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Speliotes EK, Schneider CV. PNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease. Liver Int 2025; 45:e16106. [PMID: 39559944 DOI: 10.1111/liv.16106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/03/2024] [Accepted: 09/08/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression. METHODS We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists. RESULTS The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers. CONCLUSION The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.
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Affiliation(s)
- Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Carolin Victoria Schneider
- Department of Gastroenterology, Endocrinology and Intensive Care, RWTH Aachen University, Aachen, Germany
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Magri MC, Alvarez MSM, Iogi AA, Alves GM, Manchiero C, Dantas BP, Prata TVG, Nunes AKDS, Tengan FM. Study of CXCL9-11 gene polymorphisms in liver fibrosis among patients with chronic hepatitis C. Pathog Dis 2021; 79:6105222. [PMID: 33476381 DOI: 10.1093/femspd/ftab007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/19/2021] [Indexed: 01/10/2023] Open
Abstract
Several factors are associated with the progression of chronic hepatitis C: comorbidities, lifestyle, and pathogenic factors, including immune response, apoptosis and heredity. Single nucleotide polymorphisms (SNPs) in the PNPLA3 and TM6SF2 genes are more widely studied genetic risk factors, while CXCL9-11 chemokines produced by hepatocytes in the process of infection are less well studied. Our aim was to evaluate the influence of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 in liver fibrosis when analysed together with PNPLA3 rs738409 and TM6SF2 rs58542926. The study included 219 patients with chronic hepatitis C. SNP genotyping was performed by real-time PCR. Univariate and multivariate analyses were used to detect the association between SNPs and advanced fibrosis in a recessive genetic model. All SNPs had a minimum allele frequency >5%, and CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 were in high linkage disequilibrium (D' ≥ 0.84). In the multivariate analysis, we observed that male gender (P = 0.000), older age (P = 0.025), moderate to intense inflammatory activity (P = 0.002), moderate to accentuated hepatic steatosis (P = 0.026) and the CT genotype of the TM6SF2 rs58542926 SNP (P = 0.014) presented significant associations with advanced fibrosis. Overall, the CXCL9 rs10336, CXCL10 rs3921, CXCL11 rs4619915 and PNPLA3 rs738409 SNPs did not influence liver fibrosis among patients with chronic hepatitis C.
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Affiliation(s)
- Mariana Cavalheiro Magri
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Maria Stella Montanha Alvarez
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Anny Ayumi Iogi
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Grayce Mendes Alves
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Caroline Manchiero
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Bianca Peixoto Dantas
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Thamiris Vaz Gago Prata
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Arielle Karen da Silva Nunes
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Fátima Mitiko Tengan
- Laboratorio de Investigacao Medica em Hepatologia por Virus (LIM-47), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.,Departamento de Molestias Infecciosas e Parasitarias, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 255. Bairro Cerqueira Cesar. Sao Paulo, SP, Brazil. CEP 05403-000
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Manchiero C, Nunes AKDS, Magri MC, Dantas BP, Mazza CC, Barone AA, Tengan FM. The rs738409 polymorphism of the PNPLA3 gene is associated with hepatic steatosis and fibrosis in Brazilian patients with chronic hepatitis C. BMC Infect Dis 2017; 17:780. [PMID: 29258449 PMCID: PMC5735770 DOI: 10.1186/s12879-017-2887-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 12/06/2017] [Indexed: 02/08/2023] Open
Abstract
Background Prospective studies have shown that 80% of acute hepatitis C virus (HCV) cases progress to chronic infection; approximately 10-20% of patients with these conditions will develop liver cirrhosis within 2 to 3 decades, and 1-5% will develop liver cancer. Some studies have indicated that the rs738409 polymorphism of the PNPLA3 gene is associated with steatosis and the progression of advanced fibrosis. This study assessed the contribution of the PNPLA3 rs738409 polymorphism with regard to the steatosis and degree of liver fibrosis in Brazilian patients diagnosed with chronic hepatitis C. Methods A total of 290 patients were evaluated at the Clinics Hospital of the School of Medicine, University of São Paulo, between 2010 and 2015. The inclusion criteria were age ≥ 18 years and positive anti-HCV antibody and HCV RNA tests. The participants were evaluated based on medical consultation, blood tests, and liver biopsies conducted before specific antiviral therapies were applied. The associations between the rs738409 PNPLA3 gene polymorphism and steatosis and advanced fibrosis were tested under a recessive inheritance model using logistic regression analysis, including age, gender, BMI, ethnicity/color, HOMA-IR, alcohol intake, HCV genotype 3, and the rs58542926 TM6SF2 gene polymorphism as covariates. Results The mean age of the patients was 54.9 years old (range, 28 to 82 years), and 124 (42.8%) patients were male; 226 (77.9%) were white, 43 (14.8%) were pardo, and 21 (7.2%) were black Brazilians. Of the patients included in this study, 133 (45.9%) presented with the CC genotype, 63 (21.7%) with the CG genotype, and 94 (32.4%) with the GG genotype of the PNPLA3 gene I148M variant. We observed that the associations between PNPLA3 rs738409 GG genotype and steatosis was significant (OR: 2.16; 95% CI 1.26-3.72). The same genotype was associated to advanced fibrosis too (OR:2.64; 95% CI 1.26-5.53). Conclusions Associations between the rs738409 polymorphism of the PNPLA3 gene genotype GG and hepatic steatosis and advanced fibrosis were observed. Studies are still needed to clarify the influence of these polymorphisms on hepatic steatosis and degree of fibrosis among individuals diagnosed with chronic hepatitis C. Electronic supplementary material The online version of this article (10.1186/s12879-017-2887-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Caroline Manchiero
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil
| | - Arielle Karen da Silva Nunes
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil
| | - Mariana Carvalheiro Magri
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil
| | - Bianca Peixoto Dantas
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil
| | - Celso Carmo Mazza
- Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Antonio Alci Barone
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil.,Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Fátima Mitiko Tengan
- Medical Research Laboratory for Virus (Laboratório de Investigação Médica por Vírus - LIM47) of the Clinics Hospital, School of Medicine, University of São Paulo (Universidade de São Paulo - USP), São Paulo, Brazil. .,Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paulo, Brazil.
