Systematic Reviews Open Access
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2017; 23(9): 1697-1711
Published online Mar 7, 2017. doi: 10.3748/wjg.v23.i9.1697
Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review
Anne-Claire Desbois, Patrice Cacoub, Inflammation-Immunopathology-Biotherapy Department, Sorbonne Universités, 75005 Paris, France
Anne-Claire Desbois, Patrice Cacoub, UMR_S 959, French National Institute of Health and Medical Research, 75013 Paris, France
Anne-Claire Desbois, Patrice Cacoub, FRE3632, The French National Center for Scientific Research, 75005 Paris, France
Anne-Claire Desbois, Patrice Cacoub, Department of Internal Medicine and Clinical Immunology, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, 75013 Paris, France
Author contributions: Desbois AC and Cacoub P designed research, contributed to new reagents or analytic tools, analyzed data, and wrote the paper; Desbois AC performed research.
Conflict-of-interest statement: Pr P. Cacoub has received consulting and lecturing fees from: Abbvie, Astra Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, and Merck Sharp Dohme. Dr AC Desbois has received lecturing fees from Gilead.
Data sharing statement: No additional unpublished data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Patrice Cacoub, MD, PhD, professor, Department of Internal Medicine and Clinical Immunology, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, 83 boulevard de l'hôpital, 75013 Paris, France. patrice.cacoub@aphp.fr
Telephone: +33-1-42178009 Fax: +33-1-42178033
Received: October 3, 2016
Peer-review started: October 7, 2016
First decision: October 28, 2016
Revised: November 10, 2016
Accepted: February 7, 2017
Article in press: February 8, 2017
Published online: March 7, 2017
Processing time: 153 Days and 13.8 Hours

Abstract
AIM

To summarise the literature data on hepatitis C virus (HCV)-infected patients concerning the prevalence of glucose abnormalities and associated risk.

METHODS

We conducted a PubMed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We collected the literature data on HCV-infected patients concerning the prevalence of glucose abnormalities [diabetes mellitus (DM) and insulin resistance (IR)] and associated risk [i.e., severe liver fibrosis, response to antivirals, and the occurrence of hepatocellular carcinoma (HCC)].

RESULTS

HCV infection is significantly associated with DM/IR compared with healthy volunteers and patients with hepatitis B virus infection. Glucose abnormalities were associated with advanced liver fibrosis, lack of sustained virologic response to interferon alfa-based treatment and with a higher risk of HCC development. As new antiviral therapies may offer a cure for HCV infection, such data should be taken into account, from a therapeutic and preventive point of view, for liver and non-liver consequences of HCV disease. The efficacy of antidiabetic treatment in improving the response to antiviral treatment and in decreasing the risk of HCC has been reported by some studies but not by others. Thus, the effects of glucose abnormalities correction in reducing liver events need further studies.

CONCLUSION

Glucose abnormalities are strongly associated with HCV infection and show a negative impact on the main liver related outcomes.

Key Words: Hepatitis C virus; Diabetes mellitus; Insulin resistance; Liver fibrosis; Treatment

Core tip: hepatitis C virus (HCV) infection is associated with increased rates of glucose abnormalities, including diabetes mellitus and insulin resistance. The presence of glucose abnormalities in HCV infected patients, including diabetes mellitus and insulin resistance, is associated with negative liver-related outcomes (i.e., severe liver fibrosis, decreased response to antivirals, and increased occurrence of hepatocellular carcinoma).



