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Dahboul F, Sun J, Buchard B, Abeywickrama‐Samarakoon N, Pujos‐Guillot E, Durand S, Petera M, Centeno D, Guerrieri F, Cocca M, Levrero M, Rossary A, Weil D, Di Martino V, Demidem A, Abergel A. Simultaneous Activation of Beta-Oxidation and De Novo Lipogenesis in MASLD-HCC: A New Paradigm. Liver Int 2025; 45:e70006. [PMID: 39840890 PMCID: PMC11752690 DOI: 10.1111/liv.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/26/2024] [Accepted: 01/12/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT). METHODS A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC). RESULTS Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC. CONCLUSIONS These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.
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Affiliation(s)
- Fatima Dahboul
- Human Nutrition Unit 1019, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Jihan Sun
- Human Nutrition Unit 1019, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
- EFS, INSERM, UMR RIGHTFranche‐Comté UniversityBesançonFrance
| | - Benjamin Buchard
- Human Nutrition Unit 1019, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
- Department of Digestive and Hepatobiliary MedicineCHU Clermont‐FerrandClermont‐FerrandFrance
| | | | - Estelle Pujos‐Guillot
- Human Nutrition Unit 1019, Plate‐Forme d'Exploration du Métabolisme, MetaboHUB—Clermont, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Stéphanie Durand
- Human Nutrition Unit 1019, Plate‐Forme d'Exploration du Métabolisme, MetaboHUB—Clermont, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Mélanie Petera
- Human Nutrition Unit 1019, Plate‐Forme d'Exploration du Métabolisme, MetaboHUB—Clermont, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Delphine Centeno
- Human Nutrition Unit 1019, Plate‐Forme d'Exploration du Métabolisme, MetaboHUB—Clermont, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Francesca Guerrieri
- INSERM U1052, CNRS UMR 5286Cancer Research Center of Lyon (CRCL)LyonFrance
- Institute of Hepatology Lyon (IHL)LyonFrance
| | - Massimiliano Cocca
- INSERM U1052, CNRS UMR 5286Cancer Research Center of Lyon (CRCL)LyonFrance
- Institute of Hepatology Lyon (IHL)LyonFrance
| | - Massimo Levrero
- INSERM U1052, CNRS UMR 5286Cancer Research Center of Lyon (CRCL)LyonFrance
- Institute of Hepatology Lyon (IHL)LyonFrance
- Hepatology DepartmentHospices Civils de Lyon and University of Lyon, Université Claude‐Bernard Lyon 1 (UCBL1)LyonFrance
| | - Adrien Rossary
- Human Nutrition Unit 1019, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Delphine Weil
- EFS, INSERM, UMR RIGHTFranche‐Comté UniversityBesançonFrance
- Hepatology and Digestive Intensive Care Service, Jean Minjoz HospitalBesançonFrance
| | - Vincent Di Martino
- EFS, INSERM, UMR RIGHTFranche‐Comté UniversityBesançonFrance
- Hepatology and Digestive Intensive Care Service, Jean Minjoz HospitalBesançonFrance
| | - Aicha Demidem
- Human Nutrition Unit 1019, INRAE, Clermont Auvergne UniversityClermont‐FerrandFrance
| | - Armando Abergel
- Department of Digestive and Hepatobiliary MedicineCHU Clermont‐FerrandClermont‐FerrandFrance
- Clermont Auvergne UniversityClermont‐FerrandFrance
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Zhou S, Zhu W, Guo H, Nie Y, Sun J, Liu P, Zeng Y. Microbes for lung cancer detection: feasibility and limitations. Front Oncol 2024; 14:1361879. [PMID: 38779090 PMCID: PMC11109454 DOI: 10.3389/fonc.2024.1361879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
As the second most common cancer in the world, the development of lung cancer is closely related to factors such as heredity, environmental exposure, and lung microenvironment, etc. Early screening and diagnosis of lung cancer can be helpful for the treatment of patients. Currently, CT screening and histopathologic biopsy are widely used in the clinical detection of lung cancer, but they have many disadvantages such as false positives and invasive operations. Microbes are another genome of the human body, which has recently been shown to be closely related to chronic inflammatory, metabolic processes in the host. At the same time, they are important players in cancer development, progression, treatment, and prognosis. The use of microbes for cancer therapy has been extensively studied, however, the diagnostic role of microbes is still unclear. This review aims to summarize recent research on using microbes for lung cancer detection and present the current shortcomings of microbes in collection and detection. Finally, it also looks ahead to the clinical benefits that may accrue to patients in the future about screening and early detection.
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Affiliation(s)
- Sirui Zhou
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijian Zhu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hehua Guo
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yalan Nie
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiazheng Sun
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Liu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yulan Zeng
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tsai SS, Hsu CT, Yang C. Risk of death from liver cancer in relation to long-term exposure to fine particulate air pollution in Taiwan. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2023; 86:135-143. [PMID: 36752360 DOI: 10.1080/15287394.2023.2168225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
According to the International Agency for Research on Cancer (IARC), airborne fine particulate matter (PM2.5), which is categorized as a Group I carcinogen, was found to lead to predominantly lung as well as other cancer types in humans. Hepatocellular carcinoma (HCC) is endemic in Taiwan where it is the second and fourth foremost cause of cancer deaths in men and women, respectively. Taiwan's mortality rates for liver cancer vary considerably from one region to another, suggesting that the environment may exert some influence on deaths attributed to liver cancer. The aim of this investigation was to perform an ecologic study to examine the possible link between ambient PM2.5 levels and risk of liver cancer in 66 in Taiwan municipalities. To undertake this investigation, annual PM2.5 levels and age-standardized liver cancer mortality rates were calculated for male and female residents of these areas from 2010 to 2019. Data were tested using weighted-multiple regression analyses to compute adjusted risk ratio (RR) controlling for urbanization level and physician density. Annual PM2.5 levels of each municipality were divided into tertiles. The adjusted RRs for males residing in those areas with intermediate tertile levels (21.85 to 28.21 ug/m3) and the highest tertiles levels (28.22-31.23 ug/m3) of PM2.5 were 1.29 (95% CI = 1.25-1.46) and 1.41 (95% CI = 1.36-1.46), respectively. Women in these locations shared a similar risk, 1.32 (1.25-1.4) and 1.41 (1.34-1.49), respectively. Evidence indicated that PM2.5 increased risk of mortality rates attributed to liver cancer in both men and women in Taiwan.
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Affiliation(s)
- Shang-Shyue Tsai
- Department of Healthcare Administration, I-Shou University, Kaohsiung, Taiwan
| | - Chun-Ta Hsu
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - ChunYuh Yang
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
- National Institute of Environmental Health Sciences, National Health Research Institute, Miaoli, Taiwan
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Venugopal S, Dhanoa RK, Selvamani TY, Shoukrie SI, Zahra A, Malla J, Selvaraj R, Hamouda RK, Mohammed L. Does Type 2 Diabetes Increase the Risk of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease Patients? A Systematic Review. Cureus 2023; 15:e36079. [PMID: 37065332 PMCID: PMC10101195 DOI: 10.7759/cureus.36079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 03/13/2023] [Indexed: 03/14/2023] Open
Abstract
Diabetes is associated with different types of cancers of which hepatocellular carcinoma (HCC) is one among them. In a study comparing patients with diabetes to those who do not have diabetes, it was evident that the risk of HCC is found to increase two-fold in diabetic than that in non-diabetic patients. It is clear that carcinogenesis is advanced due to diabetes in the liver by a variety of mechanisms. We searched PubMed and Google Scholar for articles from 2010 to 2021 that have an association between diabetes, nonalcoholic fatty liver disease (NAFLD), and HCC. For the development of HCC, diabetes is likely related at both the molecular and epidemiological levels. Both diabetes mellitus and hepatic malignancy have the worst impact on mankind socioeconomically. There is a significant relationship between diabetes and HCC independent of alcohol consumption and viral hepatitis. It is noteworthy that not only the elderly but also people of all age groups should monitor their hemoglobin A1C levels. Diet restriction and lifestyle modification can reduce the risk of complications like HCC; the increased physical activity itself can have a major influence on health and can manage comorbidities like diabetes, NAFLD, and HCC.
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Affiliation(s)
- Sathish Venugopal
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ravneet K Dhanoa
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Tharun Yadhav Selvamani
- General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Shoukrie I Shoukrie
- Orthopaedics and Traumatology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Anam Zahra
- Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Jyothirmai Malla
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ramaneshwar Selvaraj
- Internal Medicine/Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
- General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ranim K Hamouda
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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van Son KC, Verschuren L, Hanemaaijer R, Reeves H, Takkenberg RB, Drenth JPH, Tushuizen ME, Holleboom AG. Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2023; 15:1308. [PMID: 36831649 PMCID: PMC9954729 DOI: 10.3390/cancers15041308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.
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Affiliation(s)
- Koen C. van Son
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lars Verschuren
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Roeland Hanemaaijer
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Adriaan G. Holleboom
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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Cavalcante LN, Dezan MGF, Paz CLDSL, Lyra AC. RISK FACTORS FOR HEPATOCELLULAR CARCINOMA IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:540-548. [PMID: 36515349 DOI: 10.1590/s0004-2803.202204000-93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022]
Abstract
Non-alcoholic fatty liver disease is growing in worldwide prevalence and thus, is expected to have a higher number of NAFLD-related hepatocellular carcinoma (HCC) in the following years. This review describes the risk factors associated with HCC in NAFLD-patients. The presence of liver cirrhosis is the preponderant one. Male gender, PNPLA3 variants, diabetes, and obesity also appear to predispose to the development of HCC, even in non-cirrhotic subjects. Thus far, intensive lifestyle modifications, including glycemic control, and obesity treatment, are effective therapies for NAFLD/ non-alcoholic steatohepatitis and, therefore, probably, also for HCC. Some drugs that aimed at decreasing inflammatory activity and fibrosis, as well as obesity, were studied. Other data have suggested the possibility of HCC chemoprevention. So far, however, there is no definitive evidence for the routine utilization of these drugs. We hope, in the future, to be able to profile patients at higher risk of NAFLD-HCC and outline strategies for early diagnosis and prevention.
