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Nikolaeva L, Leybman E, Samokhvalov E, Kyuregyan K, Kichatova V, Isaeva O, Kuprianov V. Hepatitis C virus-specific markers in pediatric patients with chronic hepatitis C. Minerva Pediatr (Torino) 2025; 77:54-61. [PMID: 34859647 DOI: 10.23736/s2724-5276.21.06564-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The study aimed to investigate hepatitis C virus (HCV) specific markers in chronically infected children. The main objective was to explore the patterns of marker variability. METHODS HCV RNA, core antigen, anti-HCV IgM, and antibodies to individual viral proteins were detected using commercially available assays or experimental ELISA. RNA genotyping and recombination were performed by sequencing. RESULTS HCV RNA and core antigen were detected in serum samples of all children (N.=100). Anti-HCV IgM, anti-NS4AB IgG, and anti-NS5A IgG were revealed less often than antibodies to core and NS3 proteins. To elucidate the cause of this finding, all subjects were divided into 4 groups differing in hepatitis duration. It was anti-NS4AB only whose detection depended on the infection duration. A trend was established that the longer the hepatitis duration, the more frequently anti-HCV IgM was observed. No significant impact of HCV RNA load and NS4A/NS4B amino acid substitutions on anti-NS4AB IgG detection was found. The increase HCV genotype 3 was observed among children infected after 2000. The earliest case of infection caused by HCV intergenotype recombinant RF1_2k/1b was identified in a child vertically infected in 1997. CONCLUSIONS HCV genotypes and subtypes were found to be variable virus specific markers in children infected in 1997-2015. Over the period, there has been a trend to change the dominant HCV subtype and appearance of recombinant RF1_2k/1b in children. Among humoral markers, anti-NS4AB revealing is depended on chronic hepatitis C duration, while for anti-HCV IgM, only a trend was established. The detection of anti-NS4AB can be helpful in assessing the duration of chronic hepatitis C.
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Affiliation(s)
- Lyudmila Nikolaeva
- Department of Molecular Virology, Ivanovsky Institute of Virology, Gamaleya National Research Centre of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia -
| | - Elena Leybman
- Department of Molecular Virology, Ivanovsky Institute of Virology, Gamaleya National Research Centre of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
- Department of Children's Infectious Diseases, Pirogov Russian National Research Medical University, Ministry of Health, Moscow, Russia
| | - Evgeniy Samokhvalov
- Department of Molecular Virology, Ivanovsky Institute of Virology, Gamaleya National Research Centre of Epidemiology and Microbiology, Ministry of Health, Moscow, Russia
| | - Karen Kyuregyan
- Department of Virology, Russian Medical Academy of Continuing Professional Education, Ministry of Health, Moscow, Russia
| | - Vera Kichatova
- Department of Virology, Russian Medical Academy of Continuing Professional Education, Ministry of Health, Moscow, Russia
| | - Olga Isaeva
- Department of Virology, Russian Medical Academy of Continuing Professional Education, Ministry of Health, Moscow, Russia
| | - Victor Kuprianov
- Department of Molecular Biology of Microorganisms, Skryabin Institute of Bioengineering, Federal Research Centre "Fundamentals of Biotechnology", Russian Academy of Sciences, Moscow, Russia
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Nasr P, Jönsson C, Ekstedt M, Kechagias S. Non-metabolic causes of steatotic liver disease. METABOLISM AND TARGET ORGAN DAMAGE 2023; 3. [DOI: 10.20517/mtod.2023.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Hepatic steatosis is caused by exaggerated hepatic lipid accumulation and is a common histological and radiological finding. Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction associated steatotic liver disease (MASLD), is highly associated with metabolic syndrome and represents the most common cause of hepatic steatosis. However, since several comorbidities, lifestyle factors, and drugs can cause hepatic steatosis, MASLD is, to some extent, a diagnosis of exclusion. Nevertheless, initiatives have been taken to encompass positive (instead of negative) criteria for diagnosis - such as the presence of cardiometabolic risk factors together with hepatic steatosis. Nonetheless, before confirming a patient with MASLD, it is essential to map and evaluate other causes of fatty liver disease or steatotic liver disease. Several causes of hepatic steatosis have been identified in studies; however, the study cohorts are scarce and often anecdotal. Additionally, many studies have shown correlation without proving causation, and many are retrospective without reporting relevant patient characteristics and comorbidities - making it difficult to draw conclusions regarding the underlying etiology or present comorbidity of hepatic steatosis. In this narrative review, we aimed to identify and summarize present studies evaluating the impact of the most common and often suggested causes of hepatic steatosis.
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Sofosbuvir-based direct-acting antivirals and changes in cholesterol and low density lipoprotein-cholesterol. Sci Rep 2022; 12:9942. [PMID: 35705594 PMCID: PMC9200852 DOI: 10.1038/s41598-022-13657-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 05/05/2022] [Indexed: 11/19/2022] Open
Abstract
Worsened lipid profiles were observed in chronic hepatitis C (CHC) patients during direct-acting antivirals (DAAs) treatment, among which combination drugs confounded the effect of individual ingredient on lipid. Tenofovir alafenamide (TAF) also worsened lipid profiles in HIV patients. Structural similarity between sofosbuvir (SOF) and TAF prompted us to investigate rapid increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in CHC patients treated with SOF-based DAAs. A retrospective study was performed to analyze 487 CHC patients receiving DAAs with SVR12. Relative risks on elevating TC and LDL-C were analyzed by logistic regression to determine SOF-based over non-SOF-based regimens. TC or LDL-C levels at baseline, week-4 and SVR12 were compared by Wilcoxon matched-pairs signed rank test. Week 4 or SVR12 to baseline ratios of serum TC or LDL-C between regimens were compared by Mann–Whitney's test. 487 patients were treated with Harvoni (SOF-based, 206 patients), Epclusa (SOF-based, 124 patients), Maviret (non-SOF-based, 122 patients), or Zepatier (non-SOF-based, 35 patients). At week 4 during drug treatment, Harvoni, Epclusa, and Maviret induced statistically significant elevation of TC and LDL-C, but Zepatier did not. SOF-based regimens had 2.72-fold higher relative risk (RR) causing 10% elevation of TC (95% CI 1.84–4.02, p < 0.001) and 2.04-fold higher RR causing 10% elevation of LDL-C (95% CI 1.39–3.01, p < 0.001) than non-SOF-based DAAs. SOF-based DAAs were associated with significantly larger amplitude of increases in TC and LDL-C than non-SOF-based DAAs during the initial 4 weeks of treatment, but the increases were not sustained to SVR12.
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Seifeldein GS, Hassan EA, Imam HM, Makboul R, Idriss NK, Gaber MA, Elkady RM. Quantitative MDCT and MRI assessment of hepatic steatosis in genotype 4 chronic hepatitis C patients with fibrosis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-021-00590-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatic steatosis has been shown to worsen the course of liver disease in chronic hepatitis C (CHC) patients, and it may reduce the efficacy of antiviral therapy and accelerate disease progression. In this cross-sectional study, we aimed to evaluate the role of multidetector computed tomography and magnetic resonance imaging (MRI) in the quantitative assessment and grading of hepatic steatosis to evaluate the association between hepatic steatosis and fibrosis in Egyptian genotype 4-CHC (G4-CHC) patients.
Results
Histopathological hepatic steatosis was found in 70.3% of 155 patients. No correlation was found between the CT ratio and pathological hepatic steatosis. Proton density fat fraction, T1-fat fraction, and fat percentage correlated with histological steatosis grading (r = 0.953, p < 0.001; r = 0.380, p = 0.027 and r = 0.384, p = 0.025, respectively). An agreement between steatosis grading by histology and 1H-MRS was found in 74.2% of patients. Compared to other MRI modalities, proton density fat fraction had the highest area under the receiver operating characteristic curve (AUC), with 0.910, 0.931, and 0.975 for mild, moderate, and severe steatosis, respectively. The cutoff with the best ability to predict steatosis was > 4.95 for a proton density fat fraction (AUC = 0.958) with 95.8% sensitivity, 90% specificity, 78.5% positive predictive value, and 96.1% negative predictive value.
Conclusion
1H-MRS had good diagnostic performance in predicting hepatic steatosis in G4-CHC patients, and hence, it may offer a useful noninvasive quantitative modality for grading steatosis with clinical applicability, especially in those where a liver biopsy cannot be done.
