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Jespersen S, Bollerup S, Madsbad S, Krogh-Madsen R, Byberg S, Weis N, On behalf of The DANHEP group. Cardiometabolic Comorbidities in Patients With Chronic Hepatitis B and Impact on Incidence of Liver Complications. A Danish Nationwide Cohort Study. Int J Gen Med 2025; 18:1591-1604. [PMID: 40123812 PMCID: PMC11930244 DOI: 10.2147/ijgm.s471083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 12/21/2024] [Indexed: 03/25/2025] Open
Abstract
Purpose To evaluate liver complications in patients with chronic hepatitis B, both with and without cardiometabolic comorbidities, and to compare the incidence of cardiometabolic comorbidities in these patients with that of the general population. Study Population and Methods This nationwide registry-based cohort study included data from 2002-2020. In the primary analysis, we used multivariate Poisson regression to estimate the incidence rate and incidence rate ratio of liver complications in patients with chronic hepatitis B, stratified by the presence of cardiometabolic comorbidities. In the secondary analysis, we compared the incidence rate of developing cardiometabolic comorbidities in patients with chronic hepatitis B to those of the general population. Both analyses were adjusted for sex, age, and country of origin, while the primary analysis was additionally adjusted for time since cardiometabolic comorbidity diagnosis and calendar year. Results The primary analysis included 4731 patients with chronic hepatitis B, of whom 532 (11%) had at least one cardiometabolic comorbidity. The unadjusted overall incidence rate of liver complications in patients with cardiometabolic comorbidities was 1.0 per 100 person-years (95% confidence intervals: 0.84-1.30) compared to 0.4 per 100 person-years (95% confidence intervals: 0.30-0.42) in those without. The incidence rate ratio for liver complications was highest in the first year following the diagnosis of cardiometabolic comorbidity. The incidence rate ratio for developing cardiometabolic comorbidities in the chronic hepatitis B cohort compared to the general population, was 1.10 (95% confidence intervals: 1.02-1.19). Sensitivity analyses revealed a higher incidence rate ratio for type 2 diabetes and hypertension but a lower incidence rate ratio for hypercholesterolemia. Conclusion Patients with chronic hepatitis B and cardiometabolic comorbidities exhibit a higher incidence of liver complications, particularly in the first year following comorbidity diagnosis compared to those without comorbidities. Furthermore, patients with chronic hepatitis B have a higher incidence of cardiometabolic comorbidities than the general population.
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Affiliation(s)
- Sofie Jespersen
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Signe Bollerup
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rikke Krogh-Madsen
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stine Byberg
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Nina Weis
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - On behalf of The DANHEP group
- Department of Infectious Diseases, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Endocrinology, Copenhagen University Hospital - Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
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Dodig M, Li M, Dasarathy S, Kumarasamy S, Kasumov T, Najjar SM, McCullough AJ. Insulin increases type I collagen synthesis in hepatic stellate cells via α5β1 integrin. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Aim: A direct effect of insulin on the synthesis of extracellular matrix proteins has been described in extrahepatic organs. The current study investigates the role of insulin in type 1 collagen production in hepatic stellate cells (HSCs).
Methods: Primary HSC cultures from wild-type mice and from L-SACC1 transgenic mice that exhibit hyperinsulinemia and resultant insulin resistance due to a defect in hepatic insulin clearance were used.
Results: Insulin significantly increased type I collagen synthesis in HSC primary cultures in the presence of high but not low glucose concentrations. Although HSCs contain a functional, insulin-activated PI3 kinase signaling pathway, insulin increases type I collagen synthesis by mechanisms independent of PI3 kinase. Insulin stimulated α5β1 integrin levels and phosphorylation of focal adhesion kinase, a major signaling mediator in the integrin pathway. In addition, α5β1 integrin siRNA interference abolished insulin-mediated type I collagen synthesis by HSCs. L-SACC1 mice showed increased hepatic collagen deposition as compared to wild-type mice. HSCs isolated from L-SACC1 mice synthesize more type I collagen and α5β1 integrin than HSCs isolated from wild-type controls.
Conclusion: Insulin exerts a direct profibrotic impact on HSCs by an α5β1 integrin-mediated mechanism, independently of the PI3 kinase signaling pathway. Thus, chronic hyperinsulinemia may potentiate liver collagen deposition in insulin resistance states. This likely increases the risk of significant fibrosis burden in chronic liver disease associated with insulin resistance.
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Crocombe D, Tsochatzis EA. Natural history of nonalcoholic fatty liver disease. METABOLIC STEATOTIC LIVER DISEASE 2024:61-75. [DOI: 10.1016/b978-0-323-99649-5.00014-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 113] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Nakatsuka T, Tateishi R, Koike K. Changing clinical management of NAFLD in Asia. Liver Int 2022; 42:1955-1968. [PMID: 34459096 DOI: 10.1111/liv.15046] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/30/2021] [Accepted: 08/21/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, affecting approximately 25% of the world's population. Recently, because of the sedentary lifestyle and overnutrition resulting from urbanisation, the burden of NAFLD has rapidly increased in many Asian countries. Currently, the prevalence of NAFLD in Asia is approximately 30%, as is the case in many Western countries. In Asia, the prevalence and presentation of NAFLD vary widely across regions because of the substantial diversity in race, socioeconomic status and living environment. Furthermore, the dual aetiology of fatty liver, particularly with viral hepatitis in Asia, makes it complex and challenging to manage. Because Asians are likely to have central adiposity and insulin resistance, approximately 7%-20% of non-obese Asians with body mass indexes of less than 25 kg/m2 are estimated to have NAFLD. Accumulating evidence indicates that NAFLD is associated with various extrahepatic comorbidities such as cardiovascular disease, chronic kidney disease, malignancy, in addition to liver-specific complications. Therefore, NAFLD should be managed as a multisystem disease in conjunction with metabolic syndrome. Lifestyle modification remains the basis of NAFLD management, but few patients can achieve adequate weight loss and maintain it long term. While various pharmacological agents are in phase 3 trials for steatohepatitis, Asian patients are underrepresented in most trials. This article reviews the epidemiological trends, clinical features, optimal assessment and current management practices for NAFLD in Asia.
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Affiliation(s)
- Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
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A pharmaceutical formulation containing Cecropia pachystachya alleviates metabolic alterations in a hypercaloric diet obesity model in Swiss mice. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2022. [DOI: 10.1016/j.bcab.2022.102376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Zhu Y, Peng Z, Lu Y, Li H, Zeng X, Zhang Z, Li X, Hu C, Hu A, Zhao Q, Wang H, Yang W. Higher dietary insulinaemic potential is associated with increased risk of liver steatosis and fibrosis. Liver Int 2022; 42:69-79. [PMID: 34521152 DOI: 10.1111/liv.15057] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/17/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Hyperinsulinaemia and insulin resistance play a central role in the progression of hepatic steatosis and fibrosis, and diet can modulate insulin response. We thus hypothesised that diet with higher insulinaemic potential is associated with an increased risk of these conditions. METHODS Two empirically dietary indices for hyperinsulinaemia (EDIH) and insulin resistance (EDIR) were derived to identify food groups most predictive of fasting concentrations of C-peptide and insulin and homeostatic model assessment for insulin resistance respectively. Hepatic steatosis and fibrosis were defined by controlled attenuation parameter and liver stiffness measurement using transient elastography (TE). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. RESULTS Of the 4171 participants with TE examination, 1436 (age-standardised prevalence, 33.8%) were diagnosed with steatosis, 255 (5.6%) with advanced fibrosis and 101 (2.2%) with cirrhosis. The multivariable-adjusted ORs for participants comparing the highest to the lowest EDIH tertile were 1.17 (95% CI: 0.99-1.39, Ptrend = .005) for steatosis, 1.74 (95% CI: 1.24-2.44, Ptrend = .001) for advanced fibrosis and 2.05 (95% CI: 1.21-3.46, Ptrend = .004) for cirrhosis. Similar associations were observed for EDIR with ORs of 1.32 (95% CI: 1.11-1.55, Ptrend < .001) for steatosis and 1.43 (95% CI: 1.03-1.99, Ptrend = .006) for advance fibrosis. These positive associations remained among never drinkers and individuals who were free of hepatitis B and/or C. CONCLUSIONS Our findings suggest that hyperinsulinaemia and insulin resistance may partially underlie the influence of diet on hepatic steatosis and fibrosis, and highlight the importance of reducing or avoiding insulinaemic dietary pattern.