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Affiliation(s)
- Lourianne Nascimento Cavalcante
- Universidade Federal da Bahia, Salvador, BA, Brasil.,Hospital São Rafael, Serviço de Gastro-Hepatologia, Salvador, BA, Brasil
| | | | | | - André Castro Lyra
- Universidade Federal da Bahia, Salvador, BA, Brasil.,Hospital São Rafael, Serviço de Gastro-Hepatologia, Salvador, BA, Brasil
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Kalpadakis S, Sifaki-Pistolla D, Symvoulakis EK, Kelefiotis-Stratidakis P, Vamvakas L, Mavroudis D, Lionis C. Reporting Liver Cancer Trends in the Island of Crete, Greece: Results from a Geo-Epidemiological Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:10166. [PMID: 36011801 PMCID: PMC9408082 DOI: 10.3390/ijerph191610166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 06/15/2023]
Abstract
Liver cancer is one of the most frequent cancers in Europe and Greece. An increase in specific risk factors, such as metabolic syndrome and obesity, has been observed in Greece. Therefore, exploring temporal trends of liver cancer incidence and mortality is crucial. This study aims to assess the "burden" of malignant liver tumors (MLT) in Crete, Greece, in terms of incidence and mortality rates, and identify the high-risk areas on the island (i.e., municipalities), to suggest public health measures. Data were obtained from the Cancer Registry Center (CRC) and included all cases of MLT for the period 1992-2013 in Crete. Age-standardized incidence rates (ASIR), age-specific incidence rates (ASpIR), age-standardized mortality rates (ASMR), and age-specific mortality rates (ASpMR) were estimated. For the study period (1992-2013), incidence and mortality showed an increasing trend. Mean ASIR was found 15.3/100,000/year and mean ASMR 8.6/100,000/year. Age groups 65-69 and 75-79 years among men presented the highest rates of (ASIR = 39/100,000/year) and among women age groups of 75-79 and 80-84 years a mean ASIR (22/100,000/year). The five-year survival rate of MLT was 50% and the ten-year survival rate was 47% for both genders. Risk factors that were identified included personal history of cancer, family history of MLT or other cancer, degree of relationship, smoking, and obesity. Some municipalities of Crete were found to be high-risk areas for MLT, while differences were detected in incidence and mortality rates, and annual rate change among them. Estimated variation indicates further increase probably due to the lifestyle of the residents, economic crisis, and inadequate preventive measures.
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Affiliation(s)
- Stavros Kalpadakis
- Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dimitra Sifaki-Pistolla
- Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Emmanouil K. Symvoulakis
- Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | | | - Lambros Vamvakas
- Pathology Oncology Clinic, University Hospital of Heraklion, 71003 Heraklion, Greece
- School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dimitrios Mavroudis
- Pathology Oncology Clinic, University Hospital of Heraklion, 71003 Heraklion, Greece
- School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Christos Lionis
- Clinic of Social and Family Medicine, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
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Bathish B, Robertson H, Dillon JF, Dinkova-Kostova AT, Hayes JD. Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2. Free Radic Biol Med 2022; 188:221-261. [PMID: 35728768 DOI: 10.1016/j.freeradbiomed.2022.06.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.
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Affiliation(s)
- Boushra Bathish
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Holly Robertson
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
| | - John F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - John D Hayes
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK.
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Veltkamp C, Lan S, Korompoki E, Weiss KH, Schmidt H, Seitz HK. Hepatic Steatosis and Fibrosis in Chronic Inflammatory Bowel Disease. J Clin Med 2022; 11:jcm11092623. [PMID: 35566749 PMCID: PMC9105667 DOI: 10.3390/jcm11092623] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 02/04/2023] Open
Abstract
Background and Purpose: Chronic inflammatory bowel diseases (IBD) frequently affect extraintestinal organs including the liver. Since limited evidence suggests the presence of liver disease in IBD patients, we studied the frequency of hepatic steatosis and fibrosis in these patients and characterized disease-related factors. Methods: In this retrospective, cross-sectional, hospital-based, single-center study, consecutive patients with Crohn’s disease (CD) and ulcerative colitis (UC) were included who had undergone routine abdominal ultrasound including transhepatic elastography. Hepatic steatosis was diagnosed by hyperechogenicity on B-mode ultrasound and by measuring controlled attenuation parameter (CAP). Hepatic fibrosis was assumed if transhepatic elastography yielded a stiffness > 7 kPa. Results: 132 patients (60% CD) with a median disease duration of 10 years were included. Steatosis assessed by B-mode ultrasound and CAP correlated well. Of the IBD patients, 30.3% had non-alcoholic fatty liver (NAFL). Factors associated with NAFL were age, BMI, duration of disease, as well as serum activities of aspartate-aminotransferase (AST) and gamma-glutamyl-transpeptidase (GGT). In multivariate analysis, only disease duration was independently associated with hepatic steatosis. Hepatic fibrosis was found in 10 (8%) of all IBD patients, predominantly in patients with CD (10/11). Conclusions: Pure hepatic steatosis is common in both CD and UC, whereas hepatic fibrosis occurs predominantly in CD patients. Association of disease duration with NAFLD suggests a contribution of IBD-related pathogenetic factors. Longitudinal studies are needed to better understand the impact of IBD on hepatic disorders.
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Affiliation(s)
- Claudia Veltkamp
- Department of Gastroenterology, Hepatology and Transplantation Medicine, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
- Correspondence: ; Tel.: +49-201723-0
| | - Shuai Lan
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
| | - Eleni Korompoki
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 157 72 Athens, Greece;
| | - Karl-Heinz Weiss
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
| | - Hartmut Schmidt
- Department of Gastroenterology, Hepatology and Transplantation Medicine, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
| | - Helmut K. Seitz
- Department of Internal Medicine, Salem Hospital, 69121 Heidelberg, Germany; (S.L.); (K.-H.W.); (H.K.S.)
- Centre of Liver- and Alcohol Diseases, Ethianum Clinic, 69115 Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, 69117 Heidelberg, Germany
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Tan DJH, Ng CH, Lin SY, Pan XH, Tay P, Lim WH, Teng M, Syn N, Lim G, Yong JN, Quek J, Xiao J, Dan YY, Siddiqui MS, Sanyal AJ, Muthiah MD, Loomba R, Huang DQ. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol 2022; 23:521-530. [PMID: 35255263 PMCID: PMC9718369 DOI: 10.1016/s1470-2045(22)00078-x] [Citation(s) in RCA: 180] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/02/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma. METHODS In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios. FINDINGS Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9-18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes [p<0·0001], hypertension [p<0·0001], and hyperlipidaemia [p<0·0001]) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9-50·2 vs 14·6%, 8·7-23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0-63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0-83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92-1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63-0·99; p=0·044). There was substantial heterogeneity in most analyses (I2>75%), and all articles had low-to-moderate risk of bias. INTERPRETATION NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma. FUNDING None.
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Affiliation(s)
- Darren Jun Hao Tan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Snow Yunni Lin
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Xin Hui Pan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Phoebe Tay
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Margaret Teng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Nicholas Syn
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Grace Lim
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Jie Ning Yong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jingxuan Quek
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jieling Xiao
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mark D Muthiah
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA
| | - Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA.
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11
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Diagnostic Modalities of Non-Alcoholic Fatty Liver Disease: From Biochemical Biomarkers to Multi-Omics Non-Invasive Approaches. Diagnostics (Basel) 2022; 12:diagnostics12020407. [PMID: 35204498 PMCID: PMC8871470 DOI: 10.3390/diagnostics12020407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/05/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and its prevalence is increasing globally. NAFLD is a multifaceted disorder, and its spectrum includes steatosis to steatohepatitis, which may evolve to advanced fibrosis and cirrhosis. In addition, the presence of NAFLD is independently associated with a higher cardiometabolic risk and increased mortality rates. Considering that the vast majority of individuals with NAFLD are mainly asymptomatic, early diagnosis of non-alcoholic steatohepatitis (NASH) and accurate staging of fibrosis risk is crucial for better stratification, monitoring and targeted management of patients at risk. To date, liver biopsy remains the gold standard procedure for the diagnosis of NASH and staging of NAFLD. However, due to its invasive nature, research on non-invasive tests is rapidly increasing with significant advances having been achieved during the last decades in the diagnostic field. New promising non-invasive biomarkers and techniques have been developed, evaluated and assessed, including biochemical markers, imaging modalities and the most recent multi-omics approaches. Our article provides a comprehensive review of the currently available and emerging non-invasive diagnostic tools used in assessing NAFLD, also highlighting the importance of accurate and validated diagnostic tools.
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12
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Bernstein D, Kovalic AJ. Noninvasive assessment of fibrosis among patients with nonalcoholic fatty liver disease [NAFLD]. Metabol Open 2022; 13:100158. [PMID: 35036892 PMCID: PMC8749444 DOI: 10.1016/j.metop.2021.100158] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/02/2021] [Accepted: 12/12/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease [NAFLD] is a condition affecting a vast portion of the worldwide population. The presence of underlying fibrosis is the strongest predictor of long-term outcomes and mortality, with a graduated increase in liver-related morbidity and mortality with progression from moderate fibrosis tobiomarkers targeting collagen turnover and extracellular matrix remodeling FibroTest FAST™, Velacur™, MRE]. While many of these provide a robust, stand alone value, the accuracy of these noninvasive tests markedly increase when used in combination or in sequential order with one another. There is not a uniform consensus demonstrating superiority of any specific test. Given the growing role and accuracy of these tests, they should have an expanding role in the assessment of fibrosis across this patient population and obviate the need for liver biopsy in a large portion of patients. Future clinical studies should focus on validating these novel biomarkers, as well as optimizing the sequential or algorithmic testing when combining these noninvasive tests.