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Spaziante M, Taliani G, Marchetti G, Tavelli A, Lichtner M, Cingolani A, Cicalini S, Biliotti E, Girardi E, Antinori A, Puoti M, d’Arminio Monforte A, Cozzi-Lepri A. Impact of HCV Eradication on Lipid Metabolism in HIV/HCV Coinfected Patients: Data from ICONA and HepaICONA Foundation Cohort Study. Viruses 2021; 13:v13071402. [PMID: 34372608 PMCID: PMC8310285 DOI: 10.3390/v13071402] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES HCV shows complex interactions with lipid metabolism. Our aim was to examine total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) changes in HIV/HCV coinfected patients, after achieving sustained virological response (SVR), according to different HCV genotypes and specific antiretroviral use. METHODS HIV/HCV coinfected patients, enrolled in the ICONA and HepaICONA cohorts, who achieved DAA-driven SVR were included. Paired t-tests were used to examine whether the pre- and post-SVR laboratory value variations were significantly different from zero. ANCOVA regression models were employed to estimate the causal effect of SVR and of PI/r use on lipid changes. The interaction between the effect of eradication and HCV genotype was formally tested. RESULTS six hundred and ninety-nine HIV/HCV coinfected patients were enrolled. After HCV eradication, a significant improvement in liver function occurred, with a significant decrease in AST, ALT, GGT, and total plasmatic bilirubin. TC and LDL-C significantly increased by 21.4 mg/dL and 22.4 mg/dL, respectively (p < 0.001), after SVR, whereas there was no evidence for a change in HDL-C (p = 0.45) and triglycerides (p = 0.49). Notably, the TC and LDL-C increase was higher for participants who were receiving darunavir/ritonavir, and the TC showed a more pronounced increase among HCV genotype 3 patients (interaction-p value = 0.002). CONCLUSIONS complex and rapid changes in TC and LDL-C levels, modulated by HCV genotype and PI/r-based ART combinations, occurred in HIV/HCV coinfected patients after SVR. Further studies are needed to evaluate the clinical impact of these changes on the long-term risk of cardiovascular disease.
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Affiliation(s)
- Martina Spaziante
- Clinical Epidemiology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (M.S.); (E.G.)
| | - Gloria Taliani
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy;
- Task Force Anti-COVID, AORN San Giuseppe Moscati, 83100 Avellino, Italy
- Correspondence:
| | - Giulia Marchetti
- ASST Santi Paolo e Carlo, Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, 20122 Milan, Italy; (G.M.); (A.d.M.)
| | | | - Miriam Lichtner
- Department of Infectious Diseases, La Sapienza University, Polo Pontino, 04100 Latina, Italy;
| | - Antonella Cingolani
- Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Policlinico Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Stefania Cicalini
- HIV/AIDS Clinical Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.C.); (A.A.)
| | - Elisa Biliotti
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy;
| | - Enrico Girardi
- Clinical Epidemiology Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (M.S.); (E.G.)
| | - Andrea Antinori
- HIV/AIDS Clinical Unit, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, 00149 Rome, Italy; (S.C.); (A.A.)
| | - Massimo Puoti
- Division of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy;
| | - Antonella d’Arminio Monforte
- ASST Santi Paolo e Carlo, Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, 20122 Milan, Italy; (G.M.); (A.d.M.)
| | - Alessandro Cozzi-Lepri
- Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, UCL, London WC1N 1EH, UK;
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Abstract
Hepatits C virus (HCV) infection has been largely associated with extrahepatic comorbidities such as diseases related to dysregulation of the immune system, neuropsychiatric disorders, and cardiometabolic alterations. These clinical consequences, together with experimental evidence, suggest a potential (in)direct effect of HCV, contributing to the pathogenesis of these diseases. Various studies have reported a positive effect of viral eradication on occurrence and outcomes of extrahepatic diseases. These observations and the availability of safe and effective direct antiviral agents further underline the need to search for virological eradication in all infected individuals independent of the severity of the liver disease.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, PROMISE, Università di Palermo, Italia.
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, PROMISE, Università di Palermo, Italia
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Badawi A, Di Giuseppe G, Gupta A, Poirier A, Arora P. Bayesian network modelling study to identify factors influencing the risk of cardiovascular disease in Canadian adults with hepatitis C virus infection. BMJ Open 2020; 10:e035867. [PMID: 32371519 PMCID: PMC7228556 DOI: 10.1136/bmjopen-2019-035867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVES The present study evaluates the extent of association between hepatitis C virus (HCV) infection and cardiovascular disease (CVD) risk and identifies factors mediating this relationship using Bayesian network (BN) analysis. DESIGN AND SETTING A population-based cross-sectional survey in Canada. PARTICIPANTS Adults from the Canadian Health Measures Survey (n=10 115) aged 30 to 74 years. PRIMARY AND SECONDARY OUTCOME MEASURES The 10-year risk of CVD was determined using the Framingham Risk Score in HCV-positive and HCV-negative subjects. Using BN analysis, variables were modelled to calculate the probability of CVD risk in HCV infection. RESULTS When the BN is compiled, and no variable has been instantiated, 73%, 17% and 11% of the subjects had low, moderate and high 10-year CVD risk, respectively. The conditional probability of high CVD risk increased to 13.9%±1.6% (p<2.2×10-16) when the HCV variable is instantiated to 'Present' state and decreased to 8.6%±0.2% when HCV was instantiated to 'Absent' (p<2.2×10-16). HCV cases had 1.6-fold higher prevalence of high-CVD risk compared with non-infected individuals (p=0.038). Analysis of the effect modification of the HCV-CVD relationship (using median Kullback-Leibler divergence; DKL ) showed diabetes as a major effect modifier on the joint probability distribution of HCV infection and CVD risk (DKL =0.27, IQR: 0.26 to 0.27), followed by hypertension (0.24, IQR: 0.23 to 0.25), age (0.21, IQR: 0.10 to 0.38) and injection drug use (0.19, IQR: 0.06 to 0.59). CONCLUSIONS Exploring the relationship between HCV infection and CVD risk using BN modelling analysis revealed that the infection is associated with elevated CVD risk. A number of risk modifiers were identified to play a role in this relationship. Targeting these factors during the course of infection to reduce CVD risk should be studied further.
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Affiliation(s)
- Alaa Badawi
- Public Health Risk Sciences Division, Public Health Agency of Canada, Toronto, Ontario, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Giancarlo Di Giuseppe
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Pediatric Oncology Group of Ontario, Toronto, Ontario, Canada
| | - Alind Gupta
- Lighthouse Outcomes, Toronto, Ontario, Canada
| | - Abbey Poirier
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada
| | - Paul Arora
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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Abstract
OBJECTIVE Hepatitis C virus (HCV), cirrhosis, and HCV medications including direct-acting antivirals (DAAs) ±ribavirin may all influence the metabolic milieu. While interferon-based regimens improve glucose tolerance, evidence is limited on DAAs. Cases of elevated lactate have recently been reported in patients treated with DAAs, and lactic acidosis is a known complication of antivirals used to treat hepatitis B virus and HIV. PATIENTS AND METHODS Measures were evaluated at baseline, week 4, end of treatment, and 12-24 weeks after treatment. Mixed-effects modeling was used to determine factors influencing glucose and lactate over time. RESULTS In total, 442 patients were treated (mean age 56, 65% male, 72% genotype 1, 48% cirrhotic). Glucose did not change on or after DAA treatment from baseline (P=0.51) aside from those with untreated diabetes, which declined (P=0.02). Overall, there was a decline in lactate following HCV treatment (mean 2.4-2.1 mmol/l; P<0.001). Lactate initially increased on treatment and then decreased after treatment completion in male patients treated with ribavirin. This pattern was not observed in other groups. There was no evidence of lactic acidosis with HCV nucleotide use. CONCLUSION Distinct glucose and lactate trajectories were identified without evidence of DAA metabolic toxicity. HCV treatment does not improve random glucose levels aside from perhaps in untreated diabetic patients.
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9
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Badawi A, Di Giuseppe G, Arora P. Cardiovascular disease risk in patients with hepatitis C infection: Results from two general population health surveys in Canada and the United States (2007-2017). PLoS One 2018; 13:e0208839. [PMID: 30540839 PMCID: PMC6291240 DOI: 10.1371/journal.pone.0208839] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/25/2018] [Indexed: 02/06/2023] Open
Abstract
The role of hepatitis C virus (HCV) infection in increasing the risk of cardiovascular disease (CVD) is controversial. The objective of the present study is to estimate the 10-year risk of CVD in HCV- positive subjects and describe their profile of cardiometabolic risk markers compared to HCV-negative subjects. We conducted a cross-sectional study to estimate 10-year CVD risk, calculated using the Framingham Risk Score (FRS), in participants from the Canadian Health Measures Survey (CHMS; 2007–2015, n = 10,115) and the US-National Health and Nutrition Examination Survey (NHANES; 2007–2016, n = 16,668). Subjects included in our analysis were aged 30 to 74 years with no prior history of CVD. FRS estimates, sociodemographic and cardiometabolic risk factors were compared between HCV- positive and -negative subjects in the two surveys. HCV-positive subjects had a distinct sociodemographic profile compared to their HCV-negative counterparts. Cardiometabolic risk factors, inflammatory markers and serum levels of micronutrients were comparable between the two survey populations, both in HCV-positive and -negative subjects. The average FRS in HCV-positive patients was in the range of “intermediate” 10-year CVD risk (i.e., 10–20%) and was significantly higher (P<0.01) than their HCV-negative counterparts who were within the “low” 10-year CVD risk range (i.e., ≤10%). Using a multivariable linear regression model adjusted for ethnicity, number of metabolic syndrome components and BMI, HCV infection was significantly associated with a 2.5–3.5% absolute risk increase of 10-year CVD (P<0.01). The results of the present study suggest a potential association between HCV infection and risk of subclinical and clinical CVD. The expansion of anti-HCV therapy may also contribute to reduced CVD risk and burden in patients with chronic HCV infection and should be explored further in other datasets and population modelling studies.