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Affiliation(s)
- Yu Zhu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Anhui, China.,NHC Key Laboratory of study on Abnormal Gametes and Reproductive Tract, Anhui, China.,Anhui Provincial Key Laboratory of Population Health and Aristogenics/Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China
| | - Zhaohong Peng
- Department of Interventional Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yao Lu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hairong Li
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xufen Zeng
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Zhuang Zhang
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiude Li
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Chunqiu Hu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Anla Hu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Qihong Zhao
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Wanshui Yang
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China.,Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Anhui, China.,NHC Key Laboratory of study on Abnormal Gametes and Reproductive Tract, Anhui, China.,Anhui Provincial Key Laboratory of Population Health and Aristogenics/Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China
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The Change in Metabolic Syndrome Status and the Risk of Nonviral Liver Cirrhosis. Biomedicines 2021; 9:biomedicines9121948. [PMID: 34944764 PMCID: PMC8698513 DOI: 10.3390/biomedicines9121948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/06/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease is considered to be the hepatic component of metabolic syndrome (MetS). However, the association between changes in MetS status and the risk of liver cirrhosis (LC) has not been investigated to date. This study assessed the association between changes in MetS and subsequent nonviral LC development. Methods: Data were obtained from the Korean National Health Insurance Service. Individuals who participated in health screenings from both 2009 to 2010 and 2011 to 2012 were included. The primary outcome was LC development according to the static and dynamic MetS status. Subjects were stratified into four groups according to the change in MetS status observed from the two-year interval screening (2009–2011). Cox regression analysis was used to examine the hazard ratios of LC. Results: During a median of 7.3 years of follow-up, 24,923 incident LC cases developed among 5,975,308 individuals. After adjusting for age, sex, smoking, alcohol, regular exercise, and body mass index, the adjusted hazard ratios (95% confidence intervals) for LC development were 1.39 (1.33–1.44) for the MetS-Developed group, 1.32 (1.26–1.37) for the MetS-Recovered group, and 1.51 (1.45–1.56) for the MetS-Sustained group, relative to the MetS-Free group. Stratified analyses according to age, sex, smoking, alcohol intake, exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease showed similar results. Conclusions: Both static and dynamic MetS status are independent risk factors for LC development. The risk of LC was the highest in people with sustained MetS and was lower in the MetS-Recovered group than in the MetS-Sustained group. These results suggest that improving a person’s MetS status may be helpful in preventing LC.
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Boeckmans J, Rombaut M, Demuyser T, Declerck B, Piérard D, Rogiers V, De Kock J, Waumans L, Magerman K, Cartuyvels R, Rummens JL, Rodrigues RM, Vanhaecke T. Infections at the nexus of metabolic-associated fatty liver disease. Arch Toxicol 2021; 95:2235-2253. [PMID: 34027561 PMCID: PMC8141380 DOI: 10.1007/s00204-021-03069-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that affects about a quarter of the world population. MAFLD encompasses different disease stadia ranging from isolated liver steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although MAFLD is considered as the hepatic manifestation of the metabolic syndrome, multiple concomitant disease-potentiating factors can accelerate disease progression. Among these risk factors are diet, lifestyle, genetic traits, intake of steatogenic drugs, male gender and particular infections. Although infections often outweigh the development of fatty liver disease, pre-existing MAFLD could be triggered to progress towards more severe disease stadia. These combined disease cases might be underreported because of the high prevalence of both MAFLD and infectious diseases that can promote or exacerbate fatty liver disease development. In this review, we portray the molecular and cellular mechanisms by which the most relevant viral, bacterial and parasitic infections influence the progression of fatty liver disease and steatohepatitis. We focus in particular on how infectious diseases, including coronavirus disease-19, hepatitis C, acquired immunodeficiency syndrome, peptic ulcer and periodontitis, exacerbate MAFLD. We specifically underscore the synergistic effects of these infections with other MAFLD-promoting factors.
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Affiliation(s)
- Joost Boeckmans
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium.
| | - Matthias Rombaut
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Thomas Demuyser
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
- Center for Neurosciences, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Baptist Declerck
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Denis Piérard
- Department of Microbiology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - Vera Rogiers
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Luc Waumans
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Koen Magerman
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
- Department of Immunology and Infection, Hasselt University, Martelarenlaan 42, 3500, Hasselt, Belgium
| | - Reinoud Cartuyvels
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Jean-Luc Rummens
- Clinical Laboratory, Jessa Hospital, Stadsomvaart 11, 3500, Hasselt, Belgium
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
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Chaudhari R, Fouda S, Sainu A, Pappachan JM. Metabolic complications of hepatitis C virus infection. World J Gastroenterol 2021; 27:1267-1282. [PMID: 33833481 PMCID: PMC8015302 DOI: 10.3748/wjg.v27.i13.1267] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/10/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a systemic disease that is implicated in multiple extrahepatic organ dysfunction contributing to its protean manifestations. HCV is associated with diverse extrahepatic disorders including atherosclerosis, glucose and lipid metabolic disturbances, alterations in the iron metabolic pathways, and lymphoproliferative diseases over and above the traditional liver manifestations of cirrhosis and hepatocellular carcinoma. The orchestration between HCV major proteins and the liver-muscle-adipose axis, poses a major burden on the global health of human body organs, if not adequately addressed. The close and inseparable associations between chronic HCV infection, metabolic disease, and cardiovascular disorders are specifically important considering the increasing prevalence of obesity and metabolic syndrome, and their economic burden to patients, the healthcare systems, and society. Cellular and molecular mechanisms governing the interplay of these organs and tissues in health and disease are therefore of significant interest. The coexistence of metabolic disorders and chronic hepatitis C infection also enhances the progression to liver fibrosis and hepatocellular carcinoma. The presence of metabolic disorders is believed to influence the chronicity and virulence of HCV leading to liver disease progression. This comprehensive review highlights current knowledge on the metabolic manifestations of hepatitis C and the potential pathways in which these metabolic changes can influence the natural history of the disease.
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Affiliation(s)
- Rahul Chaudhari
- Department of Medicine, Pennsylvania Hospital of the University of Pennsylvania, Pennsylvania, PA 19104, United States
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne VIC 3000, Australia
| | - Ashik Sainu
- Department of Gastroenterology and Hepatology, Aster Oman Hospital, Al Ghubra, Muscat OM 133, Oman
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Castro GLCD, Amoras EDGS, Araújo MSMD, Conde SRSDS, Vallinoto ACR. Hepatitis C virus genotypes and associated risk factors in the state of Pará, Northern Brazil. Braz J Infect Dis 2020; 24:304-309. [PMID: 32735876 PMCID: PMC9392123 DOI: 10.1016/j.bjid.2020.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 06/07/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
Background Despite the emergence of more effective therapies, hepatitis C virus (HCV) infection remains a serious public health problem at the global level. Currently, this virus is classified into seven genotypes and 67 subgenotypes, which in turn are distributed heterogeneously in Brazil and worldwide. Studies have shown that this genetic divergence results in differences in the progression of chronic disease associated with HCV infection and its treatment. Objective The aim of this study was to report the frequency of HCV genotypes in the state of Pará, Northern Brazil, and to assess the association between genotype and different clinical and laboratory characteristics, as well as risk factors for infection. Method Data from 85 medical records of untreated patients who had chronic hepatitis C infection were analyzed; the patients were evaluated at two hospitals in Belem, Pará, Brazil. Results Circulation of genotypes 1 and 3 was detected, with a higher prevalence of genotype 1 (75.3%) than genotype 3 (24.7%). In addition, there was a predominance of subgenotype 1b (60.34%) compared to 1a (20.69%) and 3a (18.97%). Reuse of needles and/or glass syringes was significantly associated with infection by HCV genotype 1 than genotype 3; however, the small number of patients infected with genotype 3 may have biased the results. No associations between genotype and the evaluated clinical and laboratory characteristics were observed. Conclusion This study reinforces the differences in the distribution of HCV genotypes in Brazil and showed no association between HCV genotype and progression of chronic hepatitis C in the studied group.
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Affiliation(s)
| | | | | | - Simone Regina Souza da Silva Conde
- Federal University of Pará (UFPA), Institute of Health Sciences, School of Medicine, Belem, PA, Brazil; João de Barros Barreto University Hospital, Belem, PA, Brazil
| | - Antonio Carlos R Vallinoto
- Federal University of Pará (UFPA), Biological Sciences Institute, Virology Laboratory, Belem, PA, Brazil.