INTRODUCTION

Hepatitis C virus (HCV) infection is a major health problem. The World Health Organization (WHO) estimates that at least 150-170 million people, approximately 3% of the world's population, are chronically infected. These patients are known to be at risk of liver related complications, i.e., cirrhosis and hepatocellular carcinoma (HCC), with an estimated liver-related mortality of 350000 people/year. The total risks of morbidity and mortality are underestimated, because they do not take into account extrahepatic consequences of HCV infection. Numerous extrahepatic manifestations have been reported, suggesting that HCV is more a systemic disease than just a liver disorder. In large prospective cohort studies, up to two-thirds of patients with HCV infection experienced extra-hepatic manifestations[1]. The majority of available data concern HCV-related autoimmune and/or lymphoproliferative disorders, from benign mixed cryoglobulinemia to frank lymphomas, which is consistent with HCV lymphotropism[2]. More recently, other HCV-associated disorders have been reported including cardiovascular, renal, central nervous system and metabolic diseases[3]. Among the latter, some studies assessed the risk of diabetes mellitus (DM) or insulin resistance (IR) while others evaluated the impact of DM/IR on the main liver-related HCV infection outcomes (i.e., liver fibrosis, cirrhosis, HCC). However, the results appear to be conflicting, with great heterogeneity between studies.

In the present study, based on a literature data review, we aimed to analyse: (1) the risk of glucose abnormalities (GA) in HCV-infected patients; and (2) the impact of GA on the main liver-related HCV outcomes, i.e., liver fibrosis, response to interferon alfa-based treatment, and HCC.

MATERIALS AND METHODS

We conducted a PubMed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We selected surveys that had evaluated the risk of Type 2 DM or IR in HCV-infected patients compared with healthy controls or with patients with hepatitis B virus (HBV) infection. The definition of DM was usually based on a fasting plasma glucose > 1.26 g/L, or a history of diabetes mellitus, or use of oral antidiabetic agents or insulin. The definition of IR was based on the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) according to the formula: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (mIU/L)/22.5. We also included studies that assessed the association between the presence of glucose abnormalities (DM or IR) and the main HCV infection outcomes (i.e., liver fibrosis, cirrhosis, response to antiviral treatment, HCC). Conversely, studies that evaluated the impact of antiviral treatment on glucose abnormalities were included. We excluded studies with patients infected with the HBV or human immunodeficiency virus, and those for whom the entire manuscript was not available.

RESULTS
Is HCV infection associated with an increased prevalence of glucose abnormalities?

We included two types of studies: (1) those that assessed the HCV prevalence in diabetic patients compared with non-diabetics; and (2) studies that assessed the prevalence of DM and/or IR in HCV-infected patients compared with controls (healthy volunteers or HBV carriers) (Table 1).