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Affiliation(s)
- Alaa Badawi
- Public Health Risk Sciences Division, Public Health Agency of Canada, Toronto, ON, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- * E-mail:
| | | | - Paul Arora
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Division of Enteric Diseases, National Microbiology Laboratory, Public Health Agency of Canada, Toronto, ON, Canada
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Drazilova S, Gazda J, Janicko M, Jarcuska P. Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy. Can J Gastroenterol Hepatol 2018; 2018:6150861. [PMID: 30186821 PMCID: PMC6110000 DOI: 10.1155/2018/6150861] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 07/31/2018] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic hepatitis C have both higher prevalence of diabetes mellitus type 2 (T2DM) and increased cardiovascular risk compared to never infected people. Sustained viral response (SVR) achievement led to decreasing incidence and prevalence of T2DM during the interferon era of HCV treatment. Currently, direct-acting antiviral drugs (DAA) are the gold standard for treating HCV infection, while yielding SVR in nearly all patients. In chronic HCV patients with T2DM (prediabetes most likely too), DAA therapy is associated with both better fasting glucose and glycated hemoglobin (HbA1C) controls; thus reducing pharmacotherapy in a certain part of patients is possible. Papers mentioned in the review confirmed DAA role in both total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase. This alteration was accompanied by an increase in high-density lipoprotein cholesterol (HDL-C) and a decrease in triglycerides (TG) verified by most of the studies. However, the clinical significance of lipoprotein alterations caused by DAA therapy has not been explained yet. Moreover, DAA treatment of chronic hepatitis C improves hypertension control and atherosclerotic plaques. It is very likely that DAA therapeutic regimens will decrease both T2DM prevalence and cardiovascular risk in chronic hepatitis C patients; further research, however, is needed.
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Affiliation(s)
- Sylvia Drazilova
- Department of Internal Medicine, Hospital Poprad, Poprad, Slovakia
| | - Jakub Gazda
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
| | - Martin Janicko
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
| | - Peter Jarcuska
- 1st Department of Internal Medicine, PJ Safarik University, Faculty of Medicine and L Pasteur University Hospital, Kosice, Slovakia
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Petta S, Adinolfi LE, Fracanzani AL, Rini F, Caldarella R, Calvaruso V, Cammà C, Ciaccio M, Di Marco V, Grimaudo S, Licata A, Marrone A, Nevola R, Pipitone RM, Pinto A, Rinaldi L, Torres D, Tuttolomondo A, Valenti L, Fargion S, Craxì A. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J Hepatol 2018; 69:18-24. [PMID: 29505844 DOI: 10.1016/j.jhep.2018.02.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/14/2018] [Accepted: 02/19/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. MATERIALS AND METHODS One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT ≥1 mm) and carotid plaques, defined as focal thickening of ≥1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 ± 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 ± 0.29 mm, 42.8% had IMT ≥1 mm, and 42.8% had carotid plaques. RESULTS All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 ± 0.29 mm vs. 0.81 ± 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity. CONCLUSION HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term. LAY SUMMARY Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy.
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Francesca Rini
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Rosalia Caldarella
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Marcello Ciaccio
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Anna Licata
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Riccardo Nevola
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | | | - Antonio Pinto
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Daniele Torres
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Antonino Tuttolomondo
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
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12
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Harada R, Kimura M, Sato Y, Taniguchi T, Tomonari T, Tanaka T, Tanaka H, Muguruma N, Shinomiya H, Honda H, Imoto I, Sogabe M, Okahisa T, Takayama T. APOB codon 4311 polymorphism is associated with hepatitis C virus infection through altered lipid metabolism. BMC Gastroenterol 2018; 18:24. [PMID: 29382324 PMCID: PMC5791310 DOI: 10.1186/s12876-018-0747-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 01/18/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. METHODS Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequence-specific oligonucleotide probe-Luminex method. RESULTS An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). CONCLUSION An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR.
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Affiliation(s)
- Rie Harada
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Masako Kimura
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Yasushi Sato
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Tatsuya Taniguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Takahiro Tanaka
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Hironori Tanaka
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Hirohiko Shinomiya
- Department of Gastroenterology, Yoshinogawa Medical Center, Yoshinogawa, Tokushima, 776-8511 Japan
| | - Hirohito Honda
- Department of Internal Medicine, Tokushima Health Screening Center, 1-10-3, Kuramoto-cho, Tokushima, 770-0042 Japan
| | - Issei Imoto
- Department of Human Genetics, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Masahiro Sogabe
- Department of General Medicine and Community Health Science, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Toshiya Okahisa
- Department of General Medicine and Community Health Science, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503 Japan
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13
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Abstract
Hepatitis C virus (HCV) infection is a prevalent condition associated with numerous extrahepatic manifestations. Epidemiologic studies have found that HCV is associated with increased cardiovascular morbidity and mortality, in particular with carotid atherosclerosis, cerebrovascular events, and coronary heart disease. The mechanisms involved encompass a chronic systemic inflammatory state, insulin resistance, and a potential, direct infection of the vascular endothelium. Sustained virologic response with interferon-based regimens is associated with reduced cardiovascular events, although this must be validated with newer direct-acting antivirals. This clear association between HCV and cardiovascular events may have significant economical and public health implications.
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Affiliation(s)
- Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, Geneva 4 1211, Switzerland
| | - Francesco Negro
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, Geneva 4 1211, Switzerland; Division of Clinical Pathology, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, Geneva 4 1211, Switzerland.
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14
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Crouchet E, Baumert TF, Schuster C. Hepatitis C virus-apolipoprotein interactions: molecular mechanisms and clinical impact. Expert Rev Proteomics 2017; 14:593-606. [PMID: 28625086 PMCID: PMC6138823 DOI: 10.1080/14789450.2017.1344102] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. Moreover, chronic HCV infection is associated with liver steatosis and metabolic disorders. With 130-150 million people chronically infected in the world, HCV infection represents a major public health problem. One hallmark on the virus is its close link with hepatic lipid and lipoprotein metabolism. Areas covered: HCV is associated with lipoprotein components such as apolipoproteins. These interactions play a key role in the viral life cycle, viral persistence and pathogenesis of liver disease. This review introduces first the role of apolipoproteins in lipoprotein metabolism, then highlights the molecular mechanisms of HCV-lipoprotein interactions and finally discusses their clinical impact. Expert commentary: While the study of virus-host interactions has resulted in a improvement of the understanding of the viral life cycle and the development of highly efficient therapies, major challenges remain: access to therapy is limited and an urgently needed HCV vaccine remains still elusive. Furthermore, the pathogenesis of disease biology is still only partially understood. The investigation of HCV-lipoproteins interactions offers new perspectives for novel therapeutic approaches, contribute to HCV vaccine design and understand virus-induced liver disease and cancer.