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Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Meng G, Zhang B, Yu F, Li C, Zhang Q, Liu L, Wu H, Xia Y, Bao X, Shi H, Su Q, Gu Y, Fang L, Yang H, Yu B, Sun S, Wang X, Zhou M, Jia Q, Jiao H, Wang B, Guo Q, Carvalhoa LA, Sun Z, Song K, Yu M, Niu K. Soft drinks consumption is associated with nonalcoholic fatty liver disease independent of metabolic syndrome in Chinese population. Eur J Nutr 2017; 57:2113-2121. [PMID: 28702720 DOI: 10.1007/s00394-017-1485-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Excessive consumption of soft drinks is associated with nonalcoholic fatty liver disease (NAFLD). However, the association between soft drinks consumption and NAFLD is unclear in non-Caucasian adults with relatively low soft drinks consumption. The aim of this study was to assess the association between soft drinks consumption and NAFLD in Chinese adults. METHODS A cross-sectional study was conducted with 26,790 adults living in Tianjin, China. NAFLD (with elevated alanine aminotransferase [ALT]) was diagnosed by the liver ultrasonography and serum ALT concentrations. Soft drinks consumption was assessed using a validated self-administered food frequency questionnaire, and it was summarized as three categories for analysis: almost never (reference), <1 cup/week, and ≥1 cups/week. Metabolic syndrome (MetS) was defined according to the criteria of the American Heart Association scientific statements of 2009. The association between soft drinks consumption and NAFLD was assessed by multiple logistic regression analysis. RESULTS The prevalence of NAFLD and NAFLD with elevated ALT was 27.1 and 6.5%, respectively. After adjustment for potential confounding variables (including MetS), the odds ratios (95% confidence intervals) for NAFLD or NAFLD with elevated ALT across soft drinks consumption were 1.00 (reference) for almost never, 1.14 (1.02-1.27) or 1.16 (0.98-1.37) for <1 cup/week, and 1.26 (1.14-1.40) or 1.32 (1.13-1.53) for ≥1 cups/week (both P for trend <0.001), respectively. CONCLUSIONS This is the first study to demonstrate that soft drinks consumption is associated with NAFLD independent of MetS in Chinese adults with relatively low soft drinks consumption. These results suggest that reducing soft drinks consumption might be beneficial to the prevention of NAFLD.
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Affiliation(s)
- Ge Meng
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Bo Zhang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Fei Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Chunlei Li
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Qing Zhang
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Li Liu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Hongmei Wu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Yang Xia
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Xue Bao
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Hongbin Shi
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Qian Su
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Yeqing Gu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Liyun Fang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Huijun Yang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Bin Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Shaomei Sun
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Xing Wang
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Ming Zhou
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Qiyu Jia
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Huanli Jiao
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China.,Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
| | - Qi Guo
- Department of Rehabilitation and Sports Medicine, Tianjin Medical University, Tianjin, China
| | - Livia A Carvalhoa
- Department of Epidemiology and Public Health, University College London, London, UK
| | - Zhong Sun
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Kun Song
- Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China
| | - Ming Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
| | - Kaijun Niu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China. .,Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China.
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Cheng X, Yamauchi J, Lee S, Zhang T, Gong Z, Muzumdar R, Qu S, Dong HH. APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice. J Biol Chem 2017; 292:3692-3705. [PMID: 28115523 DOI: 10.1074/jbc.m116.765917] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/06/2017] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity.
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Affiliation(s)
- Xiaoyun Cheng
- From the Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China and.,the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Jun Yamauchi
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Sojin Lee
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Ting Zhang
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Zhenwei Gong
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Radhika Muzumdar
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Shen Qu
- From the Department of Endocrinology and Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China and
| | - H Henry Dong
- the Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
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Sagnelli C, Merli M, Uberti-Foppa C, Hasson H, Grandone A, Cirillo G, Salpietro S, Minichini C, Starace M, Messina E, Morelli P, Miraglia Del Giudice E, Lazzarin A, Coppola N, Sagnelli E. TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype. World J Gastroenterol 2016; 22:8509-8518. [PMID: 27784963 PMCID: PMC5064032 DOI: 10.3748/wjg.v22.i38.8509] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/06/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients.
METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner’s scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4+ cells/mm3 = 505.5).
RESULTS The 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST (P = 0.02) and alanine aminotransferase (P = 0.02) and higher fibrosis score (3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCV-genotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed.
CONCLUSION In HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.
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8
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Meyers NL, Fontaine KA, Kumar GR, Ott M. Entangled in a membranous web: ER and lipid droplet reorganization during hepatitis C virus infection. Curr Opin Cell Biol 2016; 41:117-24. [PMID: 27240021 DOI: 10.1016/j.ceb.2016.05.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. To establish and maintain chronic infection, HCV extensively rearranges cellular organelles to generate distinct compartments for viral RNA replication and virion assembly. Here, we review our current knowledge of how HCV proliferates and remodels ER-derived membranes while preserving and expanding associated lipid droplets during viral infection. Unraveling the molecular mechanisms responsible for HCV-induced membrane reorganization will enhance our understanding of the HCV life-cycle, the associated liver pathology, and the biology of the ER:lipid droplet interface in general.
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Affiliation(s)
- Nathan L Meyers
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - Krystal A Fontaine
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - G Renuka Kumar
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States
| | - Melanie Ott
- Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94941, United States.
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9
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Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Targher G, Lonardo A. Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection--Liver: The "Musketeer" in the Spotlight. Int J Mol Sci 2016; 17:355. [PMID: 27005620 PMCID: PMC4813216 DOI: 10.3390/ijms17030355] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 02/29/2016] [Accepted: 03/02/2016] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a "vicious circle", eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.
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Affiliation(s)
- Stefano Ballestri
- Operating Unit Internal Medicine, Pavullo General Hospital, Azienda USL Modena, ViaSuore di San Giuseppe Benedetto Cottolengo, 5, Pavullo, 41026 Modena, Italy.
| | - Fabio Nascimbeni
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Dante Romagnoli
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Enrica Baldelli
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy.
| | - Amedeo Lonardo
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
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Sagnelli C, Merli M, Uberti-Foppa C, Hasson H, Cirillo G, Grandone A, Salpietro S, Minichini C, Del Giudice EM, Lazzarin A, Sagnelli E, Coppola N. Impact of PNPLA3 variants on liver histology of 168 patients with HIV infection and chronic hepatitis C. Clin Microbiol Infect 2016; 22:372-378. [PMID: 26806136 DOI: 10.1016/j.cmi.2015.11.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/03/2015] [Accepted: 11/15/2015] [Indexed: 12/28/2022]
Abstract
This study analysed the impact of PNPLA3 variants on liver histology of 168 HIV/hepatitis C virus (HCV)-coinfected patients who were naïve for HCV treatment. A athologist unaware of the patients' condition graded liver fibrosis and necroinflammation (Ishak) and steatosis (Kleiner). Patients were tested for PNPLA3 variants and genotyped for the PNPLA3 rs738409 C to G variant underlying the I148M substitution. All were hepatitis B surface antigen negative and stated no alcohol abuse. The mean age was 40.6 (37.6-44.1) years, 72.6% were males, 42% had HCV genotype 3, 38.9% HCV genotype 1 and 79.2% were receiving highly active antiretroviral therapy. The 79 patients with the PNPLA3 p.148I/M or M/M variants more frequently showed severe steatosis (score 3-4) than the 89 with PNPLA3 p.148I/I (43% vs. 24.7%, p 0.001), whereas no difference was observed in the degree of necroinflammation or fibrosis. Compared with 112 patients with lower scores, 56 with severe steatosis showed higher body mass index (p 0.03), higher rate of HCV genotype 3 (55.6% vs. 35.2%, p 0.01), PNPLA3 p.148I/M or M/M (60.7% vs. 39.3%, p 0.01) and lower CD4(+) cells/mm(3) (514.00 (390.5-673.0) vs. 500.00 (399.0-627.0); p 0.002). At multivariate analysis, body mass index (p 0.01), HCV genotype 3 (p 0.006), CD4(+) cell count (p 0.005) and PNPLA3 p.148I/M or M/M variants (p 0.01) were found to be independent predictors of severe liver steatosis. The PNPLA3 p.148 I/M or M/M variants and CD4(+) cell count were the only independent predictors of severe steatosis in patients with HCV non-3 genotypes. This is the first study to show that among HIV/HCV-coinfected patients the PNPLA3 p.148I/M or M/M variant have substantially less impact on steatosis for those with HCV genotype 3 than non-genotype 3.