Table 1 Glucose abnormalities and hepatitis C virus infection.
Ref.YearCountryStudy designPatientsPatients numberControlsControls numberTesting for HCV Ab or RNAEndpointStatistical methodsAssociationStatistics
HCV infection markers in patients with type 2 diabetes mellitus
Sangiorgio et al[4]2000ItalyRetrospectiveDM1514HV1300AbHCVUnivariateYesP < 0.0001
Chen et al[5]2006TaiwanCross sectionalDM820HV905AbHCVUnivariate adjustedYesOR = 2.87 [1.51, 5.46]; P < 0.001
Huang et al[6]2007TaiwanCross sectionalDM1237HV8595RNAHCVUnivariateYes6.9% vs 4.5%; P < 0.001
Jadoon et al[7]2010PakistanNDDM3000HV10000AbHCVUnivariateYesOR = 3.03 [2.64, 3.48]; P = 0.001
Balogun et al[53]2006Nigeriacase-controlDM90HV290AbHCVUnivariateNoNS
Costa et al[54]2008BrazilCase-controlDM206HV206RNAHCVMultivariateNoNS
Glucose abnormalities in HCV infected patients vs different control groups
Vs healthy volunteers
Knobler et al[17]2000IsraelCase-controlHCV45HV288RNADMUnivariateYes33% vs 5.6%; P < 0.001
Mehta et al[8]2000United StatesCross sectionalHCV230HV9611AbDMMultivariateYesOR = 3.77 [1.8, 7.87]
Marzouk et al[18]2007EgyptCross sectionalHCV190HV575RNADMMultivariateYesHR = 3.05 [1.19, 7.81]
Shaheen et al[19]2007United StatesNDHCV239HV10144NDIRUnivariate adjustedYesOR = 1.68; P = 0.02
Huang et al[6]2007TaiwanCross sectionalHCV478HV27927RNADMMultivariateYesOR = 1.53 [1.18, 1.98]; P <0.001
Huang et al[21]2008TaiwanNDHCV683HV2515RNADM/IGT1UnivariateYesOR = 3.51 [2.7, 4.56]; P < 0.001
Park et al[20]2008South KoreaProspectiveHCV162HV2172RNAIRUnivariateYes22.5% vs 5.2%; P < 0.001
Mohamed et al[22]2009EgyptCross sectionalHCV138HV212RNAIRUnivariateYesHOMA-IR = 3.98 (normal ALT) and 2.69 (a normal ALT) vs 1.92; P < 0.001
Duseja et al[23]2009IndiaNDHCV185HV225RNAIRUnivariateYes62% vs 16%; P = 0.0002
Lonardo et al[24]2009ItalyNDHCV197HV182RNAIRUnivariateYesP < 0.001
Huang et al[25]2009TaiwanNDHCV193HV144AbIRUnivariateYesHOMA-IR 2.2 vs 1.6; P = 0.02
Mostafa et al[26]2010EgyptNDHCV329HV173/795RNADMUnivariate adjustedYesOR = 1.35 [1.06, 1.73]; P = 0.02
Miyajima et al[27]2013JapanCross sectionalHCV40HV1780/88RNAIRUnivariateYesHOMA-IR 3.0 vs 1.3; P < 0.001
Younossi et al[28]2013United StatesRetrospectiveHCV177HV19568RNADM and IRMultivariateYesOR for DM 2.3 [1.18, 4.54] OR for IR 2.06 [1.19, 3.57]
Pothineni et al[29]2014United StatesRetrospectiveHCV1434HV214799RNADMUnivariateYes11.2% vs 5.1%; P < 0.01
Dai et al[30]2013TaiwanRetrospectiveHCV160HV2480RNADMMultivariateYesOR = 1.208 [1.009, 2.799]; P = 0.004
Mehta et al[10]2003United StatesCase-controlHCV12HV21072RNADMUnivariateNoNS
Stepanova et al[11]2012United StatesNationwide surveyHCV791HV38715RNADM and IRMultivariateNoNS
Montenegro et al[9]2013ItalyProspectiveHCV616HV1856AbDMUnivariate adjustedNoNS
Ruhl et al[55]2014United StatesCross sectionalHCV277HV14571RNADMUnivariate adjustedNoNS
Vs hepatitis B virus infection
Knobler et al[17]2000IsraelCase-controlHCV45HBV90RNADMUnivariateYes33% vs 12%; P = 0.004
Ryu et al[31]2001South KoreaProspectiveHCV, F468HBV157AbDMUnivariateYes24% vs 10.4%; P = 0.001
Wang et al[32]2007TaiwanLongitudinalHCV926HBV544AbDMMultivariateYesHR = 1.7
Huang et al[6]2007TaiwanCross sectionalHCV478HBV1363RNADMUnivariateYes18% vs 11.4%; P < 0.001
Moucari et al[33]2008FranceRetrospectiveHCV500HBV2100RNAHOMA-IRUnivariateYes35% vs 5%; P < 0.001
White et al[12]2008United StatesMeta-analysisHCV34 studiesHBV/ HV-Ab/RNADMMeta-analysisYesAdjusted OR for HV 1.68 and for HBV 1.80
Rouabhia et al[34]2010AlgeriaProspective cross sectionalHCV1290HBV126RNADMMultivariateYesOR = 4.73 [1.7, 13.2]; P = 0.0029
Petta et al[56]2011ItalyRetrospectiveHCV170HBV2170RNAHOMA-IR and DMUnivariateYes42.2% vs 25.9%, P = 0.002 and 8.8% vs 3.6%, P = 0.04
Imazeki et al[57]2008JapanRetrospectiveHCV544HBV286RNADM and IRMultivariateNoNS
Tanaka et al[58]2008JapanCase-controlHCV130HBV230RNAIRMultivariateNoNS
Mavrogiannaki et al[59]2008Greeceprospective case controlHCV108HBV81RNAglucose intoleranceUnivariate adjustedNoNS
Persico et al[60]2009ItalyRetrospectiveHCV726HBV126AbDMUnivariate adjustedNoNS

