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McCary A, Sheu YS, Chesbrough K, Jonas MC. Improved Liver Fibrosis Regression After Direct-Acting Antiviral Therapy in Hepatitis C Patients: A Comparison of Patients With and Without MASLD. Clin Ther 2025:S0149-2918(25)00087-6. [PMID: 40287335 DOI: 10.1016/j.clinthera.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/12/2025] [Accepted: 03/23/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Chronic Hepatitis C (CHC) often results in liver fibrosis. Therefore, an important benefit of CHC treatment with direct-acting antiviral (DAA) medication is liver fibrosis regression. However, it is unclear how concurrent liver steatosis affects fibrosis regression following DAA therapy. Recent guidelines have defined liver steatosis associated with metabolic syndrome as metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to examine the association of MASLD with the fibrosis regression benefits of DAA treatment for CHC. METHODS We conducted an observational retrospective analysis using electronic health records of patients aged 18-65 who completed DAA therapy for CHC from 2016 through 2022. FIB-4 scores were calculated during three time periods: just prior to DAA initiation, within 6 months post-DAA completion, and within 6-12 months post-DAA completion. These scores categorized liver fibrosis as high risk (>3.25), intermediate risk (1.45-3.25), or low risk (<1.45). An ordinal logistic regression model assessed the degree of fibrosis regression across these periods in CHC patients with and without MASLD. FINDINGS We identified 845 patients with CHC who received DAA therapy, of whom 225 met MASLD criteria. Both CHC patients with and without MASLD exhibited a decrease in FIB-4 category (coefficient = -0.361, P < 0.001) within the year following DAA therapy. The reduction in FIB-4 category post-treatment was more pronounced in the MASLD group compared to the non-MASLD group, as evidenced by a significant interaction between group and time period (coefficient = -0.439, P = 0.004). IMPLICATIONS In our cohort, MASLD was associated with greater liver fibrosis regression in the year following DAA therapy for CHC. This suggests that the concurrent presence of MASLD is not associated with diminished fibrosis regression from DAA therapy. Additional research is needed to determine the exact mechanism responsible for DAA-associated fibrosis regression in patients with MASLD.
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Affiliation(s)
- Alexis McCary
- Department of Gastroenterology, Mid-Atlantic Permanente Medical Group, Upper Marlboro, Maryland; Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia.
| | - Yi-Shin Sheu
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - Karen Chesbrough
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - M Cabell Jonas
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
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Migdal AL, Jagannathan R, Qayed E, Cusi K, McCoy RG, Pasquel FJ, Miller LS. Association of Obesity, Diabetes, and Alcohol Use With Liver Fibrosis Among US Adults With Hepatitis C Virus Infection. JAMA Netw Open 2022; 5:e2142282. [PMID: 35302636 PMCID: PMC8933742 DOI: 10.1001/jamanetworkopen.2021.42282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
This cross-sectional study examines the association of obesity, diabetes, and alcohol use with liver fibrosis among treatment-naive US adults with hepatitis C virus infection seen at a safety-net hospital in Atlanta, Georgia.
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Affiliation(s)
- Alexandra L. Migdal
- Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Ram Jagannathan
- Division of Hospital Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Emad Qayed
- Division of Gastroenterology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes, and Metabolism, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida
| | - Rozalina G. McCoy
- Division of Community Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota
| | - Francisco J. Pasquel
- Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Lesley S. Miller
- Division of General Internal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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3
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Diabetes Mellitus and Risk of Hepatic Fibrosis/Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5308308. [PMID: 31080822 PMCID: PMC6475555 DOI: 10.1155/2019/5308308] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 03/27/2019] [Indexed: 02/06/2023]
Abstract
Development of cirrhosis is two- to threefold greater in patients with diabetes mellitus (DM), and in this setting, the prevalence of cirrhosis is surging worldwide. The present review served to examine clinical ties between DM and liver fibrosis and hepatic cirrhosis and explore related biologic mechanisms. Pathways contributing to various etiologies of cirrhosis in conjunction with DM were key investigative targets.
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Yen YH, Kuo FY, Kee KM, Chang KC, Tsai MC, Hu TH, Lu SN, Wang JH, Hung CH, Chen CH. Diabetes is associated with advanced fibrosis and fibrosis progression in non-genotype 3 chronic hepatitis C patients. Dig Liver Dis 2019; 51:142-148. [PMID: 30076015 DOI: 10.1016/j.dld.2018.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 07/01/2018] [Accepted: 07/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted. AIMS We investigated whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients. METHODS A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC was studied. After excluding patients with biopsy-proven or ultrasound-identified cirrhosis, there were 684 patients without cirrhosis. All 684 patients underwent hepatocellular carcinoma surveillance using ultrasound every 6 months, with a median duration of follow-up evaluation of 102.4 months. During the follow-up period, 60 patients developed cirrhosis according to ultrasound findings. RESULTS For the subgroup of 684 patients without cirrhosis, Kaplan-Meier survival analyses showed no significantly different cumulative incidences of cirrhosis (log-rank test; P = 0.71) among the patients with diabetes as compared to those without. However, after making adjustments for age, gender, fibrosis, steatosis, sustained virological response status, and obesity using Cox's proportional hazard model, diabetes was found to be an independent predictor for cirrhosis (HR = 1.9; 95% CI = 1.05-3.43, P = 0.03). CONCLUSIONS Diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients.
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Affiliation(s)
- Yi-Hao Yen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fang-Ying Kuo
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kwong-Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuo-Chin Chang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Koch LK, Yeh MM. Nonalcoholic fatty liver disease (NAFLD): Diagnosis, pitfalls, and staging. Ann Diagn Pathol 2018; 37:83-90. [PMID: 30312882 DOI: 10.1016/j.anndiagpath.2018.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with obesity, diabetes and the metabolic syndrome, not only in the Western societies, but also in most regions of the world in the 21st century. The spectrum of its histopathology ranges from steatosis to nonalcoholic steatohepatitis (NASH), with risk for progressive fibrosis that may lead to cirrhosis and hepatocellular carcinoma (HCC). Benign and malignant liver tumors have also been more frequently reported with the increasing prevalence of obesity and diabetes. This review addresses the pathology of NAFLD and NASH, and their diagnostic features, diagnostic pitfalls, grading and staging, and clinical correlation.
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Affiliation(s)
- Lisa K Koch
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
| | - Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America.
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6
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Younossi Z, Kochems K, de Ridder M, Curran D, Bunge EM, de Moerlooze L. Should adults with diabetes mellitus be vaccinated against hepatitis B virus? A systematic review of diabetes mellitus and the progression of hepatitis B disease. Hum Vaccin Immunother 2017; 13:2695-2706. [PMID: 28742983 PMCID: PMC5703367 DOI: 10.1080/21645515.2017.1353850] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite the burden of diabetes mellitus (DM), little is known about the role of this and other metabolic syndromes on the severity of hepatitis B virus (HBV) chronicity and liver disease progression. The value of hepatitis B vaccination and its impact on liver diseases and HCC has been largely demonstrated, adult vaccination coverage is however suboptimal and DM diagnosis represents an opportunity for the HCP to discuss hepatitis B and other adult vaccinations. We performed a systematic literature search to identify studies (January 2000 to January 2017) describing liver disease progression among patients with HBV by DM status. Risk factors were assessed including the relationship between HBV and non-alcoholic steatohepatitis (NASH). Data were extracted systematically and assessed descriptively. Twenty articles described liver disease progression and one article evaluated NASH among subjects with HBV by DM status. Fourteen articles reported that DM as a predictor for the outcome, including delayed seroclearance, cirrhosis, hepatocellular carcinoma, transplant/mortality and death, whereas no association on liver outcomes was found in 7 studies. In summary, our review suggests that DM is associated with the progression of severe liver outcomes in adults with HBV, although more studies are needed to understand the benefits of HBV vaccination in adults with DM and liver-diseases.