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Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease in Obese Patients Undergoing Bariatric Surgery. Obes Surg 2020; 30:2572-2578. [DOI: 10.1007/s11695-020-04514-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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AASLD-IDSA Hepatitis C Guidance Panel *, Morgan TR, AASLD‐IDSA Hepatitis C Guidance Panel. Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Hepatology 2020; 71:686-721. [PMID: 31816111 PMCID: PMC9710295 DOI: 10.1002/hep.31060] [Citation(s) in RCA: 523] [Impact Index Per Article: 104.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023]
Affiliation(s)
| | - Timothy R. Morgan
- Chief of Hepatology Veterans Affairs Long Beach Healthcare System Long Beach CA
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Haghgoo SM, Sharafi H, Alavian SM. Serum cytokines, adipokines and ferritin for non-invasive assessment of liver fibrosis in chronic liver disease: a systematic review. Clin Chem Lab Med 2019; 57:577-610. [PMID: 30231008 DOI: 10.1515/cclm-2018-0357] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
Chronic liver disease (CLD) is a major health problem worldwide. Non-alcoholic fatty liver disease (NAFLD), chronic hepatitis C (CHC), chronic hepatitis B (CHB), and alcoholic liver disease (ALD) are the most common etiologies of CLD. Liver biopsy is the gold standard for assessment of liver fibrosis, however, it is an invasive method. This review attempts to evaluate the usefulness of serum adiponectin, serum leptin, serum ferritin, serum transforming growth factor-β1 (TGF-β1), and serum platelet derived growth factor-BB (PDGF-BB) as non-invasive markers in the diagnosis of liver fibrosis/cirrhosis. A systematic search in MEDLINE, Web of Science, Scopus, and local databases was performed to identify articles published in English or Persian as of November 2017. Studies conducted among CLD patients, with biopsy proven fibrosis/cirrhosis, and providing sufficient details of patients' clinicopathological characteristics were included. In the 95 studies included, there were a total of 15,548 CLD patients. More than 83% of studies were carried out in Asia and Europe. The relationship between liver fibrosis/cirrhosis and serum levels of ferritin, adiponectin, leptin, TGF-β1, and PDGF-BB was assessed in 42, 33, 27, nine, and three studies, respectively. Serum levels of the markers, particularly ferritin, could successfully predict liver fibrosis/cirrhosis, however, these data might not be clinically replicated and further studies are needed.
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Affiliation(s)
- Seyyed Mortaza Haghgoo
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Middle East Liver Diseases (MELD) Center, Tehran, Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Middle East Liver Diseases (MELD) Center, Tehran, Iran
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15
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Fujii H, Imajo K, Yoneda M, Nakahara T, Hyogo H, Takahashi H, Hara T, Tanaka S, Sumida Y, Eguchi Y, Chayama K, Nakajima A, Nishimoto N, Kawada N. HOMA-IR: An independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2019; 34:1390-1395. [PMID: 30600551 DOI: 10.1111/jgh.14595] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/06/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Although non-alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA-IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD. METHODS This was a retrospective, cross-sectional multicenter study. We included 361 patients with biopsy-proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age ≥ 49 years, sex (women), body mass index ≥ 26.7 kg/m2 , the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level ≥ 98 mg/dL, fasting immune reactive insulin level ≥ 12.0 μU/mL, and HOMA-IR ≥ 2.90. The median HOMA-IR of the patients was 2.88 (interquartile range: 2.1-4.8). RESULTS In the estimation group, univariate and multivariate analyses showed that age, dyslipidemia, and HOMA-IR were independent predictors of advanced fibrosis. In the validation group, only age and HOMA-IR were found to be independent predictors of advanced fibrosis. CONCLUSIONS Homeostasis model assessment parameter of insulin resistance was an independent predictor of advanced liver fibrosis in nondiabetic patients with NAFLD. Given that most patients with NAFLD are nondiabetic, it is important to set goals with respect to improving IR to subsequently reduce liver fibrosis.
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Affiliation(s)
- Hideki Fujii
- Department of Hepatology, Osaka City University, Osaka, Japan.,Endowed Department of Liver Cirrhosis Therapeutics, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima Kouseiren General Hospital, Hiroshima, Japan
| | - Hirokazu Takahashi
- Department of Internal Medicine, Saga Medical School, Saga University, Nabeshima, Saga, Japan
| | - Tasuku Hara
- Department of Gastroenterology and Hepatology, Fukuchiyama City Hospital, Fukuchiyama, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan
| | - Yuichiro Eguchi
- Liver Center, Saga University Hospital, Nabeshima, Saga, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Naoki Nishimoto
- Division of Data Management, Division of Biostatistics, Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University, Osaka, Japan
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16
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Munsterman ID, van Erp M, Weijers G, Bronkhorst C, de Korte CL, Drenth JPH, van der Laak JAWM, Tjwa ETTL. A Novel Automatic Digital Algorithm that Accurately Quantifies Steatosis in NAFLD on Histopathological Whole-Slide Images. CYTOMETRY PART B-CLINICAL CYTOMETRY 2019; 96:521-528. [PMID: 31173462 PMCID: PMC6899563 DOI: 10.1002/cyto.b.21790] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/21/2019] [Accepted: 05/17/2019] [Indexed: 12/14/2022]
Abstract
Background Accurate assessment of hepatic steatosis is a key to grade disease severity in non‐alcoholic fatty liver disease (NAFLD). Methods We developed a digital automated quantification of steatosis on whole‐slide images (WSIs) of liver tissue and performed a validation study. Hematoxylin–eosin stained liver tissue slides were digitally scanned, and steatotic areas were manually annotated. We identified thresholds for size and roundness parameters by logistic regression to discriminate steatosis from surrounding liver tissue. The resulting algorithm produces a steatosis proportionate area (SPA; ratio of steatotic area to total tissue area described as percentage). The software can be implemented as a Java plug‐in in FIJI, in which digital WSI can be processed automatically using the Pathomation extension. Results We obtained liver tissue specimens from 61 NAFLD patients and 18 controls. The area under the curve of correctly classified steatosis by the algorithm was 0.970 (95% CI 0.968–0.973), P < 0.001. Accuracy of the algorithm was 91.9%, with a classification error of 8.1%. SPA correlated significantly with steatosis grade (Rs = 0.845, CI: 0.749–0.902, P < 0.001) and increased significantly with each individual steatosis grade, except between Grade 2 and 3. Conclusions We have developed a novel digital analysis algorithm that accurately quantifies steatosis on WSIs of liver tissue. This algorithm can be incorporated when quantification of steatosis is warranted, such as in clinical trials studying efficacy of new therapeutic interventions in NAFLD. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.
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Affiliation(s)
- Isabelle D Munsterman
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Merijn van Erp
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.,Microscopic Imaging Centre, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Gert Weijers
- Medical UltraSound Imaging Centre (MUSIC), Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Carolien Bronkhorst
- Department of Pathology, Jeroen Bosch Ziekenhuis's-Hertogenbosch, The Netherlands
| | - Chris L de Korte
- Medical UltraSound Imaging Centre (MUSIC), Department of Radiology and Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Eric T T L Tjwa
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands
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17
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Czaja AJ. Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications. Aliment Pharmacol Ther 2019; 49:681-701. [PMID: 30761559 DOI: 10.1111/apt.15173] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. AIMS To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. CONCLUSIONS Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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18
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Schwenger KJP, Bolzon CM, Li C, Allard JP. Non-alcoholic fatty liver disease and obesity: the role of the gut bacteria. Eur J Nutr 2018; 58:1771-1784. [PMID: 30306296 DOI: 10.1007/s00394-018-1844-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty-liver disease (NAFLD) is now considered one of the leading causes of liver disease worldwide and is associated with metabolic syndrome and obesity. There are several factors contributing to the disease state. Recent research suggests that the intestinal microbiota (IM) and bacterial products may play a role through several mechanisms which include increased energy uptake, intestinal permeability and chronic inflammation. In addition to diet and exercise, treatment options targeting the IM are being investigated and include the use of pre-, pro- and synbiotics as well as the possibility of fecal microbial transfers. This literature review explores the relationship between NAFLD and the IM as well as highlight new IM treatment options that may become available in the near future.
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Affiliation(s)
- Katherine J P Schwenger
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Colin M Bolzon
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Carrie Li
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Johane P Allard
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
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19
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Foster GR, Agarwal K, Cramp ME, Moreea S, Barclay S, Collier J, Brown AS, Ryder SD, Ustianowski A, Forton DM, Fox R, Gordon F, Rosenberg WM, Mutimer DJ, Du J, Gilbert CL, Asante-Appiah E, Wahl J, Robertson MN, Barr E, Haber B. Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial. Hepatology 2018; 67:2113-2126. [PMID: 29473975 DOI: 10.1002/hep.29852] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/29/2017] [Accepted: 01/08/2018] [Indexed: 12/16/2022]
Abstract
UNLABELLED Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).
