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Batt NM, Rodrigues B, Bloom S, Sawhney R, George ES, Hodge A, Vootukuru N, McCrae C, Sood S, Roberts SK, Dev A, Bell S, Thompson A, Ryan MC, Kemp W, Gow PJ, Sood S, Nicoll AJ. Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy. J Gastroenterol Hepatol 2024; 39:1048-1056. [PMID: 38369382 DOI: 10.1111/jgh.16501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/31/2023] [Accepted: 01/16/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND AND AIM The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.
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Affiliation(s)
- N M Batt
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
| | - B Rodrigues
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
| | - S Bloom
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
| | - R Sawhney
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
| | - E S George
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - A Hodge
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
| | - N Vootukuru
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
| | - C McCrae
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
| | - Surbhi Sood
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - S K Roberts
- Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - A Dev
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
| | - S Bell
- Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
| | - A Thompson
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia
- University of Melbourne, Parkville, Victoria, Australia
| | - M C Ryan
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia
- University of Melbourne, Parkville, Victoria, Australia
| | - W Kemp
- Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia
| | - P J Gow
- Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia
| | - Siddharth Sood
- Department of Gastroenterology and Hepatology, Melbourne Health, Parkville, Victoria, Australia
| | - A J Nicoll
- Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
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Zhao Y, Tan H, Zhang X, Zhu J. Roles of peroxisome proliferator-activated receptors in hepatocellular carcinoma. J Cell Mol Med 2024; 28:e18042. [PMID: 37987033 PMCID: PMC10902579 DOI: 10.1111/jcmm.18042] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.
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Affiliation(s)
- Yaqin Zhao
- Department of Abdominal Oncology, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin HospitalHubei University of MedicineShiyanHubeiChina
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General SurgeryThe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'anChina
| | - Jing Zhu
- Nanjing Drum Tower HospitalNanjingChina
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Fernandez CJ, Alkhalifah M, Afsar H, Pappachan JM. Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink. Pathogens 2024; 13:68. [PMID: 38251375 PMCID: PMC10821334 DOI: 10.3390/pathogens13010068] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.
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Affiliation(s)
- Cornelius J. Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, UK;
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11411, Saudi Arabia
| | - Hafsa Afsar
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK; (M.A.); (H.A.)
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, UK
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK
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Yan LJ, Yang LS, Yan YC, Tan SY, Ding ZN, Liu H, Wang DX, Dong ZR, Li T. Anthropometric indicators of adiposity and risk of primary liver cancer: A systematic review and dose-response meta-analysis. Eur J Cancer 2023; 185:150-163. [PMID: 36996625 DOI: 10.1016/j.ejca.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/29/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND AND AIMS Adiposity is associated with an increased risk of primary liver cancer (PLC). As the most commonly used indicator of adiposity, the body mass index (BMI) has been questioned for its limitations in reflecting visceral fat. This study aimed to investigate the role of different anthropometric indicators in identifying the risk of PLC by accounting for potential non-linear associations. METHODS Systematic searches were conducted in the PubMed, Embase, Cochrane Library, Sinomed, Web of Science, and CNKI databases. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship was assessed using a restricted cubic spline model. RESULTS Sixty-nine studies involving more than 30 million participants were included in the final analysis. Regardless of the indicator used, adiposity was strongly associated with an increased risk of PLC. When comparing the HRs per 1-standard deviation increment across indicators of adiposity, the association was strongest for waist-to-height ratio (WHtR) (HR = 1.39), followed by waist-to-hip ratio (WHR) (HR = 1.22), BMI (HR = 1.13), waist circumference (WC) (HR = 1.12), and hip circumference (HC) (HR = 1.12). A strong non-linear association was observed between each anthropometric parameter and the risk of PLC, regardless of whether the original or decentralised value was used. The positive association between WC and PLC risk remained substantial after adjusting for BMI. The incidence of PLC was higher with central adiposity (52.89 per 100,000 person-years, 95% CI = 50.33-55.44) than general adiposity (39.01 per 100,000 person-years, 95% CI = 37.26-40.75). CONCLUSION Central adiposity seems to contribute more to the development of PLC than general adiposity. A larger WC, independent of BMI, was strongly associated with the risk of PLC and might be a more promising predictive indicator than BMI.
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Affiliation(s)
- Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Long-Shan Yang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China.
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, PR China; Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan 250012, PR China.
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Chen YL, Hsieh CC, Chu PM, Chen JY, Huang YC, Chen CY. Roles of protein tyrosine phosphatases in hepatocellular carcinoma progression (Review). Oncol Rep 2023; 49:48. [PMID: 36660927 PMCID: PMC9887465 DOI: 10.3892/or.2023.8485] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/15/2022] [Indexed: 01/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents almost 80% of all liver cancers, is the sixth most common cancer and is the second‑highest cause of cancer‑related deaths worldwide. Protein tyrosine phosphatases (PTPs), which are encoded by the largest family of phosphatase genes, play critical roles in cellular responses and are implicated in various signaling pathways. Moreover, PTPs are dysregulated and involved in various cellular processes in numerous cancers, including HCC. Kinases and phosphatases are coordinators that modulate cell activities and regulate signaling responses. There are multiple interacting signaling networks, and coordination of these signaling networks in response to a stimulus determines the physiological outcome. Numerous issues, such as drug resistance and inflammatory reactions in the tumor microenvironment, are implicated in cancer progression, and the role of PTPs in these processes has not been well elucidated. Therefore, the present review focused on discussing the relationship of PTPs with inflammatory cytokines and chemotherapy/targeted drug resistance, providing detailed information on how PTPs can modulate inflammatory reactions and drug resistance to influence progression in HCC.
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Affiliation(s)
- Yi-Li Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
| | - Ching-Chuan Hsieh
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan, R.O.C
| | - Pei-Ming Chu
- Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Jing-Yi Chen
- Department of Medical Laboratory Science, College of Medicine, I‑Shou University, Kaohsiung 82445, Taiwan, R.O.C
| | - Yu-Chun Huang
- Aging and Diseases Prevention Research Center, Fooyin University, Kaohsiung 83102, Taiwan, R.O.C
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
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Yamagiwa Y, Tanaka K, Matsuo K, Wada K, Lin Y, Sugawara Y, Mizoue T, Sawada N, Takimoto H, Ito H, Kitamura T, Sakata R, Kimura T, Tanaka S, Inoue M. Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies. Sci Rep 2023; 13:3445. [PMID: 36859564 PMCID: PMC9977913 DOI: 10.1038/s41598-023-30467-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.
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Affiliation(s)
- Yoko Yamagiwa
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Clinical Research Centers for Medicine, International University of Health and Welfare, Tokyo, Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Keiko Wada
- Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Aichi, Japan
| | - Yumi Sugawara
- Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Mizoue
- Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Hidemi Takimoto
- Department of Nutritional Epidemiology, National Institute of Health and Nutrition, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Tetsuhisa Kitamura
- Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ritsu Sakata
- Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takashi Kimura
- Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shiori Tanaka
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
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Hu J, Ding Y, Liu W, Liu S. When AHR signaling pathways meet viral infections. Cell Commun Signal 2023; 21:42. [PMID: 36829212 PMCID: PMC9951170 DOI: 10.1186/s12964-023-01058-8] [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: 09/17/2022] [Accepted: 01/27/2023] [Indexed: 02/26/2023] Open
Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional factor widely expressed among immune, epithelial, endothelial and stromal cells in barrier tissues. It can be activated by small molecules provided by pollutants, microorganisms, food, and metabolism. It has been demonstrated that AHR plays an important role in modulating the response to many microbial pathogens, and the abnormal expression of AHR signaling pathways may disrupt endocrine, cause immunotoxicity, and even lead to the occurrence of cancer. Most humans are infected with at least one known human cancer virus. While the initial infection with these viruses does not cause major disease, the metabolic activity of infected cells changes, thus affecting the activation of oncogenic signaling pathways. In the past few years, lots of studies have shown that viral infections can affect disease progression by regulating the transmission of multiple signaling pathways. This review aims to discuss the potential effects of virus infections on AHR signaling pathways so that we may find a new strategy to minimize the adverse effects of the AHR pathway on diseases. Video Abstract.
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Affiliation(s)
- Jieke Hu
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266555, China.,Department of Pathogenic Biology, Qingdao University Medical College, 308 Ningxia Road, Qingdao, 266071, China
| | - Yuan Ding
- Department of Special Examination, Qingdao Women & Children Hospital, Qingdao, 266035, China
| | - Wen Liu
- Department of Pathogenic Biology, Qingdao University Medical College, 308 Ningxia Road, Qingdao, 266071, China.
| | - Shuzhen Liu
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266555, China.