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Affiliation(s)
- Zobair Younossi
- a Center for Liver Disease, Department of Medicine , Inova Fairfax Hospital , Falls Church , VA , USA
| | - Katrin Kochems
- b Pallas Health Research and Consultancy , Rotterdam , The Netherlands
| | - Marc de Ridder
- c Faculté de Pharmacie, Université Libre de Bruxelles , Bruxelles , Belgium
| | | | - Eveline M Bunge
- b Pallas Health Research and Consultancy , Rotterdam , The Netherlands
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7
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Brunt EM. Nonalcoholic fatty liver disease and the ongoing role of liver biopsy evaluation. Hepatol Commun 2017; 1:370-378. [PMID: 29404465 PMCID: PMC5721411 DOI: 10.1002/hep4.1055] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 05/02/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common underlying causes of chronically elevated liver tests and liver disease in adults and children worldwide and may be strongly suspected if not diagnosed by ever evolving and available serologic and imaging‐based noninvasive tests. However, the definitive diagnosis of the most progressive form of NAFLD, nonalcoholic steatohepatitis, and the identification of fibrosis stage still require liver biopsy evaluation as noninvasive testing has not replaced some of the specifics or the totality of information obtainable from liver biopsy. In this review, both the role and value of a liver biopsy evaluation in NAFLD/ nonalcoholic steatohepatitis are examined from publications related to a selected variety of settings. Details of the most commonly used semiquantitative methods of analysis are discussed, and some useful potential pitfalls for differential diagnostic consideration in liver biopsy interpretation are given. (Hepatology Communications 2017;1:370–378)
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Affiliation(s)
- Elizabeth M Brunt
- Department of Pathology and Immunology Washington University School of Medicine St Louis MO
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8
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Zuchowska A, Kwapiszewska K, Chudy M, Dybko A, Brzozka Z. Studies of anticancer drug cytotoxicity based on long-term HepG2 spheroid culture in a microfluidic system. Electrophoresis 2017; 38:1206-1216. [DOI: 10.1002/elps.201600417] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 01/10/2017] [Accepted: 01/10/2017] [Indexed: 01/24/2023]
Affiliation(s)
- Agnieszka Zuchowska
- Department of Microbioanalytics, Institute of Biotechnology; Warsaw University of Technology, Warsaw; Poland
| | - Karina Kwapiszewska
- Department of Microbioanalytics, Institute of Biotechnology; Warsaw University of Technology, Warsaw; Poland
- Institute of Physical Chemistry; Polish Academy of Sciences; Warsaw Poland
| | - Michal Chudy
- Department of Microbioanalytics, Institute of Biotechnology; Warsaw University of Technology, Warsaw; Poland
| | - Artur Dybko
- Department of Microbioanalytics, Institute of Biotechnology; Warsaw University of Technology, Warsaw; Poland
| | - Zbigniew Brzozka
- Department of Microbioanalytics, Institute of Biotechnology; Warsaw University of Technology, Warsaw; Poland
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9
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Adinolfi LE, Rinaldi L, Guerrera B, Restivo L, Marrone A, Giordano M, Zampino R. NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations. Int J Mol Sci 2016; 17:ijms17060803. [PMID: 27231906 PMCID: PMC4926337 DOI: 10.3390/ijms17060803] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Barbara Guerrera
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Luciano Restivo
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Mauro Giordano
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
| | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, Second University of Naples, Naples 80100, Italy.
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Kralj D, Jukić LV, Stojsavljević S, Duvnjak M, Smolić M, Čurčić IB. Hepatitis C Virus, Insulin Resistance, and Steatosis. J Clin Transl Hepatol 2016; 4:66-75. [PMID: 27047774 PMCID: PMC4807145 DOI: 10.14218/jcth.2015.00051] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/15/2016] [Accepted: 02/16/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.
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Affiliation(s)
- Dominik Kralj
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Lucija Virović Jukić
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Sanja Stojsavljević
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Marko Duvnjak
- Department of Gastroenterology and Hepatology, Sisters of Charity University Hospital Center, Zagreb, Croatia
| | - Martina Smolić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Ines Bilić Čurčić
- Department of Pharmacology, Faculty of Medicine, University of Osijek, Department of Endocrinology and metabolism disorders, University Hospital Center, Osijek, Osijek, Croatia
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11
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Dyal HK, Aguilar M, Bhuket T, Liu B, Holt EW, Torres S, Cheung R, Wong RJ. Concurrent Obesity, Diabetes, and Steatosis Increase Risk of Advanced Fibrosis Among HCV Patients: A Systematic Review. Dig Dis Sci 2015; 60:2813-24. [PMID: 26138651 DOI: 10.1007/s10620-015-3760-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 06/10/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Rising rates of obesity, diabetes mellitus (DM), and nonalcoholic fatty liver disease among patients with chronic hepatitis C virus infection (HCV) may contribute to more rapid disease progression. AIM To evaluate the impact of concurrent obesity, DM, and steatosis on disease progression among HCV patients. METHODS A systematic review using structured keyword search of MEDLINE and EMBASE from January 1, 2001, to July 1, 2014, was performed to identify original articles evaluating the association of obesity, DM, and steatosis with advanced fibrosis (AF) among adults with chronic HCV. Studies involving HCV patients coinfected with human immunodeficiency virus, hepatitis B virus, hepatocellular carcinoma, or other chronic liver diseases were excluded. Quality assessment utilized Newcastle-Ottawa Scale. RESULTS Twenty cohort studies met inclusion criteria for analyses. Obesity was associated with increased risk of AF in seven studies with effect size ranging from OR 1.08 to 7.69. However, four studies did not demonstrate a significant association between obesity and AF. The presence of advanced steatosis among HCV patients was associated with increased risk of AF in 12 studies (OR 1.80-14.3). Concurrent DM was associated with increased risk of AF in six studies (OR 2.25-9.24). Thirteen studies were good quality, and seven studies were fair quality. CONCLUSION Concurrent DM and steatosis are associated with increased risk of AF among chronic HCV patients. The majority of studies demonstrated significant associations of obesity with AF. Targeted interventions to optimize management of obesity-related diseases among HCV patients may help mitigate HCV disease progression.