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Affiliation(s)
- David Bernstein
- Department of Internal Medicine, Division of Hepatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, North Shore University Hospital, Hempstead, NY, USA
| | - Alexander J Kovalic
- Department of Internal Medicine, Division of Hepatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, North Shore University Hospital, Hempstead, NY, USA
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13
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Mochizuki M, Nakayama Y, Sato K, Inukai T. Focal nodular hyperplasia-like lesion in a girl with obesity and fatty liver. Pediatr Int 2022; 64:e15392. [PMID: 36270924 PMCID: PMC10107613 DOI: 10.1111/ped.15392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 10/06/2022] [Accepted: 10/14/2022] [Indexed: 01/24/2023]
Affiliation(s)
- Mie Mochizuki
- Department of Pediatrics, Kyonan Medical Center Fujikawa Hospital, Yamanashi, Japan.,Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.,Department of Pediatrics, National Hospital Organization, Kofu Hospital, Yamanashi, Japan
| | - Yasuhiro Nakayama
- Department of Internal Medicine, Kyonan Medical Center Fujikawa Hospital, Yamanashi, Japan
| | - Kazumasa Sato
- Department of Pediatrics, Kyonan Medical Center Fujikawa Hospital, Yamanashi, Japan.,Department of Pediatrics, University of Yamanashi, Yamanashi, Japan
| | - Takeshi Inukai
- Department of Pediatrics, University of Yamanashi, Yamanashi, Japan
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14
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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15
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Fatty Liver through the Ages- Non-Alcoholic Steatohepatitis (NASH). Endocr Pract 2021; 28:204-213. [PMID: 34952219 DOI: 10.1016/j.eprac.2021.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND The global epidemic of obesity and type 2 diabetes mellitus is the main driver of the growing global prevalence of non-alcoholic fatty liver disease (NAFLD). We aimed to review the current literature on NAFLD and NASH as it impacts children and adults. METHODS We performed a literature search on fatty liver specifically non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) among children and adults. RESULTS The prevalence of NAFLD in children ranges from 8%-12% while the prevalence in adults ranges 25%-48%. The prevalence of NASH among children with NAFLD is 23% while it ranges from 13% to 65% in the adults. There are similar risk factors for NAFLD among children and adults. However, in children, the diagnostic tests in the studies of NAFLD are limited to elevation of ALT level or a liver biopsy. In adults, additional diagnostic modalities, including non-invasive tests (NITs), have been used. From the spectrum of NAFLD, those with NASH are predominantly at risk of progressive liver disease to cirrhosis and liver-related mortality. NAFLD is associated with impairment of health-related quality of life and substantial economic burden. CONCLUSION The comprehensive burden (clinical, HRQL and economic) of NAFLD is high and increasing.
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16
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Bhat M, Pasini E, Pastrello C, Angeli M, Baciu C, Abovsky M, Coffee A, Adeyi O, Kotlyar M, Jurisica I. Estrogen Receptor 1 Inhibition of Wnt/β-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis. Front Oncol 2021; 11:777834. [PMID: 34881186 PMCID: PMC8645636 DOI: 10.3389/fonc.2021.777834] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/01/2021] [Indexed: 01/10/2023] Open
Abstract
Background Hepatocellular Carcinoma (HCC) is a sexually dimorphic cancer, with female sex being independently protective against HCC incidence and progression. The aim of our study was to understand the mechanism of estrogen receptor signaling in driving sex differences in hepatocarcinogenesis. Methods We integrated 1,268 HCC patient sample profiles from publicly available gene expression data to identify the most differentially expressed genes (DEGs). We mapped DEGs into a physical protein interaction network and performed network topology analysis to identify the most important proteins. Experimental validation was performed in vitro on HCC cell lines, in and in vivo, using HCC mouse model. Results We showed that the most central protein, ESR1, is HCC prognostic, as increased ESR1 expression was protective for overall survival, with HR=0.45 (95%CI 0.32-0.64, p=4.4E-06), and was more pronounced in women. Transfection of HCC cell lines with ESR1 and exposure to estradiol affected expression of genes involved in the Wnt/β-catenin signaling pathway. ER-α (protein product of ESR1) agonist treatment in a mouse model of HCC resulted in significantly longer survival and decreased tumor burden (p<0.0001), with inhibition of Wnt/β-Catenin signaling. In vitro experiments confirmed colocalization of β-catenin with ER-α, leading to inhibition of β-catenin-mediated transcription of target genes c-Myc and Cyclin D1. Conclusion Combined, the centrality of ESR1 and its inhibition of the Wnt/β-catenin signaling axis provide a biological rationale for protection against HCC incidence and progression in women.
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Affiliation(s)
- Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada.,Division of Gastroenterology & Hepatology, University of Toronto, Toronto, ON, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Elisa Pasini
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.,Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Marc Angeli
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Cristina Baciu
- Ajmera Transplant Program, University Health Network, Toronto, ON, Canada
| | - Mark Abovsky
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.,Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Angella Coffee
- Department of Pathology and University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, United States
| | - Oyedele Adeyi
- Department of Pathology and University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, United States
| | - Max Kotlyar
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.,Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.,Krembil Research Institute, University Health Network, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.,Department Computer Science, University of Toronto, Toronto, ON, Canada.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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17
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Aydin Y, Koksal AR, Thevenot P, Chava S, Heidari Z, Lin D, Sandow T, Moroz K, Parsi MA, Scott J, Cohen A, Dash S. Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis. J Hepatocell Carcinoma 2021; 8:1579-1596. [PMID: 34917553 PMCID: PMC8671108 DOI: 10.2147/jhc.s327339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/18/2021] [Indexed: 12/16/2022] Open
Affiliation(s)
- Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Srinivas Chava
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Zahra Heidari
- Chemical and Biomedical Engineering, Tulane University, New Orleans, LA, USA
| | - Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Tyler Sandow
- Department of Radiology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Mansour A Parsi
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - John Scott
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Ari Cohen
- Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA
- Correspondence: Srikanta Dash Email
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18
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Olovo CV, Huang X, Zheng X, Xu M. Faecal microbial biomarkers in early diagnosis of colorectal cancer. J Cell Mol Med 2021; 25:10783-10797. [PMID: 34750964 PMCID: PMC8642680 DOI: 10.1111/jcmm.17010] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer (CRC) is ranked as the second most common cause of cancer deaths and the third most common cancer globally. It has been described as a 'silent disease' which is often easily treatable if detected early-before progression to carcinoma. Colonoscopy, which is the gold standard for diagnosis is not only expensive but is also an invasive diagnostic procedure, thus, effective and non-invasive diagnostic methods are urgently needed. Unfortunately, the current methods are not sensitive and specific enough in detecting adenomas and early colorectal neoplasia, hampering treatment and consequently, survival rates. Studies have shown that imbalances in such a relationship which renders the gut microbiota in a dysbiotic state are implicated in the development of adenomas ultimately resulting in CRC. The differences found in the makeup and diversity of the gut microbiota of healthy individuals relative to CRC patients have in recent times gained attention as potential biomarkers in early non-invasive diagnosis of CRC, with promising sensitivity, specificity and even cost-effectiveness. This review summarizes recent studies in the application of these microbiota biomarkers in early CRC diagnosis, limitations encountered in the area of the faecal microbiota studies as biomarkers for CRC, and future research exploits that address these limitations.
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Affiliation(s)
- Chinasa Valerie Olovo
- Department of Biochemistry and Molecular BiologySchool of MedicineJiangsu UniversityZhenjiangChina
- Department of MicrobiologyFaculty of Biological SciencesUniversity of NigeriaNsukkaNigeria
| | - Xinxiang Huang
- Department of Biochemistry and Molecular BiologySchool of MedicineJiangsu UniversityZhenjiangChina
| | - Xueming Zheng
- Department of Biochemistry and Molecular BiologySchool of MedicineJiangsu UniversityZhenjiangChina
| | - Min Xu
- Department of GastroenterologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina
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19
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Curcumin Suppresses the Lipid Accumulation and Oxidative Stress Induced by Benzo[a]pyrene Toxicity in HepG2 Cells. Antioxidants (Basel) 2021; 10:antiox10081314. [PMID: 34439562 PMCID: PMC8389208 DOI: 10.3390/antiox10081314] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 01/14/2023] Open
Abstract
Benzo[a]pyrene (B[a]P) is a potentially hepatotoxic group-1 carcinogen taken up by the body through ingestion of daily foods. B[a]P is widely known to cause DNA and protein damages, which are closely related to cell transformation. Accordingly, studies on natural bioactive compounds that attenuate such chemical-induced toxicities have significant impacts on public health. This study aimed to uncover the mechanism of curcumin, the major curcuminoid in turmeric (Curcuma longa), in modulating the lipid accumulation and oxidative stress mediated by B[a]P cytotoxicity in HepG2 cells. Curcumin treatment reduced the B[a]P-induced lipid accumulation and reactive oxygen spicies (ROS) upregulation and recovered the cell viability. Cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) and Cytochrome P450 subfamily B polypeptide 1 (CYP1B1) downregulation resulting from decreased aryl hydrocarbon receptor (AhR) translocation into nuclei attenuated the effects of B[a]P-induced lipid accumulation and repressed cell viability, respectively. Moreover, the curcumin-induced reduction in ROS generation decreased the nuclear translocation of Nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of phase-II detoxifying enzymes. These results indicate that curcumin suppresses B[a]P-induced lipid accumulation and ROS generation which can potentially induce nonalcoholic fatty liver disease (NAFLD) and can shed a light on the detoxifying effect of curcumin.
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20
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Kedar Mukthinuthalapati VVP, Sewram V, Ndlovu N, Kimani S, Abdelaziz AO, Chiao EY, Abou-Alfa GK. Hepatocellular Carcinoma in Sub-Saharan Africa. JCO Glob Oncol 2021; 7:756-766. [PMID: 34043413 PMCID: PMC8457845 DOI: 10.1200/go.20.00425] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
More than 80% of global hepatocellular carcinoma (HCC) patients are estimated to occur in sub-Saharan Africa (SSA) and Eastern Asia. The most common risk factor of HCC in SSA is chronic hepatitis B virus (HBV) infection, with the incidence highest in West Africa. HBV is highly endemic in SSA and is perpetuated by incomplete adherence to birth dose immunization, lack of longitudinal follow-up care, and impaired access to antiviral therapy. HBV may directly cause HCC through somatic genetic alterations or indirectly through altered liver function and liver cirrhosis. Other risk factors of HCC in SSA include aflatoxins and, to a lesser extent, African iron overload. HIV plus HBV co-infection increases the risk of developing HCC and is increasingly becoming more common because of improving the survival of patients with HIV infection. Compared with the rest of the world, patients with HCC in SSA have the lowest survival. This is partly due to the late presentation of HCC with advanced symptomatic disease as a result of underdeveloped surveillance practices. Moreover, access to care and resource limitations further limit outcomes for the patients who receive a diagnosis in SSA. There is a need for multipronged strategies to decrease the incidence of HCC and improve its outcomes in SSA.