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Affiliation(s)
- C Sagnelli
- Department of Experimental Medicine and Surgery 'F. Magrassi e A. Lanzara', Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - M Merli
- Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - C Uberti-Foppa
- Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - H Hasson
- Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - G Cirillo
- Department of Pediatrics, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - A Grandone
- Department of Pediatrics, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - S Salpietro
- Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - C Minichini
- Department Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - E M Del Giudice
- Department of Pediatrics, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - A Lazzarin
- Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
| | - E Sagnelli
- Department Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
| | - N Coppola
- Department Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
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11
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Scheiner B, Mandorfer M, Schwabl P, Payer BA, Bucsics T, Bota S, Aichelburg MC, Grabmeier-Pfistershammer K, Stättermayer A, Ferenci P, Trauner M, Peck-Radosavljevic M, Reiberger T. The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression, Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection. PLoS One 2015; 10:e0143429. [PMID: 26599080 PMCID: PMC4658167 DOI: 10.1371/journal.pone.0143429] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 11/04/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Faster fibrosis progression and hepatic steatosis are hallmarks of HIV/HCV coinfection. A single nucleotide polymorphism (SNP) of the PNPLA3-gene is associated with development of non-alcoholic steatohepatitis and a worse outcome in alcoholic liver disease. However, the role of PNPLA3 rs738409 SNP on liver fibrosis and steatosis, portal hypertension, and virological response in HIV/HCV coinfection remains unclear. METHODS In this cross-sectional study PNPLA3 (rs738409) and IL28B (rs12979860) SNPs were determined in 177 HIV/HCV coinfected patients. Liver fibrosis and steatosis-staged by liver biopsy and transient elastography using the Controlled Attenuation Parameter (CAP)-and portal hypertension (hepatic venous pressure gradient, HVPG) were compared across PNPLA3 genotypes. RESULTS 75 (42.4%) patients tested positive for a PNPLA3 minor/major risk allele (G/C:66; G/G:9) showed comparable fibrosis stages (median F2 vs. F2; p = 0.292) and similar amounts of hepatic steatosis (CAP: 203.5 ± 41.9 vs. 215.5 ± 59.7 dB/m; p = 0.563) as compared to patients without a PNPLA3 risk allele. Advanced liver fibrosis was neither associated with PNPLA3 (p = 0.253) nor IL28B-genotype (p = 0.628), but with HCV-GT3 (p = 0.003), higher BMI (p = 0.008) and higher age (p = 0.007). Fibrosis progression rate (0.27 ± 0.41 vs. 0.20 ± 0.26 units/year; p = 0.984) and HVPG (3.9 ± 2.6 vs. 4.4 ± 3.0 mmHg; p = 0.472) were similar in patients with and without PNPLA3 risk alleles. SVR rates to PEGIFN/RBV therapy were similar across PNPLA3 genotypes. CONCLUSIONS The presence of a PNPLA3 risk allele had no independent impact on liver disease or virological response rates to PEGIFN/RBV therapy in our cohort of HIV/HCV coinfected patients.
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Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
| | - Berit Anna Payer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
| | - Theresa Bucsics
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Simona Bota
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximilian C. Aichelburg
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Katharina Grabmeier-Pfistershammer
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Albert Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna HIV & Liver Study Group, Medical University of Vienna, Vienna, Austria
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12
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Coppola N, Onorato L, Pisaturo M, Macera M, Sagnelli C, Martini S, Sagnelli E. Role of occult hepatitis B virus infection in chronic hepatitis C. World J Gastroenterol 2015; 21:11931-11940. [PMID: 26576082 PMCID: PMC4641115 DOI: 10.3748/wjg.v21.i42.11931] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 06/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult hepatitis B infection (OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV (HBsAg) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti-HBc) in serum of HBsAg-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C (CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma (HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.
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13
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Zampino R, Coppola N, Cirillo G, Boemio A, Grandone A, Stanzione M, Capoluongo N, Marrone A, Macera M, Sagnelli E, Adinolfi LE, del Giudice EM. Patatin-Like Phospholipase Domain-Containing 3 I148M Variant Is Associated with Liver Steatosis and Fat Distribution in Chronic Hepatitis B. Dig Dis Sci 2015; 60:3005-10. [PMID: 25986529 DOI: 10.1007/s10620-015-3716-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 05/10/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C. AIMS The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB). METHODS Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped. RESULTS PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score > 3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI). CONCLUSIONS In our CHB patients, the PNPLA3 polymorphisms influenced the development of liver steatosis, but not fibrosis status. The association of PNPLA3 p.I148M with liver steatosis increased with the greater amount of abdominal fat, irrespective of BMI.
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Affiliation(s)
- Rosa Zampino
- Internal Medicine and Hepatology, Second University of Naples, Via Pansini, 5-Edificio 3, 80131, Naples, Italy.