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Mak KM, Kee D, Cheng CP. A review of hepatic fibrosis-associated histopathology in aged cadavers. Anat Rec (Hoboken) 2022; 306:1031-1053. [PMID: 35446463 DOI: 10.1002/ar.24931] [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: 01/26/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 11/08/2022]
Abstract
This article reviews hepatic fibrosis-associated histopathology of aged cadavers (mean age 82 years). A study of 68 livers identified steatosis in 35.5%, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract fibrosis in 47.7%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4% of the samples as well as one hepatocellular carcinoma and six metastatic tumors. Other studies have revealed that collagens I, III, IV, V, and VI and fibronectin constitute the matrices of fibrous central veins, perisinusoidal space, portal tracts, and septa. Elastin is rich in portal tracts and fibrous septa but absent from the perisinusoidal space. Hepatic stellate cells are ubiquitous in the liver parenchyma while myofibroblasts localize in fibrotic foci. Factor VIII-related antigen expression signals sinusoidal to systemic vascular endothelium transformation while collagen IV and laminin codistribution indicates formation of perisinusoidal membranes. Their coincidence reflects focalized capillarization of sinusoids in the aged liver. In response to fibrogenesis, hepatic progenitor cells residing in the canal of Hering in the periportal parenchyma undergo expansion and migration deep into the lobule. Concomitantly, intermediate hepatocyte-like cells increase in advanced fibrosis stages, which is possibly related to hepatic regeneration. Metabolic zonation of glutamine synthetase expands from the perivenous to non-perivenous parenchyma in fibrosis progression but its expression is lost in cirrhosis, while cytochrome P-4502E1 expression is maintained in centrilobular and midlobular zones in fibrosis progression and expressed in cirrhosis. Hence, cadaveric livers provide a platform for further investigation of hepatic histopathologies associated with the aging liver.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dustin Kee
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher P Cheng
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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9
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Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis. Sci Rep 2022; 12:5562. [PMID: 35365728 PMCID: PMC8975940 DOI: 10.1038/s41598-022-09588-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 03/22/2022] [Indexed: 01/04/2023] Open
Abstract
Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.
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10
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Yang C, Wan M, Lu Y, Yang X, Yang L, Wang S, Sun G. Associations between diabetes mellitus and the risk of hepatocellular carcinoma in Asian individuals with hepatitis B and C infection: systematic review and a meta-analysis of cohort studies. Eur J Cancer Prev 2022; 31:107-116. [PMID: 35103624 DOI: 10.1097/cej.0000000000000669] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We aim to further analyze and compare associations between diabetes mellitus and the risk of hepatocellular carcinoma (HCC) in Asian individuals with hepatitis B or C virus infection by conducting an updated meta-analysis of cohort studies. Literature search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library from the beginning of indexing for each database to January 1, 2020. A total of 22 articles met the inclusion criteria, in which 18 were cohort studies and 4 were case-control studies. We identified eight cohort studies and three case-control studies that presented results on diabetes mellitus and the risk of HCC in Asian subjects with hepatitis B virus (HBV) infection: the cumulative relative risk (RR) with 95% confidence interval (CI) was 1.37 (95% CI: 1.24 to 1.51; I2 = 27.8%) for cohort studies and cumulative odds ratio (OR) with 95% CI was 1.99 (95% CI: 0.73 to 5.48; I2 = 88.4%) for case-control studies. Thirteen cohort studies and two case-control studies presented results on the association between diabetes mellitus and the risk of HCC in Asian subjects with hepatitis C virus (HCV) infection: the RR with 95% CI was 1.76 (95% CI: 1.42 to 2.17; I2 = 62.8%) for cohort studies and OR with 95% CI was 1.77 (95% CI: 1.18 to 2.64; I2 = 0.0%) for case-control studies. In summary, our meta-analysis strongly supports the association between coexistent HCV and diabetes with the increasing risk of HCC; although the results equally support diabetes mellitus being significantly associated with increased risk of HCC among patients with HBV infection, this correlation is weaker than the former.
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Affiliation(s)
- Chao Yang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, P.R. China
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11
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Wang X, Xie Q. Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) and Viral Hepatitis. J Clin Transl Hepatol 2022; 10:128-133. [PMID: 35233381 PMCID: PMC8845159 DOI: 10.14218/jcth.2021.00200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 12/04/2022] Open
Abstract
A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.
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Affiliation(s)
- Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Kim MN, Han K, Yoo J, Hwang SG, Ahn SH. Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver. Aliment Pharmacol Ther 2022; 55:97-107. [PMID: 34820871 DOI: 10.1111/apt.16706] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/13/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Population-based data are lacking regarding whether fatty liver is a risk factor for hepatocellular carcinoma (HCC) and mortality in patients with chronic viral hepatitis. AIM To investigate the association of fatty liver with HCC incidence and mortality in patients with chronic viral hepatitis using a nationwide cohort METHODS: We included 57,385 patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC) who underwent health examinations. The patients were divided into three groups: no fatty liver, fatty liver index (FLI) <30, grade 1 (G1) fatty liver: 30≤ FLI <60, and grade 2 (G2) fatty liver: FLI >60. RESULTS During a median 8.4-year follow-up, we documented 3496 HCC cases and 4146 deaths. Compared to patients with no fatty liver (n = 35,018), the risk of HCC was significantly higher in patients with G1 fatty liver (n = 14,544) (adjusted hazard ratio [aHR] = 1.50, 95% confidence interval [CI] = 1.38-1.64) and G2 fatty liver (n = 7,823) (aHR = 1.88, 95% CI = 1.67-2.12). The risk of mortality was significantly higher in patients with G1 fatty liver (aHR = 1.53, 95% CI = 1.41-1.66) and G2 fatty liver (aHR = 2.16, 95% CI = 1.94-2.42) compared to patients with no fatty liver. CONCLUSIONS Concurrent fatty liver was associated with a higher risk of HCC and mortality in patients with chronic viral hepatitis. Our results suggest the importance of management of fatty liver to reduce the risks of HCC and mortality in patients with chronic viral hepatitis.
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Affiliation(s)
- Mi Na Kim
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.,Clinical and Translational Hepatology Laboratory, Seongnam, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Juhwan Yoo
- Department of Biomedicine & Health Science, The Catholic University of Korea, Seoul, Korea
| | - Seong Gyu Hwang
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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14
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Elkhoudary AF, Elmougy R, Elsaid A, Wahba Y, Abdel-Aziz AAF. Genetic and biochemical studies of hepatic carcinoma in the Egyptian population. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2021; 26:62. [PMID: 34729070 PMCID: PMC8506241 DOI: 10.4103/jrms.jrms_846_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 03/10/2018] [Accepted: 11/13/2018] [Indexed: 12/24/2022]
Abstract
Background Hepatocellular carcinoma (HCC), a deadly malignancy of the liver, is considered the third leading reason behind cancer deaths. It is more frequent in men than in women of ages above 50. Liver disease, leading to liver cirrhosis (LC), is mostly caused by alcoholism abuse, reaction diseases of the liver, or viral hepatitis B or C infection. Interleukin-6 (IL-6) is considered an effective pro-inflammatory cytokine, which plays a crucial role in the host defense mechanism. Its level is higher in HCC patients than in LC cases, indicating that tumor cells increase the production of cytokines. The X-ray repair cross-complementing group 1 (XRCC1) gene is a major DNA repair gene. It acts as a scaffold of various activities that are concerned in the repairing method by interacting with components of base excision repair. This study aims to measure the serum concentrations of IL6 and C-reactive protein (CRP) and investigate whether XRCC1 Arg194Trp and Arg399Gln polymorphisms are related to HCC disease. Materials and Methods Whole-blood DNA was extracted from 123 HCC patients and 123 healthy volunteers. Tetra-primer amplification refractory mutation system was performed in the detection of XRCC1 Arg399Gln and Arg194Trp polymorphisms. Results Serum concentration levels of IL-6 and CRP are significantly higher in patients with HCC than in control subjects. The allelic and genotype frequency distributions of XRCC1 (Arg399Gln and Arg194Trp) are significantly increased in HCC cases compared to healthy volunteers. Conclusion Arg/Gln, Arg/Trp, Gln/Gln, and Trp/Trp genotypes are associated with higher risk HCC than the Arg/Arg genotype.
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Affiliation(s)
- Amany F Elkhoudary
- Department of Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Rehab Elmougy
- Department of Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Afaf Elsaid
- Genetics Unit, Faculty of Medicine, Children Hospital, Mansoura University, Mansoura, Egypt
| | - Yahya Wahba
- Department of Pediatrics and Genetics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Siphepho PY, Liu YT, Shabangu CS, Huang JF, Huang CF, Yeh ML, Yu ML, Wang SC. The Impact of Steatosis on Chronic Hepatitis C Progression and Response to Antiviral Treatments. Biomedicines 2021; 9:1491. [PMID: 34680608 PMCID: PMC8533513 DOI: 10.3390/biomedicines9101491] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/12/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic derangement is characteristic in patients with hepatitis C virus (HCV) infection. Aside from established liver injury, various extrahepatic metabolic disorders impact the natural history of the disease, clinical outcomes, and the efficacy of antiviral therapy. The presence of steatosis, recently redefined as metabolic-associated fatty liver disease (MAFLD), is a common feature in HCV-infected patients, induced by host and/or viral factors. Most chronic HCV-infected (CHC) patients have mild steatosis within the periportal region of the liver with an estimated prevalence of 40% to 86%. Indeed, this is higher than the 19% to 50% prevalence observed in patients with other chronic liver diseases such as chronic hepatitis B (CHB). The histological manifestations of HCV infection are frequently observed in genotype 3 (G-3), where relative to other genotypes, the prevalence and severity of steatosis is also increased. Steatosis may independently influence the treatment efficacy of either interferon-based or interferon-free antiviral regimens. This review aimed to provide updated evidence of the prevalence and risk factors behind HCV-associated steatosis, as well as explore the impact of steatosis on HCV-related outcomes.