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Affiliation(s)
| | - Kosh Agarwal
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - Matthew E Cramp
- South West Liver Unit, Derriford Hospital and Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | | | | | | | | | - Stephen D Ryder
- NIHR Biomedical Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospital NHS Trust and The University of Nottingham, Nottingham, UK
| | | | | | - Ray Fox
- Gartnavel General Hospital, Glasgow, UK
| | - Fiona Gordon
- Hepatology Joint Clinical Research Unit, Bristol, UK
| | - William M Rosenberg
- Institute for Liver and Digestive Health, University College London, London, UK
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20
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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: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [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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21
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Petta S, Valenti L, Tuttolomondo A, Dongiovanni P, Pipitone RM, Cammà C, Cabibi D, Di Marco V, Fracanzani AL, Badiali S, Nobili V, Fargion S, Grimaudo S, Craxì A. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology 2017; 66:1885-1893. [PMID: 28741298 DOI: 10.1002/hep.29395] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/01/2017] [Accepted: 07/20/2017] [Indexed: 12/13/2022]
Abstract
UNLABELLED The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). CONCLUSION The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885-1893).
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonino Tuttolomondo
- Sezione di Medicina Interna e Cardioangiologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Rosaria Maria Pipitone
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Daniela Cabibi
- Cattedra di Anatomia Patologica, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Sara Badiali
- Department of Surgery, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Valerio Nobili
- Hepatometabolic Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
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22
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Ciancio A, Bosio R, Bo S, Pellegrini M, Sacco M, Vogliotti E, Fassio G, Bianco Mauthe Degerfeld AGF, Gallo M, Giordanino C, Terzi di Bergamo L, Ribaldone D, Bugianesi E, Smedile A, Rizzetto M, Saracco GM. Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents. J Med Virol 2017; 90:320-327. [DOI: 10.1002/jmv.24954] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Alessia Ciancio
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Roberta Bosio
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Simona Bo
- Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Marianna Pellegrini
- Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Marco Sacco
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Edoardo Vogliotti
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Giulia Fassio
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | | | - Monica Gallo
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Chiara Giordanino
- Gastroenterology Unit; San Luigi Hospital; University of Turin; Torino Italy
| | - Lodovico Terzi di Bergamo
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Davide Ribaldone
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Elisabetta Bugianesi
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Antonina Smedile
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Mario Rizzetto
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
| | - Giorgio Maria Saracco
- Gastroenterology Unit; Department of Medical Sciences; AOU Città della Salute e della Scienza di Torino; University of Turin; Torino Italy
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Non-alcoholic Fatty Liver Disease in Morbidly Obese Individuals Undergoing Bariatric Surgery: Prevalence and Effect of the Pre-Bariatric Very Low Calorie Diet. Obes Surg 2017; 28:1109-1116. [DOI: 10.1007/s11695-017-2980-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Desbois AC, Cacoub P. Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review. World J Gastroenterol 2017; 23:1697-1711. [PMID: 28321170 PMCID: PMC5340821 DOI: 10.3748/wjg.v23.i9.1697] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/10/2016] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To summarise the literature data on hepatitis C virus (HCV)-infected patients concerning the prevalence of glucose abnormalities and associated risk.
METHODS We conducted a PubMed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We collected the literature data on HCV-infected patients concerning the prevalence of glucose abnormalities [diabetes mellitus (DM) and insulin resistance (IR)] and associated risk [i.e., severe liver fibrosis, response to antivirals, and the occurrence of hepatocellular carcinoma (HCC)].
RESULTS HCV infection is significantly associated with DM/IR compared with healthy volunteers and patients with hepatitis B virus infection. Glucose abnormalities were associated with advanced liver fibrosis, lack of sustained virologic response to interferon alfa-based treatment and with a higher risk of HCC development. As new antiviral therapies may offer a cure for HCV infection, such data should be taken into account, from a therapeutic and preventive point of view, for liver and non-liver consequences of HCV disease. The efficacy of antidiabetic treatment in improving the response to antiviral treatment and in decreasing the risk of HCC has been reported by some studies but not by others. Thus, the effects of glucose abnormalities correction in reducing liver events need further studies.
CONCLUSION Glucose abnormalities are strongly associated with HCV infection and show a negative impact on the main liver related outcomes.
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Karacaer Z, Okur G, Cermik H, Altun D. Is there an influence of hepatic steatosis on fibrosis and necroinflammation in young patients with chronic viral hepatitis B? Postgrad Med 2016; 128:697-700. [PMID: 27499150 DOI: 10.1080/00325481.2016.1221733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Our aim was to investigate the association of liver fibrosis and necroinflammation with HS in untreated young patients with chronic hepatitis B (CHB). MATERIALS AND METHODS A retrospective study was conducted in a military hospital in Turkey. A total of 254 subjects with CHB were included in this study. These subjects were divided into two groups: group 1 consisted of patients with hepatic steatosis (HS) according to ultrasonography (USG) and group 2 consisted of non-HS subjects. Sociodemographic, biochemical, histopathological, virological and USG results were recorded for both groups retrospectively. Statistical analysis was performed using SPSS 22.0. RESULTS The prevalence of HS was found to be 11.4%. A significant statistical difference was found between group 1 and group 2 regarding the fibrosis degree (p = 0.045). No statistically significant difference was noted between two groups for age, levels of ALT, AST, HBeAg, HBV-DNA levels, HAI scores, diagnosis age and duration of CHB. No difference was noted between the grade of HS and variables. A positive correlation was found between fibrosis groups and the grade of HS (p = 0.012, r = 0.158) and between HAI groups and the grade of HS (p = 0.029, r = 0.137). CONCLUSION The prevalence of steatosis was not higher in patients with CHB. HS is associated with advanced hepatic fibrosis, but not viral liver disease.
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Affiliation(s)
- Zehra Karacaer
- a Department of Infectious Diseases and Clinical Microbiology , Etimesgut Military Hospital , Ankara , Turkey
| | - Gokcan Okur
- b Department of Radiology , Etimesgut Military Hospital , Ankara , Turkey
| | - Hakan Cermik
- c Department of Pathology , Etimesgut Military Hospital , Ankara , Turkey
| | - Demet Altun
- d Department of Pediatrics , Etimesgut Military Hospital , Ankara , Turkey
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Song G, Xiao C, Wang K, Wang Y, Chen J, Yu Y, Wang Z, Deng G, Sun X, Zhong L, Zhou C, Qi X, Wang S, Peng Z, Wang X. Association of patatin-like phospholipase domain-containing protein 3 gene polymorphisms with susceptibility of nonalcoholic fatty liver disease in a Han Chinese population. Medicine (Baltimore) 2016; 95:e4569. [PMID: 27537584 PMCID: PMC5370810 DOI: 10.1097/md.0000000000004569] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Gene polymorphisms had been found to be associated with increased risk of nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to assess the association between rs2896019 and rs3810622 in PNPLA3 with the susceptibility to NAFLD in Han Chinese population.A total of 384 NAFLD patients and 384 controls were enrolled in the study. Blood samples collected from each subject were used for biochemical index analysis and DNA extraction. Genotyping analyses of PNPLA3 rs2896019 and rs3810622 were performed by real-time PCR methods.Results showed that patients with genotype GG of rs2896019 had a higher incidence of NAFLD than patients with genotypes GT and TT (62.4% vs 52.0% and 43.3%, respectively, P = 0.002), and a higher risk of moderate to severe NAFLD than patients with genotypes GT and TT (60.3% vs 46.2% and 40.2%, respectively, P = 0.03). Furthermore, patients with genotype GG of rs2896019 had higher levels of low-density lipoprotein (LDL, P < 0.001), ALT (P = 0.003), and AST (P = 0.002). Patients with genotype TT of rs3810622 had a higher incidence of NAFLD than patients with genotypes CT and CC (56.7% vs 48.4% and 41.5%, respectively, P = 0.013). Likewise, patients with genotype TT of rs3810622 had higher levels of ALT (P = 0.021) and blood glucose (GLU) (P = 0.034). Haplotype association analysis showed that GT haplotype conferred a statistically significant increased risk for NAFLD (OR = 1.49; 95% CI = 1.20-1.84, P < 0.01).These results suggest that PNPLA3 rs2896019 and rs3810622 polymorphisms significantly contribute to increased NAFLD risk in Han Chinese population.