| | - Nicola Coppola
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Grazia Cirillo
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Adriana Boemio
- Internal Medicine and Hepatology, Second University of Naples, Via Pansini, 5-Edificio 3, 80131, Naples, Italy
| | - Anna Grandone
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Maria Stanzione
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
| | - Nicolina Capoluongo
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Aldo Marrone
- Internal Medicine and Hepatology, Second University of Naples, Via Pansini, 5-Edificio 3, 80131, Naples, Italy
| | - Margherita Macera
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine and Hepatology, Second University of Naples, Via Pansini, 5-Edificio 3, 80131, Naples, Italy
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14
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Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
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15
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Coppola N, Rosa Z, Cirillo G, Stanzione M, Macera M, Boemio A, Grandone A, Pisaturo M, Marrone A, Adinolfi LE, Sagnelli E, Miraglia del Giudice E. TM6SF2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of PNPLA3 polymorphism. Liver Int 2015; 35:1959-63. [PMID: 25581573 DOI: 10.1111/liv.12781] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/05/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS A common non-synonymous polymorphism, E167K, in transmembrane six superfamily member 2 (TM6SF2) gene has been recently associated with an increased hepatic triglyceride content, dyslipidemia and liver fibrosis in NAFLD patients. We investigated possible associations between the TM6SF2 variants and liver lesions in chronic hepatitis C. PATIENTS AND METHODS 148 consecutive patients with biopsy proven anti-HCV/HCV-RNA-positive chronic hepatitis, naive for antiviral therapy, were genotyped for TM6SF2 E167K and PNPLA3 I148M variants. RESULTS The score of liver steatosis was higher in the 18 patients with TM6SF2 E167K variant (mean 1.9 ± 1.3) than in the 130 homozygotes for TM6SF2 167E allele (1.1 ± 1.1, P = 0.02), and the prevalence of a steatosis score ≥ 3 was 33.3% vs. 12.3% respectively (P = 0.02). No difference in necroinflammatory or fibrosis scores was found between the two groups. A general linear model identified as independent predictors of steatosis TM6SF2 E167K and PNPLA3 M148M variants and waist circumference (P = 0.0376, P = 0.0069 and P = 0.0273 respectively). CONCLUSIONS This is the first demonstration that TM6SF2 E167K variant is an independent predictor of liver steatosis in chronic hepatitis C.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Zampino Rosa
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Grazia Cirillo
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Maria Stanzione
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
| | - Margherita Macera
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Adriana Boemio
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Anna Grandone
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Aldo Marrone
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Luigi E Adinolfi
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
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Huang CF, Chen JJ, Yeh ML, Huang CI, Hsieh MY, Yang HL, Dai CY, Huang JF, Lin ZY, Chen SC, Chuang WL, Chen YL, Yu ML. PNPLA3 genetic variants determine hepatic steatosis in non-obese chronic hepatitis C patients. Sci Rep 2015; 5:11901. [PMID: 26139292 PMCID: PMC4490397 DOI: 10.1038/srep11901] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 06/08/2015] [Indexed: 02/07/2023] Open
Abstract
The influence of patatin-like phospholipase domain-containing 3 (PNPLA3) genetic variants in the development of liver steatosis in Asian chronic hepatitis C patients remains elusive. A total of 1018 biopsy-proven chronic hepatitis C patients were enrolled for evaluation. The proportions of PNPLA3 rs738409 GG genotype carriage were 7.8% (44/563), 15.8% (58/367) and 19.3% (17/88) in patients with no (liver fat content < 5%), mild (5-33%) and moderate/severe (> 66%) hepatic steatosis, respectively (trend P < 0.001). Stepwise logistic regression analysis revealed that the strongest factor independently associated with steatosis was the carriage of the PNPLA3 rs738409 GG genotype (odds ratio [OR]/95% confidence intervals [CI]:2.34/1.557-3.515, P < 0.001). Among the patients with BMI < 24 kg/m(2), carriage of the rs738409 GG genotype was the only factor associated with hepatic steatosis (OR/CI:3.44/1.824-6.500, P < 0.001). PNPLA3 genetic variants had minimal effects on hepatic steatosis among overweight or obese patients. Compared to patients with BMI < 24 kg/m(2)/non-GG genotype, those with BMI >24 kg/m(2)/GG genotype were more likely to have hepatic steatosis (OR/CI:3.87/2.292-6.524, P < 0.001). In conclusions, both PNPLA3 genetic variants and BMI played important roles in hepatic steatosis among Asian chronic hepatitis C patients. However, the genetic effect was mainly restricted to non-obese patients.
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Affiliation(s)
- Chung-Feng Huang
- Graguate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jyh-Jou Chen
- Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hua-Ling Yang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Li Chen
- Division of General Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, and Center for Lipid and Glycomedicine Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University.
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Krawczyk M, Lammert F. The PNPLA3 p.Ile148Met Variant and Obesity: brothers-in-arms. Surg Obes Relat Dis 2015; 11:894-6. [DOI: 10.1016/j.soard.2014.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 09/03/2014] [Accepted: 09/03/2014] [Indexed: 10/24/2022]
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Petta S, Vanni E, Bugianesi E, Rosso C, Cabibi D, Cammà C, Di Marco V, Eslam M, Grimaudo S, Macaluso FS, McLeod D, Pipitone RM, Abate ML, Smedile A, George J, Craxì A. PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C. Aliment Pharmacol Ther 2015; 41:939-48. [PMID: 25801076 DOI: 10.1111/apt.13169] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 01/28/2015] [Accepted: 03/02/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). AIM To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. METHODS Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. RESULTS The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002). CONCLUSION In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects.
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Affiliation(s)
- S Petta
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
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Association between complement C3 and prevalence of fatty liver disease in an adult population: a cross-sectional study from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIHealth) cohort study. PLoS One 2015; 10:e0122026. [PMID: 25856141 PMCID: PMC4391843 DOI: 10.1371/journal.pone.0122026] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 02/05/2015] [Indexed: 01/13/2023] Open
Abstract
Activation of the innate immune system plays a key role in the development of fatty liver disease (FLD). The complement system is a major humoral component of the innate immune response and complement C3 plays a central role, implying that C3 may be a powerful predictor or therapeutic target for FLD. However, few studies have assessed the association between C3 and FLD in a large population. Here we use a cross-sectional study to investigate the link between serum C3 levels and FLD. Participants were recruited from Tianjin Medical University's General Hospital-Health Management Centre. Serum C3 was measured using immunoturbidimetry method and FLD was diagnosed by liver ultrasonography. Multiple logistic regression analysis was used to examine the association between quartiles of C3 and FLD prevalence. The overall prevalence of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) were 37.3% and 10.1%, respectively. After adjusting for covariates, the odds ratio of having NAFLD or AFLD (only in males) in the fourth quartile of C3 compared with the first quartile was 4.13 times greater (95% confidence interval, 2.97-5.77) (trend P values < 0.0001) and 2.09 times greater (95% confidence interval, 1.08-4.18) (trend P values = 0.02). This is the first study to demonstrate that serum C3 levels are independently associated with a higher prevalence of NAFLD and AFLD (only in males) in an adult population. Further studies are needed to establish a causal link and determine the precise role of C3 in FLD.