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Affiliation(s)
- Phumelele Yvonne Siphepho
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
| | - Yi-Ting Liu
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ciniso Sylvester Shabangu
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Program in Tropical Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (P.Y.S.); (M.-L.Y.)
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-F.H.); (M.-L.Y.)
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Center for Cancer Research, Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.S.S.); (J.-F.H.)
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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Yoshimura Y, Hamaguchi M, Hashimoto Y, Okamura T, Nakanishi N, Obora A, Kojima T, Fukui M. Obesity and metabolic abnormalities as risks of alcoholic fatty liver in men: NAGALA study. BMC Gastroenterol 2021; 21:321. [PMID: 34372774 PMCID: PMC8353849 DOI: 10.1186/s12876-021-01893-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/30/2021] [Indexed: 11/30/2022] Open
Abstract
Background Hepatic steatosis has a pivotal role in the development of chronic liver diseases, even in alcohol-related liver disease. Alcoholic fatty liver disease is an important phenotype among alcohol-related liver diseases. While metabolic syndrome is a dominant risk factor of incident nonalcoholic fatty liver disease, the role of metabolic syndrome in alcoholic fatty liver disease has not been clarified yet. Methods A retrospective cohort study was performed at a health check-up center in Japan. Subjects consisted of male participants without fatty liver who consumed ethanol of 420 g/week or higher. Adjusted hazard ratios and 95% confidence intervals at the baseline examinations for incident alcoholic fatty liver disease were estimated using Cox model. Results A total of 640 participants were included in this study. During 3.91 years (IQR 1.63–7.09) of follow-up, 168 new cases of alcoholic fatty liver disease developed (49.1 cases per 1000 persons per year). After adjustment for age, smoking status, alcohol consumption, the hazard ratio for a 1 kg/m2 increase in body mass index was 1.2 (1.12–1.28). The hazard ratio of subjects with high triglyceride and low high-density lipoprotein-cholesterol levels were 1.56 (1.12–2.18) and 1.52 (1.03–2.25), respectively. Conclusions Obesity, high triglyceridemia, and low high-density lipoprotein-cholesterolemia are independent risk factors of alcoholic fatty liver disease in Japanese men who consumed alcohol habitually. In people with these risks, triglyceride lowering and high-density lipoprotein-cholesterol raising by improving insulin resistance and weight maintenance in addition to abstinence from alcohol would be effective in preventing the development of alcoholic fatty liver disease. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01893-4.
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Affiliation(s)
- Yuta Yoshimura
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuro Okamura
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Akihiro Obora
- Department of Gastroenterology, Asahi University Hospital, Gifu, Japan
| | - Takao Kojima
- Department of Gastroenterology, Asahi University Hospital, Gifu, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Prior antiviral treatment and mortality among patients with hepatitis C virus-related hepatocellular carcinoma: A national cohort study. PLoS One 2021; 16:e0255624. [PMID: 34343200 PMCID: PMC8330890 DOI: 10.1371/journal.pone.0255624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Background The current antiviral treatments available for hepatitis C virus (HCV) infection decrease the risk of hepatocellular carcinoma (HCC). Hence, patients with HCV infection who have not received antiviral treatment and have developed HCC may be those who missed timely antiviral treatment for HCV. However, the proportion of patients who missed timely antiviral treatment and its implications are largely unexplored. Methods A nationwide retrospective cohort of 4,592 newly diagnosed HCV-related HCC patients (2013–2017) was identified from the Korean National Health Insurance Service database. Prior antiviral treatment for HCV was defined as a history of at least one HCV-specific antiviral treatment before HCC diagnosis. The outcome was all-cause mortality. Results Prior antiviral treatment for HCV was identified in 802 (17.4%) patients, and 16%, 16%, 17%, 19%, and 19% of patients received antiviral treatment in the years 2013, 2014, 2015, 2016, and 2017, respectively (P = 0.21). During 8,085 person-years of follow-up (median, 1.4; maximum, 5.3 years of follow-up), 1,970 patients died. Mortality rates were lower in patients with prior antiviral treatment (15 deaths/100 person-years) than in those without prior antiviral treatment (27 deaths/100 person-years). The adjusted hazard ratio (95% confidence interval) for all-cause mortality on comparing patients who did and did not receive prior antiviral treatment was 0.68 (0.59, 0.79). Conclusion Timely antiviral treatment for HCV was suboptimal at the population level. Prior antiviral treatment for HCV reduced mortality rate in HCV-related HCC patients. Intensive HCV control strategies are needed to reduce the number of patients with HCV infection who miss timely HCV treatment.
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Sadeghi A, Amiri R, Akbarpour E, Mirminachi B, Sharifi AH, Merat S. Changes in liver fibrosis in patients with chronic hepatitis C after successful direct-acting antiviral therapy. Int J Clin Pract 2021; 75:e14145. [PMID: 33709413 DOI: 10.1111/ijcp.14145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/09/2021] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION AND OBJECTIVES After successful treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs), the stage of liver fibrosis decreases over time. Here, we aimed to assess the changes in the liver fibrosis stage using transient elastography (TE) after successful DAA therapy in HCV-infected cirrhotic patients who were referred to Shariati hospital from 2016 to 2017. MATERIAL AND METHODS In this observational cohort, all HCV-infected cirrhotic patients who were treated with a combination of sofosbuvir/daclatasvir, had sustained virologic response (SVR), and had undergone pre- and post-treatment TE, were enrolled. The primary outcome was the changes in TE parameters six months after the end of treatment compared with baseline. RESULTS A total of 442 eligible subjects received DAA therapy. Overall, the SVR rate was 96.6%. Of these, 149 patients had completed the protocol and were enrolled. The mean age of patients was 56.1 ± 10.3 years and the predominant sex was male (77.9%). The median (Q1 -Q3 ) liver stiffness (LS) value at baseline was 26.3 kPa (18.1-38 kPa), which significantly decreased to 20.9 kPa (12-29.7 kPa) [z = -8.45, P-value < .001]. Also, the liver steatosis of patients with baseline CAP ≥ 220 dB/m had a significant response to treatment [z = -2.3, P-value = .023]. Based on multivariate analysis, a higher baseline liver fibrosis stage was the only determinant of LS values improvement in our study. CONCLUSION Successful HCV eradication in patients with liver fibrosis results in significant improvement in LS, even in cirrhotic patients.
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Affiliation(s)
- Anahita Sadeghi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roya Amiri
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Akbarpour
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Mirminachi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir-Houshang Sharifi
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahin Merat
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Kay JE, Mirabal S, Briley WE, Kimoto T, Poutahidis T, Ragan T, So PT, Wadduwage DN, Erdman SE, Engelward BP. Analysis of mutations in tumor and normal adjacent tissue via fluorescence detection. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2021; 62:108-123. [PMID: 33314311 PMCID: PMC7880898 DOI: 10.1002/em.22419] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 12/04/2020] [Accepted: 12/11/2020] [Indexed: 06/12/2023]
Abstract
Inflammation is a major risk factor for many types of cancer, including colorectal. There are two fundamentally different mechanisms by which inflammation can contribute to carcinogenesis. First, reactive oxygen and nitrogen species (RONS) can damage DNA to cause mutations that initiate cancer. Second, inflammatory cytokines and chemokines promote proliferation, migration, and invasion. Although it is known that inflammation-associated RONS can be mutagenic, the extent to which they induce mutations in intestinal stem cells has been little explored. Furthermore, it is now widely accepted that cancer is caused by successive rounds of clonal expansion with associated de novo mutations that further promote tumor development. As such, we aimed to understand the extent to which inflammation promotes clonal expansion in normal and tumor tissue. Using an engineered mouse model that is prone to cancer and within which mutant cells fluoresce, here we have explored the impact of inflammation on de novo mutagenesis and clonal expansion in normal and tumor tissue. While inflammation is strongly associated with susceptibility to cancer and a concomitant increase in the overall proportion of mutant cells in the tissue, we did not observe an increase in mutations in normal adjacent tissue. These results are consistent with opportunities for de novo mutations and clonal expansion during tumor growth, and they suggest protective mechanisms that suppress the risk of inflammation-induced accumulation of mutant cells in normal tissue.