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Affiliation(s)
- Harleen K Dyal
- Division of Gastroenterology and Hepatology, Highland Hospital, Alameda Health System - Highland Hospital Campus, Highland Care Pavilion 5th Floor, Endoscopy Unit, 1411 East 31st Street, Oakland, CA, 94602, USA,
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12
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Marcellin P, Grotzinger K, Theodore D, Demuth D, Manns M, Bañares Cañizares R, Pike J, Forssen UM. Severity of liver disease among chronic hepatitis C patients: an observational study of 4594 patients in five European countries. J Gastroenterol Hepatol 2015; 30:364-71. [PMID: 25088088 DOI: 10.1111/jgh.12698] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/13/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Assessment of the severity of liver disease following infection with hepatitis C virus (HCV) is important in treatment selection and prognosis. As invasive liver biopsy procedures are regarded as the reference method to assess the stage of fibrosis, it is important to identify patient characteristics that are predictive of liver fibrosis severity. The aim of the study was to describe the distribution of liver severity scores, clinical characteristics, and physicians' assessment of fibrosis among HCV patients in five European countries. METHODS This cross-sectional study retrospectively reviewed the medical records of patients who were chronically infected with HCV in 2006. Patients managed for HCV at any of 60 sites in France, Germany, Italy, Spain, and the UK were included. Data collected included patient demographics and clinical characteristics. A combination of univariate and multivariate regression analyses were used to identify predictors of fibrosis severity and factors associated with undergoing biopsy. RESULTS Four thousand five hundred and ninety-four chronically infected HCV patients were included in this analysis. Management approaches differed between countries, with variations in biopsy use (59.3-18.4%) and preferred fibrosis scoring systems. Where histology results were available, 43.4%, 23.8%, and 32.9% had mild, moderate, and severe fibrosis, respectively. Factors associated with undergoing a biopsy included male gender and co-infection with hepatitis B virus. Chronic alcoholism, a lower first platelet count, and older age were predictors of increased liver fibrosis severity. CONCLUSIONS These data suggest that there are major differences in how specialists manage their HCV patients across five major European countries.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, Hôpital Beaujon, University Paris-Diderot and INSERM CRB3, Clichy, France
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13
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Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014; 147:754-64. [PMID: 25109884 DOI: 10.1053/j.gastro.2014.07.056] [Citation(s) in RCA: 250] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 07/23/2014] [Accepted: 07/25/2014] [Indexed: 12/13/2022]
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are significant causes of chronic liver disease worldwide. Both are characterized by histological lesions that can include steatosis, and each can lead to cirrhosis. It might be possible for pathologists to identify lesions and patterns of ALD and NAFLD; we review these lesions and propose methods to distinguish between the disorders. Any form of ALD can lead to end-stage liver disease, according to long-term studies of biopsy specimens and patient outcomes. Although steatosis can be a significant cofactor in progression of established chronic liver disease, or even development of hepatocellular carcinoma, only steatohepatitis indicates the presence of progressive liver disease in patients with NAFLD. Pediatric and adolescent NAFLD differ from adult nonalcoholic steatohepatitis and should be recognized as distinct conditions. Benign and malignant liver tumors have been more frequently reported with the increasing prevalence of obesity and diabetes. Histological scoring systems for ALD and NAFLD have been proposed to monitor efficacy in clinical trials and serve as prognostic factors. We review what we have learned from pathological analyses about the development of these disorders and how this information might be used to detect and treat them.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington
| | - Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
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14
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Lonardo A, Adinolfi LE, Restivo L, Ballestri S, Romagnoli D, Baldelli E, Nascimbeni F, Loria P. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20:7089-7103. [PMID: 24966582 PMCID: PMC4064057 DOI: 10.3748/wjg.v20.i23.7089] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/17/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a successful pathogen on the grounds that it exploits its host's metabolism to build up viral particles; moreover it favours its own survival by inducing chronic disease and the development of specific anatomic changes in the infected organ. Steatosis, therefore, is associated with HCV infection by necessity rather than by chance alone. Approximately 6% of HCV patients have steatohepatitis. Interestingly, HCV steatosis occurs in the setting of multiple metabolic abnormalities (hyperuricemia, reversible hypocholesterolemia, insulin resistance, arterial hypertension and expansion of visceral adipose tissue) collectively referred to as "hepatitis C-associated dysmetabolic syndrome" (HCADS). General, nonalcoholic fatty liver disease (NAFLD)-like, mechanisms of steatogenesis (including increased availability of lipogenic substrates and de novo lipogenesis; decreased oxidation of fatty substrates and export of fatty substrates) are shared by all HCV genotypes. However, genotype 3 seemingly amplifies such steatogenic molecular mechanisms reported to occur in NAFLD via more profound changes in microsomal triglyceride transfer protein; peroxisome proliferator-activated receptor alpha; sterol regulatory element-binding proteins and phosphatase and tensin homologue. HCV steatosis has a remarkable clinical impact in as much as it is an acknowledged risk factor for accelerated fibrogenesis; for impaired treatment response to interferon and ribavirin; and development of hepatocellular carcinoma. Recent data, moreover, suggest that HCV-steatosis contributes to premature atherogenesis via both direct and indirect mechanisms. In conclusion, HCV steatosis fulfills all expected requirements necessary to perpetuate the HCV life cycle. A better understanding of the physiology of HCADS will likely result in a more successful handling of disease with improved antiviral success rates.
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Central portalization correlates with fibrosis but not with risk factors for nonalcoholic steatohepatitis in steatotic chronic hepatitis C. Int J Hepatol 2014; 2014:329297. [PMID: 25525520 PMCID: PMC4265703 DOI: 10.1155/2014/329297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 11/10/2014] [Indexed: 12/23/2022] Open
Abstract
Concomitant steatosis in chronic hepatitis C is associated with fibrosis and unfavorable treatment outcome. Central zone injury in nonalcoholic steatohepatitis (NASH) manifests as central portalization, with centrizonal microvessels and ductular reaction. We investigated whether central portalization in steatotic HCV biopsies would identify patients with metabolic risk factors for NASH. Liver biopsies with chronic hepatitis C and >10% steatosis (n = 65) were evaluated for the degree of steatosis, zonation of steatosis, fibrosis, and nonalcoholic fatty liver disease (NAFLD) activity score. The presence of centrizonal microvessels, sinusoidal capillarization, ductular reaction, and CK7 positive intermediate-phenotype hepatocytes were evaluated by CD34 and CK7 immunostain. The degree of steatosis and fibrosis showed a positive correlation. Additional positive correlations were noted between centrizonal angiogenesis and NAFLD activity score and central portalization and fibrosis. However, neither central portalization nor zonation of steatosis identified patients with metabolic risk factors for NASH. Therefore, central portalization cannot be used as a surrogate marker to identify patients with metabolic risk factors for NASH in steatotic HCV biopsies. The mechanism of centrizonal injury in steatotic HCV hepatitis is not solely attributable to the metabolic risk factors for NASH.
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Guo CH, Chen PC, Ko WS. Status of essential trace minerals and oxidative stress in viral hepatitis C patients with nonalcoholic fatty liver disease. Int J Med Sci 2013; 10:730-7. [PMID: 23630437 PMCID: PMC3638296 DOI: 10.7150/ijms.6104] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 04/10/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) may be an important factor leading to altered trace mineral homeostasis, thereby accelerating the progression of hepatitis C virus (HCV) infection. Our aim was to determine whether NAFLD influenced the status of certain essential trace minerals and oxidative stress in chronic HCV-infected patients. DESIGN AND METHODS Blood biochemical parameters were determined in a group of 30 healthy, non-obese, non-diabetic participants (CNL group), and hepatitis C patients without NAFLD (HCV group, n = 30) and with NAFLD (HCV-NAFLD group, n = 32). RESULTS Concentrations of thiobarbituric acid reactive substances (TBARS; a measure of oxidative stress), C-reactive protein (CRP), ferritin, aminotransferases, lipid profiles, and insulin metabolism were markedly abnormal in both patient groups than in CNL subjects. Compared to patients in the HCV group, those with HCV-NAFLD group had lower high-density lipoprotein concentrations, higher low-density lipoprotein and homeostasis model assessment-insulin resistance (HOMA-IR) values, disrupted antioxidant enzyme activities, and elevated TBARS concentrations, as well as decreased plasma concentrations of trace minerals zinc (Zn) and selenium (Se) and increased copper (Cu). The alterations in mineral homeostasis were also linked to TBARS, CRP, ferritin, lipoproteins, and HOMA-IR values in the HCV-NAFLD group. CONCLUSIONS There is a progressive deterioration in the homeostasis of minerals (Zn, Se, and Cu) in HCV-NAFLD patients, which may reflect greater oxidative stress and inflammation. These results suggest that the disturbance in mineral metabolism by NAFLD has an impact on the effectiveness of treatment for chronic HCV infection.
