in cancer and liver diseases. Branched-chain amino acids may also play a role in treatment of patients with sepsis or trauma, contributing to improved clinical outcomes and survival. Branched-chain amino acids, 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 in vitro and human and animal model studies have provided evidence for the biological activity of BCAAs, findings have been conflicting, and the mechanisms of action of these amino acids are still poorly understood. This review addresses several aspects related to BCAAs, including their transport, oxidation, and mechanisms of action, as well as their role in nutritional therapy and immunomodulation.
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Affiliation(s)
- Andrea Bonvini
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Audrey Y Coqueiro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Julio Tirapegui
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Philip C Calder
- Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Marcelo M Rogero
- Department of Nutrition, Faculty of Public Health, University of São Paulo, São Paulo, Brazil
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27
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Tajiri K, Shimizu Y. Branched-chain amino acids in liver diseases. Transl Gastroenterol Hepatol 2018; 3:47. [PMID: 30148232 PMCID: PMC6088198 DOI: 10.21037/tgh.2018.07.06] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/06/2018] [Indexed: 02/05/2023] Open
Abstract
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.
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Affiliation(s)
- Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
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28
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Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2018. [DOI: 10.1016/j.rgmxen.2017.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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29
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Ruiz-Margáin A, Macías-Rodríguez RU, Ríos-Torres SL, Román-Calleja BM, Méndez-Guerrero O, Rodríguez-Córdova P, Torre A. Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2018; 83:9-15. [PMID: 28408059 DOI: 10.1016/j.rgmx.2017.02.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 01/19/2017] [Accepted: 02/02/2017] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- A Ruiz-Margáin
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - R U Macías-Rodríguez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - S L Ríos-Torres
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - B M Román-Calleja
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - O Méndez-Guerrero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - P Rodríguez-Córdova
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - A Torre
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.
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Park JG, Tak WY, Park SY, Kweon YO, Jang SY, Lee YR, Bae SH, Jang JY, Kim DY, Lee JS, Suk KT, Kim IH, Lee HJ, Chung WJ, Jang BK, Suh JI, Heo J, Lee WK. Effects of branched-chain amino acids (BCAAs) on the progression of advanced liver disease: A Korean nationwide, multicenter, retrospective, observational, cohort study. Medicine (Baltimore) 2017; 96:e6580. [PMID: 28614215 PMCID: PMC5478300 DOI: 10.1097/md.0000000000006580] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 03/13/2017] [Accepted: 03/18/2017] [Indexed: 02/07/2023] Open
Abstract
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.
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Affiliation(s)
- Jung Gil Park
- Department of Internal Medicine, College of Medicine, Yeungnam University
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu
| | - Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea
| | - Jae Young Jang
- Department of Internal Medicine, College of Medicine, Soonchunhyang University
| | - Do Young Kim
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul
| | - June Sung Lee
- Department of Internal Medicine, Ilsan Paik Hospital, College of Medicine, Inje University College of Medicine, Goyang
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon
| | - In Hee Kim
- Department of Internal Medicine, School of Medicine, Chonbuk National University, Chungju
| | - Heon Ju Lee
- Department of Internal Medicine, College of Medicine, Yeungnam University
| | - Woo Jin Chung
- Department of Internal Medicine, School of Medicine, Keimyung University, Daegu
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Keimyung University, Daegu
| | - Jeong Ill Suh
- Department of Internal Medicine, College of Medicine, Dongguk University, Gyeongju
| | - Jeong Heo
- Department of Internal Medicine, School of Medicine, Pusan National University, Pusan
| | - Won Kee Lee
- Medical Research Collabration Center in KNUH and School of Medicine, Kyungpook National University, Daegu, Korea
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Does Nutrition Matter in Liver Disease? LIVER PATHOPHYSIOLOGY 2017. [DOI: 10.1016/b978-0-12-804274-8.00053-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Setoyama H, Tanaka M, Nagumo K, Naoe H, Watanabe T, Yoshimaru Y, Tateyama M, Sasaki M, Watanabe H, Otagiri M, Maruyama T, Sasaki Y. Oral branched-chain amino acid granules improve structure and function of human serum albumin in cirrhotic patients. J Gastroenterol 2017; 52:754-765. [PMID: 27873095 PMCID: PMC5437197 DOI: 10.1007/s00535-016-1281-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 10/24/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The 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. RESULTS There 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.