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Affiliation(s)
- Jennifer E. Kay
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Sheyla Mirabal
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
| | | | - Takafumi Kimoto
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Theofilos Poutahidis
- Laboratory of Pathology, Faculty of Veterinary Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Greece
| | | | - Peter T. So
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA
| | - Dushan N. Wadduwage
- The John Harvard Distinguished Science Fellows Program, Harvard University, Cambridge, MA
- Center for Advanced Imaging, Harvard University, Cambridge, MA, USA
| | - Susan E. Erdman
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA
| | - Bevin P. Engelward
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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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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Kay J, Thadhani E, Samson L, Engelward B. Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst) 2019; 83:102673. [PMID: 31387777 DOI: 10.1016/j.dnarep.2019.102673] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/15/2019] [Accepted: 07/18/2019] [Indexed: 12/22/2022]
Abstract
The relationships between inflammation and cancer are varied and complex. An important connection linking inflammation to cancer development is DNA damage. During inflammation reactive oxygen and nitrogen species (RONS) are created to combat pathogens and to stimulate tissue repair and regeneration, but these chemicals can also damage DNA, which in turn can promote mutations that initiate and promote cancer. DNA repair pathways are essential for preventing DNA damage from causing mutations and cytotoxicity, but RONS can interfere with repair mechanisms, reducing their efficacy. Further, cellular responses to DNA damage, such as damage signaling and cytotoxicity, can promote inflammation, creating a positive feedback loop. Despite coordination of DNA repair and oxidative stress responses, there are nevertheless examples whereby inflammation has been shown to promote mutagenesis, tissue damage, and ultimately carcinogenesis. Here, we discuss the DNA damage-mediated associations between inflammation, mutagenesis and cancer.
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Affiliation(s)
- Jennifer Kay
- Department of Biological Engineering, United States.
| | | | - Leona Samson
- Department of Biological Engineering, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, United States
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22
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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24
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Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
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Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
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25
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AISF position paper on HCV in immunocompromised patients. Dig Liver Dis 2019; 51:10-23. [PMID: 30366813 DOI: 10.1016/j.dld.2018.09.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 09/17/2018] [Accepted: 09/18/2018] [Indexed: 02/06/2023]
Abstract
This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era.
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26
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Abdelaziz AO, Shousha HI, Said EM, Soliman ZA, Shehata AA, Nabil MM, Abdelmaksoud AH, Elbaz TM, Abdelsalam FM. Evaluation of liver steatosis, measured by controlled attenuation parameter, in patients with hepatitis C-induced advanced liver fibrosis and hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2018; 30:1384-1388. [PMID: 30179227 DOI: 10.1097/meg.0000000000001196] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Steatosis is a documented feature of chronic hepatitis C (CHC). There is an association between steatosis decrease and fibrosis progression. The association between steatosis and advanced fibrosis versus hepatocellular carcinoma (HCC) development has not been precisely evaluated. The controlled attenuation parameter (CAP) was applied as an immediate and efficient process to detect and quantify hepatic steatosis with adequate accuracy. AIMS The aim of this study was to assess the difference in liver steatosis between patients with hepatitis C virus-related advanced hepatic fibrosis versus HCC. PATIENTS AND METHODS This cross-sectional study included 130 patients with HCC, attending the multidisciplinary HCC clinic, Cairo University, and 54 patients with CHC between October 2015 and June 2016. Clinical and laboratory characteristics were recorded. Liver stiffness and CAP were obtained by using the FibroScan 502, touch. RESULTS All included patients had genotype 4. The mean CAP value was significantly lower in HCC (209.5±57.1 dB/m) versus CHC (259.9±54.9 dB/m). Receiver operating characteristic curve revealed an area under the curve of 0.75 for the differentiation between groups. At a cutoff value of 237 dB/m, sensitivity was 72.3%, specificity was 70.7%, positive likelihood ratio was 2.5, and negative likelihood ratio was 0.4 in the differentiation between CHC versus HCC. Logistic regression analysis revealed an odds ratio of 6.4 for the diagnosis of HCC with CAP of less than 237 dB/m. Multivariate analysis, controlling for age, sex, BMI, triglycerides, and cholesterol levels, revealed a significantly increased odds for HCC diagnosis (odds ratio: 4.3, P=0.006). CONCLUSION The progression of CHC is associated with a decrease in steatosis, particularly toward advanced fibrosis and HCC. Steatosis reduction less than 237 dB/m is likely to be associated with HCC.
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Affiliation(s)
| | | | - Ebada M Said
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Ahmed A Shehata
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Ahmed H Abdelmaksoud
- Diagnostic and Interventional Radiology, Faculty of Medicine, Cairo University, Cairo
| | | | - Fatma M Abdelsalam
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt
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27
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Ohashi H, Nishioka K, Nakajima S, Kim S, Suzuki R, Aizaki H, Fukasawa M, Kamisuki S, Sugawara F, Ohtani N, Muramatsu M, Wakita T, Watashi K. The aryl hydrocarbon receptor-cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly. J Biol Chem 2018; 293:19559-19571. [PMID: 30381393 DOI: 10.1074/jbc.ra118.005033] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/24/2018] [Indexed: 12/12/2022] Open
Abstract
Viruses hijack and modify host cell functions to maximize viral proliferation. Hepatitis C virus (HCV) reorganizes host cell metabolism to produce specialized membrane structures and to modify organelles such as double-membrane vesicles and enlarged lipid droplets (LDs), thereby enabling virus replication and assembly. However, the molecular bases of these host-HCV interactions are largely unknown. Here, using a chemical screen, we demonstrate that the benzamide derivative flutamide reduces the host capacity to produce infectious HCV. Flutamide disrupted the formation of enlarged LDs in HCV-infected cells, thereby abolishing HCV assembly. We also report that aryl hydrocarbon receptor (AhR), a known flutamide target, plays a key role in mediating LD accumulation and HCV production. This AhR function in lipid production was also observed in HCV-uninfected Huh-7 cells and primary human hepatocytes, suggesting that AhR signaling regulates lipid accumulation independently of HCV infection. We further observed that a downstream activity, that of cytochrome P450 1A1 (CYP1A1), was the primary regulator of AhR-mediated lipid production. Specifically, blockade of AhR-induced CYP1A1 up-regulation counteracted LD overproduction, and overproduction of CYP1A1, but not of CYP1B1, in AhR-inactivated cells restored lipid accumulation. Of note, HCV infection up-regulated the AhR-CYP1A1 pathway, resulting in the accumulation of enlarged LDs. In conclusion, we demonstrate that the AhR-CYP1A1 pathway has a significant role in lipid accumulation, a hallmark of HCV infection that maximizes progeny virus production. Our chemical-genetic analysis reveals a new strategy and lead compounds to control hepatic lipid accumulation as well as HCV infection.
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Affiliation(s)
- Hirofumi Ohashi
- From the Department of Virology II and.,the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | - Kazane Nishioka
- From the Department of Virology II and.,the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | - Syo Nakajima
- From the Department of Virology II and.,the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | - Sulyi Kim
- From the Department of Virology II and
| | | | | | - Masayoshi Fukasawa
- the Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Shinji Kamisuki
- the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | - Fumio Sugawara
- the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | - Naoko Ohtani
- the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and
| | | | | | - Koichi Watashi
- From the Department of Virology II and .,the Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan, and.,CREST, Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
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28
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Liu L, Huang Y, Zhang K, Song S, Li S, Li Y, Lan Y. Hepatitis B core antigen regulates dendritic cell proliferation and apoptosis through regulation of PKC/NF‑κB signaling pathway. Mol Med Rep 2018; 18:5726-5732. [PMID: 30365118 DOI: 10.3892/mmr.2018.9604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 07/19/2018] [Indexed: 11/05/2022] Open
Abstract
Hepatitis B core antigen (HBcAg) possesses unusual immunologic features. However, the biological roles and mechanisms of HBcAg in dendritic cell proliferation and apoptosis remain to be elucidated. In the present study, DC2.4 cells were treated with different concentrations of HBcAg (10, 20 and 30 µg/ml). MTT assay and flow cytometry (Annexin V/propidium iodide analysis) were performed to investigate changes in cell proliferation and apoptosis. Western blot analysis was conducted to examine the changes in nuclear factor (NF)‑κB and protein kinase C (PKC) signaling pathways. NF‑κB inhibitor pyrrolidine dithiocarbamate (PDTC) and PKC inhibitor Chelerythrine were used to block these two signaling pathways. It was identified that HBcAg increased proliferation and decreased apoptosis in a dose‑dependent manner. Western blotting results demonstrated that HBcAg upregulated p‑PKC, p‑IκB, p‑P65, tumor necrosis factor‑α and B‑cell lymphoma 2 (Bcl‑2) levels, and downregulated cleaved caspase 3, demonstrating that HBcAg activated the PKC and NF‑κB signaling pathways. NF‑κB inhibitor PDTC reduced the effects of HBcAg on DC2.4 proliferation (0.6 fold vs. 0.25 fold) and apoptosis (0.43 fold vs. 0.17 fold), and on Bcl‑2 expression levels. PKC inhibitor Chelerythrine reduced the biological effects of HBcAg; it reduced proliferation (0.67 fold vs. 0.23 fold) and upregulated apoptosis (0.43 fold vs. 0.13 fold). Chelerythrine also blocked NF‑κB activity and the HBcAg‑induced Bcl‑2 increase, suggesting the effect on Bcl‑2 from HBcAg was dependent on the PKC/NF‑κB signaling pathway. In conclusion, HBcAg promoted proliferation and inhibited apoptosis through the PKC/NF‑κB/Bcl‑2 signaling pathway in DC2.4 cells.