Six studies evaluated HCV prevalence rates in diabetic patients compared with non-diabetic healthy volunteers. The number of participants ranged from 180 to 13000. Four out of the six studies showed a significant increased prevalence of HCV infection markers [HCV antibodies (n = 3), HCV RNA (n = 1)] in DM patients, with an odds ratio (OR) between 2.87 and 3.03[4-7]. Of note, only one study used multivariate logic regression analysis, while another adjusted the risk for age, gender, body mass index (BMI) and alanine aminotransferase (ALT) levels. One study showed an increased HCV antibody prevalence rate in DM patients with abnormal ALT levels.

Thirty-two studies evaluated DM and/or IR prevalence rates in HCV patients compared with either healthy volunteers (n = 20) or HBV patients (n = 12). The size of cohorts ranged from 50 to 39506 subjects. All but four studies assessed DM/IR prevalence in HCV-RNA positive patients. In 10 out of 20 studies that compared HCV patients with healthy volunteers, multivariate or univariate analyses with adjustment for age, gender, BMI, socio-economic status and ethnicity were performed. Thirteen studies evaluated DM prevalence (n = 11) or occurrence (n = 2), while others (n = 9) assessed IR in HCV infected patients. Overall, 16 out of 20 studies found a significant association between the presence of glucose abnormalities (DM/IR) and HCV infection, including 7 out of 10 studies with multivariate or adjusted analyses (OR between 1.2 and 3.77). One study reported a higher risk of DM only in patients older than 40 years[8]. Four studies reported "negative" results. Three out these four studies showed a higher risk of DM only in specific populations (i.e., HCV patients with increased ALT levels[9], HCV patients older than 55 years with a BMI > 25 kg/m2[10], and a cohort studied between 1988 and 1994, but not in the more recent cohort)[11].

When compared with HBV infected patients, 7 out of 11 studies found a significant association of HCV with DM. In one meta-analysis[12], a positive HCV viremia was associated with an increased risk of DM compared with controls (adjusted OR = 1.68) and with HBV patients (adjusted OR = 1.80).

Are diabetes mellitus or insulin resistance associated with liver fibrosis severity in HCV infected patients?

Thirty studies investigated whether DM/IR was associated with liver fibrosis severity in HCV patients (Table 2). Studies were performed in Asia (Taiwan n = 3, Japan n = 3, other n = 1), Europe (n = 13), the United States and Australia (n = 5), Saudi Arabia (n = 1), Turkey (n = 1) and Egypt (n = 3). The mean size of the cohorts was 451 patients (min-max range 10 to 3068). The authors searched for an association between liver fibrosis severity and DM (n = 9), IR (n = 19) or impaired fasting plasma glucose (n = 2). All but two studies performed multivariate analyses. Twenty-six out of thirty studies reported a significant association of glucose abnormalities with liver fibrosis severity (OR from 1.28 to 13.72). Three of the four "negative" studies were done on small cohorts. There were some differences related to HCV genotypes, but no systematic relationship was found.