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Affiliation(s)
| | - Vikash Sewram
- Department of Global Health, Faculty of Medicine and Health Sciences, African Cancer Institute, Stellenbosch University, Cape Town, South Africa
| | - Ntokozo Ndlovu
- University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
| | - Stephen Kimani
- The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | | | | | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY.,Weill Medical College at Cornell University, New York, NY
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21
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So R, Chen J, Mehta AJ, Liu S, Strak M, Wolf K, Hvidtfeldt UA, Rodopoulou S, Stafoggia M, Klompmaker JO, Samoli E, Raaschou-Nielsen O, Atkinson R, Bauwelinck M, Bellander T, Boutron-Ruault MC, Brandt J, Brunekreef B, Cesaroni G, Concin H, Forastiere F, van Gils CH, Gulliver J, Hertel O, Hoffmann B, de Hoogh K, Janssen N, Lim YH, Westendorp R, Jørgensen JT, Katsouyanni K, Ketzel M, Lager A, Lang A, Ljungman PL, Magnusson PKE, Nagel G, Simonsen MK, Pershagen G, Peter RS, Peters A, Renzi M, Rizzuto D, Sigsgaard T, Vienneau D, Weinmayr G, Severi G, Fecht D, Tjønneland A, Leander K, Hoek G, Andersen ZJ. Long-term exposure to air pollution and liver cancer incidence in six European cohorts. Int J Cancer 2021; 149:1887-1897. [PMID: 34278567 DOI: 10.1002/ijc.33743] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/25/2021] [Accepted: 06/16/2021] [Indexed: 12/24/2022]
Abstract
Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the "Effects of low-level air pollution: A study in Europe" (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO2 ), particulate matter with diameter <2.5 μm (PM2.5 ), black carbon (BC), warm-season ozone (O3 ), and eight elemental components of PM2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 μg/m3 ), PM2.5 (1.12, 0.92-1.36 per 5 μg/m3 ), and BC (1.15, 1.00-1.33 per 0.5 10-5 /m) and liver cancer incidence. Associations with NO2 and BC persisted in two-pollutant models with PM2.5 . Most components of PM2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM2.5 or NO2 . Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.
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Affiliation(s)
- Rina So
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jie Chen
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Amar J Mehta
- Statistics Denmark, Copenhagen, Denmark.,Section of Epidemiology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Shuo Liu
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maciej Strak
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.,National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Kathrin Wolf
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
| | | | - Sophia Rodopoulou
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Massimo Stafoggia
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Epidemiology, Lazio Region Health Service / ASL Roma 1, Rome, Italy
| | - Jochem O Klompmaker
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.,National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Evangelia Samoli
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Ole Raaschou-Nielsen
- Danish Cancer Society Research Centre, Copenhagen, Denmark.,Department of Environmental Science, Aarhus University, Roskilde, Denmark
| | - Richard Atkinson
- Population Health Research Institute and MRC-PHE Centre for Environment and Health, St George's, University of London, London, UK
| | - Mariska Bauwelinck
- Interface Demography, Department of Sociology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Tom Bellander
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
| | | | - Jørgen Brandt
- Department of Environmental Science, Aarhus University, Roskilde, Denmark.,iClimate, Aarhus University interdisciplinary Centre for Climate Change, Roskilde, Denmark
| | - Bert Brunekreef
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Giulia Cesaroni
- Department of Epidemiology, Lazio Region Health Service / ASL Roma 1, Rome, Italy
| | - Hans Concin
- Agency for Preventive and Social Medicine, Bregenz, Austria
| | - Francesco Forastiere
- Environmental Research Group, School of Public Health, Imperial College, London, UK.,Institute for Biomedical Research and Innovation (IRIB), National Research Council, Palermo, Italy
| | - Carla H van Gils
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - John Gulliver
- Centre for Environmental Health and Sustainability & School of Geography, Geology and the Environment, University of Leicester, Leicester, UK
| | - Ole Hertel
- Department of Bioscience, Aarhus University, Roskilde, Denmark
| | - Barbara Hoffmann
- Institute of Occupational, Social and Environmental Medicine, Centre for Health and Society, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany
| | - Kees de Hoogh
- Swiss Tropical and Public Health Institute, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Nicole Janssen
- National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Youn-Hee Lim
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rudi Westendorp
- Section of Epidemiology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Jeanette T Jørgensen
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Klea Katsouyanni
- Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece.,Environmental Research Group, School of Public Health, Imperial College London, London, UK
| | - Matthias Ketzel
- Department of Environmental Science, Aarhus University, Roskilde, Denmark.,Global Centre for Clean Air Research (GCARE), University of Surrey, Guildford, UK
| | - Anton Lager
- Department of Global Public Health, Karolinksa Institutet, Stockholm, Sweden
| | - Alois Lang
- Agency for Preventive and Social Medicine, Bregenz, Austria
| | - Petter L Ljungman
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Gabriele Nagel
- Agency for Preventive and Social Medicine, Bregenz, Austria.,Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | - Mette K Simonsen
- Department of Neurology and Parker Institute, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Göran Pershagen
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
| | - Raphael S Peter
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.,Ludwig-Maximilians University, Munich, Germany
| | - Matteo Renzi
- Department of Epidemiology, Lazio Region Health Service / ASL Roma 1, Rome, Italy
| | - Debora Rizzuto
- Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Stockholm University and The Stockholm Gerontology Research Center, Stockholm, Sweden
| | - Torben Sigsgaard
- Department of Public Health, Environment Occupation and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark
| | - Danielle Vienneau
- Swiss Tropical and Public Health Institute, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Gudrun Weinmayr
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | - Gianluca Severi
- CESP, UMR 1018, Universit´e Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France.,Department of Statistics, Computer Science and Applications "G. Parenti" (DISIA), University of Florence, Florence, Italy
| | - Daniela Fecht
- UK Small Area Health Statistics Unit, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
| | - Anne Tjønneland
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Danish Cancer Society Research Centre, Copenhagen, Denmark
| | - Karin Leander
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden
| | - Gerard Hoek
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
| | - Zorana J Andersen
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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22
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Orabi D, Berger NA, Brown JM. Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention. Cancers (Basel) 2021; 13:3473. [PMID: 34298687 PMCID: PMC8307710 DOI: 10.3390/cancers13143473] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the rise and becoming a major contributor to the development of hepatocellular carcinoma (HCC). Reasons for this include the rise in obesity and metabolic syndrome in contrast to the marked advances in prevention and treatment strategies of viral HCC. These shifts are expected to rapidly propel this trend even further in the coming decades, with NAFLD on course to become the leading etiology of end-stage liver disease and HCC. No Food and Drug Administration (FDA)-approved medications are currently available for the treatment of NAFLD, and advances are desperately needed. Numerous medications with varying mechanisms of action targeting liver steatosis and fibrosis are being investigated including peroxisome proliferator-activated receptor (PPAR) agonists and farnesoid X receptor (FXR) agonists. Additionally, drugs targeting components of metabolic syndrome, such as antihyperglycemics, have been found to affect NAFLD progression and are now being considered in the treatment of these patients. As NAFLD drug discovery continues, special attention should be given to their relationship to HCC. Several mechanisms in the pathogenesis of NAFLD have been implicated in hepatocarcinogenesis, and therapies aimed at NAFLD may additionally harbor independent antitumorigenic potential. This approach may provide novel prevention and treatment strategies.
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Affiliation(s)
- Danny Orabi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of General Surgery, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Nathan A. Berger
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - J. Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
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23
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Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, Jang BK, Kim SG, Ahn SB, Kim H, Jun DW, Choi JI, Song DS, Kim W, Jeong SW, Kim MY, Koh H, Jeong S, Lee JW, Cho YK. KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021; 27:363-401. [PMID: 34154309 PMCID: PMC8273632 DOI: 10.3350/cmh.2021.0178] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, SoonChunHyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Joon-Il Choi
- Department of Radiology, Seoul St.Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hong Koh
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Sujin Jeong
- Division of Pediatric Gastroenterology Hepatology and Nutrition, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Yong Kyun Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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24
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Cammarota A, D'Alessio A, Pressiani T, Rimassa L, Personeni N. Systemic Treatment for Older Patients with Unresectable Hepatocellular Carcinoma. Drugs Aging 2021; 38:579-591. [PMID: 34152589 DOI: 10.1007/s40266-021-00871-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2021] [Indexed: 12/25/2022]
Abstract
The incidence rate of hepatocellular carcinoma is growing and age at diagnosis is increasing; however, despite the unprecedented wealth of therapeutic options for advanced HCC, its optimal management in some categories, such as older adults, is yet to be defined. Even though age is not an exclusion criterion per se, most of the landmark trials enrolled a limited number of senior patients, raising some concerns on the potential benefit of active treatments in this group. The identification of more vulnerable patients remains a crucial issue in clinical practice. In fact, the suitability assessment for systemic therapy through performance status metrics might underestimate or conversely overestimate the fitness of older patients, failing to detect other relevant impairments. Thus, the assessment of frailty through geriatric screening scales is largely necessary. In addition, most of the available data relate to the use of sorafenib, while very little is known about the most recent therapeutic agents. Age subgroup analyses provided by many of the pivotal trials did not find significant efficacy or safety differences across ages; however, the most widely used cut-off age of 65 years may not be very informative for the current older population. Regarding immunotherapy, the clinical benefit reported with immune checkpoint inhibitors reassures their safe use in senior patients and supports further investigations to assess their efficacy in this population.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy. .,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
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25
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Lin BZ, Lin TJ, Lin CL, Liao LY, Chang TA, Lu BJ, Chen KY. Differentiation of clinical patterns and survival outcomes of hepatocellular carcinoma on hepatitis B and nonalcoholic fatty liver disease. J Chin Med Assoc 2021; 84:606-613. [PMID: 33871391 DOI: 10.1097/jcma.0000000000000530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The main etiologies of hepatocellular carcinoma (HCC) were often hepatitis B virus (HBV) or C and alcohol, rarely autoimmune and biliary diseases. Nonalcoholic fatty liver disease (NAFLD) has been an emerging role that could lead to chronic liver disease, nonalcoholic steatohepatitis, cirrhosis, and eventually HCC in recent years. The aim of our study is to investigate and compare the clinical features of HCC in patients with NAFLD and HBV, including age, gender, cirrhosis, liver function tests, largest tumor size, and cancer stage at the time of diagnosis. The survival outcome was compared between the two groups and the significant predictors of mortality were also analyzed in all patients with HCC. METHODS Most patients with HCC were recruited from the database of Cancer Registries in Taipei City Hospital, Ren-Ai Branch, from 2011 to 2017; and the other patients consecutively from the HCC multidisciplinary conference between January 2018 and December 2019. NAFLD was defined as nonviral hepatitis B (negative HBsAg and either positive anti-HBs or negative anti-HBc), nonviral hepatitis C (negative antihepatitis C virus [HCV]), nonalcoholic (alcohol consumption of <30 g/d for men and <20 g/d for women) liver disease, or present or past histological or ultrasonographic evidence of fatty liver. Totally, 23 NAFLD-related and 156 HBV-related HCC patients were enrolled in our study for further analysis. RESULTS NAFLD-related HCC patients were significantly older (median age: 70.0 [61.0-79.0] years vs. 63.0 [56.0-72.0] years, p = 0.012) and heavier (median body mass index [BMI]: 26.6 [24.2-30] kg/m2 vs. 24.8 [22.0-27.1] kg/m2, p = 0.044) than those with HBV-related HCC. They were also more susceptible to diabetes mellitus (DM), and 60.9% (14 of 23) of them had this comorbidity compared with 29.5% (46 of 156) of those with HBV-related HCC (p = 0.003). Only 34.8% (8 of 23) and 71.2% (111 of 156) of patients with NAFLD- and HBV-related HCC were cirrhotic, respectively (p = 0.001). However, gender, tobacco use, international normalized ratio, albumin, creatinine, and cholesterol levels were not significantly different between the two groups. Tumor characteristics such as the Barcelona clinic liver cancer stage, largest tumor size, tumor number, extrahepatic metastasis, and treatment modalities had no significant difference between such groups.According to the Kaplan-Meier method analysis, the overall survival was not significantly different between these two patient groups (log-rank test, p = 0.101). To evaluate which patient group would lead to poor prognosis, we analyzed the survival of all patients through multivariate Cox proportional hazard regression after controlling other factors that may influence the hazard ratio. The analysis revealed that NAFLD and HBV infection as the cause of HCC are not risk factors of poor prognosis. CONCLUSION In conclusion, our study showed NAFLD-related HCC patients were older, heavier, and more had DM than HBV-related. In addition, more NAFLD-related HCC patients were noncirrhotic than HBV-related. The survival rate was similar between NAFLD and HBV-related HCC patients.