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Affiliation(s)
- Lan Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yanxin Huang
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Kaili Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Shupeng Song
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Shuangxing Li
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yongguo Li
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yinghua Lan
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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29
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Zahra M, Azzazy H, Moustafa A. Transcriptional Regulatory Networks in Hepatitis C Virus-induced Hepatocellular Carcinoma. Sci Rep 2018; 8:14234. [PMID: 30250040 PMCID: PMC6155139 DOI: 10.1038/s41598-018-32464-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 09/04/2018] [Indexed: 01/09/2023] Open
Abstract
Understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of hepatitis C virus (HCV) infection is critical for the development of diagnostic and therapeutic approaches. Systems biology provides a roadmap by which these elements may be integrated. In this study, a previously published dataset of 124 microarray samples was analyzed in order to determine differentially expressed genes across four tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed for each pairwise comparison between the 4 tissue types/conditions. Based on our analysis, it is predicted that the disruption in the regulation of transcription factors such as AP-1, PPARγ, and NF-κB could contribute to the liver progression from cirrhosis to steatosis and eventually to HCC. Whereas the condition of the liver digresses, the downregulation of miRNAs' (such as miR-27, Let-7, and miR-106a) expression makes the transition of the liver through each pathological stage more apparent. This preliminary data can be used to guide future experimental work. An understanding of the transcriptional regulatory attributes acts as a road map to help design interference strategies in order to target the key regulators of progression of HCV induced HCC.
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Affiliation(s)
- Marwa Zahra
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt
| | - Hassan Azzazy
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt. .,Department of Chemistry, The American University in Cairo, School of Sciences & Engineering, New Cairo, 11835, Egypt.
| | - Ahmed Moustafa
- Biotechnology Graduate Program, American University, New Cairo, 11835, Egypt.,Department of Biology, The American University in Cairo, New Cairo, 11835, Egypt
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30
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Goossens N, de Vito C, Mangia A, Clément S, Cenderello G, Barrera F, D'Ambrosio R, Coppola N, Zampino R, Stanzione M, Adinolfi LE, Wedemeyer H, Semmo N, Müllhaupt B, Semela D, Malinverni R, Moradpour D, Heim M, Trincucci G, Rubbia-Brandt L, Negro F. Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review. J Viral Hepat 2018. [PMID: 29532619 DOI: 10.1111/jvh.12891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.
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Affiliation(s)
- N Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland
| | - C de Vito
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - A Mangia
- Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - S Clément
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - G Cenderello
- Division of Infectious Diseases, Galliera Hospital, Genova, Italy
| | - F Barrera
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, NSW, Australia
| | - R D'Ambrosio
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy
| | - N Coppola
- Department of Mental Health and Preventive Medicine, Second University of Naples, Napoli, Italy
| | - R Zampino
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, Italy
| | - M Stanzione
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Napoli, Italy
| | - L E Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, Italy
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research, Hannover-Braunschweig, Germany
| | - N Semmo
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
| | - B Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - D Semela
- Division of Gastroenterology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | | | - D Moradpour
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
| | - M Heim
- Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - G Trincucci
- Department of Pathology and Immunology, Geneva University, Geneva, Switzerland
| | - L Rubbia-Brandt
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | - F Negro
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland.,Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
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31
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Trivedi S, Murthy S, Sharma H, Hartlage AS, Kumar A, Gadi S, Simmonds P, Chauhan LV, Scheel TKH, Billerbeck E, Burbelo PD, Rice CM, Lipkin WI, Vandergrift K, Cullen JM, Kapoor A. Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model. Hepatology 2018; 68:435-448. [PMID: 28859226 PMCID: PMC5832584 DOI: 10.1002/hep.29494] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/01/2017] [Accepted: 08/29/2017] [Indexed: 12/14/2022]
Abstract
UNLABELLED The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity, and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus from wild rats (Rattus norvegicus), RHV-rn1; acquired the complete viral genome sequence; and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' untranslated regions. We used site-directed and random mutagenesis to determine that only the first of the two microRNA-122 seed sites in the viral 5' untranslated region is required for viral replication and persistence in rats. Next, we used the clone-derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV-rn1 possesses several HCV-defining hallmarks: hepatotropism, propensity to persist, and the ability to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV-rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct-acting antiviral therapy, sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats. CONCLUSION We developed RHV-rn1-infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV-related viral persistence, immunity, and pathogenesis. (Hepatology 2018).
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Affiliation(s)
- Sheetal Trivedi
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Satyapramod Murthy
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Himanshu Sharma
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Alex S. Hartlage
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA,Medical Scientist Training Program, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210
| | - Arvind Kumar
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Sashi Gadi
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, OX1 3SY, UK
| | - Lokendra V. Chauhan
- Center for Infection and Immunity, Columbia University, New York, NY 10032, USA
| | - Troels K. H. Scheel
- Copenhagen Hepatitis C Program, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark,Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065
| | - Eva Billerbeck
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065
| | | | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York 10065
| | - W. Ian Lipkin
- Center for Infection and Immunity, Columbia University, New York, NY 10032, USA
| | - Kurt Vandergrift
- Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA 16802
| | - John M. Cullen
- College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
| | - Amit Kapoor
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA,Department of Pediatrics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210,Corresponding author. , Amit Kapoor, Ph.D., Associate Professor, Department of Pediatrics, College of Medicine, The Ohio State University, Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, Ohio 43205
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32
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Ramnath D, Irvine KM, Lukowski SW, Horsfall LU, Loh Z, Clouston AD, Patel PJ, Fagan KJ, Iyer A, Lampe G, Stow JL, Schroder K, Fairlie DP, Powell JE, Powell EE, Sweet MJ. Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes. JCI Insight 2018; 3:120274. [PMID: 30046009 DOI: 10.1172/jci.insight.120274] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 06/12/2018] [Indexed: 12/23/2022] Open
Abstract
Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.
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Affiliation(s)
- Divya Ramnath
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Katharine M Irvine
- Centre for Liver Disease Research and.,Faculty of Medicine, Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Samuel W Lukowski
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Leigh U Horsfall
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Zhixuan Loh
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Preya J Patel
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | | | - Abishek Iyer
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Guy Lampe
- Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Jennifer L Stow
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Kate Schroder
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - David P Fairlie
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Joseph E Powell
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
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33
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Hegarty R, Deheragoda M, Fitzpatrick E, Dhawan A. Paediatric fatty liver disease (PeFLD): All is not NAFLD - Pathophysiological insights and approach to management. J Hepatol 2018; 68:1286-1299. [PMID: 29471012 DOI: 10.1016/j.jhep.2018.02.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/11/2018] [Accepted: 02/13/2018] [Indexed: 12/14/2022]
Abstract
The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.
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Affiliation(s)
- Robert Hegarty
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Maesha Deheragoda
- Liver Histopathology, Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Emer Fitzpatrick
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom.
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34
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Marcellin F, Fontaine H, Serfaty L, Sogni P, Carrieri MP. Cannabinoids and reduced risk of hepatic steatosis in HIV-HCV co-infection: paving the way for future clinical research. Expert Rev Anti Infect Ther 2018; 16:377-380. [DOI: 10.1080/14787210.2018.1473764] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Fabienne Marcellin
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France
- ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
| | - Hélène Fontaine
- INSERM, U1016, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, Paris, France
- Hepatology Unit, Groupe hospitalier Cochin-Hôtel Dieu, AP-HP, Paris, France
| | - Lawrence Serfaty
- Service d'Hépato-Gastro-Entérologie et d'Assistance Nutritive, Hôpital de Hautepierre, Strasbourg, France
| | - Philippe Sogni
- Service d’Hépatologie, AP-HP, Hôpital Cochin, Paris, France
- Université Paris Descartes, Paris, France
| | - Maria Patrizia Carrieri
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France
- ORS PACA, Observatoire Régional de la Santé Provence-Alpes-Côte d’Azur, Marseille, France
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Abstract
Molecular pathological epidemiology (MPE) is a new discipline which emerged as an integrated approach of molecular pathology and epidemiology and was introduced for the first time by Professor Shuji Ogino and Professor Meir Stampfer in the year of 2010. MPE studies in hepatocellular carcinoma (HCC) investigate the relationship among risk factors, molecular biomarkers, and initiation, progression, and prognosis of HCC, which can be used for exploring the molecular mechanisms of HCC and for the molecular classification of the high risk population. Type 2 diabetes mellitus (DM) has been confirmed as an established risk factor for HCC, and MPE can be helpful to better understand the underlying molecular mechanisms. On December 20, 2017, the first China-Japan Symposium on HCC-MPE was held successfully in Beijing. HCC-MPE provides the opportunities and challenges to solve some problems of HCC, and I believe that it can be helpful to improve the early diagnosis, molecular typing, personalized prevention and treatment, and prognosis of HCC.