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Affiliation(s)
- Guohe Song
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Chao Xiao
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Kai Wang
- Department of General Surgery, Children's Hospital of Zhengzhou, Henan, P. R. China
| | - Yupeng Wang
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Jian Chen
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Yang Yu
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Zhaowen Wang
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Guilong Deng
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Xing Sun
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Lin Zhong
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Chongzhi Zhou
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Xiaosheng Qi
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Shuyun Wang
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Zhihai Peng
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
| | - Xiaoliang Wang
- Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai
- Correspondence: Xiaoliang Wang, Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, No.100, Haining Road, Shanghai 200080, P. R. China (e-mail: )
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Kim JY, Lee C, Oh M, Im JA, Lee JW, Chu SH, Lee H, Jeon JY. Relationship between non-alcoholic fatty liver disease, metabolic syndrome and insulin resistance in Korean adults: A cross-sectional study. Clin Chim Acta 2016; 458:12-7. [PMID: 27020118 DOI: 10.1016/j.cca.2016.03.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 03/22/2016] [Accepted: 03/22/2016] [Indexed: 12/18/2022]
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Petta S, Valenti L, Marra F, Grimaudo S, Tripodo C, Bugianesi E, Cammà C, Cappon A, Di Marco V, Di Maira G, Dongiovanni P, Rametta R, Gulino A, Mozzi E, Orlando E, Maggioni M, Pipitone RM, Fargion S, Craxì A. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J Hepatol 2016; 64:682-90. [PMID: 26596542 DOI: 10.1016/j.jhep.2015.10.016] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 09/16/2015] [Accepted: 10/12/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIM Homozygosity for a common non-coding rs4374383 G>A polymorphism in MERTK (myeloid-epithelial-reproductive tyrosine kinase) has been associated with the protection against fibrosis progression in chronic hepatitis C. The main study objective was to assess whether MERTK AA genotype influences liver fibrosis, and secondarily MERTK expression in patients with non-alcoholic fatty liver disease (NAFLD). We also investigated whether MERTK is expressed in human hepatic stellate cells (HSC) and in murine models of fibrogenesis. METHODS We considered 533 consecutive patients who underwent liver biopsy for suspected non-alcoholic steatohepatitis (NASH) without severe obesity from two Italian cohorts. As controls, we evaluated 158 patients with normal liver enzymes and without metabolic disturbances. MERTK rs4374383 genotype was assessed by 5'-nuclease assays. MERTK expression was analysed in mouse models of fibrosis, and the effect of the MERTK ligand GAS6 were investigated in human HSC. RESULTS Clinically significant fibrosis (stage F2-F4) was observed in 19% of patients with MERTK AA compared to 30% in those with MERTK GG/GA (OR 0.43, CI 0.21-0.88, p=0.02; adjusted for centre, and genetic, clinical-metabolic and histological variables). The protective rs4374383 AA genotype was associated with lower MERTK hepatic expression. MERTK was overexpressed in the liver of NAFLD patients with F2-F4 fibrosis and in in vivo models of fibrogenesis. Furthermore, exposure of cultured human HSC to the MERTK ligand GAS6, increased cell migration and induced procollagen expression. These effects were counteracted by inhibition of MERTK activity, which also resulted in apoptotic death of HSC. CONCLUSIONS The rs4374383 AA genotype, associated with lower intrahepatic expression of MERTK, is protective against F2-F4 fibrosis in patients with NAFLD. The mechanism may involve modulation of HSC activation.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Fabio Marra
- Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy
| | | | - Claudio Tripodo
- Cattedra di Anatomia Patologica, University of Palermo, Italy
| | - Elisabetta Bugianesi
- Division of Gastro-Hepatology, Department of Medical Sciences, San Giovanni Battista Hospital, University of Torino, Torino, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy
| | - Andrea Cappon
- Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy
| | - Giovanni Di Maira
- Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Raffaela Rametta
- Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | | | - Enrico Mozzi
- Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Emanuele Orlando
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy
| | - Marco Maggioni
- Pathology, Fondazione IRCCS Ca' Granda Policlinico, Milano, Italy
| | | | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy
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Dyal HK, Aguilar M, Bartos G, Holt EW, Bhuket T, Liu B, Cheung R, Wong RJ. Diabetes Mellitus Increases Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients: A Systematic Review. Dig Dis Sci 2016; 61:636-45. [PMID: 26703125 DOI: 10.1007/s10620-015-3983-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 11/26/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Rising rates of obesity, diabetes mellitus (DM), and nonalcoholic fatty liver disease (NAFLD) among chronic hepatitis C (HCV) patients may contribute to higher hepatocellular carcinoma (HCC) risk. AIM To perform a systematic review evaluating the impact of DM, body mass index (BMI), or steatosis on HCC risk among chronic HCV patients. METHODS A structured keyword search of PubMed from January 1, 2001, to July 1, 2014, was performed to identify original articles evaluating the association of DM, BMI, or steatosis with HCC among adults with chronic HCV. Studies involving HCV patients co-infected with human immunodeficiency virus, hepatitis B virus, or other chronic liver diseases with the exception of NAFLD were excluded. Quality assessment utilized the Newcastle-Ottawa scale. RESULTS Nine studies (seven cohorts, two case-controls) met inclusion criteria for the final analysis. Five of seven studies analyzing DM demonstrated significantly increased HCC risk associated with concurrent DM with effect sizes ranging from HR 1.73 (95 % CI 1.30-2.30) to RR 3.52 (95 % CI 1.29-9.24). One of three studies analyzing BMI demonstrated a significant association with HCC risk (BMI ≥ 30.0 vs. BMI < 23: RR 4.13, 95 % CI 1.38-12.40). Two of the three studies analyzing steatosis demonstrated significantly higher risk of HCC associated with steatosis ranging from RR 2.81 (95 % CI 1.49-4.41) to OR 6.39 (95 % CI 1.04-39.35). CONCLUSIONS Concurrent DM is associated with increased HCC risk among chronic HCV patients. BMI and steatosis may also increase HCC risk, but the limitations of the current studies do not allow us to draw strong conclusions.
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Affiliation(s)
- Harleen K Dyal
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Maria Aguilar
- Department of Medicine, Alameda Health System - Highland Hospital, 1411 East 31st Street, Oakland, CA, USA.
| | - Gabriella Bartos
- Department of Medicine, Alameda Health System - Highland Hospital, 1411 East 31st Street, Oakland, CA, USA.
| | - Edward W Holt
- Division of Hepatology, Department of Transplantation, California Pacific Medical Center, 2340 Clay Street, 3rd Floor, San Francisco, CA, 94115, USA.
| | - Taft Bhuket
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Benny Liu
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Stanford, CA, 94305, USA.
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital, Highland Hospital - Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA.
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Vanni E, Bugianesi E, Saracco G. Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality? Dig Liver Dis 2016; 48:105-11. [PMID: 26614641 DOI: 10.1016/j.dld.2015.10.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 10/05/2015] [Accepted: 10/16/2015] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro-inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mellitus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C-infected patients.
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Affiliation(s)
- Ester Vanni
- Gastro-hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elisabetta Bugianesi
- Gastro-hepatology Unit, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giorgio Saracco
- Gastroenterology Unit, Oncology Department, University of Turin, Italy.
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Ress C, Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol 2016; 22:1664-1673. [PMID: 26819531 PMCID: PMC4721997 DOI: 10.3748/wjg.v22.i4.1664] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/20/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD.
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Abdel-Razik A, Mousa N, Shabana W, Refaey M, ElMahdy Y, Elhelaly R, Elzehery R, Zalata K, Arafa M, Elbaz S, Hafez M, Awad M. A novel model using mean platelet volume and neutrophil to lymphocyte ratio as a marker of nonalcoholic steatohepatitis in NAFLD patients: multicentric study. Eur J Gastroenterol Hepatol 2016; 28:e1-e9. [PMID: 26469357 DOI: 10.1097/meg.0000000000000486] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Nonalcoholic fatty liver disease (NAFLD) is a leading cause of progressive and chronic liver injury. Mean platelet volume (MPV) and the neutrophil-lymphocyte ratio (N/L ratio) may be considered cheap and simple markers of inflammation in many disorders. We aimed to investigate the clinical utility of MPV and the N/L ratio to predict fibrosis in NAFLD patients and the presence of nonalcoholic steatohepatitis (NASH). MATERIALS AND METHODS A total of 873 patients with biopsy-proven NAFLD and 150 healthy controls were included. Patients were divided into two groups: non-NASH group (n=753) and NASH group (n=120). Liver biopsy, MPV, lymphocyte, and neutrophil counts were registered; the N/L ratio was calculated. Proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) were measured by an ELISA. RESULTS NASH patients had higher MPV compared with non-NASH patients (10.9±1.8 and 9.5±1.6 fl, respectively, P<0.001). MPV correlated positively with the NAFLD activity score, proinflammatory cytokines, and C-reactive protein (CRP) (P<0.001). Patients with advanced fibrosis (F3-4) had increased MPV (11.3±0.9 fl) compared with patients with early fibrosis (F1-2) (10.2±0.8 fl, P<0.001). NASH patients had an increased N/L ratio compared with non-NASH cases (2.6±1.1 and 1.9±0.7 fl, respectively, P<0.001). The N/L ratio correlated positively with NAFLD activity score, proinflammatory cytokines, and CRP (P<0.001). In addition, patients with advanced fibrosis (F3-4) had an N/L ratio (2.5±1.1) comparable with that of patients with early fibrosis (F1-2) (1.8±0.9) (P<0.001). CONCLUSION MPV and the N/L ratio were elevated in NASH patients versus non-NASH cases, and in patients with advanced fibrosis (F3-4) versus early fibrosis (F1-2). They can be used as noninvasive novel markers to predict advanced disease.