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Affiliation(s)
- Chih-Hung Guo
- Micro-Nutrition & Biomedical Nutrition Labs, Institute of Biomedical Nutrition, Hung Kuang University, Taichung 433, Taiwan, Republic of China
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Brunt EM, Neuschwander-Tetri BA, Burt AD. Fatty liver disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:293-359. [DOI: 10.1016/b978-0-7020-3398-8.00006-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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El-Serag HB, Lechel A, Rudolph KL. Epidemiology and Molecular Mechanisms of Hepatocarcinogenesis. ZAKIM AND BOYER'S HEPATOLOGY 2012:142-156. [DOI: 10.1016/b978-1-4377-0881-3.00010-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Darling JM, Lemon SM, Fried MW. Hepatitis C. SCHIFF'S DISEASES OF THE LIVER 2011:582-652. [DOI: 10.1002/9781119950509.ch25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abstract
In chronic viral hepatitis, the role of liver biopsy as a diagnostic test has seen a decline, paralleled by its increasing importance for prognostic purposes. Nowadays, the main indication for liver biopsy in chronic viral hepatitis is to assess the severity of the disease, in terms of both necro-inflammation (grade) and fibrosis (stage), which is important for prognosis and therapeutic management. Several scoring systems have been proposed for grading and staging chronic viral hepatitis and there is no a general consensus on the best system to be used in the daily practice. All scoring systems have their drawbacks and all may be affected by sampling and observer variability. Whatever the system used, a histological score is a reductive approach since damage in chronic viral hepatitis is a complex biological process. Thus, scoring systems are not intended to replace the detailed, descriptive, pathology report. In fact, lesions other than those scored for grading and staging may have clinical relevance and should be assessed and reported. This paper aims to provide a systematic approach to the interpretation of liver biopsies obtained in cases of chronic viral hepatitis, with the hope of helping general pathologists in their diagnostic practice.
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Sanyal AJ. Role of insulin resistance and hepatic steatosis in the progression of fibrosis and response to treatment in hepatitis C. Liver Int 2011; 31 Suppl 1:23-8. [PMID: 21205134 DOI: 10.1111/j.1478-3231.2010.02397.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hepatitis C is a common cause of chronic viral infection of the liver. It is associated with insulin resistance and the development of type 2 diabetes mellitus. It is also associated with the development of hepatic steatosis. The presence of hepatic steatosis is associated with an increased risk of having hepatic fibrosis. This is also associated with the severity of insulin resistance. These findings are specifically germane for those with genotype1 infection. Genotype 3 infection independently causes steatosis and successful treatment of the virus is followed by resolution of steatosis. In genotype 1 infection, the presence of hepatic steatosis is also a risk factor for failure to respond to pegylated interferon and ribavirin therapy. Unfortunately efforts to treat insulin resistance prior to antiviral therapy have not been very successful. Newer efforts focused on the role of specific micro RNAs in mediating the metabolic effects of hepatitis C virus infection may provide to ameliorate the metabolic risks of HCV infection.
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Affiliation(s)
- Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0341, USA.
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Midgard H, Bang C, Raknerud N, Dalgard O. Liver fibrosis in hepatitis C patients of Pakistani versus Scandinavian origin. Scand J Gastroenterol 2010; 45:1503-8. [PMID: 20698740 DOI: 10.3109/00365521.2010.510571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aim of this study was to examine the significance of native country for the stage of liver fibrosis in a population of HCV patients of Pakistani or Scandinavian origin living in Oslo. PATIENTS AND METHODS We included 122 consecutive HCV patients at two hepatitis clinics in Oslo, 73 of Scandinavian and 49 of Pakistani origin. Inclusion criteria were being HCV RNA positive, treatment naïve and having an adequate liver biopsy. The biopsies were scored according to the Metavir index, which scores fibrosis on a scale from 0 to 4 and necroinflammatory activity on a scale from 0 to 3. Steatosis was scored according to the percentage of hepatocytes having lipid droplets in their cytoplasm. Demographical, clinical, virological and biochemical data for the two groups were registered from the patient files. RESULTS The median age was 43 and 42 years and 53% and 51% were male among the Scandinavian and Pakistani patients, respectively. Among the patients of Pakistani origin 18/49 (37%) had bridging fibrosis (F3) or cirrhosis (F4) compared to 11/73 (15%) Scandinavian patients (p=0.006). The mean fibrosis score was 1.78 in the Pakistani and 0.82 in the Scandinavian group (p<0.001). The mean necroinflammatory activity score was 1.22 and 0.78 in the Pakistanis and Scandinavians, respectively (p<0.001). In the Pakistani group more patients had ≥5% steatosis (59% vs. 33%; p=0.004), diabetes mellitus (24% vs. 0%; p<0.001), overweight (46% vs. 34%; p=0.232), genotype 3 (84% vs. 42%; p<0.001) and ALT and AST levels above the reference range (84% vs. 64%; p=0.020 and 88% vs. 68%; p=0.014) compared to the Scandinavian. Multivariate regression analyses identified age ≥40 years (OR 10.13; 95% CI 2.65-39.12) and genotype 3 (OR 5.02; 95% CI 1.19-21.17) as independent predictors of bridging fibrosis/cirrhosis. CONCLUSIONS In HCV patients of similar age, those of Pakistani origin had more advanced liver disease than those of Scandinavian origin. Possible explanations are longer duration of the infection and higher occurrence of diabetes mellitus, liver steatosis and genotype 3 in the Pakistani group.
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Affiliation(s)
- Håvard Midgard
- Department of Gastroenterology, Aker University Hospital, Oslo, Norway.
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Abstract
Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease (NAFLD) are measured. Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD, i.e. nonalcoholic steatohepatitis (NASH) and fibrosis. Included in the lesions of NAFLD are steatosis, lobular and portal inflammation, hepatocyte injury in the forms of ballooning and apoptosis, and fibrosis. However, patterns of these lesions are as distinguishing as the lesions themselves. Liver injury in adults and children due to NAFLD may have different histological patterns. In this review, the rationale for liver biopsy, as well as the histopathological lesions, the microscopically observable patterns of injury, and the differential diagnoses of NAFLD and NASH are discussed.
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Noninvasive liver steatosis quantification using MRI techniques combined with blood markers. Eur J Gastroenterol Hepatol 2010; 22:973-82. [PMID: 20665947 DOI: 10.1097/meg.0b013e32833775fb] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AIMS To evaluate the accuracy of different techniques of MRI steatosis quantification, based on histological grading and quantification of liver steatosis. PATIENTS AND METHODS Twenty-three patients (21 with nonalcoholic fatty liver disease and two controls) were included. Steatosis was evaluated in liver specimens using histological grading (five grades) and steatosis area (% of liver surface) was computed using an inhouse automated image analysis. The following five MRI quantification techniques were performed: two-point Dixon, three-point Dixon, DUAL, spin echo method and a new technique called multi-echo gradient-echo (MFGRE). Interobserver (two observers) and intersite (three different liver sites) agreements were evaluated for the two best-performing methods. RESULTS Steatosis area was correlated with steatosis grade: Rs (Spearman coefficient) = 0.82, P value of less than 0.001. The steatosis area was significantly different between S0-S2 and S3-S4 grades: 4.2 + or - 2.4 versus 16.4 + or - 8.9% (P< 0.001). Correlations between the MRI techniques and steatosis area (or grading) were: MFGRE, Rs = 0.72 (0.78); spin echo method, Rs = 0.72 (0.76); DUAL, Rs =0.71 (0.76); two-point Dixon, Rs = 0.71 (0.75); three-point Dixon, Rs = 0.67 (0.77). Interobserver (Ric = 0.99) and intersite (Ric = 0.97) agreements were excellent for the liver steatosis measurement by MFGRE. The noninvasive diagnosis of the steatosis area was improved by adding blood markers like ALT and triglycerides to MFGRE (aR2: 0.805). CONCLUSION MRI, and in particular the MFGRE method, provides accurate and automatic quantification for the noninvasive evaluation of liver steatosis, either as a single measurement or in combination with blood variables.