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36
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Bao C, Pedersen NL, Yang R, Marseglia A, Xu W, Wang Y, Qi X, Xu W. Diabetes in midlife and risk of cancer in late life: A nationwide Swedish twin study. Int J Cancer 2018; 143:793-800. [PMID: 29566433 DOI: 10.1002/ijc.31365] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 02/14/2018] [Accepted: 02/28/2018] [Indexed: 12/11/2022]
Abstract
The association between diabetes and cancer risk remains controversial. Hence, we examined whether midlife diabetes is related to the risk of cancer in late-life, and whether genetic and early-life environmental factors play a role in this association. This study included 25,154 twin individuals born in 1958 or earlier from the Swedish Twin Registry. Information on cancer diagnosis in late life (aged ≥ 65) during 1998-2014, was derived from the National Patient and Cancer Registries. Diabetes was ascertained based on self- or informant-reported history, patient registry and antidiabetic medication use. Midlife diabetes was defined when diabetes was diagnosed before 65 years. Data were analyzed following two strategies: (i) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models, and (ii) co-twin control analysis for cancer-discordant twin pairs using conditional logistic regression. Overall, 1,766 (7.0%) had midlife diabetes and 5,293 (21.0%) had cancer in late-life. In multiadjusted GEE models, the odds ratios (95% CIs) of diabetes were 10.55 (2.95-37.67) for pharynx cancer, 5.78 (1.72-19.40) for small intestine cancer, 2.37 (1.14-4.91) for liver cancer and 0.48 (0.35-0.67) for prostate cancer. In people with diabetes, diabetes duration was dose-dependently associated with cancer risk. In conditional logistic regression analysis of 176 prostate cancer-discordant twin pairs, the association between midlife diabetes and prostate cancer in later life became stronger. Midlife diabetes increases the risk of pharynx, small intestine and liver cancers, but reduces prostate cancer risk in late life. Genetic and early-life environmental factors may partially contribute to the diabetes-prostate cancer association.
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Affiliation(s)
- Cuiping Bao
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Psychology, University of Southern California, Los Angeles, California
| | - Rongrong Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Anna Marseglia
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Weige Xu
- Department of Radiology, Tianjin Gongan Hospital, Tianjin, China
| | - Yaogang Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xiuying Qi
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Weili Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.,Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden
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37
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Nam SY. Obesity-Related Digestive Diseases and Their Pathophysiology. Gut Liver 2018; 11:323-334. [PMID: 27890867 PMCID: PMC5417774 DOI: 10.5009/gnl15557] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Accepted: 12/25/2015] [Indexed: 12/13/2022] Open
Abstract
Obesity is a growing medical and public health problem worldwide. Many digestive diseases are related to obesity. In this article, the current state of our knowledge of obesity-related digestive diseases, their pathogenesis, and the medical and metabolic consequences of weight reduction are discussed. Obesity-related digestive diseases include gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyp and cancer, nonalcoholic fatty liver disease, hepatitis C-related disease, hepatocellular carcinoma, gallstone, cholangiocarcinoma, and pancreatic cancer. Although obesity-related esophageal diseases are associated with altered mechanical and humoral factors, other obesity-related digestive diseases seem to be associated with obesity-induced altered circulating levels of adipocytokines and insulin resistance. The relationship between functional gastrointestinal disease and obesity has been debated. This review provides a comprehensive evaluation of the obesity-related digestive diseases, including pathophysiology, obesity-related risk, and medical and metabolic effects of weight reduction in obese subjects.
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Affiliation(s)
- Su Youn Nam
- Department of Gastroenterology, Gastric Cancer Center, Kyungpook National University Medical Center, Daegu, Korea
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38
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Chitturi S, Wong VWS, Chan WK, Wong GLH, Wong SKH, Sollano J, Ni YH, Liu CJ, Lin YC, Lesmana LA, Kim SU, Hashimoto E, Hamaguchi M, Goh KL, Fan J, Duseja A, Dan YY, Chawla Y, Farrell G, Chan HLY. The Asia-Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017-Part 2: Management and special groups. J Gastroenterol Hepatol 2018; 33:86-98. [PMID: 28692197 DOI: 10.1111/jgh.13856] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/31/2017] [Accepted: 06/25/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Shiv Chitturi
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Wah-Kheong Chan
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Simon Kin-Hung Wong
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | | | - Yen-Hsuan Ni
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Hepatitis Research Center, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yu-Cheng Lin
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | | | - Seung Up Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Khean-Lee Goh
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jiangao Fan
- Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yogesh Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Geoff Farrell
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong
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39
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de la Torre AN, Castaneda I, Ahmad M, Ekholy N, Tham N, Herrera IB, Beaty P, Malapero RJ, Ayoub F, Slim J, Johnson MB. Audio-computer-assisted survey interview and patient navigation to increase chronic viral hepatitis diagnosis and linkage to care in urban health clinics. J Viral Hepat 2017. [PMID: 28636784 DOI: 10.1111/jvh.12744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Intravenous drug use and sexual practices account for 60% of hepatitis C (HCV) and B (HBV) infection. Disclosing these activities can be embarrassing and reduce risk reporting, blood testing and diagnosis. In diagnosed patients, linkage to care remains a challenge. Audio-computer-assisted survey interview (Audio-CASI) was used to guide HCV and HBV infection testing in urban clinics. Risk reporting, blood testing and serology results were compared to historical controls. A patient navigator (PN) followed up blood test results and provided patients with positive serology linkage to care (LTC). Of 1932 patients surveyed, 574 (30%) were at risk for chronic viral hepatitis. A total of 254 (44.3%) patients were tested, 34 (13.5%) had serology warranting treatment evaluation, and 64% required HBV vaccination. Of 16 patients with infection, seven HCV and three HBV patients started treatment following patient LTC. Of 146 HBV-naïve patients, 70 completed vaccination. About 75% and 49% of HCV antibody and HBV surface antigen-positive patients were born between 1945 and 1965. Subsequently, automated HCV testing of patients born between 1945 and 1965 was built into our hospital electronic medical records. Average monthly HCV antibody testing increased from 245 (January-June) to 1187 (July-October). Patient navigator directed LTC for HCV antibody-positive patients was 61.6%. In conclusion, audio-CASI can identify patients at risk for HCV or HBV infection and those in need of HBV vaccination in urban medical clinics. Although blood testing once a patient is identified at risk for infection needs to increase, a PN is useful to provide LTC of newly diagnosed patients.
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Affiliation(s)
- A N de la Torre
- Liver Surgery, St Joseph's Medical Center, Paterson, NJ, USA.,Liver Surgery, New Jersey Medical School Rutgers University, Newark, NJ, USA
| | - I Castaneda
- Liver Surgery, St Joseph's Medical Center, Paterson, NJ, USA
| | - M Ahmad
- Hepatology, St Joseph's Medical Center, Paterson, NJ, USA
| | - N Ekholy
- Internal Medicine, St Joseph's Medical Center, Paterson, NJ, USA
| | - N Tham
- Segundo Ruiz Belvis Community Health Center - Gotham Health, Bronx, NY, USA
| | - I B Herrera
- Internal Medicine, New Jersey Medical School Rutgers University, Newark, NJ, USA
| | - P Beaty
- Metropolitan Family Health Network FQHC, Jersey City, NJ, USA
| | | | - F Ayoub
- Liver Surgery, St Joseph's Medical Center, Paterson, NJ, USA
| | - J Slim
- Division of Infectious Deceases, St. Michael's Medical Center, Newark, NJ, USA
| | - M B Johnson
- Family Medicine, Howard University, Washington, DC, USA
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40
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Ogasawara N, Kobayashi M, Akuta N, Kominami Y, Fujiyama S, Kawamura Y, Sezaki H, Hosaka T, Suzuki F, Saitoh S, Suzuki Y, Arase Y, Ikeda K, Kobayashi M, Kumada H. Serial changes in liver stiffness and controlled attenuation parameter following direct-acting antiviral therapy against hepatitis C virus genotype 1b. J Med Virol 2017; 90:313-319. [DOI: 10.1002/jmv.24950] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 09/07/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Nobuhiko Ogasawara
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Masahiro Kobayashi
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Norio Akuta
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yoko Kominami
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Shunichiro Fujiyama
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yusuke Kawamura
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Hitomi Sezaki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Tetsuya Hosaka
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Fumitaka Suzuki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Satoshi Saitoh
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Yasuji Arase
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | - Kenji Ikeda
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
| | | | - Hiromitsu Kumada
- Department of Hepatology and Okinaka Memorial Institute for Medical Research; Toranomon Hospital; Tokyo Japan
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41
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Camara AKS, Zhou Y, Wen PC, Tajkhorshid E, Kwok WM. Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target. Front Physiol 2017; 8:460. [PMID: 28713289 PMCID: PMC5491678 DOI: 10.3389/fphys.2017.00460] [Citation(s) in RCA: 249] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 06/16/2017] [Indexed: 12/23/2022] Open
Abstract
Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl-2 family of proteins and hexokinase. Therefore, regulation of VDAC1 is crucial not only for metabolic functions of mitochondria, but also for cell survival. In fact, multiple lines of evidence have confirmed the involvement of VDAC1 in several diseases. Consequently, modulation or dysregulation of VDAC1 function can potentially attenuate or exacerbate pathophysiological conditions. Understanding the role of VDAC1 in health and disease could lead to selective protection of cells in different tissues and diverse diseases. The purpose of this review is to discuss the role of VDAC1 in the pathogenesis of diseases and as a potentially effective target for therapeutic management of various pathologies.