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Affiliation(s)
- Bou-Zenn Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
| | - Tsung-Jung Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
- University of Taipei, Taipei, Taiwan, ROC
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
| | - Li-Ying Liao
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
| | - Ting-An Chang
- Department of Pathology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
| | - Buo-Jia Lu
- Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan, ROC
| | - Kuan-Yang Chen
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, ROC
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26
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Varghese DS, Ali BR. Pathological Crosstalk Between Oxidized LDL and ER Stress in Human Diseases: A Comprehensive Review. Front Cell Dev Biol 2021; 9:674103. [PMID: 34124059 PMCID: PMC8187772 DOI: 10.3389/fcell.2021.674103] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/26/2021] [Indexed: 02/05/2023] Open
Abstract
The oxidative modification of the major cholesterol carrying lipoprotein, oxLDL, is a biomarker as well as a pathological factor in cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), obesity and other metabolic diseases. Perturbed cellular homeostasis due to physiological, pathological and pharmacological factors hinder the proper functioning of the endoplasmic reticulum (ER), which is the major hub for protein folding and processing, lipid biosynthesis and calcium storage, thereby leading to ER stress. The cellular response to ER stress is marked by a defensive mechanism called unfolded protein response (UPR), wherein the cell adapts strategies that favor survival. Under conditions of excessive ER stress, when the survival mechanisms fail to restore balance, UPR switches to apoptosis and eliminates the defective cells. ER stress is a major hallmark in metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), neurological and cardiovascular diseases. Though the pathological link between oxLDL and ER stress in cardiovascular diseases is well-documented, its involvement in other diseases is still largely unexplored. This review provides a deep insight into the common mechanisms in the pathogenicity of diseases involving oxLDL and ER stress as key players. In addition, the potential therapeutic intervention of the targets implicated in the pathogenic processes are also explored.
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Affiliation(s)
- Divya Saro Varghese
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.,Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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27
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Imamura Y, Mawatari S, Oda K, Kumagai K, Hiramine Y, Saishoji A, Kakihara A, Nakahara M, Oku M, Hosoyamada K, Kanmura S, Moriuchi A, Miyahara H, Akio Ido. Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross-sectional study. Hepatol Res 2021; 51:570-579. [PMID: 33675676 DOI: 10.1111/hepr.13631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/13/2021] [Accepted: 02/28/2021] [Indexed: 02/08/2023]
Abstract
AIM Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population. METHODS Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI-predominant BC and FFM-dominant BC. Fatty liver was determined using abdominal ultrasonography. RESULTS The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women. CONCLUSIONS Increasing FMI-predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.
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Affiliation(s)
- Yasushi Imamura
- Department of Hepatology, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yasunari Hiramine
- Department of Hepatology, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Akiko Saishoji
- Department of Hepatology, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Atsuko Kakihara
- Department of Hepatology, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Mai Nakahara
- Department of Nephrology, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Manei Oku
- Department of Nephrology, Kajikionsen Hospital, Aira, Japan
| | - Kaori Hosoyamada
- Department of Diabetes, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akihiro Moriuchi
- Department of Gastroenterology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | - Hironori Miyahara
- Medical Health Care Center, Kagoshima Kouseiren Hospital, Kagoshima, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr 2021; 10:59-75. [PMID: 33575290 DOI: 10.21037/hbsn.2019.08.08] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
Importance Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC. Objective To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases. Evidence Review MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included. Findings Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. Conclusions and Relevance This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.
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Affiliation(s)
- Daniel Geh
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Derek M Manas
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity. Metabolites 2021; 11:metabo11010054. [PMID: 33466889 PMCID: PMC7830343 DOI: 10.3390/metabo11010054] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/29/2020] [Accepted: 01/12/2021] [Indexed: 12/24/2022] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.
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Statin Use is Protective Against Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Case-control Study. J Clin Gastroenterol 2020; 54:733-740. [PMID: 31567625 DOI: 10.1097/mcg.0000000000001260] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND GOAL The incidence of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is rising. We aimed to characterize risk factors for NAFLD-HCC development. METHODS We performed a retrospective case-control study of HCC cases from a cohort of NAFLD patients who underwent at least 2 computed tomography scans. NAFLD-HCC cases confirmed on contrast imaging and/or biopsy were included. Controls were NAFLD patients without HCC matched by sex and age. Clinical variables were assessed. Visceral adipose tissue and subcutaneous adipose tissue were measured by computed tomography at 2 timepoints: before HCC diagnosis and at diagnosis. RESULTS We identified 102 subjects [34 HCC cases, 68 controls, 65% (n=66) males, mean age: 69 y] from 2002 to 2016. Cirrhosis was present in 91%. In multivariate analysis, statin use was protective against HCC [odds ratio (OR)=0.20, 95% confidence interval (CI): 0.07-0.60, P=0.004], while hypertension was a risk factor for HCC (OR=5.80, 95% CI: 2.01-16.75, P=0.001). In multivariate analysis, visceral adipose tissue in males was higher before HCC diagnosis and declined by HCC diagnosis in 86%, which was a significant difference compared with controls (OR=2.78, 95% CI: 1.10-7.44, P=0.04). CONCLUSIONS In a cohort of NAFLD-HCC patients, statin use was protective against HCC, while hypertension conferred an increased risk. Visceral adiposity at baseline was not a risk factor, but was higher in male patients before HCC development, declining in the majority by HCC diagnosis.
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Younossi ZM, Corey KE, Alkhouri N, Noureddin M, Jacobson I, Lam B, Clement S, Basu R, Gordon SC, Ravendhra N, Puri P, Rinella M, Scudera P, Singal AK, Henry L. Clinical assessment for high-risk patients with non-alcoholic fatty liver disease in primary care and diabetology practices. Aliment Pharmacol Ther 2020; 52:513-526. [PMID: 32598051 DOI: 10.1111/apt.15830] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/21/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important. AIM To provide practical guidance to providers on how to identify these patients and link them to specialty care. METHODS US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments. RESULTS The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available. CONCLUSION Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.
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Wu H, Zhong Z, Wang A, Yuan C, Ning K, Hu H, Wang C, Yin X. LncRNA FTX represses the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via regulating the M1/M2 polarization of Kupffer cells. Cancer Cell Int 2020; 20:266. [PMID: 32595415 PMCID: PMC7315496 DOI: 10.1186/s12935-020-01354-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/15/2020] [Indexed: 01/06/2023] Open
Abstract
Background The effect of lncRNA FTX on non-alcoholic fatty liver disease (NAFLD) conversion to hepatocellular carcinoma (HCC) is unclear. Methods In our study, C57BL/6 mice was fed with high fat diet for obtaining NAFLD mouse model, and diethylnitrosamine induced the formation of HCC tumor. The expression of iNOS and CD206 in tissues were examined using immunohistochemistry. In addition, qRT-PCR was implemented to detect the expression of FTX and mRNAs. The percentage of M1 and M2 Kupffer cells (KCs) were determined using flow cytometry. The pathological change in liver tissues was displayed by H&E staining. Besides, immunofluorescence assay was performed to ensure the primary KCs through labeling F4/80. Results Here, we found that the expression of FTX and the ratio of M1/M2 KCs in liver tissues from NAFLD-transformed HCC (NAFLD-HCC) patients lower than in liver tissues from NAFLD patients. Subsequently, we revealed that the expression of FTX and M1/M2 KCs ratio were downregulated during NAFLD conversion to HCC. Importantly, increasing of FTX inhibited HCC tumor growth, improved liver damage and promoted M1 polarization of KCs during NAFLD conversion to HCC, while these effects of FTX were reversed by inactivating of KCs. Finally, in vitro experiments, our data indicated that FTX facilitated the M1 polarization of KCs. Conclusion In conclusion, our results demonstrated that upregulation of FTX suppressed NAFLD conversion to HCC though promoting M1 polarization of KCs. Our findings presented a new regulatory mechanism for NAFLD conversion to HCC, and provided a new biomarker for inhibiting this conversion.
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Affiliation(s)
- Huajun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Zhiwei Zhong
- Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Anji Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Chunhui Yuan
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Ke Ning
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Huanhuan Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Chao Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
| | - Xiangbao Yin
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province China
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Hayashi M, Yamada S, Tanabe H, Takami H, Inokawa Y, Sonohara F, Shimizu D, Hattori N, Kanda M, Tanaka C, Nakayama G, Koike M, Fujiwara M, Kodera Y. High Serum Uric Acid Levels Could Be a Risk Factor of Hepatocellular Carcinoma Recurrences. Nutr Cancer 2020; 73:996-1003. [PMID: 32538144 DOI: 10.1080/01635581.2020.1779758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported. METHODS A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (>6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner. RESULTS About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo, P = 0.033], whereas no difference was observed in overall survival (MST: both not reached, P = 0.771). RFS of high SUA patients at 1POY also showed significantly poorer outcomes than low SUA patients (MST: 29.3 vs. 57.0 mo, P = 0.049). CONCLUSIONS High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.