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Geng N, Xin YN, Xia HHX, Jiang M, Wang J, Liu Y, Chen LZ, Xuan SY. Association of PNPLA3 I148M Variant With Chronic Viral Hepatitis, Autoimmune Liver Diseases and Outcomes of Liver Transplantation. HEPATITIS MONTHLY 2015; 15:e26459. [PMID: 26034504 PMCID: PMC4449891 DOI: 10.5812/hepatmon.15(4)2015.26459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 02/15/2015] [Accepted: 03/01/2015] [Indexed: 02/07/2023]
Abstract
CONTEXT The PNPLA3 I148M variant has been recognized as a genetic determinant of liver fat content and a genetic risk factor of liver damage progression associated with steatohepatitis. The I148M variant is associated with many chronic liver diseases. However, its potential association with inflammatory and autoimmune liver diseases has not been established. EVIDENCE ACQUISITION We systemically reviewed the potential associations of I148M variant with chronic viral hepatitis, autoimmune liver diseases and the outcome of liver transplantation, explored the underlying molecular mechanisms and tried to translate them into more individualized decision-making and personalized medicine. RESULTS There were associations between I148M variant and chronic viral hepatitis and autoimmune liver diseases and differential associations of I148M variant in donors and recipients with post-liver transplant outcomes. I148M variant may activate the development of steatosis caused by host metabolic disorders in chronic viral hepatitis, but few researches were found to illustrate the mechanisms in autoimmune liver diseases. The peripherally mediated mechanism (via extrahepatic adipose tissue) may play a principal role in triglyceride accumulation regardless of adiponutrin activity in the graft liver. CONCLUSIONS Evidences have shown the associations between I148M variant and mentioned diseases. I148M variant induced steatosis may be involved in the mechanism of chronic viral hepatitis and genetic considered personalized therapies, especially for PSC male patients. It is also crucial to pay attention to this parameter in donor selection and prognosis estimation in liver transplantation.
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Affiliation(s)
- Ning Geng
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Yong-Ning Xin
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. Tel: +86-53288905508, Fax: +86-53282031522, E-mail:
| | | | - Man Jiang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
| | - Jian Wang
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Yang Liu
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Li-Zhen Chen
- Qingdao Municipal Hospital, Medical College, Qingdao University, Qingdao, P. R. China
| | - Shi-Ying Xuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, P. R. China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, P. O. Box: 266021, Qingdao, P. R. China. Tel: +86-53288905508, Fax: +86-53282031522, E-mail:
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Huang CF, Dai CY, Yeh ML, Huang CI, Tai CM, Hsieh MH, Liang PC, Lin YH, Hsieh MY, Yang HL, Huang JF, Lin ZY, Chen SC, Yu ML, Chuang WL. Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection. J Hepatol 2015; 62:512-8. [PMID: 25457210 DOI: 10.1016/j.jhep.2014.10.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/06/2014] [Accepted: 10/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. METHODS The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. RESULTS Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). CONCLUSIONS The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.
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Affiliation(s)
- Chung-Feng Huang
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chi-Ming Tai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hua-Ling Yang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Nakaoka K, Hashimoto S, Kawabe N, Nitta Y, Murao M, Nakano T, Shimazaki H, Kan T, Takagawa Y, Ohki M, Kurashita T, Takamura T, Nishikawa T, Ichino N, Osakabe K, Yoshioka K. PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients. SPRINGERPLUS 2015; 4:83. [PMID: 25713769 PMCID: PMC4334918 DOI: 10.1186/s40064-015-0870-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/03/2015] [Indexed: 12/15/2022]
Abstract
Aim To investigate associations between patatin-like phospholipase domain-containing 3 (PNPLA3) genotypes and fibrosis and hepatocarcinogenesis in Japanese chronic hepatitis C (CHC) patients. Methods Two hundred and thirty-one patients with CHC were examined for PNPLA3 genotypes, liver stiffness measurements (LSM), and hepatocellular carcinoma (HCC) from May 2010 to October 2012 at Fujita Health University Hospital. The rs738409 single nucleotide polymorphism (SNP) encoding for a functional PNPLA3 I148M protein variant was genotyped using a TaqMan predesigned SNP genotyping assay. LSM was determined as the velocity of a shear wave (Vs) with an acoustic radiation force impulse. Vs cut-off values for cirrhosis were set at 1.55 m/s. We excluded CHC patients with a sustained virological response or relapse after interferon treatment. Results PNPLA3 genotypes were CC, CG, and GG for 118, 72, and 41 patients, respectively. Multivariable logistic regression analysis selected older age (OR = 1.06; 95% CI: 1.03–1.09; p < 0.0001), higher body mass index (BMI) (OR= 1.12; 95% CI: 1.03–1.22; p = 0.0082), and PNPLA3 genotype GG (OR = 2.07; 95% CI: 0.97–4.42; p = 0.0599) as the factors independently associated with cirrhosis. When 137 patients without past history of interferon treatment were separately assessed, multivariable logistic regression analysis selected older age (OR = 1.05; 95% CI: 1.02–1.09; p = 0.0034), and PNPLA3 genotype GG (OR = 3.35; 95% CI: 1.13–9.91; p = 0.0291) as the factors independently associated with cirrhosis. Multivariable logistic regression analysis selected older age (OR = 1.12; 95% CI: 1.07–1.17; p < 0.0001), PNPLA3 genotype GG (OR = 2.62; 95% CI: 1.15–5.96; p = 0.0218), and male gender (OR = 1.83; 95% CI: 0.90–3.71); p = 0.0936) as the factors independently associated with HCC. Conclusion PNPLA3 genotype I148M is one of risk factors for developing HCC in Japanese CHC patients, and is one of risk factors for progress to cirrhosis in the patients without past history of interferon treatment.
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Affiliation(s)
- Kazunori Nakaoka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Senju Hashimoto
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Naoto Kawabe
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Yoshifumi Nitta
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Michihito Murao
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Takuji Nakano
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Hiroaki Shimazaki
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Toshiki Kan
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Yuka Takagawa
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Masashi Ohki
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Takamitsu Kurashita
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Tomoki Takamura
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Toru Nishikawa
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
| | - Naohiro Ichino
- Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192 Japan
| | - Keisuke Osakabe
- Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192 Japan
| | - Kentaro Yoshioka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, Aichi 470-1192 Japan
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Abstract
Hepatocellular carcinoma (HCC) is a development of severe liver disease frequently due to HBV and/or HCV infection. The aim of this retrospective study was to evaluate the development of HCC in patients with HBV-HCV chronic infection compared with patients with single HBV or HCV infection and the viral and host factors correlated to HCC in co-infected patients. We studied 268 patients with histology proven chronic hepatitis: 56 had HBV-HCV co-infection (HBV-HCV group), 46 had HBV infection (HBV group) and 166 had HCV infection (HCV group). Patients were followed up for at least 3 years. Viral and host factors were studied. HCC was more frequent in HBV-HCV group (14%) compared with HBV (2%, p = 0.006) and HCV monoinfected (4%, p = 0.006). The Mantel-Haenszel test used to investigate the relationship between HBV-HCV co-infection and development of HCC indicated an association between development of HCC and HBV-HCV co-infection (p < 0.001). In the HBV-HCV group, patients with HCC were significantly older (p = 0.000), had longer disease duration (p = 0.001), higher blood glucose levels (p = 0.001), lower levels of steatosis (p = 0.02), higher levels of fibrosis (p = 0.000), higher HCV RNA (p = 0.01) than those without HCC. ALT, lipid profile, PNPLA3 variant distribution and HBV viral load did not differ among co-infected patients with or without HCC. In conclusion HCC was more frequent in our patients with HBV-HCV co-infection, than in those with HBV or HCV mono-infection; possible associated risk factors for HCC development seem a long duration of disease, high levels of fibrosis and carbohydrate intolerance.