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Affiliation(s)
- Emilie Crouchet
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
| | - Thomas F. Baumert
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Inserm, U1110: Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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15
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Stättermayer AF, Traussnigg S, Aigner E, Kienbacher C, Huber-Schönauer U, Steindl-Munda P, Stadlmayr A, Wrba F, Trauner M, Datz C, Ferenci P. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome. J Trace Elem Med Biol 2017; 39:100-107. [PMID: 27908400 DOI: 10.1016/j.jtemb.2016.08.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/02/2016] [Accepted: 08/18/2016] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial including metabolic, genetic (e.g. PNPLA3 [patatin-like phospholipase domain-containing 3 gene]), viral factors and drugs. Besides, there is evidence for a role of copper deficiency. Aim of the study was to evaluate the role of hepatic copper content, PNPLA3 in NAFLD patients with and without metabolic syndrome (MetS). METHODS One-hundred seventy-four NAFLD patients, who underwent liver biopsy for diagnostic work-up, were studied. Diagnosis of MetS was based on the WHO Clinical Criteria. Steatosis was semiquantified as percentage of fat containing hepatocytes and was graded according to Brunt. Histological features of non-alcoholic steatohepatitis (NASH) were assessed using the Bedossa classification. Hepatic copper content (in μg/g dry weight) was measured by flame atomic absorption spectroscopy. SNP rs738409 in PNPLA3 was investigated by RT-PCR. RESULTS Mean hepatic copper content was 22.3 (19.6-25.1) μg/g. The mean percentage of histologically lipid containing hepatocytes was 42.2% (38.3-46.0) and correlated inversely with hepatic copper content (ρ=-0.358, P<0.001). By subgroup analysis this inverse correlation remained significant only in patients without MetS (OR: 0.959 [CI95%: 0.926-0.944], P=0.020). Presence of minor allele (G) of PNPLA3 was also associated with moderate/severe steatosis (≥33%) both in patients with (OR: 2.405 [CI95%: 1.220-4.744], P=0.011) and without MetS (OR: 2.481 [CI95%: 1.172-5.250], P=0.018), but was only associated with NASH (OR: 2.002 [CI95%: 1.062-3.772], P=0.032) and liver fibrosis (OR: 2.646 [CI95%: 1.299-5.389], P=0.007) in patients without MetS. CONCLUSION Hepatic copper content and PNPLA3 mutations are associated with disease activity in NAFLD patients without MetS. Presence of MetS appears to mask the effects of hepatic copper and PNPLA3.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Stefan Traussnigg
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Private Medical University, Salzburg, Austria
| | - Christian Kienbacher
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | | | - Petra Steindl-Munda
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | | | - Friedrich Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, KH Oberndorf, Oberndorf, Austria
| | - Peter Ferenci
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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16
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Pateria P, Jeffrey GP, MacQuillan G, Speers D, Ching H, Chinnaratha MA, Watts GF, Adams LA. The association between chronic hepatitis C infection and cardiovascular risk. Intern Med J 2016; 46:63-70. [PMID: 26477784 DOI: 10.1111/imj.12936] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/29/2015] [Accepted: 10/10/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Vascular disease is a common cause of death in patients with chronic hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is unclear. AIMS To determine whether patients with CHC have increased subclinical vascular disease and whether genotype or antiviral treatment modifies this risk. METHODS Fifty CHC patients and 22 age-matched and sex-matched healthy controls underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery flow-mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12) undergoing antiviral treatment 18 months after initiation of treatment. RESULTS Baseline vascular risk factors and measures of arterial stiffness, endothelial dysfunction and CIMT were not different between cases and controls (P > 0.2 for all). Genotype 1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 ± 3.5% vs 10.9 ± 5.2%, P = 0.03) and higher right CIMT (0.6 ± 0.1 mm vs 0.5 ± 0.07 mm, P = 0.04) compared with non-genotype 1. Patients who achieved sustained virological response (7/12) showed significant improvement in insulin resistance (homeostasis model of assessment of insulin resistance 2.3 ± 1.2 vs 1.8 ± 0.8, P = 0.02) and arterial stiffness (PWV 7.4 ± 1.1 m/s vs 6.5 ± 0.6 m/s, P = 0.04). CONCLUSIONS Subclinical vascular disease is not greater in CHC subjects compared with controls. However, among CHC subjects, genotype 1 infection is associated with greater endothelial dysfunction and increased carotid-intima medial thickness compared with non-genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial stiffness.
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Affiliation(s)
- P Pateria
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G P Jeffrey
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - G MacQuillan
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - D Speers
- PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre
| | - H Ching
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
| | - M A Chinnaratha
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital
| | - G F Watts
- School of Medicine and Pharmacology, University of Western Australia.,Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia
| | - L A Adams
- Department of Gastroenterology and Hepatology, Sir Charles Gairdner Hospital.,School of Medicine and Pharmacology, University of Western Australia
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17
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Mauss S, Berger F, Wehmeyer MH, Ingiliz P, Hueppe D, Lutz T, Simon KG, Schewe K, Rockstroh JK, Baumgarten A, Christensen S. Effect of antiviral therapy for HCV on lipid levels. Antivir Ther 2016; 21:81-88. [PMID: 27685337 DOI: 10.3851/imp3094] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND HCV has complex interactions with human lipid metabolism leading to down regulation of cholesterol levels. Interferon (IFN) therapy has been shown to decrease cholesterol even further. With the availability of second-generation direct-acting antiviral agents (DAA) the effect of suppressing and eliminating HCV on lipid metabolism warrants reevaluation. METHODS Prospective German multicentre cohort on HCV- and HIV-HCV-infected patients treated with direct-antiviral agents (GECCO). Lipids were assessed at baseline, during and after therapy. Wilcoxon test corrected for multiple testing was used. RESULTS For the analysis, 520 patients with chronic hepatitis C were available. Patients with chronic hepatitis C were treated as follows: sofosbuvir (SOF)/pegylated IFN (PEG-IFN)/ribavirin (RBV; HCV=34, HIV-HCV=36), SOF/RBV (HCV=47, HIV-HCV=16), SOF/simeprevir (HCV=9, HCV-HIV=2), SOF/daclatasvir +/- RBV (HCV=27, HIV-HCV=47), SOF/ledipasvir +/- RBV (HCV=147, HCV-HIV=100) and ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- RBV (2D, HCV=2, HCV-HIV=6; 3D, HCV=39, HCV-HIV=8). On treatment there was a statistically significant increase in total cholesterol for any IFN-free DAA regimen, which was maintained after end of therapy. Changes of total cholesterol were driven by changes in low-density lipoprotein cholesterol, whereas high-density lipoprotein cholesterol remained unchanged. In contrast, total cholesterol decreased on SOF/PEG-IFN/RBV and increased after end of therapy above baseline levels. Triglycerides increased during treatment with SOF/PEG-IFN/RBV, but not on DAA-only regimens. CONCLUSIONS Suppressing and eliminating HCV with IFN-free DAA regimens increased cholesterol levels, but had no effect on triglycerides. In contrast IFN-based therapy decreased cholesterol and increased triglycerides during treatment and led to increases in cholesterol after achieving sustained virological response.
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Affiliation(s)
- Stefan Mauss
- Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
| | - Florian Berger
- Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
| | - Malte H Wehmeyer
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Karl G Simon
- Practice for Gastroenterology, Leverkusen, Germany
| | - Knud Schewe
- Infektionsmedizinisches Centrum Hamburg, Hamburg, Germany
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18
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Younossi ZM, Stepanova M, Estep M, Negro F, Clark PJ, Hunt S, Song Q, Paulson M, Stamm LM, Brainard DM, Subramanian GM, McHutchison JG, Patel K. Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin. J Hepatol 2016; 64:29-36. [PMID: 26341824 DOI: 10.1016/j.jhep.2015.08.027] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 08/21/2015] [Accepted: 08/24/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) modulates host lipid metabolism for its replication and lifecycle. Our aims were to assess changes in the serum lipid and distal (post-squalene) cholesterol biosynthesis metabolite profile of HCV genotypes (GT) 2 and 3 patients treated with sofosbuvir+ribavirin. METHODS Serum samples [baseline, treatment week 12, 4weeks post-treatment] were analyzed for apolipoproteins B and E (apoB/E), total cholesterol, HDL, LDL, and 11 post-squalene sterol metabolites using a GC/MS platform. RESULTS We selected 127 patients (GT2 n=50, GT3 n=77), 50% cirrhotic patients, and 42% who experienced a virological relapse. At baseline, GT3 patients had lower level of serum lipids, apoB/E, 7-dehydrocholesterol, desmosterol, lathosterol, compared to GT2 (p<0.006). Baseline lathosterol was lower in relapsers with cirrhosis compared to cirrhotic patients with SVR (p=0.003). From baseline to treatment week 12, serum lipids, apoB/E, and key sterol pathway metabolites (7-dehydrocholesterol, desmosterol, lathosterol, lanosterol) increased in GT3. In contrast, in GT2 patients, apoB/E and dihydrolanosterol decreased with viral suppression (p<0.025). At follow-up week 4, cirrhotic SVR patients showed substantially greater increases in apoB and total sterols compared to cirrhotic relapsers regardless of HCV genotype. After adjustment for genotype and gender, baseline lathosterol was independently associated with virologic response (p=0.04). CONCLUSION HCV GT3 is associated with reduced circulation of lipids involved in the distal cholesterol biosynthesis pathway, resulting in relative hypocholesterolemia. HCV suppression during sofosbuvir+ribavirin restores distal sterol metabolites indicating viral interference with de novo lipogenesis or selective retention by hepatocytes.
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.
| | - Maria Stepanova
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Michael Estep
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | | | | | - Sharon Hunt
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | | | | | | | | | | | | | - Keyur Patel
- Division of Gastroenterology, Duke University Medical Center, Durham, NC, United States
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19
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Gondeau C, Pageaux GP, Larrey D. Hepatitis C virus infection: Are there still specific problems with genotype 3? World J Gastroenterol 2015; 21:12101-13. [PMID: 26576095 PMCID: PMC4641128 DOI: 10.3748/wjg.v21.i42.12101] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/07/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease and the main indication for liver transplantation worldwide. As promising specific treatments have been introduced for genotype 1, clinicians and researchers are now focusing on patients infected by non-genotype 1 HCV, particularly genotype 3. Indeed, in the golden era of direct-acting antiviral drugs, genotype 3 infections are no longer considered as easy to treat and are associated with higher risk of developing severe liver injuries, such as cirrhosis and hepatocellular carcinoma. Moreover, HCV genotype 3 accounts for 40% of all HCV infections in Asia and is the most frequent genotype among HCV-positive injecting drug users in several countries. Here, we review recent data on HCV genotype 3 infection/treatment, including clinical aspects and the underlying genotype-specific molecular mechanisms.