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Affiliation(s)
- Ahmed Abdel-Razik
- Departments of aTropical Medicine bGeneral Surgery cClinical Pathology dPathology eInternal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura fTropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig gEndemic Diseases and Gastroenterology Department hInternal Medicine Department, Aswan University, Aswan, Egypt
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Patel S, Jinjuvadia R, Patel R, Liangpunsakul S. Insulin Resistance is Associated With Significant Liver Fibrosis in Chronic Hepatitis C Patients: A Systemic Review and Meta-Analysis. J Clin Gastroenterol 2016; 50:80-4. [PMID: 26302498 PMCID: PMC4674302 DOI: 10.1097/mcg.0000000000000400] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The role of insulin resistance (IR) on fibrosis progression in hepatitis C virus (HCV) patients has not been systematically evaluated. Therefore, this systemic review aimed to summarize the available epidemiologic evidence to evaluate the strength of association between IR and advanced liver fibrosis in these patients. METHODS We performed a systemic literature search in PubMed, OvidSP, and MEDLINE from January 1990 to April 2015 without language restriction using the following search terms: insulin resistance, liver fibrosis, cirrhosis, diabetes mellitus, and chronic hepatitis C. Publication bias was assessed using the Begg and Egger tests and with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-Analysis, version 2 software. RESULTS A total of 3659 participants with HCV infection from 14 studies were included in the analysis. After adjusting for publication bias, the relative risk (RR) for significant hepatic fibrosis among HCV subjects with IR was 1.63 [95% confidence interval (CI), 1.34-2.01]. Subgroup analysis by genotypes showed RR of 2.16 (95% CI, 1.52-3.06) for genotype 1; however, the association was no longer significant when we analyzed the data for HCV genotype 3; RR=1.40 (95% CI, 0.8-2.45). CONCLUSION Our study showed significant association between IR and significant hepatic fibrosis in patients with HCV genotype 1 infection.
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Affiliation(s)
- Suhag Patel
- Division of Gastroenterology, Department of Medicine, Detroit Medical Center/Wayne State University, Detroit, Michigan
| | - Raxitkumar Jinjuvadia
- Henry Ford Hospital, Division of Gastroenterology, Department of Medicine, Detroit, Michigan
| | - Ravi Patel
- Detroit Medical Center, Detroit, Michigan
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center and Roudebush Veterans Administration Medical Center, Indianapolis, Indiana
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Zhao HY, Li J, Xu M, Wang TG, Sun WW, Chen Y, Bi YF, Wang WQ, Ning G. Elevated whole blood viscosity is associated with insulin resistance and non-alcoholic fatty liver. Clin Endocrinol (Oxf) 2015; 83:806-11. [PMID: 25823525 DOI: 10.1111/cen.12776] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 01/08/2015] [Accepted: 03/19/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Accumulating evidences demonstrate that abnormalities in whole blood viscosity (WBV) have been implicated in insulin resistance which may lead to non-alcoholic fatty liver disease (NAFLD). However, epidemiological studies exploring the association between WBV and NAFLD were not available. OBJECTIVE Our objective was to evaluate the association between WBV levels and risk of prevalent NAFLD. DESIGN This was a cross-sectional population-based study performed in Shanghai, China. PATIENTS A total of 8673 participants aged 40 years or older were included. MEASUREMENTS WBV was calculated from haematocrit and plasma protein concentration, at a shear rate of 208(-1) s, by a validated equation. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Insulin resistance (IR) was assessed by homeostasis model assessment (HOMA-IR). RESULTS The overall prevalence of NAFLD was 30·2% in this population. With the increase of WBV level, participants have larger waist circumference (WC), more severe insulin resistance and the prevalence of NAFLD increased significantly with elevated WBV quartiles. Compared with those in the lowest quartiles, adults in the highest quartile of WBV levels have higher prevalence of NAFLD (adjusted odds ratio 1·77, 95% confidence interval [CI] 1·48-2·13) and IR (2·72, 95% CI 2·26-3·27). CONCLUSIONS Elevated WBV is associated with prevalence of NAFLD and IR in middle-aged and elderly Chinese population.
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Affiliation(s)
- Hong-yan Zhao
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jing Li
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Min Xu
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Tian-ge Wang
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wan-wan Sun
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ying Chen
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yu-fang Bi
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wei-qing Wang
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, The National Clinical Research Center for Metabolic Diseases of Ministry of Health, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, E-Institute of Shanghai Universities, Shanghai, China
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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Shavakhi A, Torki M, Khodadoostan M, Shavakhi S. Effects of cumin on nonalcoholic steatohepatitis: A double blind, randomised, controlled trial. Adv Biomed Res 2015; 4:212. [PMID: 26605241 PMCID: PMC4627178 DOI: 10.4103/2277-9175.166149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
Background: This study was designed to evaluate the effect of cumin on nonalcoholic steatohepatitis (NASH) in compare to placebo. Materials and Methods: One hundred patients with histopathological diagnosis NASH in two groups of case and control received oral cumin capsule or placebo thrice daily for 6 months. Clinical and laboratory data were body mass index (BMI), serum triglyceride, serum total cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting blood sugar (FBS), steatosis grade, and side-effects and were measured at baseline and after treatment period using standard clinical chemistry techniques. The grade of steatosis was assessed by liver sonography in 3 stages (mild, moderate and severe). Results: Of 100 eligible patients during follow-up 10/50 cases and 9/50 controls were excluded. At baseline and after treatment BMI, triglyceride, cholesterol, ALT, AST, HDL, LDL, and FBS were not statistically significant between groups (P ≥ 0.5). BMI, triglyceride, cholesterol, ALT, AST, LDL, and FBS after treatment decreased compare to baseline but were not statistically significant (P ≥ 0.5). The mean of changes in the level of BMI, triglyceride, cholesterol, ALT, LDL and FBS were not statistically significant (P ≥ 0.5). The mean of changes in AST and HDL between groups was significant (P < 0.05). The grade of steatosis before and after treatment between studied groups was not statistically significant (P ≥ 0.5). Side-effects were not statistically significant among the two groups. Conclusion: Findings show that there the effect of cumin in in the treatment of NASH was not significantly different in compare to placebo.
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Affiliation(s)
- Ahmad Shavakhi
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masoumeh Torki
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Khodadoostan
- Department of Internal Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sara Shavakhi
- Medical Students' Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
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36
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Gondeau C, Pageaux GP, Larrey D. Hepatitis C virus infection: Are there still specific problems with genotype 3? World J Gastroenterol 2015; 21:12101-13. [PMID: 26576095 PMCID: PMC4641128 DOI: 10.3748/wjg.v21.i42.12101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/07/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease and the main indication for liver transplantation worldwide. As promising specific treatments have been introduced for genotype 1, clinicians and researchers are now focusing on patients infected by non-genotype 1 HCV, particularly genotype 3. Indeed, in the golden era of direct-acting antiviral drugs, genotype 3 infections are no longer considered as easy to treat and are associated with higher risk of developing severe liver injuries, such as cirrhosis and hepatocellular carcinoma. Moreover, HCV genotype 3 accounts for 40% of all HCV infections in Asia and is the most frequent genotype among HCV-positive injecting drug users in several countries. Here, we review recent data on HCV genotype 3 infection/treatment, including clinical aspects and the underlying genotype-specific molecular mechanisms.
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37
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Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int 2015; 35:2203-17. [PMID: 26123841 DOI: 10.1111/liv.12903] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 06/09/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and is one of the leading causes of cancer-related death. The risk factors for HCC include cirrhosis, chronic viral hepatitis, heavy alcohol intake and metabolic diseases such as obesity, type 2 diabetes and metabolic syndrome. Insulin resistance is a common denominator of all of these conditions and is tethered to hyperinsulinaemia. Here, we give an overview of the recent advances linking hyperinsulinaemia to HCC development and progression. In particular, we summarise the underlying causes of hyperinsulinaemia in the setting of chronic liver diseases. We present epidemiological evidence linking metabolic diseases to HCC risk and HCC-related mortality, as well as the pathogenic cellular and molecular mechanisms explaining this relation. A better understanding of the mechanisms by which insulin participates in HCC biology might ultimately provide novel opportunities for prevention and treatment.