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Affiliation(s)
- Hiroko Setoyama
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Motohiko Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Kohei Nagumo
- Department of Biopharmaceutics, School of Pharmacy, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto 862-0973 Japan
| | - Hideaki Naoe
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Youko Yoshimaru
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Masakuni Tateyama
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
| | - Masato Sasaki
- Kumamoto Rosai Hospital, Yatsushiro City, Kumamoto 866-0826 Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, School of Pharmacy, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto 862-0973 Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto City, Kumamoto 860-0082 Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, School of Pharmacy, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto 862-0973 Japan
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuou-ku, Kumamoto City, Kumamoto 860-8556 Japan
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Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016; 51:629-50. [PMID: 27246107 DOI: 10.1007/s00535-016-1216-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/12/2016] [Indexed: 02/04/2023]
Abstract
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.
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Abstract
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.
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Affiliation(s)
- Kerstin Schütte
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis. Mediators Inflamm 2015; 2015:872152. [PMID: 26494949 PMCID: PMC4606163 DOI: 10.1155/2015/872152] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 07/08/2015] [Accepted: 07/13/2015] [Indexed: 02/07/2023] Open
Abstract
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.
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Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015; 47:603-15. [PMID: 25534430 PMCID: PMC4329055 DOI: 10.1007/s00726-014-1894-9] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 12/03/2014] [Indexed: 02/07/2023]
Abstract
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.
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Affiliation(s)
- April D. Lake
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
| | - Petr Novak
- Biology Centre ASCR, Institute of Plant Molecular Biology, České Budějovice, Czech Republic
| | - Petia Shipkova
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Nelly Aranibar
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Donald G. Robertson
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | - Michael D. Reily
- Bristol-Myers Squibb Co, Pharmaceutical Candidate Optimization, Princeton, NJ, USA
| | | | - Richard R. Vaillancourt
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
| | - Nathan J. Cherrington
- Department of Pharmacology and Toxicology, The University of Arizona, 1703 East Mabel St, PO Box 210207, Tucson, AZ 85721, USA
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Abstract
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.
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Affiliation(s)
- Christopher J Lynch
- Cellular and Molecular Physiology Department, The Pennsylvania State University, 500 University Drive, MC-H166, Hershey, PA 17033, USA
| | - Sean H Adams
- Arkansas Children's Nutrition Center, and Department of Pediatrics, University of Arkansas for Medical Sciences, 15 Children's Way, Little Rock, AR 72202, USA
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Kanekawa T, Nagai H, Kanayama M, Sumino Y. Importance of branched-chain amino acids in patients with liver cirrhosis and advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy. Cancer Chemother Pharmacol 2014; 74:899-909. [PMID: 25138286 DOI: 10.1007/s00280-014-2564-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 07/07/2014] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
- Takenori Kanekawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), Faculty of Medicine, School of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ku, Tokyo, 143-8541, Japan
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Smith RJ. Nutrition and metabolism in hepatocellular carcinoma. Hepatobiliary Surg Nutr 2014; 2:89-96. [PMID: 24570922 DOI: 10.3978/j.issn.2304-3881.2012.11.02] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 11/05/2012] [Indexed: 01/01/2023]
Abstract
Hepatocellular carcinoma is the fifth most common human cancer worldwide, with an overall 5-year survival in the range of 10%. In addition to the very substantial role of chronic viral hepatitis in causing hepatocellular carcinoma, nutritional status and specific nutritional factors appear to influence disease risk. This is apparent in the increased risk associated with non-alcoholic hepatic cirrhosis occurring in the context of obesity, the metabolic syndrome, and type 2 diabetes. Specific nutrients and ingested toxins, including ethanol, aflatoxin, microcystins, iron, and possibly components of red meat, also are associated with increased hepatocellular carcinoma risk. Other dietary components, including omega-3 fatty acids and branched chain amino acids, may have protective effects. Recent data further suggest that several metabolic regulatory drugs, including metformin, pioglitazone, and statins, may have the potential to decrease the risk of hepatocellular carcinoma. The available data on these nutritional and metabolic factors in causing hepatocellular carcinoma are reviewed with the goal of identifying the strength of current knowledge and directions for future investigation.