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Kawaguchi T, Sata M. Importance of hepatitis C virus-associated insulin resistance: Therapeutic strategies for insulin sensitization. World J Gastroenterol 2010; 16:1943-52. [PMID: 20419831 PMCID: PMC2860071 DOI: 10.3748/wjg.v16.i16.1943] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection. Generally, persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases. However, these complications are not major causes of death in patients with HCV-associated insulin resistance. Indeed, insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection. Mounting evidence indicates that HCV-associated insulin resistance may cause (1) hepatic steatosis; (2) resistance to anti-viral treatment; (3) hepatic fibrosis and esophageal varices; (4) hepatocarcinogenesis and proliferation of hepatocellular carcinoma; and (5) extrahepatic manifestations. Thus, HCV-associated insulin resistance is a therapeutic target at any stage of HCV infection. Although the risk of insulin resistance in HCV-infected patients has been documented, therapeutic guidelines for preventing the distinctive complications of HCV-associated insulin resistance have not yet been established. In addition, mechanisms for the development of HCV-associated insulin resistance differ from lifestyle-associated insulin resistance. In order to ameliorate HCV-associated insulin resistance and its complications, the efficacy of the following interventions is discussed: a late evening snack, coffee consumption, dietary iron restriction, phlebotomy, and zinc supplements. Little is known regarding the effect of anti-diabetic agents on HCV infection, however, a possible association between use of exogenous insulin or a sulfonylurea agent and the development of HCC has recently been reported. On the other hand, insulin-sensitizing agents are reported to improve sustained virologic response rates. In this review, we summarize distinctive complications of, and therapeutic strategies for, HCV-associated insulin resistance. Furthermore, we discuss supplementation with branched-chain amino acids as a unique insulin-sensitizing strategy for patients with HCV-associated insulin resistance.
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Persico M, Masarone M, La Mura V, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol 2009. [PMID: 19152451 DOI: 10.3748/wjg.v15.i4.462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). METHODS We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). RESULTS Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. CONCLUSION These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.
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Affiliation(s)
- Marcello Persico
- Internal Medicine and Hepatology Unit, Second University of Naples, Via F. Petrarca, 101/b, Naples 80122, Italy.
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Brunt EM, Kleiner DE, Wilson LA, Unalp A, Behling CE, Lavine JE, Neuschwander-Tetri BA, NASH Clinical Research NetworkA list of members of the Nonalcoholic Steatohepatitis Clinical Research Network can be found in the Appendix. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009; 49:809-20. [PMID: 19142989 PMCID: PMC2928479 DOI: 10.1002/hep.22724] [Citation(s) in RCA: 285] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with "more than mild" in adults were older age (P < 0.0001), female gender (P = 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P = 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P = 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). "More than mild" in the pediatric biopsies correlated with younger age (P = 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with "more than mild" were steatosis amount (P = 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, "more than mild" was associated with steatosis location (P = 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). CONCLUSION Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease.
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Affiliation(s)
- Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
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Persico M, Masarone M, Mura VL, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol 2009; 15:462-466. [PMID: 19152451 PMCID: PMC2653368 DOI: 10.3748/wjg.15.462] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Revised: 10/31/2008] [Accepted: 11/07/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). METHODS We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). RESULTS Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. CONCLUSION These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.
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Pathology of fatty liver: differential diagnosis of non-alcoholic fatty liver disease. ACTA ACUST UNITED AC 2008. [DOI: 10.1016/j.mpdhp.2008.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Abstract
OBJECTIVE The inflammatory subtype of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, is becoming one of the most important causes of chronic liver disease. In this article, we discuss the epidemiology, pathogenesis, and clinical and radiologic diagnosis of the subtypes of nonalcoholic fatty liver disease. CONCLUSION We discuss the current and evolving imaging tests in the evaluation of hepatic fatty content, inflammation, and fibrosis.
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Petta S, Cammà C, Di Marco V, Alessi N, Cabibi D, Caldarella R, Licata A, Massenti F, Tarantino G, Marchesini G, Craxì A. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol 2008; 103:1136-44. [PMID: 18477344 DOI: 10.1111/j.1572-0241.2008.01813.x] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV). METHODS Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis. RESULTS Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of >/=3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422-6.098), low platelets (OR 0.994, 95% CI 0.981-0.999), low cholesterol (OR 0.987, 95% CI 0.976-0.998), high ferritin (OR 1.002, 95% CI 1.001-1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463-4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) (P= 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other (P= 0.42). CONCLUSIONS In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.
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Affiliation(s)
- Salvatore Petta
- Cattedra ed Unità Operativa di Gastroenterologia, University of Palermo, Palermo, Italy
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Blonsky JJ, Harrison SA. Review article: nonalcoholic fatty liver disease and hepatitis C virus--partners in crime. Aliment Pharmacol Ther 2008; 27:855-65. [PMID: 18315584 DOI: 10.1111/j.1365-2036.2008.03672.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) are frequent causes of chronic liver disease. In recent years, there have been significant revelations as regards the relationship between NAFLD and CHC. AIM To conduct a systematic, evidence-based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. METHODS The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included. RESULTS Hepatic steatosis affects up to 80% of patients with CHC and is dependent on both viral and host factors. While insulin resistance (IR) is associated with hepatic steatosis and hepatitis C virus, genotype-specific pathogenic mechanisms have been identified and are currently the focus of intense investigation in the literature. Clinical implications of concurrent NAFLD, CHC and IR include increased disease progression, elevated risk of hepatocellular carcinoma, and decreased response to antiviral therapy. CONCLUSIONS NAFLD and IR are common in patients with CHC virus infection. IR is a driving force in the development of hepatic steatosis. Because of the clinical implications of hepatic steatosis and IR in the setting of CHC, further studies evaluating treatments, which may increase response to antiviral therapy, are needed.
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Affiliation(s)
- J J Blonsky
- Division of Gastroenterology and Hepatology, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA
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Ohki T, Tateishi R, Sato T, Masuzaki R, Imamura J, Goto T, Yamashiki N, Yoshida H, Kanai F, Kato N, Shiina S, Yoshida H, Kawabe T, Omata M. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clin Gastroenterol Hepatol 2008; 6:459-64. [PMID: 18387499 DOI: 10.1016/j.cgh.2008.02.012] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is not fully elucidated whether obesity enhances hepatocarcinogenesis in patients with chronic hepatitis C. The aim of this study was to investigate the relationship between body weight and risk of hepatocarcinogenesis in chronic hepatitis C patients. METHODS We enrolled 1431 patients with chronic hepatitis C who visited our liver clinic between 1994 and 2004, excluding those with hepatocellular carcinoma (HCC) at their visit or with a previous history of HCC. They were divided into 4 groups according to body mass index (BMI): underweight (< or =18.5 kg/m(2), N = 112); normal (18.5 to less than 25 kg/m(2), N = 1023); overweight (25 to less than 30 kg/m(2), N = 265); and obese (>30 kg/m(2), N = 31). We assessed the impact of obesity on the hepatocarcinogenesis adjusted by multivariate Cox proportional hazard regression with other risk factors found significant in univariate analysis. RESULTS During the follow-up period (mean, 6.1 y), HCC developed in 340 patients, showing cumulative incidence rates of 10.5%, 19.7%, and 36.8% at 3, 5, and 10 years, respectively. The incidence differed significantly among the BMI groups (P = .007). Adjusting for other significant factors, overweight and obesity were shown to be an independent risk factor of HCC, with a hazard ratio of 1.86 (95% confidence interval, 1.09-3.16; P = .022) and 3.10 (95% confidence interval, 1.41-6.81; P = .005) as compared with the underweight patients. CONCLUSIONS The risk of HCC in patients with chronic hepatitis C increases in proportion to BMI in a wide range of its values, from underweight to obese.