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Affiliation(s)
- Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Tanabe
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Simoes Eugénio M, Farooq M, Dion S, Devisme C, Raguenes-Nicol C, Piquet-Pellorce C, Samson M, Dimanche-Boitrel MT, Le Seyec J. Hepatocellular Carcinoma Emergence in Diabetic Mice with Non-Alcoholic Steatohepatitis Depends on Diet and Is Delayed in Liver Exhibiting an Active Immune Response. Cancers (Basel) 2020; 12:cancers12061491. [PMID: 32521615 PMCID: PMC7352283 DOI: 10.3390/cancers12061491] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 12/23/2022] Open
Abstract
The increase of the sedentary lifestyle and high-calorie diet have modified the etiological landscape of hepatocellular carcinoma (HCC), with a recrudescence of non-alcoholic fatty liver disease (NAFLD), especially in Western countries. The purpose of our study was to evaluate the impact of high-fat diet feeding on non-alcoholic steatohepatitis (NASH) establishment and HCC development. Streptozotocin-induced diabetic male mice were fed with high-fat-high-cholesterol diet (HFHCD) or high-fat-high-sugar diet (HFHSD) from 1 to 16 weeks. Even if liver tumors appear regardless of the high-fat diet, two distinct physiopathological patterns were evidenced, with much more severe NASH hallmarks (liver injury, inflammation and fibrosis) in diabetic mice fed with HFHCD. The mild hepatic injury, weak inflammation and fibrosis observed in HFHSD were interestingly associated with earlier emergence of more numerous liver tumors. When activated helper and cytotoxic T cells, detected by flow cytometry, infiltrated the liver of HFHCD-fed diabetic mice, a delay in the appearance of tumor nodules and a limitation of their numbers were observed, suggesting that the immune activities partly controlled tumor emergence. These data highlighted two different mouse models of HCC progression in diabetic mice depending on diet, which could be useful to evaluate new therapeutic approaches for HCC by targeting the immune response.
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Affiliation(s)
- Mélanie Simoes Eugénio
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Muhammad Farooq
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
- Department of Clinical Sciences, College of Veterinary and Animal Sciences, Jhang 35200, Pakistan
| | - Sarah Dion
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Christelle Devisme
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Céline Raguenes-Nicol
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Claire Piquet-Pellorce
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Michel Samson
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
| | - Marie-Thérèse Dimanche-Boitrel
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
- Correspondence: (M.-T.D.-B.); (J.L.S.); Tel.: +33-(0)2-23-23-48-99 (M.-T.D.-B.); +33-(0)2-23-23-48-62 (J.L.S.)
| | - Jacques Le Seyec
- University Rennes 1, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, F-35000 Rennes, France; (M.S.E.); (M.F.); (S.D.); (C.D.); (C.R.-N.); (C.P.-P.); (M.S.)
- Correspondence: (M.-T.D.-B.); (J.L.S.); Tel.: +33-(0)2-23-23-48-99 (M.-T.D.-B.); +33-(0)2-23-23-48-62 (J.L.S.)
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Loomba R, Lim JK, Patton H, El-Serag HB. AGA Clinical Practice Update on Screening and Surveillance for Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology 2020; 158:1822-1830. [PMID: 32006545 PMCID: PMC8012107 DOI: 10.1053/j.gastro.2019.12.053] [Citation(s) in RCA: 246] [Impact Index Per Article: 49.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 12/17/2019] [Accepted: 12/26/2019] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a leading etiology for chronic liver disease with an immense public health impact and affects >25% of the US and global population. Up to 1 in 4 NAFLD patients may have nonalcoholic steatohepatitis (NASH). NASH is associated with significant morbidity and mortality due to complications of liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Recent data confirm that HCC represents the fifth most common cancer and is the second leading cause of cancer-related death worldwide, and NAFLD has been identified as a rapidly emerging risk factor for this malignancy. NAFLD-associated liver complications are projected to become the leading indication for liver transplantation in the next decade. Despite evidence that NAFLD-associated HCC may arise in the absence of cirrhosis, is often diagnosed at advanced stages, and is associated with lower receipt of curative therapy and with poorer survival, current society guidelines provide limited guidance/recommendations addressing HCC surveillance in patients with NAFLD outside the context of established cirrhosis. Limited data are presently available to guide clinicians with respect to which patients with NAFLD should undergo HCC surveillance, optimal screening tools, frequency of monitoring, and the influence of coexisting host- and disease-related risk factors. Herein we present an evidence-based review addressing HCC risk in patients with NAFLD and provide Best Practice Advice statements to address key issues in clinical management.
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Affiliation(s)
- Rohit Loomba
- Nonalcoholic Fatty Liver Disease Research Center, Division of Gastroenterology Department of Medicine, University of California San Diego, La Jolla, California; Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California.
| | - Joseph K. Lim
- Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
| | - Heather Patton
- Southern California Permanente Medical Group, San Diego, California,Division of Gastroenterology and Hepatology, Veterans Affairs San Diego Healthcare System, San Diego, California
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The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review. Cells 2020; 9:cells9041047. [PMID: 32331389 PMCID: PMC7226571 DOI: 10.3390/cells9041047] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.
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Liu X, Ju W, Huo C, Zhang S, Wang X, Huang K. Overweight and Obesity as Independent Factors for Increased Risk of Hepatocellular Cancer-Related Mortality: A Meta-Analysis. J Am Coll Nutr 2020; 40:287-293. [PMID: 32281914 DOI: 10.1080/07315724.2020.1751007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Obesity is related to the amplified risk of developing hepatocellular cancer, but its outcome on hepatocellular cancer-related mortality remains uncertain. Hence, the present study aimed to perform a meta-analysis study to evaluate the relationship between weight and hepatocellular cancer-related deaths. Through a systematic literature search up to December 2019, 7 observational studies with 2,349,834 subjects, 4834 hepatocellular cancer-related deaths were identified reporting relationships between body mass index (BMI), and hepatocellular cancer-related mortality. Odd ratio (OR) with 95% confidence intervals (CIs) was calculated comparing obese, BML > 30kg/m2, and overweight, BMI, 25-29.9 kg/m2 to subjects with normal BMI using the dichotomous method with a random-effect model. In obese subjects, males (OR, 1.84; 95% CI, 1.25-2.70) and females (OR, 1.26; 95% CI, 1.11-1.44), had higher hepatocellular cancer-related mortality compared to normal BMI subjects. However, overweight males (OR, 1.12; 95% CI, 0.98-1.28) and overweight females (OR, 1.06; 95% CI, 0.95-1.18), did not have such risk with moderate heterogeneity. The extent of increased mortality was higher in obese males compared to obese females. The impact of obesity on hepatocellular cancer-related mortality was observed in all populations with less extant in the black population. Based on this meta-analysis, obesity may have an independent relationship with up to the 1.84-fold risk of hepatocellular cancer-related mortality. This relationship was more pronounced in males than in females. Key teaching pointsBeing overweight is related to the amplified risk of developing hepatocellular cancer.Obesity's affect on hepatocellular cancer-related mortality remains uncertain.Based on this meta-analysis, obesity may have an independent relationship with up to the 1.84-fold risk of hepatocellular cancer-related mortality.This relationship was more pronounced in males than in females.
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Affiliation(s)
- Xiaoyu Liu
- Department of Oncology, Dezhou People's Hospital, Dezhou, Shandong Province, China
| | - Wenhui Ju
- Department of rehabilitation medicine, Dezhou People's Hospital, Dezhou, Shandong Province, China
| | - Chuanhong Huo
- Department of Infectious Disease, Dezhou people's Hospital, Dezhou, Shandong Province, China
| | - Shuhong Zhang
- Department of Oncology, Dezhou People's Hospital, Dezhou, Shandong Province, China
| | - Xingang Wang
- Nursing Department, Dezhou People's Hospital, Dezhou, Shandong Province, China
| | - Kai Huang
- Department of Oncology, Dezhou People's Hospital, Dezhou, Shandong Province, China
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El-Daly UM, Saber MM, Abdellateif MS, Nassar HR, Namour AE, Ismail YM, Zekri ARN. The Possible Role of Adipokines in HCV Associated Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2020; 21:599-609. [PMID: 32212784 PMCID: PMC7437316 DOI: 10.31557/apjcp.2020.21.3.599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Indexed: 01/14/2023] Open
Abstract
Background: Adipokines play an important role in the regulation of inflammation and tumor progression. Aim: Assessment of the possible role of adiponectin, leptin and visfatin in HCV associated hepatocellular carcinoma (HCC). Methods: patients were classified into 85 patients with HCV associated HCC, 100 patients with chronic hepatitis C viral (HCV) infection compared to 50 normal control (NC) subjects. All subjects included in the study were assessed for HCV infection by seropositive HCV antibodies, as well as HCV RNA by RT-PCR. Serum levels of adiponectin, leptin and visfatin were assessed using enzyme linked immunosorbent assay (ELISA). The data were correlated to the relevant clinic-pathological features of the patients, and the overall survival (OS) rate. Results: There was a significant difference in the serum levels of adiponectin and visfatin among HCC, HCV and NC groups (P<0.001). The serum levels of leptin and alpha fetoprotein (AFP) were significantly higher in HCC group (P<0.001). There was a significant association between the serum level of adiponectin and advanced Child class liver cirrhosis (P=0.03), as well as with poor performance status (ECOG, P=0.02). Serum leptin associated significantly with the number of lesions in the liver (P=0.006), visfatin associated with increased mortality rate (P<0.001). Adiponectin, leptin and visfatin associated significantly with liver cirrhosis in HCV patients (P<0.01). Leptin achieved the highest sensitivity (98.8%). visfatin achieved the highest specificity (100%) and PPV (100%) for detection of HCC. The combination of serum leptin and visfatin for the diagnosis of HCV associated HCC showed sensitivity, specificity, PPV, NPV and accuracy (100%, 96.6%, 93.4%, 100% and 97.4%; respectively). Conclusion: Adiponectin, leptin and visfatin have an important role(s) in the pathogenesis of HCV associated HCC.