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Affiliation(s)
- Robert J Smith
- Alpert Medical School of Brown University, Ocean State Research Institute, Providence Veterans Administration Medical Center, 830 Chalkstone Avenue, Providence, RI 02908, USA
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Mandair DS, Rossi RE, Pericleous M, Whyand T, Caplin M. The impact of diet and nutrition in the prevention and progression of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2014; 8:369-82. [PMID: 24597926 DOI: 10.1586/17474124.2014.894879] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. There is growing evidence for a chemopreventive role of nutrition in the development of HCC in at risk populations. Bibliographical searches were performed in PubMed for the terms 'nutrition and hepatocellular carcinoma', 'nutrition and liver cancer', 'nutrition and hepatic cancer', 'diet and hepatocellular carcinoma', 'diet and liver cancer'. High dietary sugar intake should be discouraged in at risk populations. Coffee, polyphenols, vanadium, dietary fibre, fruits and vegetables show encouraging results in terms of chemoprevention. Red meat intake may be associated with increased risk of HCC. The evidence for fatty acids is inconclusive, but they might exert anti-cancer effects. Inconclusive results are available on vitamins, selenium probiotics and prebiotics. There is increasing evidence that diet may play an important role in the development of HCC, and may also have a chemopreventive role in at risk populations.
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Metcalfe EL, Avenell A, Fraser A. Branched-chain amino acid supplementation in adults with cirrhosis and porto-systemic encephalopathy: systematic review. Clin Nutr 2014; 33:958-65. [PMID: 24656171 DOI: 10.1016/j.clnu.2014.02.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 02/19/2014] [Accepted: 02/27/2014] [Indexed: 12/12/2022]
Abstract
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 to 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.
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Affiliation(s)
- Emma Louise Metcalfe
- Health Services Research Unit, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; Department of Gastroenterology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK.
| | - Alison Avenell
- Health Services Research Unit, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
| | - Andrew Fraser
- Department of Gastroenterology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK
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Takeda H, Nishikawa H, Iguchi E, Ohara Y, Sakamoto A, Saito S, Nishijima N, Nasu A, Komekado H, Kita R, Kimura T, Osaki Y. Effect of treatment with branched-chain amino acids during sorafenib therapy for unresectable hepatocellular carcinoma. Hepatol Res 2014; 44:302-12. [PMID: 23607614 DOI: 10.1111/hepr.12125] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 02/17/2013] [Accepted: 03/27/2013] [Indexed: 02/08/2023]
Abstract
AIM To examine the effect of branched-chain amino acid (BCAA) therapy for patients with unresectable hepatocellular carcinoma (HCC) treated with sorafenib. METHODS Seventy-eight subjects with unresectable HCC with a serum level of albumin of 3.5 g/dL or less treated with sorafenib were evaluated. They were classified into two groups: those receiving BCAA granules (n = 34; BCAA group) or a regular diet (n = 44; control group). We compared overall survival and administration period of sorafenib, and analyzed absolute changes in serum levels of albumin during sorafenib therapy in 41 patients who continued sorafenib therapy for 1 month or more with a follow up of more than 3 months. RESULTS Median survival time (MST) in BCAA and control groups was 350 and 143 days (P = 0.007), respectively. Median administration period of sorafenib in the two groups was 59 and 41 days (P = 0.018). In the 41 patients described above, at 1 month, there was no significant change in the serum level of albumin between the two groups, but at 3 months, the difference in the absolute change in the serum level of albumin in the two groups reached significance (P = 0.023). In these subgroup analyses, the administration period of sorafenib as well as the MST in the BCAA group were significantly longer than those in the control group (P = 0.020 and = 0.004). CONCLUSION BCAA treatment during sorafenib therapy in HCC patients is useful for maintaining hepatic functional reserve, which may help to avoid early discontinuance of sorafenib therapy and improve survival.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Nishikawa H, Osaki Y. Clinical significance of therapy using branched-chain amino acid granules in patients with liver cirrhosis and hepatocellular carcinoma. Hepatol Res 2014; 44:149-58. [PMID: 23819582 DOI: 10.1111/hepr.12194] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 06/24/2013] [Accepted: 06/25/2013] [Indexed: 02/07/2023]
Abstract
The liver is the major organ for the metabolism of protein, fat and carbohydrate. A nutritional approach is required in the treatment of cirrhosis, which is frequently complicated with protein-energy malnutrition. Several advanced treatment approaches for hepatocellular carcinoma (HCC) have been established in the past decade. HCC is often complicated by cirrhosis, so treatment of the underlying liver diseases is also necessary to improve the prognosis. Branched-chain amino acid (BCAA) granules were developed originally for the treatment of hypoalbuminemia associated with decompensated cirrhosis. However, subsequent studies found various other pharmacological actions of this agent. We review the clinical significance of therapy using BCAA granules in patients receiving different treatment approaches for cirrhosis and HCC based on the published work as well as our own data.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Shimizu M, Shirakami Y, Hanai T, Imai K, Suetsugu A, Takai K, Shiraki M, Moriwaki H. Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids. Mol Nutr Food Res 2013; 58:124-35. [PMID: 24273224 DOI: 10.1002/mnfr.201300538] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 09/10/2013] [Accepted: 09/16/2013] [Indexed: 12/11/2022]
Abstract
The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy.