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20
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Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
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Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
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21
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Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014; 61:S69-78. [PMID: 25443347 DOI: 10.1016/j.jhep.2014.08.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
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Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
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22
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Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology 2014; 59:2403-12. [PMID: 24155107 DOI: 10.1002/hep.26905] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 10/18/2013] [Indexed: 12/14/2022]
Abstract
UNLABELLED Genotype 3 of the hepatitis C virus (HCV) has been long considered an easy-to-treat infection, with higher cure rates (∼70%) than other viral genotypes with the standard combination of pegylated interferon-α and ribavirin. However, the relative insensitivity of this genotype to most protease inhibitors and the recent unexpected data on decreased effectiveness of sofosbuvir have raised questions on how to achieve universal cure, a goal that seems reasonable for other genotypes. In addition, increasing clinical and experimental data show that HCV genotype 3 may be associated not only with severe steatosis, but also with accelerated fibrosis progression rate and increased oncogenesis. CONCLUSION Currently available data suggest that we should increase our efforts to understand the virology and pathogenesis of HCV genotype 3, aiming at better and more potent, genotype-targeted treatments.
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Affiliation(s)
- Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
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23
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Stättermayer AF, Scherzer T, Beinhardt S, Rutter K, Hofer H, Ferenci P. Review article: genetic factors that modify the outcome of viral hepatitis. Aliment Pharmacol Ther 2014; 39:1059-1070. [PMID: 24654629 PMCID: PMC7159786 DOI: 10.1111/apt.12717] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 12/10/2013] [Accepted: 03/01/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Genetic factors can play an important role for treatment response and disease progression in chronic viral hepatitis. AIM To review the influence of host genetic factors on the clinical course as well as on treatment response in patients with viral hepatitis. METHODS Review of the literature. RESULTS A landmark genome-wide association study (GWAS) identified polymorphisms in the IL28B gene on chromosome 19 (19q13.13) associated with response to therapy with pegylated interferon-α (PEG-IFN) and ribavirin (RBV) and spontaneous viral clearance in acute hepatitis C. Furthermore, IL28B genotype is associated with changes of lipid metabolism and insulin resistance. A further GWAS demonstrated that ITPA genetic variants protect HCV genotype 1 patients from RBV-induced anaemia. Another polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) is associated with hepatic steatosis. Difficult-to-treat hepatitis C patients homozygous for GG had an up to five-fold lower chance of viral clearance on PEG/RBV than non-GG patients. In chronic hepatitis B patients treated with PEG-IFN several retrospective analyses of IL28B rs12980275 and rs12979860 genotypes yielded conflicting results which can be explained by the heterogeneity between the study populations. Some variants of the HLA-DP locus (HLA-DPA1 A allele and HLA-DPB1) protect against progression of chronic hepatitis B infection. CONCLUSIONS The determination of IL28B polymorphisms may be useful to individualise treatment options when using PEG/RBV based therapies for chronic hepatitis C infection. In contrast, so far identified genetic factors play only a minor role in chronic hepatitis B infection.
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Affiliation(s)
- A. F. Stättermayer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - T. Scherzer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - S. Beinhardt
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - K. Rutter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - H. Hofer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - P. Ferenci
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
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Stättermayer AF, Rutter K, Beinhardt S, Wrba F, Scherzer TM, Strasser M, Hofer H, Steindl-Munda P, Trauner M, Ferenci P. Role of FDFT1 polymorphism for fibrosis progression in patients with chronic hepatitis C. Liver Int 2014; 34:388-395. [PMID: 23870067 DOI: 10.1111/liv.12269] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 06/17/2013] [Indexed: 01/02/2023]
Abstract
BACKGROUND In chronic hepatitis C (CHC), steatosis is associated with fibrosis and impaired response to antiviral therapy. Recently, a polymorphism of single nucleotide polymorphism SNP rs2645424 of farnesyl diphosphate farnesyl transferase 1 (FDFT1) was identified in NAFLD/NASH as a possible causal link to steatosis and fibrosis progression. SNP rs738409 in the adiponutrin gene (PNPLA3) is a well described factor for steatosis. This study evaluated the relation of these SNPs on steatosis, fibrosis and treatment response in CHC. METHODS The SNPs rs738409478 and rs2645424 were determined by real-time PCR in 478 patients with CHC (m/f: 314/164; mean age: 44.9 ± 10.7; GT1: 387, GT4: 91) who completed treatment with peg-IFN-α-2a/ribavirin. All had a pretreatment liver biopsy. Steatosis and fibrosis were graded by board-certified pathologists according to Brunt and METAVIR respectively. RESULTS The distribution of FDFT1 rs2645424 was GG: 186 (38.9%), AG: 222 (46.4%) and AA: 70 (14.6%) and of the rs738409 PNPLA3 allele: CC: 269 (56.3%), CG: 177 (37.0%) and GG: 32 (6.7%). Overall, FDTF1 polymorphism was not linked to the extent of steatosis or fibrosis. However, in patients without steatosis the AA genotype was associated with advanced fibrosis [AA: 8/20 (40.0%), AG: 6/70 (8.5%), GG: 9/57 (16.1%), P = 0.003]. In contrast, the minor PNPLA3 allele was associated with both steatosis and advanced fibrosis (P < 0.001). Both SNPs did not influence treatment response. CONCLUSION The minor allele in FDFT1 was associated with advanced fibrosis in the non-steatotic but not in the steatotic subgroup. This may reflect different metabolic pathways in fibrosis progression for steatotic and non-steatotic patients with CHC.
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Affiliation(s)
- Albert F Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Ferenci P. Treatment of Chronic Hepatitis C, Genotype 4. CURRENT HEPATITIS REPORTS 2013; 12:246-250. [DOI: 10.1007/s11901-013-0178-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013; 19:7896-7909. [PMID: 24307784 PMCID: PMC3848138 DOI: 10.3748/wjg.v19.i44.7896] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 10/13/2013] [Indexed: 02/06/2023] Open
Abstract
This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.
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Ydreborg M, Westin J, Rembeck K, Lindh M, Norrgren H, Holmberg A, Wejstål R, Norkrans G, Cardell K, Weiland O, Lagging M. Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection. PLoS One 2013; 8:e80172. [PMID: 24244641 PMCID: PMC3828208 DOI: 10.1371/journal.pone.0080172] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 10/09/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of hepatitis C virus (HCV) infection as well as outcome following pegylated interferon and ribavirin therapy among genotype 1 infected patients. Additionally the presence of the otherwise favorable IL28B genetic variants in the context of HCV genotype 3 infection reportedly entail more pronounced liver fibrosis and steatosis. The present study aimed to evaluate the impact of IL28B SNP variability on liver stiffness as accessed by transient elastography. METHODS Seven hundred and seventy-one Swedish HCV infected patients sequentially undergoing liver stiffness measurement by means of Fibroscan® in the context of a real-life trial had samples available for IL28B genotyping (rs12979860) and HCV genotyping. RESULTS CC(rs12979860) was more common among HCV genotype 2 or 3 infected treatment-naïve patients than among those infected with genotype 1 (P<0.0001). Additionally CC(rs12979860) among HCV genotype 3 infected patients was associated with higher liver stiffness values (P = 0.004), and higher AST to platelet ratio index (APRI; p = 0.02) as compared to carriers of the T allele. Among HCV genotype 1 infected patients, CC(rs12979860) was significantly associated with higher viral load (P = 0.001), with a similar non-significant trend noted among HCV genotype 3 infected patients. CONCLUSION This study confirms previous reports that the CC(rs12979860) SNP is associated with more pronounced liver pathology in patients chronically infected with HCV genotype 3 as compared to genotype 1, suggesting that IL28B genetic variants differently regulates the course of HCV infection across HCV genotypes.
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Affiliation(s)
- Magdalena Ydreborg
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Johan Westin
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Karolina Rembeck
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Hans Norrgren
- Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden
| | - Anna Holmberg
- Department of Infectious Diseases, Skåne University Hospital, Lund, Sweden
| | - Rune Wejstål
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Kristina Cardell
- Department of Infectious Diseases, Linköping University Hospital, Linköping, Sweden
| | - Ola Weiland
- Department of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Karolinska, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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Hepatitis C virus, cholesterol and lipoproteins--impact for the viral life cycle and pathogenesis of liver disease. Viruses 2013; 5:1292-324. [PMID: 23698400 PMCID: PMC3712309 DOI: 10.3390/v5051292] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/10/2013] [Accepted: 04/27/2013] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects.