Table 2 Glucose abnormalities and severe liver fibrosis in hepatitis C virus-infected patients.
Ref.YearCountryNumber of HCV patientsPatient profileGlucose abnormalityStatistical methodAssociation with severe fibrosis1GenotypesStatistics
Konrad et al[42]2000Germany10Non DMFPGMultivariateYesAllP = 0.01
Sud et al[61]2004Australia170-HOMA-IRMultivariateYesAllOR = 1.47 [1.14, 1.89]; P = 0.003
Muzzi et al[62]2005Switzerland221Non DMHOMA-IRMultivariateYesAll (except G3)OR = 1.57 [1.04, 2.39]
D'souza et al[63]2005United Kingdom59-HOMA-IRMultivariateYesAllP = 0.001
Taura et al[64]2006Japan83-HOMA-IRMultivariateYesAllOR = 7.32 [1.59, 33.73]; P = 0.01
Leandro et al[65]2006Italy3068-DMMultivariateYesG1OR = 4.52 [1.07, 19.1]; P = 0.011
Bugianesi et al[66]2006Italy132G3 with steatosisHOMA-IRMultivariateYesG3OR = 2.98 [1.13, 7.89]; P = 0.028
Kita et al[67]2007Japan68Post tranfusion hepatitisDMMultivariateYesAllOR = 8.4 [2.23, 31.54]; P = 0.002
Petta et al[68]2008Italy201G1DMMultivariateYesG1OR = 2.69 [1.46, 4.95]; P < 0.001
Moucari et al[33]2008France500-HOMA-IRMultivariateYesAllOR = 1.8 [1.16, 2.81]; P = 0.009
Cua et al[69]2008Australia346G1, G3, untreatedIRMultivariateYesG3OR = 3.15 [1.56, 6.35]; P = 0.001
Hsu et al[70]2009Taiwan528G1, G2FPGMultivariateYesG1OR = 13.72 [2.15, 87.7]; P < 0.05
Moucari et al[71]2009France226G4HOMA-IRMultivariateYesG4OR = 3.86 [1.859, 8.034]; P < 0.001
Persico et al[60]2009Italy726-DMMultivariateYesAllP < 0.05
Hung et al[14]2011Taiwan1470-DMUnivariateYesAllP < 0.001
Patel et al[72]2011Asia263G2, G3HOMA-IRMultivariateYesG2 and G3OR = 8.42 [2.1, 34.3]; P = 0.003
Mohamed et al[73]2011Egypt50G4HOMA-IRMultivariateYesG4OR = 3.73; P = 0.001
Miyaaki et al[74]2011Japan171-DMMultivariateYesAllOR = 8.739 [2.85, 26.85]; P = 0.0002
Conjeevaram et al[75]2011United States341G1HOMA-IRMultivariateYesG1OR = 1.28 [1.07, 1.51]; P = 0.005
Petta et al[56]2011Italy170G1HOMA-IRMultivariateYesG1OR = 2.64 [1.11, 6.28]; P = 0.02
Khattab et al[76]2012Egypt107G4HOMA-IRMultivariateYesG4OR = 1.87 [1.09, 8.29]; P = 0.04
Ziada et al[77]2012Egypt140Non DMHOMA-IRMultivariateYesAllOR = 1.92 [0.97, 3.4]; P = 0.049
Thompson et al[13]2012United States1038Non DMHOMA-IRMultivariateYesAllOR = 1.6 [1.1, 2.33]; P = 0.02
Alfaleh et al[78]2013Saudi Arabia157-DMMultivariateYesAll (except G4)OR = 0.37 [0.148, 0.927]; P = 0.034
Dokmeci et al[79]2014Turkey104-HOMA-IRMultivariateYesAllOR = 3.36 [1.32, 31.25]; P = 0.021
Huang et al[80]2015Taiwan1077-DMMultivariateYesAllOR = 1.81 [1.14, 2.65]; P = 0.002
Fartoux et al[81]2005France141Non DMHOMA-IRUnivariateNoNoNS
Elgouhari et al[82]2008United States183-DMMultivariateNoNoNS
Petta et al[83]2009Italy156Non DMHOMA-IRMultivariateNoNoNS
Rueger et al[84]2014Switzerland1461-DMMultivariateNoNoNS
Do diabetes mellitus and insulin resistance have an impact on the virological response to HCV treatment?