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Affiliation(s)
- Hamza Chettouh
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Marie Lequoy
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Laetitia Fartoux
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Service d'Hépatologie, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Corinne Vigouroux
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Laboratoire Commun de Biologie et Génétique Moléculaires AP-HP, Hôpital Saint-Antoine, Paris, France.,ICAN, Institute of Cardiometabolism and Nutrition, Paris, France
| | - Christèle Desbois-Mouthon
- Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
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38
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Turola E, Petta S, Vanni E, Milosa F, Valenti L, Critelli R, Miele L, Maccio L, Calvaruso V, Fracanzani AL, Bianchini M, Raos N, Bugianesi E, Mercorella S, Di Giovanni M, Craxì A, Fargion S, Grieco A, Cammà C, Cotelli F, Villa E. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis. Dis Model Mech 2015; 8:1037-1046. [PMID: 26183212 PMCID: PMC4582103 DOI: 10.1242/dmm.019950] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 07/08/2015] [Indexed: 12/13/2022] Open
Abstract
Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to 'The Pathology Committee of the NASH Clinical Research Network'. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.
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Affiliation(s)
- Elena Turola
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Salvatore Petta
- Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy
| | - Ester Vanni
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Fabiola Milosa
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Rosina Critelli
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Luca Miele
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Livia Maccio
- Department of Pathology, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Vincenza Calvaruso
- Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy
| | - Anna L Fracanzani
- Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Marcello Bianchini
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Nazarena Raos
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Serena Mercorella
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Marisa Di Giovanni
- Department of Pathology, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Antonio Craxì
- Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Section Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Antonio Grieco
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Calogero Cammà
- Division of Gastroenterology, DiBiMIS, University of Palermo, 90128 Palermo, Italy
| | - Franco Cotelli
- Department of Biosciences, University of Milan, 20122 Milan, Italy
| | - Erica Villa
- Gastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy
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Pereira K, Salsamendi J, Casillas J. The Global Nonalcoholic Fatty Liver Disease Epidemic: What a Radiologist Needs to Know. J Clin Imaging Sci 2015; 5:32. [PMID: 26167390 PMCID: PMC4485197 DOI: 10.4103/2156-7514.157860] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 04/26/2015] [Indexed: 01/10/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from a benign steatosis to hepatocellular carcinoma (HCC). Metabolic syndrome, mainly obesity, plays an important role, both as an independent risk factor and in the pathogenesis of NAFLD. With the progressive epidemics of obesity and diabetes mellitus, the prevalence of NAFLD and its associated complications is expected to increase dramatically. Therapeutic strategies for treating NAFLD and metabolic syndrome, particularly obesity, are continuously being refined. Their goal is the prevention of NAFLD by the management of risk factors, prevention of progression of the disease, as well as management of complications, ultimately preventing morbidity and mortality. Optimal management of NAFLD and metabolic syndrome requires a multidisciplinary collaboration between the government as well as the health system including the nutritionist, primary care physician, radiologist, hepatologist, oncologist, and transplant surgeon. An awareness of the clinical presentation, risk factors, pathogenesis, diagnosis, and management is of paramount importance to a radiologist, both from the clinical perspective as well as from the imaging standpoint. With expertise in imaging modalities as well as minimally invasive percutaneous endovascular therapies, radiologists play an essential role in the comprehensive management, which is highlighted in this article, with cases from our practice. We also briefly discuss transarterial embolization of the left gastric artery (LGA), a novel method that promises to have an enormous potential in the minimally invasive management of obesity, with details of a case from our practice.
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Affiliation(s)
- Keith Pereira
- Department of Interventional Radiology, Jackson Memorial Hospital, University of Miami Hospital, Miami, Florida, USA
| | - Jason Salsamendi
- Department of Interventional Radiology, Jackson Memorial Hospital, University of Miami Hospital, Miami, Florida, USA
| | - Javier Casillas
- Department of Diagnostic Radiology (Body Imaging), Jackson Memorial Hospital, University of Miami Hospital, Miami, Florida, USA
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40
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Tuttolomondo A, Maida C, Pinto A. Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes. World J Orthop 2015; 6:62-76. [PMID: 25621212 PMCID: PMC4303791 DOI: 10.5312/wjo.v6.i1.62] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 06/06/2014] [Accepted: 08/27/2014] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcerations have been extensively reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an "ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection". Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it's possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a "adipo-vascular" axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This "adipo-vascular axis" in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy.
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41
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Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014; 61:S69-78. [PMID: 25443347 DOI: 10.1016/j.jhep.2014.08.003] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
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Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
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42
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Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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Affiliation(s)
- Katherine J P Schwenger
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
| | - Johane P Allard
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
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44
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Schwenger KJP, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20:1712-1723. [PMID: 24587650 PMCID: PMC3930971 DOI: 10.3748/wjg.v20.i7.1712] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/05/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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45
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Petta S, Miele L, Bugianesi E, Cammà C, Rosso C, Boccia S, Cabibi D, Di Marco V, Grimaudo S, Grieco A, Pipitone RM, Marchesini G, Craxì A. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One 2014; 9:e87523. [PMID: 24498332 PMCID: PMC3911959 DOI: 10.1371/journal.pone.0087523] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 12/22/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND AIMS Variant in glucokinase regulatory protein (GCKR), associated with lipid and glucose traits, has been suggested to affect fatty liver infiltration. We aimed to assess whether GCKR rs780094 C→T SNP influences the expression of steatosis, lobular inflammation and fibrosis in NAFLD patients, after correction for PNPLA3 genotype. METHODS In 366 consecutive NAFLD patients (197 from Sicily, and 169 from center/northern Italy), we assessed anthropometric, biochemical and metabolic features; liver biopsy was scored according to Kleiner. PNPLA3 rs738409 C>G and GCKR rs780094 C>T single nucleotide polymorphisms were also assessed. RESULTS At multivariate logistic regression analysis in the entire NAFLD cohort, the presence of significant liver fibrosis (>F1) was independently linked to high HOMA (OR 1.12, 95% CI 1.01-1.23, p = 0.02), NAFLD activity score ≥ 5 (OR 4.09, 95% CI 2.45-6.81, p<0.001), and GCKR C>T SNP (OR 2.06, 95% CI 1.43-2.98, p<0.001). Similar results were observed considering separately the two different NAFLD cohorts. GCKR C>T SNP was also associated with higher serum triglycerides (ANOVA, p = 0.02) in the entire cohort. CONCLUSIONS In patients with NAFLD, GCKR rs780094 C>T is associated with the severity of liver fibrosis and with higher serum triglyceride levels.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Luca Miele
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Dept. of Medical Sciences, University of Turin, Turin, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Chiara Rosso
- Division of Gastroenterology, Dept. of Medical Sciences, University of Turin, Turin, Italy
| | - Stefania Boccia
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Daniela Cabibi
- Cattedra di Anatomia Patologica, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Antonio Grieco
- Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Rosaria Maria Pipitone
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
| | - Giulio Marchesini
- Dipartimento di Medicina e Gastroenterologia, “Alma Mater Studiorum,” Università di Bologna, Bologna, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy
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Abstract
The metabolic syndrome and the hepatitis C virus (HCV) infection are 2 global health care challenges with a complex interaction. Insulin resistance, a central component of the metabolic syndrome, is epidemiologically and pathophysiologically intrinsically linked to HCV infection. Insulin resistance and diabetes affect clinical outcomes in patients with liver disease related to HCV, namely, incidence of hepatocellular carcinoma, liver-related mortality, fibrosis progression rate, response to antiviral therapy, and possibly the incidence of cardiovascular events. Viral and metabolic steatosis and its interactions with HCV and the metabolic syndrome are discussed. Management and the need for further research conclude the article.