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Zampino R, Coppola N, Cirillo G, Boemio A, Minichini C, Marrone A, Stanzione M, Starace M, Durante-Mangoni E, Sagnelli E, Restivo L, Salzillo G, Fascione MC, Nevola R, Giudice EMD, Adinolfi LE. Insulin resistance and steatosis in HBV-HCV co-infected patients: Role of PNPLA3 polymorphisms and impact on liver fibrosis progression. World J Hepatol 2014; 6:677-684. [PMID: 25276284 PMCID: PMC4179147 DOI: 10.4254/wjh.v6.i9.677] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 07/08/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate steatosis, insulin resistance (IR) and patatin-like phospholipase domain-containing 3 (PNPLA3) and their relation to disease progression in hepatitis B and C viruses (HCV-HBV) co-infected patients.
METHODS: Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled: 66 had HBV-HCV, 66 HBV and 198 HCV infection. Prevalence of steatosis, IR and PNPLA3 polymorphisms and their relation to anthropometric, biochemical, virological and histological parameters were evaluated.
RESULTS: Prevalence of steatosis in group HBV-HCV was similar to that in HCV (47.0% vs 49.5%, respectively); group HBV showed the lowest steatosis (33.3%). Group HBV-HCV had a lesser degree of steatosis than HCV (P = 0.016), lower HCV RNA levels (P = 0.025) and lower prevalence and degree of IR (P = 0.01). PNPLA3 polymorphisms were associated with steatosis. Group HBV-HCV showed higher levels of liver fibrosis than group HCV (P = 0.001), but similar to that observed in HBV group. In HBV-HCV group, liver fibrosis was not associated with steatosis, IR or PNPLA3. HBV infection was the independent predictor of advanced liver fibrosis.
CONCLUSION: HBV-HCV co-infected patients have lower degree of hepatic steatosis, IR and HCV RNA than HCV mono-infected; co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.
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Maglio C, Pirazzi C, Pujia A, Valenti L, Romeo S. The PNPLA3 I148M variant and chronic liver disease: When a genetic mutation meets nutrients. Food Res Int 2014. [DOI: 10.1016/j.foodres.2014.01.055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Petruzziello A, Coppola N, Loquercio G, Marigliano S, Giordano M, Azzaro R, Diodato AM, Iervolino V, Di Costanzo G, Di Macchia CA, Di Meo T, Paradiso L, Ferro R, Giuliano P, Russo F, Pasquale G, Cacciapuoti C. Distribution pattern of hepatitis C virus genotypes and correlation with viral load and risk factors in chronic positive patients. Intervirology 2014; 57:311-8. [PMID: 25170801 DOI: 10.1159/000363386] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 05/02/2014] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatitis C virus (HCV) has emerged as a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. The purpose of this study was to describe the distribution pattern of HCV genotypes in chronic hepatitis patients in the Campania region of southern Italy and estimate their association with risk factors and viral load. MATERIALS AND METHODS 404 consecutive HCV ribonucleic acid-positive patients were included in the study. HCV genotyping was carried out by the HCV line probe assay test and viral load estimation by the TaqMan real-time PCR system. RESULTS The predominant genotype was 1 (63.6%), followed by genotype 2 (29.4%), 3 (6.2%) and 4 (0.8%). Subtype 1b was more frequent in females than in males. Conversely, genotype 3 was more frequent in males. No significant difference was observed in age distribution of HCV genotypes. Surgery and dental therapy were the most frequent risk factors for genotype 1 and intravenous drug abuse and tattooing for genotype 3. Patients with genotype 1 more frequently showed high HCV viral load when compared to those with genotypes 2 and 3. CONCLUSION The present study revealed that HCV genotypes 1 and 2 accounted for over 95% of all HCV infections in the Campania region, and genotype 1 was more frequently associated with a higher viral load when compared to genotypes 2 and 3.
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Affiliation(s)
- Arnolfo Petruzziello
- Laboratory of Virology and Molecular Biology 'V. Tridente', Transfusion Service, Department of Haemathology, Istituto Nazionale Tumori - Fondazione 'G. Pascale', IRCCS Italia, Naples, Italy
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Gentile I, Buonomo AR, Zappulo E, Coppola N, Borgia G. GS-9669: a novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12:1179-86. [PMID: 25096404 DOI: 10.1586/14787210.2014.945432] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) is an RNA virus that chronically infects 2-3% of the world's population. About 25% of these chronic carriers evolve towards liver cirrhosis, a disease that is significantly associated with reduced survival and quality of life. Antiviral therapy can eradicate the infection - a process that is associated with a reduced disease progression rate. Several oral direct agents have been developed and tested for the treatment of HCV infection. This review focuses on the mechanism of action, pharmacokinetics, efficacy, safety and resistance of GS-9669, a non-nucleoside inhibitor of viral polymerase, active against HCV genotype 1. In combination with other oral antivirals, GS-9669 results: in very high rates of viral eradication (90-100%) in patients with HCV genotype 1 infection, with a good tolerability and safety profile. In conclusion, GS-9669 is a good candidate to be used in interferon-free combinations for the treatment of chronic HCV infection.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples 'Federico II', via S. Pansini 5,I-80131 Naples, Italy
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Gentile I, Buonomo AR, Borgia G. Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection. Expert Rev Anti Infect Ther 2014; 12:1033-43. [PMID: 25074011 DOI: 10.1586/14787210.2014.940898] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy
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Gentile I, Buonomo AR, Zappulo E, Minei G, Morisco F, Borrelli F, Coppola N, Borgia G. Asunaprevir, a protease inhibitor for the treatment of hepatitis C infection. Ther Clin Risk Manag 2014; 10:493-504. [PMID: 25061308 PMCID: PMC4079632 DOI: 10.2147/tcrm.s66731] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
According to the World Health Organization, approximately 150 million people worldwide are chronic carriers of hepatitis C virus (HCV). HCV infection can evolve into cirrhosis of the liver and its complications, which are ultimately responsible for more than 350,000 deaths every year. Antiviral therapy, when successful, is able to decrease the rate of progression and increase survival. Two types of therapies are currently available, ie, interferon-based therapies and interferon-free ones. The latter have several advantages in terms of safety and tolerability, and could be used even in the most advanced stages of the disease. However, their use is restricted to some viral genotypes (genotype 2 and 3) and they are expensive. Several molecules are in an advanced phase of development. This review deals with the pharmacokinetics, pharmacodynamics, tolerability, and safety of asunaprevir, an inhibitor of HCV nonstructural 3 protease. Asunaprevir exerts optimal in vitro activity particularly against HCV genotypes 1 and 4, and its pharmacokinetic profile enables twice daily administration. The drawback of asunaprevir, and of all protease inhibitors, is its low barrier to resistance. Consequently, it is used in association with other drugs to prevent resistance. Specifically, when combined with daclatasvir, an NS5A inhibitor, asunaprevir results in a very high rate of viral eradication in both treatment-naïve and treatment-experienced patients, with a sustained virological response rate of 80%-90%. Tolerability is fair; in fact, asunaprevir is associated with a transient increase in aminotransferase levels, which is mild in most cases. In conclusion, asunaprevir is a good candidate component of interferon-free combinations and may revolutionize the treatment of chronic HCV infection in the near future.