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Affiliation(s)
- Takamasa Ohki
- Department of Gastroenterology, University of Tokyo, Hongo, Tokyo, Japan
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Minakari M, Sameni FK, Shalmani HM, Molaee M, Zali MR. Hepatic steatosis in Iranian patients with chronic hepatitis C. Med Princ Pract 2008; 17:126-30. [PMID: 18287796 DOI: 10.1159/000112966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2007] [Accepted: 03/31/2007] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To evaluate the frequency and severity of fibrosis, and also the association of various viral and host factors of steatosis in Iranian patients with hepatitis C (CHC). SUBJECTS AND METHODS Eighty treatment-naive CHC patients, age 37.6 +/- 11.77 years, were studied. Percutaneous liver biopsy was performed for all patients. Based on pathology reports, patients were divided into two groups: with and without significant steatosis. Hepatitis C virus RNA (HCV-RNA), various viral and host factors, and biochemical findings and genotyping of HCV were compared in the two groups. RESULTS Of the 80 patients, 42 (52.5%) had pathologic evidence of significant steatosis. The mean serum level of cholesterol, triglyceride, glucose, and gamma-glutamyl transpeptidase as well as the mean body mass index, viral load, stage of fibrosis and frequency of genotype 3 were significantly higher in the patients with than those without steatosis (p < 0.05). In multivariate analysis, only genotype 3 and viral load had significant association with steatosis. In patients with genotype 3 infection, the mean viral load in those with and without steatosis was 1,623,357 +/- 833,543.46 and 821,262.1 +/- 924,480 copies/ml, respectively, and the difference was statistically significant (p = 0.009). The mean viral load in patients with genotype 1 infection was not significantly different between the two groups. The mean stage of fibrosis was higher in the group that had significant steatosis (p < 0.05). CONCLUSION Steatosis is a common finding in Iranian patients with CHC. Infection with HCV genotype 3 and high viral load in these patients are associated with significant steatosis.
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Affiliation(s)
- Mohammad Minakari
- Department of Gastroenterology, Isfahan University of Medical Sciences, Isfahan, Iran.
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Abstract
Patients with chronic hepatitis C virus (HCV) infection and disease-related complications - among them cirrhosis and liver failure - pose a particular management challenge. Some of these patients may fail to respond to current therapy (non-responders), and some are affected so severely that treatment puts them at an unacceptable risk for complications. Treatment with pegylated interferon (peg-IFN) plus ribavirin improves hepatic enzyme levels and eradicates the virus in approximately 50% of patients; however, a significant number of patients do not respond to therapy or relapse following treatment discontinuation. Several viral, hepatic and patient-related factors influence response to IFN therapy; many of these factors cannot be modified to improve long-term outcomes. Identifying risk factors and measuring viral load early in the treatment can help to predict response to IFN therapy and determine the need to modify or discontinue treatment. Retreatment options for patients who have failed therapy are limited. Retreatment with peg-IFN has been successful in some patients who exhibit an inadequate response to conventional IFN treatment, particularly those who have relapsed. Consensus IFN, another option in treatment-resistant patients, has demonstrated efficacy in the retreatment of non-responders and relapsers. Although the optimal duration of retreatment and the benefits and safety of maintenance therapy have not been determined, an extended duration is likely needed. This article reviews the risk factors for HCV treatment resistance and discusses the assessment and management of difficult-to-treat patients.
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Affiliation(s)
- Nyingi Kemmer
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA
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Bedossa P, Moucari R, Chelbi E, Asselah T, Paradis V, Vidaud M, Cazals-Hatem D, Boyer N, Valla D, Marcellin P. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46:380-7. [PMID: 17659580 DOI: 10.1002/hep.21711] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Although steatosis is a common histological feature in chronic hepatitis C (CHC), nonalcoholic steatohepatitis (NASH) has not yet been clearly characterized in this context. The aim of this prospective study was to investigate the characteristics of patients with NASH and CHC. Biopsies were categorized as CHC alone (178 patients [57%]), CHC+steatosis (94 patients [34%]), or CHC+NASH (24 patients [9%]). Patients with CHC+NASH had significantly higher AST and triglyceride levels and lower high-density lipoprotein (HDL) cholesterol or total cholesterol than patients with CHC+steatosis. They also showed more steatosis and higher METAVIR fibrosis stage than patients with CHC+steatosis. Genotype 3 was more frequent in patients with CHC+NASH than in patients with CHC+steatosis or CHC alone. Patients with genotype 3 and CHC+NASH were similar to those with CHC+steatosis or with CHC alone according to triglyceride or the homeostasis model for assessment of insulin resistance (HOMA-IR), whereas in patients with genotype 1, HOMA-IR and triglyceride increased progressively from CHC alone to CHC+steatosis to CHC+NASH. In multivariate analysis, triglyceride and HDL cholesterol were predictors of NASH in patients with genotype 1, whereas in patients with genotype 3, AST was the only predictor. CONCLUSION Patients with CHC+NASH differ significantly from those with CHC+steatosis and CHC alone in terms of biological and metabolic parameters and more advanced histopathological lesions. NASH is more common in genotype 3 and is not associated with metabolic dysfunctions in this subgroup, suggesting that NASH may complicate steatosis in CHC irrespective of etiology of steatosis.
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Affiliation(s)
- Pierre Bedossa
- Service d'Anatomie Pathologique, CNRS UMR 8149, Clichy, France.
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El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-76. [PMID: 17570226 DOI: 10.1053/j.gastro.2007.04.061] [Citation(s) in RCA: 4257] [Impact Index Per Article: 236.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 04/18/2007] [Indexed: 02/06/2023]
Abstract
Primary liver cancer, which consists predominantly of hepatocellular carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality. HCC has several interesting epidemiologic features including dynamic temporal trends; marked variations among geographic regions, racial and ethnic groups, and between men and women; and the presence of several well-documented environmental potentially preventable risk factors. Moreover, there is a growing understanding on the molecular mechanisms inducing hepatocarcinogenesis, which almost never occurs in healthy liver, but the cancer risk increases sharply in response to chronic liver injury at the cirrhosis stage. A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve our current concepts for screening and treatment of this disease.
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Affiliation(s)
- Hashem B El-Serag
- Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine, Houston Center for Quality of Care and Utilization Studies, Houston, Texas, USA.
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40
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Bondini S, Kallman J, Wheeler A, Prakash S, Gramlich T, Jondle DM, Younossi ZM. Impact of non-alcoholic fatty liver disease on chronic hepatitis B. Liver Int 2007; 27:607-11. [PMID: 17498244 DOI: 10.1111/j.1478-3231.2007.01482.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The impact of superimposed non-alcoholic fatty liver disease (NAFLD) is well established in patients with chronic hepatitis C (CH-C), but the impact in patients with chronic hepatitis B (CH-B) is less clear. AIM This study aims to evaluate the prevalence of NAFLD in patients with CH-B and the association with viral and host factors, particularly in patients with metabolic syndrome (MS). DESIGN Data from patients with CH-B was obtained from our databases. Patients with excessive alcohol use were excluded. Hepatitis B virus (HBV) genotyping by INNO-LIPA was available for some patients. The presence of MS was defined according to the Adult Treatment Panel III (ATP III). All biopsies were read by two hepatopathologists using Metavir, modified histologic activity index (MHAI), as well as a NAFLD pathologic protocol. Patients were classified as (1) those without NAFLD; (2) those with simple hepatic steatosis; (3) and those with superimposed non-alcoholic steatohepatitis (NASH). Factors associated with superimposed NAFLD, its subtypes, and hepatic fibrosis were also analysed. RESULTS Subjects included 153 HBV patients [66% male, age 50.5+/-27.5 years, body mass index 24.7+/-3.7 kg/m(2), waist 83.2+/-10.9 cm; 8.5% Caucasian, 67% Asian, aspartate aminotransferase (AST) 63.2+/-88.2 IU/l, alanine aminotransferase (ALT) 98.6+/-164.6 IU/l, glucose 111.6+/-50.5 mg/dl, HBV-DNA 1.8 x 10(8)+/-1.9 x 10(6) copies/ml, 7% with MS, 13% with diabetes, 20% with arterial hypertension and 8.5% with dyslipidaemia]. Liver biopsy was available for 64 subjects [19% had superimposed NAFLD, 13% had superimposed NASH, 86% had some degree of fibrosis, and 39% had advanced fibrosis (Ishak >3)]. Patients with HBV and superimposed NASH were significantly older (55 vs. 42 years, P=0.008), more likely to have hypertension (63% vs. 15%, P=0.006) and dyslipidaemia (50% vs. 8%, P=0.006), and had a larger waist circumference (92 vs. 83 cm, P=0.03). The presence of fibrosis was associated with higher waist circumference (84 vs. 80 cm, P=0.03), higher HBV-DNA (1.9 x 10(8) vs. 5 x 10(6) copies/ml, P=0.005), and elevated ALT >40 IU/l (73.6% vs. 33.3%, P=0.02). CONCLUSIONS The components of MS (obesity, hypertension, and dyslipidaemia) are associated with the presence of NASH in patients with CH-B. The presence of hepatic fibrosis seems to be associated with known host and viral factors as well as the presence of abdominal obesity.