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Affiliation(s)
- Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, 4 rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland
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47
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García-Monzón C, Lo Iacono O, Crespo J, Romero-Gómez M, García-Samaniego J, Fernández-Bermejo M, Domínguez-Díez A, Rodríguez de Cía J, Sáez A, Porrero JL, Vargas-Castrillón J, Chávez-Jiménez E, Soto-Fernández S, Díaz A, Gallego-Durán R, Madejón A, Miquilena-Colina ME. Increased soluble CD36 is linked to advanced steatosis in nonalcoholic fatty liver disease. Eur J Clin Invest 2014; 44:65-73. [PMID: 24134687 DOI: 10.1111/eci.12192] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 10/15/2013] [Indexed: 12/24/2022]
Abstract
BACKGROUND Soluble CD36 (sCD36) clusters with insulin resistance, but no evidence exists on its relationship with hepatic fat content. We determined sCD36 to assess its link to steatosis in nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) patients. MATERIALS AND METHODS Two hundred and twenty-seven NAFLD, eighty-seven CHC, and eighty-five patients with histologically normal liver (NL) were studied. Steatosis was graded by Kleiner's histological scoring system. Serum sCD36 and hepatic CD36 expression was assessed by immunoassay and immunohistochemistry, respectively. RESULTS In NAFLD, serum sCD36 levels were significantly higher in simple steatosis than in NL (361.4 ± 286.4 vs. 173.9 ± 137.4 pg/mL, respectively; P < 0.001), but not in steatohepatitis (229.6 ± 202.5 pg/mL; P = 0.153). In CHC, serum sCD36 levels were similar regardless of the absence (428.7 ± 260.3 pg/mL) or presence of steatosis (387.2 ± 283.6 pg/mL; P = 0.173). A progressive increase in serum sCD36 values was found in NAFLD depending on the histological grade of steatosis (P < 0.001), but not in CHC (P = 0.151). Serum sCD36 concentrations were independently associated with advanced steatosis in NAFLD when adjusted by demographic and anthropometric features [odds ratio (OR), 1.001; 95% confidence interval (CI), 1.000 to 1.002; P = 0.021] and by metabolic variables (OR, 1.002; 95% CI, 1.000 to 1.003; P = 0.001). Interestingly, a significant correlation was observed between hepatic CD36 and serum sCD36 (ρ = 0.499, P < 0.001). CONCLUSIONS Increased serum sCD36 is an independent factor associated with advanced steatosis in NAFLD.
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Affiliation(s)
- Carmelo García-Monzón
- Liver Research Unit, University Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa, CIBEREHD, Madrid, Spain
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48
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Kosters A, Sun D, Wu H, Tian F, Felix JC, Li W, Karpen SJ. Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXRα) determines male-female differences in the expression of hepatic lipid processing genes in mice. PLoS One 2013; 8:e71538. [PMID: 23977068 PMCID: PMC3747242 DOI: 10.1371/journal.pone.0071538] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 06/28/2013] [Indexed: 02/06/2023] Open
Abstract
Many hepatic functions including lipid metabolism, drug metabolism, and inflammatory responses are regulated in a sex-specific manner due to distinct patterns of hepatic gene expression between males and females. Regulation for the majority of these genes is under control of Nuclear Receptors (NRs). Retinoid X Receptor alpha (RXRα) is an obligate partner for multiple NRs and considered a master regulator of hepatic gene expression, yet the full extent of RXRα chromatin binding in male and female livers is unclear. ChIP-Seq analysis of RXRα and RNA Polymerase2 (Pol2) binding was performed livers of both genders and combined with microarray analysis. Mice were gavage-fed with the RXR ligand LG268 for 5 days (30 mg/kg/day) and RXRα-binding and RNA levels were determined by ChIP-qPCR and qPCR, respectively. ChIP-Seq revealed 47,845 (male) and 46,877 (female) RXRα binding sites (BS), associated with ∼12,700 unique genes in livers of both genders, with 91% shared between sexes. RXRα-binding showed significant enrichment for 2227 and 1498 unique genes in male and female livers, respectively. Correlating RXRα binding strength with Pol2-binding revealed 44 genes being male-dominant and 43 female-dominant, many previously unknown to be sexually-dimorphic. Surprisingly, genes fundamental to lipid metabolism, including Scd1, Fasn, Elovl6, and Pnpla3-implicated in Fatty Liver Disease pathogenesis, were predominant in females. RXRα activation using LG268 confirmed RXRα-binding was 2-3 fold increased in female livers at multiple newly identified RXRα BS including for Pnpla3 and Elovl6, with corresponding ∼10-fold and ∼2-fold increases in Pnpla3 and Elovl6 RNA respectively in LG268-treated female livers, supporting a role for RXRα regulation of sexually-dimorphic responses for these genes. RXRα appears to be one of the most widely distributed transcriptional regulators in mouse liver and is engaged in determining sexually-dimorphic expression of key lipid-processing genes, suggesting novel gender- and gene-specific responses to NR-based treatments for lipid-related liver diseases.
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Affiliation(s)
- Astrid Kosters
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Deqiang Sun
- Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Hao Wu
- Department of Biostatistics, School of Public Health, Emory University, Atlanta, Georgia, United States of America
| | - Feng Tian
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Julio C. Felix
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Wei Li
- Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Saul J. Karpen
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
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49
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Doycheva I, Patel N, Peterson M, Loomba R. Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes. J Diabetes Complications 2013; 27:293-300. [PMID: 23312215 PMCID: PMC4167586 DOI: 10.1016/j.jdiacomp.2012.10.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 10/06/2012] [Accepted: 10/09/2012] [Indexed: 12/23/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist due to shared risk factors. Their rising prevalence parallels the growing epidemic of obesity and insulin resistance (IR). In patients with T2DM and biopsy-proven NAFLD, a significantly higher prevalence of nonalcoholic steatohepatitis (NASH) (63-87%), any fibrosis (22-60%), and advanced fibrosis (4-9%) is noted. Possible risk factors for more advanced liver disease include concomitant metabolic syndrome with three or more components, visceral obesity, older age, increased duration of diabetes, and family history of diabetes. Liver biopsy is strongly suggested in these patients. Cardiovascular disease (CVD) and malignancy are the leading causes of death in this population, but a growing body of evidence shows liver-related mortality as an important cause of death, including an increased rate of hepatocellular carcinoma (HCC) in diabetes. The presence of NAFLD in T2DM is also associated with increased overall mortality. We aim with this review to summarize the results from studies investigating NAFLD in T2DM and to outline the factors that predict more advanced liver histology as well as the impact of these hepatic changes on CVD, overall and liver-related mortality.
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Affiliation(s)
- Iliana Doycheva
- Department of Medicine, Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Niraj Patel
- Department of Medicine, Division of General Internal Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Michael Peterson
- Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Rohit Loomba
- Department of Medicine, Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego, La Jolla, CA 92093, USA
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50
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Petta S, Rosso C, Leung R, Abate ML, Booth D, Salomone F, Gambino R, Rizzetto M, Caviglia P, Smedile A, Grimaudo S, Cammà C, Craxì A, George J, Bugianesi E. Effects of IL28B rs12979860 CC genotype on metabolic profile and sustained virologic response in patients with genotype 1 chronic hepatitis C. Clin Gastroenterol Hepatol 2013; 11:311-7.e1. [PMID: 23220171 DOI: 10.1016/j.cgh.2012.11.022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 11/01/2012] [Accepted: 11/21/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with genotype 1 chronic hepatitis C (G1 CHC) frequently develop steatosis and insulin resistance (IR), caused by metabolic and viral factors. These accelerate the progression of liver disease and reduce the response to therapy. A sustained virologic response (SVR) to therapy in patients with G1 CHC is associated strongly with polymorphisms near the interleukin-28B (IL28B) gene, but the interaction between IL28B genotype and IR, and their combined effects on SVR, have not been defined. We tested the association between the IL28B rs12979860 single-nucleotide polymorphism and metabolic features, including IR, and evaluated their effects on SVR. METHODS We performed genotype analysis of IL28B rs12979860 for 434 white G1 CHC patients who underwent consecutive biopsy analysis at 3 tertiary centers. Metabolic profile analyses included assessments of lipid levels and IR by the homeostasis model assessment. RESULTS Patients with the CC polymorphism in IL28B had higher levels of total and low-density lipoprotein cholesterol, lower levels of triglycerides, and a lower prevalence of IR and moderate-severe steatosis (P < .05) than patients without this genotype. By multiple logistic regression analysis, body mass index (odds ratio [OR], 1.223; P < .001), level of triglycerides (OR, 1.007; P = .006), the CC polymorphism in IL28B (OR, 0.378; P = .001), and levels of HCV RNA greater than 850,000 IU/mL (OR, 1.803; P = .01) were associated with IR. The CC polymorphism in IL28B (OR, 8.350; P < .001) and IR (OR, 0.432; P = .005), but not steatosis (OR, 0.582; P = 0.25), was associated with an SVR. CONCLUSIONS In white patients with G1 CHC, the IL28B rs12979860 CC genotype is associated with reduced IR. IL28B rs12979860 genotype and IR by the homeostasis model assessment strongly affect the outcome of antiviral therapy.
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Affiliation(s)
- Salvatore Petta
- Division of Gastroenterology, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Palermo, Italy.
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