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Affiliation(s)
- Usama M El-Daly
- Department of Medical Oncology, Damietta Oncology Center, Damietta,, Egypt
| | - Magdy M Saber
- Department of Medical Oncology and Malignant Hematology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Hanan R Nassar
- Department of Medical Oncology and Malignant Hematology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Alfred E Namour
- Department of Medical Oncology and Malignant Hematology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Yahia M Ismail
- Department of Medical Oncology and Malignant Hematology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Abdel-Rhaman N Zekri
- Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
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Shen Y, Risch H, Lu L, Ma X, Irwin ML, Lim JK, Taddei T, Pawlish K, Stroup A, Brown R, Wang Z, Jia W, Wong L, Mayne ST, Yu H. Risk factors for hepatocellular carcinoma (HCC) in the northeast of the United States: results of a case-control study. Cancer Causes Control 2020; 31:321-332. [PMID: 32060838 DOI: 10.1007/s10552-020-01277-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE HCC incidence has been continuously rising in the US for the past 30 years. To understand the increase in HCC risk, we conducted a case-control study in Connecticut, New Jersey and part of New York City. METHODS Through rapid case ascertainment and random digit dialing, we recruited 673 incident HCC patients and 1,166 controls. Information on demographic and anthropometric characteristics, lifestyle factors, medical and family cancer histories, were ascertained through telephone interviews using a structured questionnaire. Saliva specimens were collected for testing hepatitis C virus (HCV) antibodies. Unconditional logistic regression models were utilized to calculate odds ratio (OR) and 95% confidence interval (CI) to determine HCC associations with risk factors. RESULTS The study confirmed that HCV infection and obesity were important risk factors for HCC, ORs 110 (95% CI 59.2-204) and 2.13 (95% CI 1.52-3.00), respectively. High BMI and HCV infection had synergy in association with elevated HCC risk. Patients both obese and infected with HCV had HCC detected on average nearly 10 years earlier than those with neither factor. Diabetes, cigarette smoking and heavy alcohol intake were all associated with increased risk of HCC, whereas aspirin and other NSAID use were associated with reduced risk. HCC cases tended to attain less education, with lower household incomes, unmarried, and to have had more sexual partners than the controls. CONCLUSIONS Individuals at risk of HCC in the US comprise a unique population with low socioeconomic status and unhealthy lifestyle choices. Given the multifactorial nature, a comprehensive approach is needed in HCC prevention.
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Affiliation(s)
- Yi Shen
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Harvey Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Xiaomei Ma
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Melinda L Irwin
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Joseph K Lim
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Tamar Taddei
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Karen Pawlish
- New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, NJ, USA
| | - Antoinette Stroup
- Rutgers Cancer Institute, Rutgers School of Public Health, New Brunswick, NJ, USA
| | - Robert Brown
- Department of Medicine, Weill Cornell Medical College, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Zhanwei Wang
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Wei Jia
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Linda Wong
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Susan T Mayne
- Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD, USA
| | - Herbert Yu
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
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Zhang B, Zhang C, Zhang X, Li N, Dong Z, Sun G, Sun X. Atorvastatin promotes AMPK signaling to protect against high fat diet-induced non-alcoholic fatty liver in golden hamsters. Exp Ther Med 2020; 19:2133-2142. [PMID: 32104276 PMCID: PMC7027324 DOI: 10.3892/etm.2020.8465] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 12/11/2019] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by diffuse fatty acid degeneration and excess fat accumulation in the liver. Notably, the currently available medications used to treat NAFLD remain limited. The aim of the present study was to investigate the protective role of atorvastatin (Ato) against NAFLD in golden hamsters fed a high fat diet (HFD) and in HepG2 cells treated with palmitate, and identify the underlying molecular mechanism. Ato (3 mg/kg) was administered orally every day for 8 weeks to the hamsters during HFD administration. Hamsters in the model group developed hepatic steatosis with high serum levels of triglyceride, cholesterol, insulin and C-reactive protein, which were effectively reduced by treatment with Ato. Additionally, the relative liver weight of hamsters treated with Ato was markedly lower compared with that of the model group. Hematoxylin and eosin, and oil red O staining indicated that the livers of the animals in the model group exhibited large and numerous lipid droplets, which were markedly decreased after Ato treatment. Western blot analysis indicated that Ato inhibited fat accumulation in the liver through the AMP-activated protein kinase (AMPK)-dependent activation of peroxisome proliferator activated receptor α (PPARα), peroxisome proliferator-activated receptor-γ coactivator 1 α and their target genes. Furthermore, in vitro, Ato inhibited PA-induced lipid accumulation in HepG2 cells. This inhibitory effect was attenuated following Compound C treatment, indicating that AMPK may be a potential target of Ato. In conclusion, the increase in AMPK-mediated PPARα and its target genes may represent a novel molecular mechanism by which Ato prevents NAFLD.
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Affiliation(s)
- Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China.,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, P.R. China.,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, P.R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, P.R. China
| | - Chenyang Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China.,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, P.R. China.,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, P.R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, P.R. China
| | - Xuelian Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China.,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, P.R. China.,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, P.R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, P.R. China
| | - Nannan Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China
| | - Zhengqi Dong
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China
| | - Guibo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China.,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, P.R. China.,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, P.R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, P.R. China
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, P.R. China.,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, P.R. China.,Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, P.R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, P.R. China
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Fang M, Yao M, Yang J, Zheng WJ, Wang L, Yao DF. Abnormal CD44 activation of hepatocytes with nonalcoholic fatty accumulation in rat hepatocarcinogenesis. World J Gastrointest Oncol 2020; 12:66-76. [PMID: 31966914 PMCID: PMC6960074 DOI: 10.4251/wjgo.v12.i1.66] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 07/26/2019] [Accepted: 10/02/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing, and NAFLD has become one of the most common chronic liver diseases worldwide. With abnormal CD44 activation, the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Thus, the molecular mechanism of CD44 in NAFLD needs to be identified.
AIM To investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.
METHODS Sprague-Dawley rats were fed a high-fat (HF) for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide (0.05%) to induce HCC. Rats were sacrificed every 2 wk, and subsequently divided into the groups based on liver pathological examination (hematoxylin and eosin staining): NAFLD, denaturation, precancerosis, HCC, and control. Liver CD44 mRNA was detected by OneArray. Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density. Serum CD44, alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, and AFP levels were quantitatively tested.
RESULTS Elevated CD44 was first reported in hepatocarcinogenesis, with increasing expression from NAFLD to HCC at the protein or mRNA level. The CD44 integral optic density values were significantly different between the control group and the NAFLD (t = 25.433, P < 0.001), denaturation (t = 48.822, P < 0.001), precancerosis (t = 27.751, P < 0.001), and HCC (t = 16.239, P < 0.001) groups, respectively. Hepatic CD44 can be secreted into the blood, and serum CD44 levels in HCC or precancerous rats were significantly higher (P < 0.001) than those in any of the other rats. Positive correlations were found between liver CD44 and CD44 mRNA (rs = 0.373, P = 0.043) and serum CD44 (rs = 0.541, P = 0.002) and between liver CD44 mRNA and serum CD44 (rs = 0.507, P = 0.004). Moreover, significant correlations were found between liver CD44 and liver AFP (rs = 0.572, P = 0.001), between serum CD44 and serum AFP (rs = 0.608, P < 0.001), and between CD44 mRNA and AFP mRNA (rs = 0.370, P = 0.044).
CONCLUSION The data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.
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Affiliation(s)
- Miao Fang
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Min Yao
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Jie Yang
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Jie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Stefano JT, de Mello Malta F, de Campos PB, Andrade PF, Paranaguá-Vezzozo DC, Carrilho FJ, Oliveira CP. HCC in Patients with NAFLD/NASH. NAFLD AND NASH 2020:191-203. [DOI: 10.1007/978-3-030-37173-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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de Campos PB, Oliveira CP, Stefano JT, Martins-Filho SN, Chagas AL, Herman P, D'Albuquerque LC, Alvares-da-Silva MR, Longatto-Filho A, Carrilho FJ, Alves VAF. Hepatocellular carcinoma in non-alcoholic fatty liver disease (NAFLD) - pathological evidence for a predominance of steatohepatitic inflammatory non-proliferative subtype. Histol Histopathol 2019; 35:729-740. [PMID: 31858523 DOI: 10.14670/hh-18-194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES This study evaluated clinical and pathological aspects of patients with hepatocellular carcinoma (HCC) secondary to non-alcoholic fatty liver disease (NAFLD) and related these factors to immunohistochemical markers representative of the proliferative class. METHODS We evaluated 35 HCC nodules from 21 patients diagnosed with NAFLD undergoing liver resection (n=12) or liver transplantation (n=8) or both (n=1). Demographic, clinical and biochemical data were compared to histological features and to immunohistochemical reactivity for K19 and Ki-67. RESULTS Cirrhosis was present in 58% of patients. Ages ranged from 50 to 77 years. Sixteen patients (76%) were male and had type 2 diabetes mellitus, 81% had arterial hypertension, and 90% had BMI above 25 kg/m². Alpha-fetoprotein levels were normal in 62% of patients. Twenty-five (70%) nodules were diagnosed as "steatohepatitic HCC". Only 32% of the nodules presented high levels of Ki-67 (>10%) and/or K19 (>5%), although 63% were poorly differentiated (G.3/G.4) according to Edmondson & Steiner grading system. K19 positivity (>5%) was associated with higher degree of intratumoral inflammation (G.2/G.3), and with fibrosis, both at the center of the tumor and at the tumor front, whereas Ki-67 positivity (>10%) was associated with ballooning of neoplastic cells and occurred in more than 70% in non-cirrhotic patients. CONCLUSION NAFLD-related HCC was found in non-cirrhotic patients in 42% of cases, alpha-fetoprotein level was normal in 63% and "steatohepatitic HCC" was the predominant histological type. Immunoexpression of K19 and/or Ki-67 occurred in 32% of the nodules and were associated with intratumoral inflammation and ballooning, suggesting that HCC in MtS may be preferentially "an inflammatory, non-proliferative subtype of HCC".