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Stättermayer AF, Rutter K, Beinhardt S, Scherzer TM, Stadlmayr A, Hofer H, Wrba F, Steindl-Munda P, Krebs M, Datz C, Trauner M, Ferenci P. Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C. J Hepatol 2012; 57:492-498. [PMID: 22634340 DOI: 10.1016/j.jhep.2012.04.036] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Revised: 03/20/2012] [Accepted: 04/05/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C. METHODS Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed. RESULTS Insulin resistance (HOMA-IR ≥ 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 ± 1.61 (mean ± SD) and 2.94 ± 2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 ± 3.15; F0-2: 2.38 ± 2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 ± 21.5 vs. 9.1 ± 14.2; p<0.001), HOMA-IR ≥ 3.0 (17.7 ± 17.8 vs. 8.8 ± 15.4%; p<0.001), and BMI > 25.0 kg/m(2) (14.7 ± 17.0 vs. 9.1 ± 16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance. CONCLUSIONS Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Oehler V, Filipe A, Montserret R, da Costa D, Brown G, Penin F, McLauchlan J. Structural analysis of hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase. J Virol 2012; 86:7818-28. [PMID: 22593157 PMCID: PMC3421639 DOI: 10.1128/jvi.00457-12] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 05/07/2012] [Indexed: 12/19/2022] Open
Abstract
The maturation of the hepatitis C virus (HCV) core protein requires proteolytic processing by two host proteases: signal peptidase (SP) and the intramembrane-cleaving protease signal peptide peptidase (SPP). Previous work on HCV genotype 1a (GT1a) and GT2a has identified crucial residues required for efficient signal peptide processing by SPP, which in turn has an effect on the production of infectious virus particles. Here we demonstrate that the JFH1 GT2a core-E1 signal peptide can be adapted to the GT3a sequence without affecting the production of infectious HCV. Through mutagenesis studies, we identified crucial residues required for core-E1 signal peptide processing, including a GT3a sequence-specific histidine (His) at position 187. In addition, the stable knockdown of intracellular SPP levels in HuH-7 cells significantly affects HCV virus titers, further demonstrating the requirement for SPP for the maturation of core and the production of infectious HCV particles. Finally, our nuclear magnetic resonance (NMR) structural analysis of a synthetic HCV JFH1 GT2a core-E1 signal peptide provides an essential structural template for a further understanding of core processing as well as the first model for an SPP substrate within its membrane environment. Our findings give deeper insights into the mechanisms of intramembrane-cleaving proteases and the impact on viral infections.
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Affiliation(s)
- Verena Oehler
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Ana Filipe
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Roland Montserret
- Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, UMR 5086, CNRS, Université de Lyon, Lyon, France
| | - Daniel da Costa
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Gaie Brown
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - François Penin
- Bases Moléculaires et Structurales des Systèmes Infectieux, IBCP, UMR 5086, CNRS, Université de Lyon, Lyon, France
| | - John McLauchlan
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
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Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour JF, Geier A, Gerlach TJ, Heim MH, Malinverni R, Negro F, Regenass S, Badenhoop K, Bojunga J, Sarrazin C, Zeuzem S, Müller T, Berg T, Bochud PY, Moradpour D. A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C. PLoS One 2012; 7:e40159. [PMID: 22808108 PMCID: PMC3395683 DOI: 10.1371/journal.pone.0040159] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 06/01/2012] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. METHODOLOGY/PRINCIPAL FINDINGS Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D(3) (25[OH]D(3)) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D(3)<20 ng/mL) during all seasons, but 25(OH)D(3) serum levels were not associated with treatment outcome. CONCLUSIONS/SIGNIFICANCE Our study suggests a role of bioactive vitamin D (1,25[OH](2)D(3), calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D(3) is not a suitable predictor of treatment outcome.
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Affiliation(s)
- Christian M. Lange
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Stephanie Bibert
- Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Zoltan Kutalik
- Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Philippe Burgisser
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | | | - Jean-Francois Dufour
- University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Andreas Geier
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Tilman J. Gerlach
- Division of Gastroenterology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Markus H. Heim
- Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | | | - Francesco Negro
- Division of Gastroenterology and Hepatology, University Hospital Geneva, Geneva, Switzerland
| | - Stephan Regenass
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Klaus Badenhoop
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Jörg Bojunga
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Christoph Sarrazin
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany
| | - Tobias Müller
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité Campus Virchow Klinikum, Berlin, Germany
| | - Thomas Berg
- Klinik für Gastroenterologie und Rheumatologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Pierre-Yves Bochud
- Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012; 56 Suppl 1:S56-65. [PMID: 22300466 DOI: 10.1016/s0168-8278(12)60007-5] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Given the pandemic spread of the hepatitis C virus (HCV) infection and the metabolic syndrome (MS), the burden of their interaction is a major public health issue, bound to increase in the near term. A better appreciation of the clinical consequences of the relationship between HCV and MS is needed, not only due to their potential synergism on liver disease severity, but also because of the multifaceted interactions between HCV and glucose and lipid metabolism. HCV infection per se does not carry an increased risk of MS, but is able to perturb glucose homeostasis through several direct and indirect mechanisms, leading to both hepatic and extrahepatic insulin resistance. This translates into accelerated liver disease progression (including the development of hepatocellular carcinoma), reduced response to antivirals and, in susceptible individuals, increased risk of developing full-blown type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Possibly as a result of HCV-induced insulin resistance, and despite a paradoxically favourable lipid profile, the cardiovascular risk is moderately increased in chronic hepatitis C. In addition, the interaction with the MS further increases the risks of cirrhosis, hepatocellular carcinoma, diabetes, and cardiovascular events. Thus, targeted lifestyle and pharmacological measures are urgently warranted in chronic hepatitis C with metabolic alterations.
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Lange CM, Kutalik Z, Morikawa K, Bibert S, Cerny A, Dollenmaier G, Dufour JF, Gerlach TJ, Heim MH, Malinverni R, Müllhaupt B, Negro F, Moradpour D, Bochud PY. Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy. Hepatology 2012; 55:1038-47. [PMID: 22095909 DOI: 10.1002/hep.24787] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2011] [Accepted: 10/21/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. CONCLUSION In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.
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Affiliation(s)
- Christian M Lange
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland.
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36
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Depla M, d'Alteroche L, Le Gouge A, Moreau A, Hourioux C, Meunier JC, Gaillard J, de Muret A, Bacq Y, Kazemi F, Avargues A, Roch E, Piver E, Gaudy-Graffin C, Giraudeau B, Roingeard P. Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis. PLoS One 2012; 7:e33749. [PMID: 22479436 PMCID: PMC3315576 DOI: 10.1371/journal.pone.0033749] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 02/16/2012] [Indexed: 12/14/2022] Open
Abstract
Most clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses.
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Affiliation(s)
- Marion Depla
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
| | - Louis d'Alteroche
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
- Service d'Hépatogastroentérologie, Hôpital Trousseau, CHRU de Tours, Tours, France
| | - Amélie Le Gouge
- INSERM CIC 0202, Université François Rabelais and CHRU de Tours, Tours, France
| | - Alain Moreau
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
| | - Christophe Hourioux
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
- Unité de Biologie Cellulaire, Hôpital Bretonneau, CHRU de Tours, Tours, France
- Plate-Forme RIO des Microscopies, PPF ASB, Université François Rabelais, Tours, France
| | | | - Julien Gaillard
- Plate-Forme RIO des Microscopies, PPF ASB, Université François Rabelais, Tours, France
| | - Anne de Muret
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Trousseau, CHRU de Tours, Tours, France
| | - Yannick Bacq
- Service d'Hépatogastroentérologie, Hôpital Trousseau, CHRU de Tours, Tours, France
| | - Farhad Kazemi
- Service d'Hépatogastroentérologie, Centre Hospitalier de Blois, Blois, France
| | - Aurélie Avargues
- INSERM CIC 0202, Université François Rabelais and CHRU de Tours, Tours, France
| | - Emmanuelle Roch
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
| | - Eric Piver
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
- Service de Biochmie, Hôpital Trousseau, CHRU de Tours, Tours, France
| | - Catherine Gaudy-Graffin
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie, Hôpital Bretonneau, CHRU de Tours, Tours, France
| | - Bruno Giraudeau
- INSERM CIC 0202, Université François Rabelais and CHRU de Tours, Tours, France
| | - Philippe Roingeard
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
- Unité de Biologie Cellulaire, Hôpital Bretonneau, CHRU de Tours, Tours, France
- Plate-Forme RIO des Microscopies, PPF ASB, Université François Rabelais, Tours, France
- * E-mail:
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Grossi PA, Costa AN, Fehily D, Blumberg EA, Kuehnert MJ, Fishman JA, Ison MG, Lattes R, Kotton CN, Lilleri D, Kabanova A, Lanzavecchia A, Gerna G, Razonable RR, Comoli P, Zecca M, Basso S, Ginevri F, Grossi A, Schena FP, Rimola A, Burra P, De Martin E, Rodriguez-Castro KI, Fagiuoli S, Pasulo L, Bruno R, Andreone P, Loggi E, Arena F, Rossolini GM, Sganga G, Cozza V. Infections and organ transplantation: new challenges for prevention and treatment--a colloquium. Transplantation 2012; 93:S4-S39. [PMID: 22374265 DOI: 10.1097/tp.0b013e3182481347] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Paolo A Grossi
- Infectious Diseases Department, University of Insubria, Varese, ISMETT-UPMC Palermo, National Center for Transplantation, Rome, Italy.