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Affiliation(s)
- Amadou K S Camara
- Department of Anesthesiology, Medical College of WisconsinMilwaukee, WI, United States.,Cardiovascular Center, Medical College of WisconsinMilwaukee, WI, United States
| | - YiFan Zhou
- Department of Assay Development, HD BiosciencesShanghai, China
| | - Po-Chao Wen
- Department of Biochemistry, Beckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-ChampaignUrbana, IL, United States
| | - Emad Tajkhorshid
- Department of Biochemistry, Beckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-ChampaignUrbana, IL, United States
| | - Wai-Meng Kwok
- Department of Anesthesiology, Medical College of WisconsinMilwaukee, WI, United States.,Cardiovascular Center, Medical College of WisconsinMilwaukee, WI, United States.,Department of Pharmacology and Toxicology, Medical College of WisconsinMilwaukee, WI, United States
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42
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Price JC, Ma Y, Scherzer R, Korn N, Tillinghast K, Peters MG, Noworolski SM, Tien PC. Human immunodeficiency virus-infected and uninfected adults with non-genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection. Hepatology 2017; 65:853-863. [PMID: 27981599 PMCID: PMC5319911 DOI: 10.1002/hep.28968] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/02/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
UNLABELLED Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids + water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF ≥ 0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA-IR) and liver fibrosis defined using the aspartate aminotransferase-to-platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV-monoinfected (28%), followed by the HCV-monoinfected (19%) and HIV/HCV-coinfected (11%) (P = 0.003 across groups). Compared with uninfected participants-and after adjusting for demographics, lifestyle, and metabolic factors-HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], -39% to 6%), 38% (95% CI, -55% to -12%), and 42% (95% CI, -59% to -18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA-IR were independently associated with greater LFF. CONCLUSION Contrary to expectations, HIV/HCV-coinfected and HCV-monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non-genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853-863).
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Affiliation(s)
- Jennifer C. Price
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Yifei Ma
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Rebecca Scherzer
- Department of Medicine, University of California, San Francisco, 94122 USA,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, CA, 94121, USA
| | - Natalie Korn
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Kyle Tillinghast
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Marion G. Peters
- Department of Medicine, University of California, San Francisco, 94122 USA
| | - Susan M. Noworolski
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 94122 USA
| | - Phyllis C. Tien
- Department of Medicine, University of California, San Francisco, 94122 USA,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, CA, 94121, USA
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43
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Shiffman ML, Gunn NT. Impact of hepatitis C virus therapy on metabolism and public health. Liver Int 2017; 37 Suppl 1:13-18. [PMID: 28052632 DOI: 10.1111/liv.13282] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 10/20/2016] [Indexed: 12/22/2022]
Abstract
Chronic hepatitis C virus (HCV) is associated with insulin resistance (IR) and leads to type 2 diabetes mellitus (T2DM) and hepatic steatosis in many patients. These metabolic complications of HCV have been shown to accelerate the progression of fibrosis to cirrhosis and increase the risk of hepatocellular carcinoma. The metabolic syndrome is a common disorder that also includes IR, T2DM and hepatic steatosis. Approximately 20%-30% of patients with chronic HCV also have co-existent metabolic syndrome. The cause of steatosis in patients with the features of both the metabolic syndrome and chronic HCV is sometime difficult to determine. Patients with metabolic syndrome and chronic HCV are also at risk of developing renal, cardiovascular and cerebrovascular disease. Recent data suggest that HCV is an independent risk factor for renal, coronary and cerebral vascular disease, and may increase mortality associated with these disorders. The treatment of HCV can now result in a sustained virological response and cure nearly all patients with chronic HCV. The eradication of HCV reduces the risk of developing IR and T2DM, improves IR and 2TDM, reduces the risk of developing chronic kidney disease, end-stage renal disease, acute cardiac syndrome and stroke in patients with 2TDM. Thus, treatment of chronic HCV can provide a significant public health benefit, but only if all patients with chronic HCV are identified and universally treated.
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Affiliation(s)
- Mitchell L Shiffman
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
| | - Nadege T Gunn
- Liver Institute of Virginia, Bon Secours Health System, Richmond and Newport News, VA, USA
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44
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Nirei K, Matsumura H, Kumakawa M, Matsumoto N, Nakamura H, Yamagami H, Matsuoka S, Moriyama M. Steatosis influences the clinical profiles and long-term outcomes of interferon-treated chronic hepatitis C and liver cirrhosis patients. Int J Med Sci 2017; 14:45-52. [PMID: 28138308 PMCID: PMC5278658 DOI: 10.7150/ijms.17202] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 11/01/2016] [Indexed: 12/30/2022] Open
Abstract
Objective: This study aimed to assess the relationship between steatosis and long-term outcomes of patients with chronic hepatitis C (CH) and liver cirrhosis (LC). Patients and methods: The study population included 282 subjects with CH or LC who underwent liver biopsy at our institute. All patients achieved a sustained virological response (SVR) to interferon (IFN). Clinical characteristics, including age, gender and body mass index (BMI), were compared. The liver biopsy specimens of all patients were examined and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal and portal areas; F (fibrosis) stage; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; bile duct damage; hepatic steatosis. Results: Of the 282 patients, 112 (39.7%) were free of steatosis. The other 170 patients (60.3%) had steatosis. The blood biochemical parameters of the patients with hepatic steatosis were significantly poorer than those of patients free of steatosis. Inflammatory cell infiltration and F stage were both significantly more severe in patients with than in those without steatosis. The incidences of hepatocellular carcinoma differed significantly between the two groups. However, the incidences of hepatocellular carcinoma did not differ significantly between the groups with BMI above and below 25. Conclusion: We consider hepatic steatosis to potentially affect the blood biochemical parameters and clinical profiles of Japanese patients with CH due to hepatitis virus type C. Patients with this form of CH showed favorable clinical responses to IFN. Furthermore, fibrosis and steatosis appear to affect the long-term outcomes of these patients. However, BMI alone cannot be used to predict HCC development.