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Affiliation(s)
- Ivan Gentile
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonio Riccardo Buonomo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Emanuela Zappulo
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppina Minei
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Filomena Morisco
- Section of Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Francesco Borrelli
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Guglielmo Borgia
- Section of Infectious Diseases, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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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] [Accepted: 04/03/2014] [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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Coppola N, Zampino R, Sagnelli C, Bellini G, Marrone A, Stanzione M, Capoluongo N, Boemio A, Minichini C, Adinolfi LE, Maione S, Giudice EMD, Sagnelli E, Rossi F. Cannabinoid receptor 2-63 QQ variant is associated with persistently normal aminotransferase serum levels in chronic hepatitis C. PLoS One 2014; 9:e99450. [PMID: 24940753 PMCID: PMC4062424 DOI: 10.1371/journal.pone.0099450] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 05/14/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND AIM To evaluate in anti-HCV-positive patients the clinical impact of the rs35761398 variant of the CNR2 gene leading to the substitution of Gln (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with Arg (R). PATIENTS AND METHODS 253 consecutive anti-HCV-/HCV-RNA-positive patients were enrolled, of whom 53 were HCV carriers with persistently normal ALT (PNALT group) and 200 had a history of steadily abnormal serum ALT values (abnormal ALT group). All patients were naive for antiviral therapy and were screened for the CNR2 rs35761398 polymorphism by a TaqMan assay. RESULTS Subjects in the PNALT group, compared with those in the abnormal ALT group were older (58.5±12 vs. 50.7±12.4 years, p = 0.001), more frequently female (66% vs. 42%, p = 0.003), with lower body mass index (BMI) (24.5±3.1 vs. 26.6±4.6, p = 0.003), and more frequently with HCV genotype 2 (43.1% vs 17.7%, p = 0.0002) and CB2-63 QQ variant (34% vs. 11%, p = 0.0001). Considering all 253 patients, no difference in the demographic, biochemical, or virological data was observed between patients in the different CB2-63 variants. The logistic regression analysis identified CB2-63 QQ, HCV genotype 2, older age and lower BMI as independent predictors of PNALT (p<0.00001). DISCUSSION The CB2-63 QQ variant in HCV patients was independently associated with the PNALT status.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
- * E-mail:
| | - Rosa Zampino
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
| | - Giulia Bellini
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Aldo Marrone
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Maria Stanzione
- Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy
| | - Nicolina Capoluongo
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Adriana Boemio
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | | | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Francesca Rossi
- Department of Pediatrics, Second University of Naples, Naples, Italy
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Kalafati IP, Borsa D, Dedoussis GVZ. The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor. Curr Nutr Rep 2014. [DOI: 10.1007/s13668-014-0085-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Gentile I, Coppola N, Buonomo AR, Zappulo E, Borgia G. Investigational nucleoside and nucleotide polymerase inhibitors and their use in treating hepatitis C virus. Expert Opin Investig Drugs 2014; 23:1211-23. [PMID: 24848437 DOI: 10.1517/13543784.2014.921680] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION About 150 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV). Successful antiviral treatment can stop the progression of the disease toward liver cirrhosis, hepatocellular carcinoma and death. IFN has been the drug of choice and the backbone of all combinations in the past two decades. However, an IFN-free combination (sofosbuvir and ribavirin) has been recently approved for genotypes 2 and 3 patients with many other drugs in preclinical and clinical development. AREAS COVERED This review focuses on investigational nucleoside or nucleotide inhibitors of viral polymerase that are potential treatments of HCV. The article reviews drugs that are currently under investigational status. EXPERT OPINION Currently, mericitabine has the most robust data but its efficacy appears to be less than optimal. Other drugs such as ALS-2200 (and its diastereomer VX-135) and BMS-986094 are promising but the data in humans are too scanty to draw conclusions about their future role at this current point in time. Other promising molecules are LG-7501, ACH-3422 and EP-NI266, although no clinical studies have been performed thus far, so this must be rectified. Another drug of promise GS-6620 has displayed a high degree of pharmacokinetic and pharmacodynamic variability, which makes further development unlikely.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463083 ; +39 0 81 7463190 ;
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Marzuillo P, Giudice EMD, Santoro N. Pediatric non-alcoholic fatty liver disease: New insights and future directions. World J Hepatol 2014; 6:217-225. [PMID: 24799990 PMCID: PMC4009477 DOI: 10.4254/wjh.v6.i4.217] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 02/25/2014] [Accepted: 03/18/2014] [Indexed: 02/06/2023] Open
Abstract
One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.
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Coppola N, Marrone A, Pisaturo M, Starace M, Signoriello G, Gentile I, Adinolfi LE, Sagnelli E, Zampino R. Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection. Eur J Clin Microbiol Infect Dis 2014; 33:559-67. [PMID: 24081499 DOI: 10.1007/s10096-013-1985-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 09/11/2013] [Indexed: 12/27/2022]
Abstract
The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p = 0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.
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Affiliation(s)
- N Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Via L. Armanni 5, 80133, Naples, Italy,
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Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs 2014; 23:719-28. [PMID: 24666106 DOI: 10.1517/13543784.2014.902049] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1. AREAS COVERED This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172 , a second-generation inhibitor of HCV NS3/4A protease. EXPERT OPINION The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 - 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery (Ed. 18) , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463178 ; +39 0 81 7463190 ;
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Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs 2014; 23:561-71. [DOI: 10.1517/13543784.2014.892581] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, Waljee AK. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109:325-34. [PMID: 24445574 PMCID: PMC5610907 DOI: 10.1038/ajg.2013.476] [Citation(s) in RCA: 264] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 12/05/2013] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease. METHODS We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model. RESULTS Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20-1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12-1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27-2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96-1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed. CONCLUSIONS PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.