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38
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Rembeck K, Alsiö Å, Christensen PB, Färkkilä M, Langeland N, Buhl MR, Pedersen C, Mørch K, Westin J, Lindh M, Hellstrand K, Norkrans G, Lagging M. Impact of IL28B-related single nucleotide polymorphisms on liver histopathology in chronic hepatitis C genotype 2 and 3. PLoS One 2012; 7:e29370. [PMID: 22253715 PMCID: PMC3258245 DOI: 10.1371/journal.pone.0029370] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 11/27/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND AIMS Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory. METHODS Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology. RESULTS IL28B CC(rs12979860) genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CC(rs12979860) genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients. CONCLUSION This study shows that the CC(rs12979860) SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.
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Affiliation(s)
- Karolina Rembeck
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Åsa Alsiö
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | | | - Martti Färkkilä
- Department of Gastroenterology, Helsinki University, Helsinki, Finland
| | - Nina Langeland
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Institute of Medicine, University of Bergen, Bergen, Norway
| | - Mads Rauning Buhl
- Department of Infectious Diseases, Aarhus University, Aarhus, Denmark
| | - Court Pedersen
- Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark
| | - Kristine Mørch
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Institute of Medicine, University of Bergen, Bergen, Norway
| | - Johan Westin
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Lindh
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Kristoffer Hellstrand
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Gunnar Norkrans
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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40
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Abstract
PURPOSE HCV chronic infection still presents a very serious epidemiological and clinical problem. Apart from its cytopathic effect on liver parenchyma, its detrimental effect on lipid and carbohydrate metabolism has recently been emphasized. The aim of the study was to assess lipid and carbohydrate parameters in children with chronic HCV-related hepatitis. MATERIAL/METHODS The study comprised 41 children with chronic hepatitis C (CHC) aged between 7 and 18 years, and 30 healthy controls. The anthropometric measurements of the subjects were taken, and, after overnight fasting, serum glucose, insulin, total bilirubin, AST, ALT, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride levels were investigated. The HOMA IR insulin resistance index was also calculated. RESULTS The values for mean body mass index (BMI), glucose, insulin, bilirubin, LDL-cholesterol, HDL-cholesterol, triglycerides, HDL/C index and HOMA IR levels did not differ significantly between the two groups. AST and ALT were significantly higher in the control group. The serum levels of cholesterol and LDL-cholesterol showed a tendency toward lower values in the control group. We found positive correlation between serum levels of insulin and HOMA IR with staging (respectively r=0.336, P < 0.04 and r=0.386, P < 0.02). CONCLUSIONS In children with CHC and a relatively short duration of the disease, lipid and glucose disorders are not observed. Correlations between insulin and HOMA IR with staging suggest the ability of HCV to contribute to fibrosis through interference with glucose metabolism.
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Adinolfi LE, Restivo L, Zampino R, Lonardo A, Loria P. Metabolic alterations and chronic hepatitis C: treatment strategies. Expert Opin Pharmacother 2011; 12:2215-2234. [PMID: 21883025 DOI: 10.1517/14656566.2011.597742] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Chronic hepatitis C (HCV) infection is considered a metabolic disease. It is associated with a specific metabolic syndrome, HCV-associated dysmetabolic syndrome (HCADS), consisting of steatosis, hypocholesterolemia and insulin resistance/diabetes. These metabolic derangements contribute to a decrease in sustained virological response (SVR) to pegylated-interferon-α-ribavirin as standard of care (SOC), and are associated with progression of liver fibrosis. AREAS COVERED The review, highlighting the impact of HCADS and metabolic syndrome components of HCV disease progression and SOC, discusses current knowledge and perspectives on metabolic therapeutic strategies aimed at improving SVR rate of SOC for chronic hepatitis C. EXPERT OPINION HCV, features of HCADS and of metabolic syndrome may coexist in the same patient, thus all components of the metabolic syndrome must be assessed to individualize treatment. The results of therapeutic trials evaluating metabolic strategies combined with current SOC indicate that weight loss is a critical part of treatment which will improve both disease outcome and therapeutic response to SOC. Similarly, statins seem to improve response rate to SOC representing, once confirmed to be safe, an important therapeutic tool for HCV-infected patients. Findings from studies using insulin sensitizers combined with SOC are not conclusive and do not justify the use of this class of drugs in clinical practice.
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Affiliation(s)
- Luigi E Adinolfi
- Second University of Naples, Internal Medicine and Hepatology, Department of Gerontology, Geriatrics and Metabolic Diseases, 80100 Naples, Italy
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42
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Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5:503-16. [PMID: 21780897 DOI: 10.1586/egh.11.43] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.
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Affiliation(s)
- Vincent Kaddai
- Department of Pathology and Immunology, Centre Médical Universitaire, Rue Michel-Servet 1, Geneva, Switzerland
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43
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Abstract
Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.
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Affiliation(s)
- Akira Honda
- Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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44
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Miyazaki T, Honda A, Ikegami T, Saitoh Y, Hirayama T, Hara T, Doy M, Matsuzaki Y. Hepatitis C virus infection causes hypolipidemia regardless of hepatic damage or nutritional state: An epidemiological survey of a large Japanese cohort. Hepatol Res 2011; 41:530-41. [PMID: 21501354 DOI: 10.1111/j.1872-034x.2011.00803.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIM Infection with hepatitis C virus (HCV) is the leading cause of liver cirrhosis that develops into hepatocellular carcinoma. Previous studies have shown in vitro that lipids within hepatocytes are crucially important for a series of HCV infection-proliferation-release processes. On the other hand, in the patients with HCV, the serum total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C) levels have been reported to be lower. We conducted an epidemiological survey of a large cohort and investigated whether the lower serum lipid levels were caused by a direct or the secondary effects of HCV infection (i.e. hepatic damage or nutritional disorder). METHODS Among 146 857 participants (male, 34%; female, 66%) undergoing public health examinations between 2002 and 2007 in Ibaraki Prefecture, Japan, the HCV positive rates determined by HCV antibody/antigen and/or RNA tests were 1.37% and 0.67% in males and females, respectively. RESULTS In addition to Total-C and LDL-C, serum high-density lipoprotein cholesterol and triglyceride concentrations were also significantly lower in the HCV positive subjects compared with the negative subjects, regardless of sex, age or nutritional state evaluated by body mass index. Multivariate analysis showed that HCV infection was the strongest among the factors to be significantly associated with the lower level of these lipids. Particularly, the hypolipidemia was also confirmed in the HCV positive subjects with normal aminotransferase levels (alanine aminotransferase ≤30 and aspartate aminotransferase ≤30). CONCLUSION This epidemiological survey in a large Japanese cohort suggests that the HCV infection itself might directly cause hypolipidemia, irrespective of host factors including age, hepatic damage and nutritional state.
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Affiliation(s)
- Teruo Miyazaki
- Department of Development for Community Medicine, Tokyo Medical University Center for Collaborative Research Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center Ibaraki Prefectural Institute of Public Health, Mito Ibaraki Prefectural Central Hospital, Kasama, Japan
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André P, Ramière C, Scholtes C, Curtil C, Lotteau V. Role of nuclear receptors in hepatitis B and C infections. Clin Res Hepatol Gastroenterol 2011; 35:169-75. [PMID: 21316326 DOI: 10.1016/j.clinre.2011.01.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2010] [Revised: 12/26/2010] [Accepted: 01/03/2011] [Indexed: 02/04/2023]
Abstract
Nuclear receptors are key regulators of many cellular functions including energy supply by the direct control of the expression of target genes. They constitute a super-family of transcription factors activated by ligands, hormones or metabolites, and therefore, sensible to host metabolic stimuli. Viral replication and production requires energy and elementary building blocks from the infected cells. Hepatitis B and C virus replication is modulated in part by liver nuclear receptors that regulate the glucose and lipid metabolism. However, nuclear receptors control the two viruses' replication by different mechanisms. The expression of hepatitis B virus genes is directly under the control of nuclear receptors, which bind to the viral genome regulatory regions. Viral replication and production may, therefore, be optimal when cells receive the correct metabolic signals. Hepatitis C virus replication and production depend to a large extent on lipidogenesis and lipoprotein secretion. The role of nuclear receptors in controlling hepatitis C replication may be to turn on the cellular mode that would provide the appropriate metabolic environment for viral replication.
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Affiliation(s)
- Patrice André
- INSERM U851, IFR 128 biosciences Lyon Gerland, université de Lyon 1, 21 avenue Tony-Garnier, Lyon, France.