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Affiliation(s)
- Silvia Bondini
- Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA 22003-6800, USA
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Alsatie M, Kwo PY, Gingerich JR, Qi R, Eckert G, Cummings OW, Imperiale TF. A multivariable model of clinical variables predicts advanced fibrosis in chronic hepatitis C. J Clin Gastroenterol 2007; 41:416-21. [PMID: 17413613 DOI: 10.1097/01.mcg.0000225593.93577.64] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND A noninvasive method to identify advanced hepatic fibrosis (AHF) in chronic hepatitis C (CHC) could preclude the need for routine liver biopsy. Recent evidence suggests that obesity may contribute to hepatic fibrosis in hepatitis C virus infection. GOALS To determine whether clinical variables, including body mass index (BMI), can predict risk of AHF. STUDY Retrospective review of untreated CHC patients evaluated between 1993 and 2002 without clinical or physical evidence of end-stage liver disease. Liver biopsies were scored for fibrosis, steatosis, and inflammation. Multivariable analysis was used to derive and internally validate a prediction equation. A clinical index was created from the equation by assigning points for each variable. The risk of AHF was measured for each risk category. RESULTS Two hundred eighty-six satisfied inclusion criteria, of which 86 (30%) had AHF. In the derivation subgroup (N=190), 5 factors were independently associated with AHF: diabetes mellitus, platelets count <150,000, aspartate aminotransferase > or =65 IU/mL, international normalized ratio > or =1.1, and bilirubin > or =0.85 mg/dL. The corresponding risk index contained 3 categories: low-risk (score of 0), intermediate risk (scores of 1 to 3), and high risk (scores of > or =4), in which the respective risks of AHF were 9%, 34%, and 92%. Inclusion of BMI did not improve model performance. CONCLUSIONS A model for estimating AHF risk in CHC performed well in this population. BMI had no effect on the risk of AHF. If this model can be validated in other patient cohorts, it could preclude the need for liver biopsy in patients with scores of 0 or > or =4.
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Affiliation(s)
- Mazen Alsatie
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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42
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Ciccaglione AR, Marcantonio C, Tritarelli E, Equestre M, Vendittelli F, Costantino A, Geraci A, Rapicetta M. Activation of the ER stress gene gadd153 by hepatitis C virus sensitizes cells to oxidant injury. Virus Res 2007; 126:128-38. [PMID: 17368854 DOI: 10.1016/j.virusres.2007.02.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2006] [Revised: 02/08/2007] [Accepted: 02/09/2007] [Indexed: 02/07/2023]
Abstract
HCV induces endoplasmic reticulum (ER) stress which correlates with transcriptional induction of ER stress genes. Previously, we reported that expression of HCV structural proteins activates the ER stress and pro-apoptotic gene gadd153 which plays a relevant role in cell death induced by oxidative stress. In the present study, using human hepatic cell lines Huh7 carrying a full-length HCV replicon, we demonstrated that replication and expression of the complete set of HCV proteins were associated with elevated expression of gadd153. Analysis of gadd153 promoter activity revealed that both the ATF4 and the ATF6 pathways, which are typically induced during ER stress response, contribute to the induction of gadd153 in HCV replicon cells. Activation of the ATF4 pathway was confirmed by identification of increased levels of ATF4 protein in replicon cells. Importantly, we showed that, following H2O2 treatment, gadd153 gene reached higher levels of expression in replicon cells. Consistent with the marked induction of the pro-apoptotic gene gadd153, HCV replicon cells showed an increased vulnerability to oxidant injury. Treatment of replicon cells with a specific small interfering RNA, targeted to gadd153 gene, reduced basal expression of gadd153 and decreased cell death following H2O2. These findings suggest that gadd153 may play a major role in sensitivity of HCV replicon cell to oxidative stress.
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Affiliation(s)
- A R Ciccaglione
- Department of Infectious, Parasitic and Immune-Mediated Disease, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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Abstract
Fatty liver disease is currently recognized as a common cause of liver test elevation, paralleling the worldwide 'epidemic' of obesity in adults and children. In many clinical practices, there is recognition that liver biopsy evaluation is the only means of diagnosis (or exclusion) of fatty liver disease, as neither laboratory tests nor imaging studies to date can provide complete data related to amount of steatosis, inflammation, liver cell injury, fibrosis, and architectural remodeling. Liver biopsy evaluation also provides a means of 'grading and staging' the lesions of fatty liver disease and of detecting clinically unsuspected processes. Liver biopsy evaluation is often the primary end point in clinical trials of treatment, thus, standardization of diagnosis and methods of grading and staging have become important. In this review, these concepts as well as the pathophysiologic bases for them are discussed.
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Affiliation(s)
- Elizabeth M Brunt
- Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome, which is becoming an increasingly common cause of chronic liver disease. Histological changes typically mainly affect perivenular regions of the liver parenchyma and include an overlapping spectrum of steatosis, steatohepatitis and persinusoidal or pericellular fibrosis, in some cases leading to cirrhosis. Once cirrhosis has developed, typical hepatocellular changes are often no longer conspicuous, leading to such cases being mistakenly diagnosed as 'cryptogenic'. Portal inflammation, ductular reaction and periportal fibrosis can also be seen as part of the morphological spectrum of NAFLD, particularly in the paediatric population. Hepatocellular carcinoma has also been described as a complication of NAFLD-associated cirrhosis. NAFLD is also an important cofactor in other chronic liver diseases, especially hepatitis C. Histological assessments have an important role to play in the diagnosis and management of NAFLD. These include making the potentially important distinction between simple steatosis and steatohepatitis and providing pointers to the aetiology, including cases where a dual pathology exists. A number of systems have been devised for grading and staging the severity of fatty liver disease. These require further evaluation, but have a potentially important role to play in determining prognosis and monitoring therapeutic responses.
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Affiliation(s)
- S G Hübscher
- Department of Pathology, University of Birmingham, Birmingham, UK.
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45
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Massard J, Ratziu V, Thabut D, Moussalli J, Lebray P, Benhamou Y, Poynard T. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol 2006; 44:S19-24. [PMID: 16356583 DOI: 10.1016/j.jhep.2005.11.009] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cirrhosis is the end-stage consequence of fibrosis progression in patients with chronic hepatitis C. The median time from infection to cirrhosis is 30 years, with a high inter-individual variability, which is now better understood. Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male gender, alcohol consumption, HIV co-infection and low CD4 count. Metabolic conditions such as steatosis, being overweight and diabetes are emerging as independent co-factors of fibrogenesis. The recent validation of non-invasive biomarkers should facilitate the study of fibrosis progression in large populations.