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Affiliation(s)
- Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hiroshi Matsumura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Mariko Kumakawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan 30-1 Oyaguchi Kamicho, Itabashiku, Tokyo 173-8610, Japan
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Affiliation(s)
- R.R. Elmehdawi
- Department of Internal Medicine, Faculty of Medicine, Garyounis University, Libya
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Yang JD, Mohamed HA, Cvinar JL, Gores GJ, Roberts LR, Kim WR. Diabetes Mellitus Heightens the Risk of Hepatocellular Carcinoma Except in Patients With Hepatitis C Cirrhosis. Am J Gastroenterol 2016; 111:1573-1580. [PMID: 27527741 PMCID: PMC6040826 DOI: 10.1038/ajg.2016.330] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 07/01/2016] [Indexed: 02/07/2023]
Abstract
OBJECTIVES As most hepatocellular carcinoma (HCC) patients have cirrhosis, the association between diabetes and HCC may be confounded by the fact that diabetes is common in patients with cirrhosis. The aim of this study is to investigate whether diabetes increases the risk of HCC in patients with cirrhosis and whether the etiology of liver disease modifies the association between diabetes and HCC. METHODS All liver cirrhosis patients who had repeated radiographic evaluation of the liver (that is, ultrasound, computed tomography, or magnetic resonance image) at Mayo Clinic Rochester between January 2006 and December 2011 were included. The Cox proportional hazard regression analysis was used to investigate the effect of diabetes on the risk of HCC. RESULTS A total of 739 patients met the eligibility criteria, of whom 253 (34%) had diabetes. After a median follow-up of 38 months, 69 (9%) patients developed HCC. In patients without hepatitis C virus (HCV) infection, diabetes was significantly associated with the risk of developing HCC (hazard ratio (HR)=2.1, 95% confidence interval (CI)=1.1-4.1), whereas in patients with HCV, there was no association (HR=0.8, 95% CI=0.4-1.8). When adjusted for covariates, the interaction between HCV and diabetes remained significant (HR for non-HCV=1.9, 95% CI=0.9-3.7; HR for HCV=0.6, 95% CI=0.2-1.3). Lack of association between diabetes and HCC was externally validated in 410 patients with HCV cirrhosis enrolled in the HALT-C trial. CONCLUSIONS Diabetes increases the risk of HCC in patients with non-HCV cirrhosis. In HCV cirrhosis patients who already have very high risk, diabetes may not increase the risk any further.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Hager Amed Mohamed
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Jessica L. Cvinar
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - W. Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
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Gao C. Molecular pathological epidemiology in diabetes mellitus and risk of hepatocellular carcinoma. World J Hepatol 2016; 8:1119-1127. [PMID: 27721917 PMCID: PMC5037325 DOI: 10.4254/wjh.v8.i27.1119] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/28/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Molecular pathological epidemiology (MPE) is a multidisciplinary and transdisciplinary study field, which has emerged as an integrated approach of molecular pathology and epidemiology, and investigates the relationship between exogenous and endogenous exposure factors, tumor molecular signatures, and tumor initiation, progression, and response to treatment. Molecular epidemiology broadly encompasses MPE and conventional-type molecular epidemiology. Hepatocellular carcinoma (HCC) is the third most common cause of cancer-associated death worldwide and remains as a major public health challenge. Over the past few decades, a number of epidemiological studies have demonstrated that diabetes mellitus (DM) is an established independent risk factor for HCC. However, how DM affects the occurrence and development of HCC remains as yet unclearly understood. MPE may be a promising approach to investigate the molecular mechanisms of carcinogenesis of DM in HCC, and provide some useful insights for this pathological process, although a few challenges must be overcome. This review highlights the recent advances in this field, including: (1) introduction of MPE; (2) HCC, risk factors, and DM as an established independent risk factor for HCC; (3) molecular pathology, molecular epidemiology, and MPE in DM and HCC; and (4) MPE studies in DM and risk of HCC. More MPE studies are expected to be performed in future and I believe that this field can provide some very important insights on the molecular mechanisms, diagnosis, personalized prevention and treatment for DM and risk of HCC.
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Iwasa S, Sato N, Wang CW, Cheng YH, Irokawa H, Hwang GW, Naganuma A, Kuge S. The Phospholipid:Diacylglycerol Acyltransferase Lro1 Is Responsible for Hepatitis C Virus Core-Induced Lipid Droplet Formation in a Yeast Model System. PLoS One 2016; 11:e0159324. [PMID: 27459103 PMCID: PMC4961368 DOI: 10.1371/journal.pone.0159324] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 06/30/2016] [Indexed: 12/28/2022] Open
Abstract
Chronic infection with the hepatitis C virus frequently induces steatosis, which is a significant risk factor for liver pathogenesis. Steatosis is characterized by the accumulation of lipid droplets in hepatocytes. The structural protein core of the virus induces lipid droplet formation and localizes on the surface of the lipid droplets. However, the precise molecular mechanisms for the core-induced formation of lipid droplets remain elusive. Recently, we showed that the expression of the core protein in yeast as a model system could induce lipid droplet formation. In this study, we probed the cellular factors responsible for the formation of core-induced lipid-droplets in yeast cells. We demonstrated that one of the enzymes responsible for triglyceride synthesis, a phospholipid:diacylglycerol acyltransferase (Lro1), is required for the core-induced lipid droplet formation. While core proteins inhibit Lro1 degradation and alter Lro1 localization, the characteristic localization of Lro1 adjacent to the lipid droplets appeared to be responsible for the core-induced lipid droplet formation. RNA virus genomes have evolved using high mutation rates to maintain their ability to replicate. Our observations suggest a functional relationship between the core protein with hepatocytes and yeast cells. The possible interactions between core proteins and the endoplasmic reticulum membrane affect the mobilization of specific proteins.
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Affiliation(s)
- Shingo Iwasa
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, 981–8558, Japan
| | - Naoko Sato
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, 981–8558, Japan
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980–8578, Japan
| | - Chao-Wen Wang
- Institute of Plant and Microbial Biology, Academia Sinica, Nangang, Taipei, 11529, Taiwan
| | - Yun-Hsin Cheng
- Institute of Plant and Microbial Biology, Academia Sinica, Nangang, Taipei, 11529, Taiwan
| | - Hayato Irokawa
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, 981–8558, Japan
| | - Gi-Wook Hwang
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980–8578, Japan
| | - Akira Naganuma
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980–8578, Japan
| | - Shusuke Kuge
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, 981–8558, Japan
- * E-mail: ;
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Cardoso AC, Beaugrand M, de Ledinghen V, Douvin C, Poupon R, Trinchet JC, Ziol M, Bedossa P, Marcellin P. Diagnostic performance of controlled attenuation parameter for predicting steatosis grade in chronic hepatitis B. Ann Hepatol 2016; 14:826-36. [PMID: 26436354 DOI: 10.5604/16652681.1171762] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND & AIMS A novel controlled attenuation parameter (CAP) using the signals acquired by the FibroScan® has been developed as a method for evaluating steatosis. The aim of this study is to assess the performance of the CAP for the detection and quantification of steatosis in patients with chronic hepatitis B (CHB). MATERIAL AND METHODS 136 subjects with CHB underwent liver biopsy and FibroScan® within 60 days. CAP was evaluated retrospectively using raw FibroScan® data. Steatosis was graded as follows: S0 (steatosis < 10% of hepatocytes), S1 (10 to < 30%), S2 (30 to < 60%) or S3 (≥ 60%). Performance was evaluated by area under the receiver operating characteristic (AUROC) curve. RESULTS Proportions of each steatosis grade (S0-S3) were 78, 10, 9 and 3%, respectively. Using univariate analysis, liver stiffness measurement (LMS) significantly correlated with fibrosis (τ = 0.43; P < 10-10), sex, necro-inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis (P < 10-8) and perisinusoidal fibrosis (P = 0.008) using multivariate analysis. CAP correlated with steatosis (τ = 0.38, P < 10-7), body mass index, NASH, fibrosis and perisinusoidal fibrosis using univariate analysis, but only steatosis (P < 10-10) and perisinusoidal fibrosis (P = 0.002) using multivariate analysis. AUROCs for LSM were: 0.77 (0.69-0.85), 0.87 (0.80-0.95), and 0.93 (0.83-1.00), respectively, for fibrosis stages F ≥ 2, F ≥ 3 and F = 4. AUROCs for CAP were: 0.82 (0.73-0.92), 0.82 (0.69-0.95), and 0.97 (0.84-1.00) for ≥ S1, ≥ S2 and S3 steatosis, respectively. CONCLUSIONS In conclusión CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients.
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Affiliation(s)
- Ana C Cardoso
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
| | | | - Victor de Ledinghen
- Department of Hepatology, Hôpital Haut-Leveque, CHU Bordeaux Pessac, France and INSERM U1053, Université Bordeaux Segalen, Bordeaux, France
| | | | - Raoul Poupon
- Department of Hepatology, Hôpital Saint Antoine, Paris, France
| | | | - Marianne Ziol
- Department of Anatomy and Pathology, Hospital Group Paris-Seine-Saint Denis, Hôpital Jean Verdier, AP-PH, Bondy, France and Paris 13 University, Sorbonne Paris Cité, UFR SMBH, Bobigny, France
| | - Pierre Bedossa
- Department of Anatomy Pathology and INSERM U773-CRB3, Hôpital Beaujon, Clichy, France
| | - Patrick Marcellin
- Department of Hepatology and INSERM U773-CRB3, Hôpital Beaujon, APHP, University of Paris 7, Clichy, France
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Balandaram G, Kramer LR, Kang BH, Murray IA, Perdew GH, Gonzalez FJ, Peters JM. Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice. Toxicology 2016; 363-364:1-9. [PMID: 27427494 PMCID: PMC5278792 DOI: 10.1016/j.tox.2016.07.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 07/05/2016] [Accepted: 07/13/2016] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPARβ/δ in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPARβ/δ in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPARβ/δ in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPARβ/δ inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Pparβ/δ-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPARβ/δ compared to controls. Combined, these results suggest that ligand activation of PPARβ/δ attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells.
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Affiliation(s)
- Gayathri Balandaram
- Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA
| | - Lance R Kramer
- Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA
| | - Boo-Hyon Kang
- Chemon Nonclinical Research Institute, 240 Nampyeong-ro, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Iain A Murray
- Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA
| | - Gary H Perdew
- Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
| | - Jeffrey M Peters
- Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
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