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46
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Feeney ER, Mallon PWG. HIV and HAART-Associated Dyslipidemia. Open Cardiovasc Med J 2011; 5:49-63. [PMID: 21643501 PMCID: PMC3106351 DOI: 10.2174/1874192401105010049] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Revised: 01/01/2011] [Accepted: 01/06/2011] [Indexed: 01/09/2023] Open
Abstract
Effective highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV) infection has led to marked improvement in life-expectancy for those infected with HIV. Despite reductions in the incidence of AIDS with effective treatment, patients continue to experience considerable morbidity and mortality from non-AIDS illness such as premature cardiovascular disease, liver failure and renal failure. These morbidities, particularly premature cardiovascular disease, are thought to be related to a combination of the effects of an ageing HIV-infected population coupled with long-term effects of HIV infection and antiretroviral therapy (ART). One of the principle drivers behind the well documented increase in the risk of cardiovascular disease in HIV-infected patients is dyslipidemia. This review will focus on the clinical presentation of HIV and ART-associated dyslipidemia, what is known of its patho-physiology, including associations with use of specific antiretroviral medications, and suggest screening and management strategies.
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Affiliation(s)
- Eoin R Feeney
- HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
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47
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Lee SH, Choi HC, Jeong SH, Lee KH, Chung JI, Park YS, Hwang JH, Kim JW, Kim N, Lee DH, Choi HC, Yoon CJ, Kang SG. Hepatocellular carcinoma in older adults: clinical features, treatments, and survival. J Am Geriatr Soc 2011; 59:241-50. [PMID: 21275934 DOI: 10.1111/j.1532-5415.2010.03273.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To evaluate the clinical features, treatments, stages, and survival in older adults with hepatocellular carcinoma (HCC). DESIGN A consecutive case study with retrospective medical record review. SETTING University hospital (tertiary referral center) in Korea. PARTICIPANTS Two hundred sixty-two participants with HCC diagnosed between May 1, 2003, and December 31, 2006. MEASUREMENTS Clinical characteristics, treatments, four staging systems for HCC, and survival in older (≥65, n=113) and younger (<65, n=149) people with HCC. RESULTS The older HCC group were less likely to have hepatitis B virus infection and diffuse tumors and had more comorbidities, poorer performance status, smaller tumor area, and multinodular disease. There were no significant differences between the two groups with regard to Child-Pugh-Turcotte score, Model for End Stage Liver Disease (MELD) score, Child class, alpha-fetoprotein levels, and tumor stage at diagnosis. Approximately 88% of subjects were treated regardless of age, but resection was performed less frequently in the older participants. Older participants with HCC had overall survival and liver-related mortality similar to those of the younger participants, although they had poorer performance, greater comorbidity, and less likelihood of receiving surgery than the younger patients. CONCLUSION This study supports the effectiveness and safety of nonsurgical treatment for older adults with HCC. Further study is needed to elucidate the reasons for similar prognoses in the older adults in spite of the greater burdens of comorbidities and poorer performance status.
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Affiliation(s)
- Sang Hyub Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea
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Serum lipids in European chronic HCV genotype 1 patients during and after treatment with pegylated interferon-α-2a and ribavirin. Eur J Gastroenterol Hepatol 2010; 22:1303-7. [PMID: 20729742 DOI: 10.1097/meg.0b013e32833de92c] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS Chronic hepatitis C alters the host's lipid metabolism and hepatitis C virus (HCV) eradication may be followed by an increase of serum cholesterol to adverse levels. We therefore aimed to determine the impact of chronic hepatitis C and its treatment on circulating lipids in a large European cohort of HCV genotype 1 patients. METHODS The serum lipid profile of 575 HCV genotype 1-infected patients was characterized before, during and after treatment with pegylated interferon-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks within a randomized controlled clinical trial. RESULTS Total baseline cholesterol levels were significantly higher in patients with sustained virologic response (SVR) compared to nonresponders/relapsers (177 vs. 167 mg/dl, P=0.01), and low-cholesterol levels were an independent negative predictor of SVR (P=0.084). During the antiviral treatment, cholesterol levels substantially decreased as a putative marker of interferon-activity, but rebounded above baseline in patients with SVR (177-188 mg/dl, P=0.02), and to baseline in nonresponders/relapsers. Proportions of patients with cholesterol (>240 mg/dl) at baseline and after HCV eradication were 4 and 6%, respectively. Significant differences of triglyceride levels in patients with and without SVR were only observed at follow-up (136 and 117 mg/dl, respectively, P=0.028) but not at baseline. CONCLUSION Our study reports a substantial pretreatment hypocholesterolemia in European HCV genotype 1 patients with nonresponse to interferon-α-based therapy and lower pretreatment cholesterol levels were an independent predictor of not attaining SVR. After treatment-induced HCV eradication median cholesterol levels increased above baseline, but the proportion of patients with high-risk cholesterol levels remained relatively low.
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Krssák M, Hofer H, Wrba F, Meyerspeer M, Brehm A, Lohninger A, Steindl-Munda P, Moser E, Ferenci P, Roden M. Non-invasive assessment of hepatic fat accumulation in chronic hepatitis C by 1H magnetic resonance spectroscopy. Eur J Radiol 2010; 74:e60-e66. [PMID: 19406596 DOI: 10.1016/j.ejrad.2009.03.062] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2008] [Revised: 01/27/2009] [Accepted: 03/30/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Liver biopsy is the standard method for diagnosis of hepatic steatosis, but is invasive and carries some risk of morbidity. AIMS AND METHODS Quantification of hepatocellular lipid content (HCL) with non-invasive single voxel (1)H magnetic resonance spectroscopy (MRS) at 3T was compared with histological grading and biochemical analysis of liver biopsies in 29 patients with chronic hepatitis C. Body mass index, indices of insulin resistance (homeostasis model assessment index, HOMA-IR), serum lipids and serum liver transaminases were also quantified. RESULTS HCL as assessed by (1)H MRS linearly correlated (r=0.70, p<0.001) with histological evaluation of liver biopsies and was in agreement with histological steatosis staging in 65% of the patients. Biochemically assessed hepatic triglyceride contents correlated with HCL measured with (1)H MRS (r=0.63, p<0.03) and allowed discriminating between none or mild steatosis versus moderate or severe steatosis. Patients infected with hepatitis C virus genotype 3 had a higher prevalence of steatosis (62%) which was not explained by differences in body mass or whole body insulin resistance. When these patients were excluded from correlation analysis, hepatic fat accumulation positively correlated with insulin resistance in the remaining hepatitis C patients (HCL vs. HOMA-IR, r=0.559, p<0.020, n=17). CONCLUSION Localized (1)H MRS is a valid and useful method for quantification of HCL content in patients with chronic hepatitis C and can be easily applied to non-invasively monitoring of steatosis during repeated follow-up measurements in a clinical setting.
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Affiliation(s)
- Martin Krssák
- Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Austria
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50
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Milner KL, van der Poorten D, Trenell M, Jenkins AB, Xu A, Smythe G, Dore GJ, Zekry A, Weltman M, Fragomeli V, George J, Chisholm DJ. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology 2010; 138:932-41.e1-3. [PMID: 19962985 DOI: 10.1053/j.gastro.2009.11.050] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 11/18/2009] [Accepted: 11/20/2009] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C (CHC) is associated with insulin resistance (IR), liver steatosis (genotype 3), and increased diabetes risk. The site and mechanisms of IR are unclear. METHODS We compared cross-sectionally 29 nonobese, normoglycemic males with CHC (genotypes 1 and 3) to 15 adiposity and age-matched controls using a 2-step hyperinsulinemic-euglycemic clamp with [6,6-(2)H(2)] glucose to assess insulin sensitivity in liver and peripheral tissues and (1)H-magnetic resonance spectroscopy to evaluate liver and intramyocellular lipid. Insulin secretion was assessed after intravenous glucose. RESULTS Insulin secretion was not impaired in CHC. Peripheral insulin sensitivity was 35% higher in controls vs CHC (P < .001) during high-dose (264.3 +/- 25 [standard error] mU/L) insulin (P < .001); this was negatively associated with viral load (R(2) = .12; P = .05) and subcutaneous fat (R(2) = .41; P < .001). IR was similar in both genotypes despite 3-fold increased hepatic fat in genotype 3 (P < .001). Hepatic glucose production (P = .25) and nonesterified free fatty acid (P = .84) suppression with insulin were not different between CHC and controls inferring no adipocyte IR, and suggesting IR is mainly in muscle. In CHC, intramyocellular lipid was nonsignificantly increased but levels of glucagon (73.8 +/- 3.6 vs 52.8 +/- 3.1 ng/mL; P < .001), soluble tumor necrosis factor receptor 2 (3.1 +/- 0.1 vs 2.3 +/- 0.1 ng/mL; P < .001), and Lipocalin-2 (36.4 +/- 2.9 vs 19.6 +/- 1.6 ng/mL; P < .001) were elevated. CONCLUSIONS CHC represents a unique infective/inflammatory model of IR, which is predominantly in muscle, correlates with subcutaneous, not visceral, adiposity, and is independent of liver fat.
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Affiliation(s)
- Kerry-Lee Milner
- Garvan Institute for Medical Research, University of New South Wales 2010, Sydney, Australia
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