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Affiliation(s)
- Julien Massard
- Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
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Papatheodoridis GV, Chrysanthos N, Savvas S, Sevastianos V, Kafiri G, Petraki K, Manesis EK. Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis. J Viral Hepat 2006; 13:303-310. [PMID: 16637860 DOI: 10.1111/j.1365-2893.2005.00677.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus has been reported to have an increased prevalence and to be associated with more severe fibrosis in patients with chronic hepatitis C. We evaluated the prevalence of diabetes mellitus in patients with chronic hepatitis B or C as well as the possible association between presence of diabetes and extent of liver fibrosis. In total, 434 consecutive patients with histologically documented hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) were studied. The relationships of diabetes and epidemiological, somatomorphic, laboratory and histological patient characteristics were evaluated. Liver histological lesions were blindly evaluated according to the Ishak's classification. Diabetes was present in 58 (13%) patients, without any difference between those with chronic hepatitis B (14%) or C (13%). Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (7.7%) than 3-4 (10.4%) than 5-6 (29.2%) (P < 0.001). The presence of diabetes was independently associated with higher gamma-glutamyl-transpeptidase (GGT) levels and more severe fibrosis or presence of cirrhosis (P < 0.001) as well as with presence of hepatic steatosis and increased serum triglycerides levels (P < 0.02). In the noncirrhotic patients, diabetes was significantly associated with older age and higher GGT levels, but not with the extent of fibrosis. In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.
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Affiliation(s)
- G V Papatheodoridis
- Academic Department of Internal Medicine, Hippokration General Hospital, Athens, Greece.
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Perumalswami P, Kleiner DE, Lutchman G, Heller T, Borg B, Park Y, Liang TJ, Hoofnagle JH, Ghany MG. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology 2006; 43:780-7. [PMID: 16557550 DOI: 10.1002/hep.21078] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatic steatosis is common in patients with chronic hepatitis C (CHC) and is reported to be a risk factor for progression of fibrosis. The aims of this study were to evaluate the interactions between hepatic steatosis and fibrosis in a well-defined cohort of patients with CHC. The computerized pathology database at the National Institutes of Health Clinical Center was searched for patients with CHC who had undergone liver biopsy between 1980 and 2003. Biopsies were scored for necroinflammation using a modified histology activity index, fibrosis using the Ishak system, and steatosis as either none (<5% of cells), mild (5%-25%), or moderate-to-severe (>25%). Four hundred ninety-four patients were identified. The mean age was 44 +/- 9.8 years; 60% were male, 80% Caucasian, and 65% were infected with genotype 1. Steatosis was mild in 31% and moderate to severe in 9% of patients. In univariate analysis, steatosis was associated with increased age, body weight, body mass index (BMI), alanine aminotransferase (ALT) levels, histological necroinflammatory activity, and fibrosis. However, in multivariate analysis, steatosis was associated only with increased age, BMI, and ALT levels and not with fibrosis. One hundred thirty-six patients had 2 liver biopsies separated by 0.5 to 17 years. Worsening of fibrosis occurred in 40% of patients and correlated independently with increasing age, periportal necroinflammation, and ALT elevations but not with steatosis. In conclusion, in this cohort of patients with CHC, steatosis was associated with older age, higher BMI, and higher serum ALT levels but not with the presence of or subsequent progression of fibrosis.
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Affiliation(s)
- Ponni Perumalswami
- Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA
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Thomopoulos KC, Arvaniti V, Tsamantas AC, Dimitropoulou D, Gogos CA, Siagris D, Theocharis GJ, Labropoulou-Karatza C. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol 2006; 18:233-237. [PMID: 16462535 DOI: 10.1097/00042737-200603000-00002] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The clinical significance of hepatic steatosis in chronic hepatitis B virus patients is poorly understood. The purpose of this study was to determine risk factors for liver steatosis in chronic hepatitis B patients and its relationship with fibrosis. METHODS We retrospectively evaluated liver biopsies from patients with chronic hepatitis B treated in our department. Patients co-infected with other viruses (hepatitis C virus, HIV) or suffering from liver disease of any other cause were excluded from the study, as well as patients consuming alcohol above 30 g/day for males or 20 g/day for females. Liver steatosis, necroinflammation and fibrosis were assessed. RESULTS A total of 233 patients with chronic hepatitis B were included in the study. The mean age was 44.7+/-16.2 years. There were 164 men (70.4%) and 69 women (29.6%). The majority of patients were HbeAg-negative, 196/233 (84.1%). Thirty-seven patients had cirrhosis (15.9%). Steatosis was present in 42 patients (18%). Steatosis was independently associated with fasting glucose level (P=0.019) and being overweight (body mass index >or=25; P=0.021). No correlation was found with stage of fibrosis, grade of inflammation, alcohol use or other parameters. Ninety-four out of 233 patients (40.3%) had advanced fibrosis. Patients with advanced fibrosis were older than those with minimal or no fibrosis (47.6+/-17 versus 42.3+/-15.2 years, P=0.024) and more frequently had a higher grade of necroinflammation activity (57/94 (60.6%) versus 26/139 (18.7%), P<0.0001). There was no significant association between advanced fibrosis and the presence of steatosis or mild alcohol consumption. CONCLUSION Hepatic steatosis is present in 18% of our patients with biopsy-proven chronic hepatitis B. Steatosis is independently associated only with body mass index and fasting glucose level, risk factors for metabolic steatohepatitis, and was not correlated with the degree of fibrosis.
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49
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Abstract
Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Studies have identified both host and viral factors associated with disease progression. The importance of general factors such as age at infection, gender, immune status and alcohol consumption has long been recognized; however recently, polymorphisms in a wide array of genes have also been shown to be associated with progressive fibrosis. How specific viral proteins may contribute to disease progression has also been studied. This review highlights what is currently known about the factors associated with progressive liver injury in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.
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Affiliation(s)
- Jordan J Feld
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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50
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Abstract
The overall prevalence of steatosis in patients with Hepatitis C virus (HCV) chronic infection is 55.5% (range 34.8-81.2%). This is a two to threefold increase compared with the prevalence of steatosis in chronic hepatitides because of other aetiologies and of the figures expected on the grounds of a steatosis-HCV chance association. HCV genotype 3 (HCV-3) has specific epidemiological features; furthermore, as compared with HCV-non-3 genotypes, it is associated with a higher prevalence (74.1%vs 47.9%, P < 0.01) and with more severe grades of steatosis (prevalence of grade 3 steatosis 29.6 vs 5.5 P < 0.01). Host and viral factors play a role, although to a variable extent, in the pathogenesis of HCV-3 and non-3 steatosis. HCV load and body mass index are associated with steatosis in HCV-3 and in HCV-non-3 patients respectively. Serum cholesterol levels and liver steatosis at baseline follow an inverse relationship in HCV infection. As hypocholesterolaemia corrects only in those sustained responders to antiviral treatment both in genotype 3 and in non-3 genotypes, the occurrence of a virally induced, acquired and reversible hypobetalipoproteinaemia seems plausible. Steatosis affects the natural course of HCV infection: it is associated with fibrosis, a possible mediator of increased risk to develop type 2 diabetes, it impairs the response to antiviral treatment in HCV-3 patients and might constitute a risk factor for the development of hepatocellular carcinoma. These observations indicate the need to evaluate the efficacy of combined antiviral and 'metabolic' approaches vs standard antiviral regimes in patients with steatosis and HCV chronic infection.
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Affiliation(s)
- A Lonardo
- Unità Operativa di Medicina Interna e Gastroenterologia, Nuovo Ospedale Civile-Estense di Baggiovara, Modena, Italy.
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