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Affiliation(s)
| | - Claudia P Oliveira
- University of São Paulo Medical School, São Paulo, SP, Brasil. .,Laboratory of Clinical and Experimental Gastroenterology (LIM-07) Department of Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - José T Stefano
- Laboratory of Clinical and Experimental Gastroenterology (LIM-07) Department of Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Sebastião N Martins-Filho
- Department of Pathology (LIM-14), Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Aline L Chagas
- Department of Gastroenterology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Paulo Herman
- Department of Gastroenterology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Luiz C D'Albuquerque
- Department of Gastroenterology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Mário R Alvares-da-Silva
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Brasil
| | - Adhemar Longatto-Filho
- Department of Pathology (LIM-14), Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Flair J Carrilho
- University of São Paulo Medical School, São Paulo, SP, Brasil.,Laboratory of Clinical and Experimental Gastroenterology (LIM-07) Department of Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
| | - Venancio A F Alves
- University of São Paulo Medical School, São Paulo, SP, Brasil.,Department of Pathology (LIM-14), Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo, São Paulo, SP, Brasil
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Evaluation of AGP Fucosylation as a Marker for Hepatocellular Carcinoma of Three Different Etiologies. Sci Rep 2019; 9:11580. [PMID: 31399619 PMCID: PMC6689003 DOI: 10.1038/s41598-019-48043-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 07/26/2019] [Indexed: 02/08/2023] Open
Abstract
A mass spectrometric analysis platform has been developed to determine whether glycosylation patterns of alpha-1 acid glycoprotein (AGP) could be used as a marker for early detection of hepatocellular carcinoma (HCC) in different etiologies, i.e. non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALC), and hepatitis C virus (HCV). MALDI-MS profiling of N-glycans of AGP purified from 20 μL of patient serum in HCC (n = 72) and liver cirrhosis (n = 58) showed that a unique trifucosylated tetra-antennary glycan (m/z 3490.76) was predominantly identified in HCCs but was absent in healthy subjects and the majority of cirrhosis patients. Receiver operation characteristic (ROC) curve analysis showed that the trifucosylated N-glycan of AGP (triFc_AGP) could differentiate HCC from cirrhosis with an area under the curve (AUC) of 0.707, 0.726 and 0.751 for NASH, ALC and HCV, respectively. When combining triFc_AGP with INR and AFP, the panel had the greatest benefit in detection of NASH-related HCCs, with a significantly improved AUC of 0.882 for all NASH HCCs and 0.818 for early NASH HCCs compared to AFP alone (0.761 and 0.641, respectively). Moreover, triFc_AGP could serve as a potential marker for monitoring AFP-negative HCC patients.
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Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis. Am J Clin Oncol 2019; 41:874-881. [PMID: 28537989 DOI: 10.1097/coc.0000000000000388] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. MATERIALS AND METHODS Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m(2)) and overweight (BMI, 25 to 29.9 kg/m(2)) individuals with normal BMI individuals using random-effects model. RESULTS On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. CONCLUSIONS On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.
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Tanaka N, Kimura T, Fujimori N, Nagaya T, Komatsu M, Tanaka E. Current status, problems, and perspectives of non-alcoholic fatty liver disease research. World J Gastroenterol 2019; 25:163-177. [PMID: 30670907 PMCID: PMC6337019 DOI: 10.3748/wjg.v25.i2.163] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/24/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) based on the existence of ballooned hepatocytes, although the states have been known to transform into each other. Moreover, since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus, identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs.
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Affiliation(s)
- Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- International Research Center for Agricultural Food Industry, Shinshu University, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tadanobu Nagaya
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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The Changing Face of Hepatocellular Carcinoma: Forecasting Prevalence of Nonalcoholic Steatohepatitis and Hepatitis C Cirrhosis. J Clin Exp Hepatol 2019; 9:50-55. [PMID: 30765939 PMCID: PMC6363953 DOI: 10.1016/j.jceh.2018.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/08/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES The purpose of this research is to analyze the past and forecast the future prevalence of Hepatitis C Virus (HCV) and Nonalcoholic Steatohepatitis (NASH) and their respective contribution to Hepatocellular Carcinoma (HCC) incidence in the setting of novel anti-viral agents and rising obesity rates in the United States. METHODS Existing data of HCV and NASH prevalence in the United States utilizing the National Health and Nutrition Examination Survey (NHANES) and Organ Procurement and Transplantation Network (OPTN) was collected and analyzed to project future prevalence trends. RESULTS Prevalence of NASH and HCV are expected to increase and decline respectively over the next two decades with alcoholic cirrhosis expected to stay relatively unchanged. The estimated prevalence of NASH equaled and overtook the projected prevalence of HCV in 2007 at approximately 3 million persons. Estimates of NASH's contribution to HCC overtook HCV-HCC in 2015 at an approximately 25 million persons. Projection models suggest HCV prevalence declining to 1 million active cases by 2025, while NASH potentially increases to 17-42 million depending on a linear or exponential trendline. Projections of NASH-HCC similarly outpace HCV-HCC by 2025 with 45 million or 106 million (linear, exponential) versus 18 million persons respectively. CONCLUSIONS The future prevalence of HCV and NASH are expected to become further divergent with NASH emerging as the major contributor of cirrhosis and HCC in the United States.
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Liver Transplantation for NASH-Related Hepatocellular Carcinoma Versus Non-NASH Etiologies of Hepatocellular Carcinoma. Transplantation 2018; 102:640-647. [PMID: 29319620 DOI: 10.1097/tp.0000000000002043] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver transplant (LT) for nonalcoholic steatohepatitis (NASH) related hepatocellular carcinoma (HCC) is not well characterized in the literature. The aim of the study was to examine characteristics and outcomes of patients who had LT for NASH-HCC (NASH) versus HCC from other liver diseases (non-NASH). METHODS Using a 2-center retrospective design, all patients from 2004 to 2014 that received LT for HCC were analyzed. Subgroup analysis stratified patients according to Milan criteria. RESULTS Nine hundred twenty-nine patients were transplanted for HCC. Sixty (6.5%) of 929 had HCC in the context of NASH. There were no significant differences between groups for pretransplant or explant tumor characteristics. The actuarial 1-, 3- and 5-year overall survival was 98%, 96%, and 80% in NASH versus 95%, 84%, and 78% in non-NASH (P = 0.1). No differences in tumor recurrence were observed in patients within and beyond Milan in the NASH group. Multivariate Cox regression demonstrated NASH status to be a protective factor for recurrence among patients with tumors beyond Milan (hazard ratio, 0.21; 95% confidence interval, 0.05-0.86; P = 0.029). CONCLUSION After LT, outcomes are similar between NASH and non-NASH etiologies for HCC. The hypothesis that patients with more advanced HCC tumors in the context of NASH may have more favorable outcomes after LT has been generated, but requires further study.
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Tête A, Gallais I, Imran M, Chevanne M, Liamin M, Sparfel L, Bucher S, Burel A, Podechard N, Appenzeller BMR, Fromenty B, Grova N, Sergent O, Lagadic-Gossmann D. Mechanisms involved in the death of steatotic WIF-B9 hepatocytes co-exposed to benzo[a]pyrene and ethanol: a possible key role for xenobiotic metabolism and nitric oxide. Free Radic Biol Med 2018; 129:323-337. [PMID: 30268890 DOI: 10.1016/j.freeradbiomed.2018.09.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 09/20/2018] [Accepted: 09/26/2018] [Indexed: 12/15/2022]
Abstract
We previously demonstrated that co-exposing pre-steatotic hepatocytes to benzo[a]pyrene (B[a]P), a carcinogenic environmental pollutant, and ethanol, favored cell death. Here, the intracellular mechanisms underlying this toxicity were studied. Steatotic WIF-B9 hepatocytes, obtained by a 48h-supplementation with fatty acids, were then exposed to B[a]P/ethanol (10 nM/5 mM, respectively) for 5 days. Nitric oxide (NO) was demonstrated to be a pivotal player in the cell death caused by the co-exposure in steatotic hepatocytes. Indeed, by scavenging NO, CPTIO treatment of co-exposed steatotic cells prevented not only the increase in DNA damage and cell death, but also the decrease in the activity of CYP1, major cytochrome P450s of B[a]P metabolism. This would then lead to an elevation of B[a]P levels, thus possibly suggesting a long-lasting stimulation of the transcription factor AhR. Besides, as NO can react with superoxide anion to produce peroxynitrite, a highly oxidative compound, the use of FeTPPS to inhibit its formation indicated its participation in DNA damage and cell death, further highlighting the important role of NO. Finally, a possible key role for AhR was pointed out by using its antagonist, CH-223191. Indeed it prevented the elevation of ADH activity, known to participate to the ethanol production of ROS, notably superoxide anion. The transcription factor, NFκB, known to be activated by ROS, was shown to be involved in the increase in iNOS expression. Altogether, these data strongly suggested cooperative mechanistic interactions between B[a]P via AhR and ethanol via ROS production, to favor cell death in the context of prior steatosis.
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Affiliation(s)
- Arnaud Tête
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Isabelle Gallais
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Muhammad Imran
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Martine Chevanne
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Marie Liamin
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Lydie Sparfel
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Simon Bucher
- Univ Rennes, Inserm, Inra, Institut NUMECAN (Nutrition Metabolisms and Cancer) - UMR_S 1241, UMR_A 1341, F-35000 Rennes, France
| | - Agnès Burel
- Univ Rennes, Biosit - UMS 3480, US_S 018, F-35000 Rennes, France
| | - Normand Podechard
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Brice M R Appenzeller
- HBRU, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg
| | - Bernard Fromenty
- Univ Rennes, Inserm, Inra, Institut NUMECAN (Nutrition Metabolisms and Cancer) - UMR_S 1241, UMR_A 1341, F-35000 Rennes, France
| | - Nathalie Grova
- HBRU, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg
| | - Odile Sergent
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Dominique Lagadic-Gossmann
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France.
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Kaltenecker D, Themanns M, Mueller KM, Spirk K, Suske T, Merkel O, Kenner L, Luís A, Kozlov A, Haybaeck J, Müller M, Han X, Moriggl R. Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression. Cytokine 2018; 124:154569. [PMID: 30389231 DOI: 10.1016/j.cyto.2018.10.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/05/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022]
Abstract
The rising prevalence of obesity came along with an increase in associated metabolic disorders in Western countries. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and is linked to primary stages of liver cancer development. Growth hormone (GH) regulates various vital processes such as energy supply and cellular regeneration. In addition, GH regulates various aspects of liver physiology through activating the Janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 pathway. Consequently, disrupted GH - JAK2 - STAT5 signaling in the liver alters hepatic lipid metabolism and is associated with NAFLD development in humans and mouse models. Interestingly, while STAT5 as well as JAK2 deficiency correlates with hepatic lipid accumulation, recent studies suggest that these proteins have unique ambivalent functions in chronic liver disease progression and tumorigenesis. In this review, we focus on the consequences of altered GH - JAK2 - STAT5 signaling for hepatic lipid metabolism and liver cancer development with an emphasis on lessons learned from genetic knockout models.
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Affiliation(s)
- Doris Kaltenecker
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Madeleine Themanns
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Medical University of Vienna, Vienna, Austria
| | - Kristina M Mueller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Katrin Spirk
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Medical University of Vienna, Vienna, Austria
| | - Tobias Suske
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Olaf Merkel
- Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; Institute of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Andreia Luís
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Andrey Kozlov
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Austria; Department of Pathology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Xiaonan Han
- Key Laboratory of Human Disease Comparative Medicine, the Ministry of Health; Institute of Laboratory Animal Sciences (ILAS), Chinese Academy of Medical Science (CAMS) and Peking Union Medical College (PUMC), Beijing, PR China; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
| | - Richard Moriggl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Medical University of Vienna, Vienna, Austria.
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