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Affiliation(s)
- Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
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Kawaguchi T, Taniguchi E, Sata M. Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract 2013; 28:580-8. [PMID: 23945292 DOI: 10.1177/0884533613496432] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Branched-chain amino acids (BCAAs) constituting of valine, leucine, and isoleucine act as both substrates of proteins and as key regulators for various nutrient metabolisms. Patients with liver cirrhosis frequently lack sufficient BCAAs and therefore suffer from various metabolic disorders. Hepatic encephalopathy (HE) is a severe metabolic disorder with neurologic manifestations such as flapping tremors and coma in patients with liver cirrhosis. In addition, a mild form of HE known as minimal HE (MHE) is an important social issue because it occurs in up to 80% of patients with chronic liver disease and affects prognosis and activities of daily living, possibly resulting in falls and motor vehicle accidents. Although HE/MHE can be caused by various pathological conditions, including in an accumulation of mercaptans, short-chain fatty acids, and alterations in the gut flora, hyperammonemia has also been implicated in an important pathogenesis of HE/MHE. Besides urea cycle of liver, ammonia can be detoxified in the skeletal muscles by the amidation process for glutamine synthesis using BCAAs. Thus, BCAA supplementation may enhance detoxification of ammonia in skeletal muscle and may be a possible therapeutic strategy for HE/MHE. In this review, we summarize the clinical impacts of BCAA supplementation on HE/MHE and discuss possible mechanisms for a BCAA-induced improvement of HE/MHE. Furthermore, we present some modifications of oral BCAA therapy for improvement of efficacy in HE treatment. We also briefly describe pleiotropic benefits of BCAAs on life-threatening events and overall prognosis in patients with liver cirrhosis.
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Affiliation(s)
- Takumi Kawaguchi
- Takumi Kawaguchi, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
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Takaguchi K, Moriwaki H, Doyama H, Iida M, Yagura M, Shimada N, Kang M, Yamada H, Kumada H. Effects of branched-chain amino acid granules on serum albumin level and prognosis are dependent on treatment adherence in patients with liver cirrhosis. Hepatol Res 2013; 43:459-66. [PMID: 23046471 PMCID: PMC3708103 DOI: 10.1111/j.1872-034x.2012.01097.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 08/26/2012] [Accepted: 08/27/2012] [Indexed: 12/19/2022]
Abstract
AIM To test if the treatment adherence to branched-chain amino acid (BCAA) granules influences the serum albumin level and prognosis in prospective 2984 patients with decompensated liver cirrhosis who were prescribed BCAA granules containing 952 mg of L-isoleucine, 1904 mg of L-leucine and 1144 mg of L-valine at 4.15 g/sachet three times a day after meals. METHODS The primary end-point was the time to the event defined as "hospital admission due to progression of hepatic failure", and factors affecting this outcome were explored. Changes in serum albumin level were evaluated as the secondary end-point. RESULTS Patients were divided into the good adherence group (those who reported to have taken "nearly all" prescribed doses) and the poor adherence group (those who reported to have taken "approximately half" or "less" doses), because such stratification was validated by treatment responses in plasma BCAA/tyrosine ratio. Factors related to the primary end-point were age, drug adherence during 6 months of study treatment, previous hepatic cancer, current clinical manifestations, previous clinical manifestations, baseline serum albumin level, platelet count and total bilirubin level. The cumulative event-free survival was significantly higher in the good adherence group. Increase in the serum albumin level was also greater in the good adherence group. CONCLUSION Higher BCAA treatment adherence better raised the serum albumin level, leading to improvement of event-free survival. These results indicate the importance of patient instruction for the adequate use of BCAA granules.