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Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Hema Manjunath
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Adam C. Yopp
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Muhammad S. Beg
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jorge A. Marrero
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Akbar K. Waljee
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Coppola N, Zampino R, Bellini G, Macera M, Marrone A, Pisaturo M, Boemio A, Nobili B, Pasquale G, Maione S, Adinolfi LE, Perrone L, Sagnelli E, Miraglia Del Giudice E, Rossi F. Association between a polymorphism in cannabinoid receptor 2 and severe necroinflammation in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2014; 12:334-40. [PMID: 23707465 DOI: 10.1016/j.cgh.2013.05.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 04/15/2013] [Accepted: 05/04/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The cannabinoid receptor 2 (CB2) has been implicated in liver disease. The single-nucleotide polymorphism rs35761398 in cannabinoid receptor 2 gene (CNR2), which encodes the CB2, substitutes glutamine (Q) 63 with arginine (R), and reduces the function of the gene product. We investigated the effects of CNR2 rs35761398 in patients with hepatitis C virus (HCV) infection. METHODS We studied 169 consecutive patients with asymptomatic chronic hepatitis (tested positive for anti-HCV and HCV RNA) at 2 liver units in southern Italy. First, liver biopsy samples were collected from July 2009 through December 2011. All patients were naive to antiviral therapy; CNR2 genotype was determined by polymerase chain reaction analysis. RESULTS Patients with the CB2-63 QQ variant had higher serum levels of aminotransferase than those with the CB2-63 QR or RR variants; they also had higher histologic activity index (HAI) scores (8.6 ± 3.8) than patients without the CB2-63 RR variant (5.3 ± 3.6; P < .005) or those with the CB2-63 QR variant (5.8 ± 3.3; P < .001). Patients with the different variants of CNR2 did not differ in fibrosis stage or steatosis score. Moderate or severe chronic hepatitis (HAI score, >8) was identified more frequently (55.5%) in patients with the CB2-63 QQ variant than in those with the 63 QR (20%; P < .005) or RR variants (17.4%; P < .005). In logistic regression analysis, the CB2-63 QQ variant and fibrosis score were independent predictors of moderate or severe chronic hepatitis (HAI score, >8; P < .0001). CONCLUSIONS The CB2-63 QQ variant of CNR2 is associated with more severe inflammation and hepatocellular necrosis in patients with HCV infection.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy.
| | - Rosa Zampino
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Giulia Bellini
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Margherita Macera
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Aldo Marrone
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | | | - Adriana Boemio
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Bruno Nobili
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Giuseppe Pasquale
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine and Hepatology, Second University of Naples, Naples, Italy
| | - Laura Perrone
- Department of Pediatrics, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | | | - Francesca Rossi
- Department of Pediatrics, Second University of Naples, Naples, Italy
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Zampino R, Florio A, Coppola N, Cirillo G, Macera M, Marrone A, Adinolfi LE, Del Giudice EM. PNPLA3 I148M variant as a risk factor for carotid atherosclerosis in chronic hepatitis C. Int J Cardiol 2014; 172:291-2. [PMID: 24461483 DOI: 10.1016/j.ijcard.2013.12.231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 12/30/2013] [Indexed: 01/29/2023]
Affiliation(s)
- Rosa Zampino
- Internal Medicine and Hepatology, Second University of Naples, Italy.
| | - Anna Florio
- Vascular Surgery, Second University of Naples, Italy
| | - Nicola Coppola
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Italy
| | - Grazia Cirillo
- Department of Pediatrics, Second University of Naples, Italy
| | - Margherita Macera
- Department of Public Medicine, Section of Infectious Diseases, Second University of Naples, Italy
| | - Aldo Marrone
- Internal Medicine and Hepatology, Second University of Naples, Italy
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Marzuillo P, Grandone A, Perrone L, del Giudice EM. Weight loss allows the dissection of the interaction between abdominal fat and PNPLA3 (adiponutrin) in the liver damage of obese children. J Hepatol 2013; 59:1143-4. [PMID: 23845393 DOI: 10.1016/j.jhep.2013.06.027] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 06/21/2013] [Accepted: 06/24/2013] [Indexed: 12/17/2022]
Affiliation(s)
- Pierluigi Marzuillo
- Department of women and children and general and specialized surgery, Seconda Univesità degli studi di Napoli, Napoli, Italy.
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Zampino R, Marrone A, Restivo L, Guerrera B, Sellitto A, Rinaldi L, Romano C, Adinolfi LE. Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol 2013; 5:528-540. [PMID: 24179612 PMCID: PMC3812455 DOI: 10.4254/wjh.v5.i10.528] [Citation(s) in RCA: 166] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 08/06/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023] Open
Abstract
The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.
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Sagnelli E, Pisaturo M, Stanzione M, Messina V, Alessio L, Sagnelli C, Starace M, Pasquale G, Coppola N. Clinical presentation, outcome, and response to therapy among patients with acute exacerbation of chronic hepatitis C. Clin Gastroenterol Hepatol 2013; 11:1174-1180.e11. [PMID: 23591280 DOI: 10.1016/j.cgh.2013.03.025] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 03/12/2013] [Accepted: 03/28/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC. METHODS We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and 31 controls-once before enrollment in the study and once during the follow-up period. RESULTS HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%). CONCLUSIONS Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy.
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Sagnelli C, Uberti-Foppa C, Pasquale G, De Pascalis S, Coppola N, Albarello L, Doglioni C, Lazzarin A, Sagnelli E. Factors influencing liver fibrosis and necroinflammation in HIV/HCV coinfection and HCV monoinfection. Infection 2013; 41:959-67. [PMID: 23839212 DOI: 10.1007/s15010-013-0502-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Accepted: 06/25/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To define differences in liver histology between HIV/HCV coinfection and HCV monoinfection, and to investigate possible causative factors. METHODS Liver biopsies (LBs) from 440 consecutive HIV/HCV-coinfected patients (Group HIV/HCV) and 374 consecutive HCV-monoinfected patients (Group HCV) were evaluated for necroinflammation and fibrosis (Ishak) by a pathologist unaware of the clinical and laboratory data. All patients were HBsAg-negative, with no history of alcohol abuse and naïve to anti-HCV treatment. At LB, 78.4% of patients in Group HIV/HCV were on an antiretroviral regimen. RESULTS HIV/HCV-coinfected patients compared to the HCV-monoinfected patients were younger (p < 0.0001), more frequently males (p < 0.0001), and had HCV genotype 3 (p < 0.0001); they showed a good immunological condition (CD4+ cell count: 518 ± 166 cells/mm(3)). Patients in Group HIV/HCV more frequently showed a fibrosis score ≥4 (27.5 vs. 20.6%, p < 0.05) and a necroinflammation score ≥9 (25.9 vs. 13.4%; p < 0.0001). The prevalence of patients with fibrosis score ≥4 was significantly higher in older age classes in both Group HIV/HCV (p < 0.005) and Group HCV (p < 0.05). A necroinflammation score ≥9 was significantly higher in older age classes only in Group HIV/HCV (p < 0.05). A multivariate analysis for Group HIV/HCV revealed that the patient age and nadir of CD4+ cell count were independently associated to higher degrees of fibrosis, the patient age and antiretroviral treatment were associated to higher degrees of necroinflammation, and HCV genotype 3 was associated to higher degrees of steatosis. CONCLUSION The data suggest a need for early anti-HCV treatment in both HCV-monoinfected and HIV/HCV-coinfected patients.
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Affiliation(s)
- C Sagnelli
- Clinic of Infectious Diseases and Department of Pathology, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy,
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