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Affiliation(s)
- Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central HospitalKagawa
| | - Hisataka Moriwaki
- Department of Medicine, Gifu University Graduate School of MedicineGifu
| | - Hisashi Doyama
- Department of Gastroenterology, Ishikawa Prefectural Central HospitalKanazawa
| | - Masayuki Iida
- Department of Internal Medicine, Nagoya Midori Municipal HospitalNagoya
| | - Michiyasu Yagura
- Department of Gastroenterology, National Hospital Organization Tokyo National HospitalTokyo
| | - Noritomo Shimada
- Department of Internal Medicine, Medical Plaza Heiwadai HospitalChiba
| | - Masahiro Kang
- Department of Internal Medicine, Sato Daiichi HospitalOita, Japan
| | - Haruki Yamada
- Department of Internal Medicine, Social Insurance Chuo General HospitalTokyo
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Kitagawa T, Yokoyama Y, Kokuryo T, Nagino M. Protective effects of branched-chain amino acids on hepatic ischemia-reperfusion-induced liver injury in rats: a direct attenuation of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 2013; 304:G346-55. [PMID: 23275614 DOI: 10.1152/ajpgi.00391.2012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We determined whether there is a protective effect of branched-chain amino acid (BCAA) on hepatic ischemia-reperfusion (I/R)-induced acute liver injury. Wister rats were divided into the following four groups: simple laparotomy with vehicle; simple laparotomy with BCAA (1 g/kg body wt orally); I/R (30 min clamp) with vehicle; and I/R with BCAA. Serum liver function tests and the gene expression of adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule) and vasoconstrictor-related genes (endothelin-1) in the liver were examined. In the in vivo study, portal venous pressure, leukocyte adhesion, and hepatic microcirculation were evaluated. Furthermore, Kupffer cells were isolated and cultured with various concentrations of BCAA in the presence or absence of lipopolysaccharide (LPS). Increased levels of liver function tests following I/R were significantly attenuated by BCAA treatment. The increased expression of adhesion molecules and endothelin-1 was also significantly attenuated by BCAA treatment. Moreover, increased portal venous pressure, enhanced leukocyte adhesion, and deteriorated hepatic microcirculation following I/R were all improved by BCAA treatment. In the experiment using isolated Kupffer cells, the expression of interleukin-6, interleukin-1β, and endothelin-1 in response to LPS stimulation was attenuated by BCAA in a dose-dependent fashion. These results indicate that perioperative oral administration of BCAA has excellent therapeutic potential to reduce I/R-induced liver injury. These beneficial effects may result from the direct attenuation of Kupffer cell activation under stressful conditions.
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Affiliation(s)
- Tomomi Kitagawa
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Ishikawa T. Early administration of branched-chain amino acid granules. World J Gastroenterol 2012; 18:4486-4490. [PMID: 22969221 PMCID: PMC3435773 DOI: 10.3748/wjg.v18.i33.4486] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2012] [Revised: 05/21/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
The effect of malnutrition on survival in patients with decompensated liver cirrhosis has not been well defined. Nutritional intervention with branched-chain amino acid (BCAA) can increase serum albumin concentration in patients with decompensated cirrhosis but its effects on survival are unclear. The BCAA to tyrosine ratio (BTR) is a surrogate marker (the normal range of BTR is between 4.41 and 10.05, and a Fischer's ratio of 1.8 corresponds to a BTR of 3.5) in patients with decompensated liver cirrhosis, and BCAA inhibits hepatic carcinogenesis in patients with compensated cirrhosis. This review discusses data regarding the effect of early administration of BCAA granules based on the ratio of BCAA to BTR on prognosis in patients with cirrhosis.
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Abstract
BACKGROUND Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between malnutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both. OBJECTIVES To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease. SEARCH METHODS The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references. SELECTION CRITERIA Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements. DATA COLLECTION AND ANALYSIS The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi(2) test and I(2) statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions. MAIN RESULTS Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I(2) = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I(2) = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I(2) = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error. AUTHORS' CONCLUSIONS The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
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50
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Koretz RL, Avenell A, Lipman TO. Nutritional support for liver disease. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2012. [PMID: 22592729 DOI: 10.1002/14651858.cd008344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between malnutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both. OBJECTIVES To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease. SEARCH METHODS The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references. SELECTION CRITERIA Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements. DATA COLLECTION AND ANALYSIS The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi(2) test and I(2) statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions. MAIN RESULTS Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I(2) = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I(2) = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I(2) = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error. AUTHORS' CONCLUSIONS The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.
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