Twenty-six studies and three meta-analyses investigated whether GA had an impact on the response to interferon alfa-based antiviral treatment (Table 3). The studies originated from Europe (n = 11), Asia (n = 4), Egypt (n = 4), the United States (n = 5), Australia (n = 1) and Saudi Arabia (n = 1). They included a mean of 503 patients (50 to 5944). Nineteen out of twenty-eight studies showed a significant negative effect of GA in response to interferon alfa-based therapy [i.e., lower sustained viral response (SVR) rates], including 15 multivariate analyses and 3 meta-analyses. Of note, studies that did not find an impact of GA on SVR rates had some limitations, including small size of cohorts (60-600 patients), only G1 or G4 patients (3 out of 10 studies), and only Italian patients (4 out of 10). Two of them evaluated patients treated with peginterferon/ribavirin and telaprevir. The three meta-analyses found a significant association between IR and the absence of SVR, regardless of the genotype (OR for G1 = 2.2, G2 = 3, G3 = 4.45 and G4 = 6.7, respectively).

Table 3 Impact of glucose abnormalities on virological response after interferon alpha based treatment.
Ref.YearCountryPatients numberPatient profileAssociationStatistical methodImpact on virological responseGenotypesStatistics
D'souza et al[63]2005United Kingdom59HOMA-IRMultivariateYesAllOR of SVR: 0.44 [0.22, 0.88]; P = 0.02
Tarantino et al[85]2005Italy80GMIUnivariateYesAll40% vs 7.5%; P = 0.0009
Romero-Gomez et al[86]2005Spain159HOMA-IRMultivariateYesAllOR of SVR 0.55 [0.33, 0.93]; P = 0.012
Jian Wu et al[87]2006China98HOMA-IRMultivariateYesAllOR of SVR: 0.17; P = 0.015
Backus et al[88]2007United States5944G1, G2, G3DMMultivariatesYesAll and G1OR = 0.76 [0.64, 0.71]; P = 0.002
Conjeevaram et al[89]2007United States401G1HOMA-IRMultivariatesYesG1OR = 0.87 [0.77, 0.99]; P = 0.028
Elgouhari et al[82]2008United States183DMMultivariateYesAllOR of SVR 0.22 [0.07, 0.55]; P = 0.003
Poustchi et al[90]2008Australia82G2, G3 non DMHOMA-IRMultivariateYesG2, G3OR of SVR 0.16 [0.03, 0.77]; P = 0.02
Romero-Gomez et al[91]2008Spain1059FPGMultivariateYesAllOR of SVR 0.56 [0.34, 0.93]; P < 0.02
Moucari et al[71]2009France226G4HOMA-IRMultivariateYes-OR of SVR: 0.19 [0.07, 0.51]; P = 0.001
Dai et al[92]2009Taiwan330G1, G2HOMA-IRMultivariateYesG1, G2OR of SVR 0.872 [0.79, 097]; P = 0.01
Hung et al[115]2010Taiwan1470DMMultivariateYesAllOR of SVR 0.69 [0.5, 0.96]; P = 0.029
Khattab et al[93]2010Egypt131Non DM, G4HOMA-IRMultivariateYesG4OR of SVR 0.07 [0.01, 0.43]; P = 0.004
Deltenre et al[94]2011France2732G1-6IRMeta-analysisYesAll-
Eslam et al[95]20112129G1-6IRMeta-analysisYesAllOR of SVR 0.35 [0.24, 0.51]; P = 0.0004
Del Campo et al[96]2012Spain240Non DMHOMA-IRMultivariateYesG1, G4OR of SVR 0.44 [0.17, 0.97]; P = 0.04
Ziada et al[77]2012Egypt140Non DMHOMA-IRMultivariateYesAllOR of SVR 0.41 [0.18, 0.9]; P = 0.003
Laurito et al[97]2013Brazil2238G1-6IRMeta-analysisYesAllOR of SVR 0.41 [0.3, 0.56]; P = 0.022
Abd El-Wahab et al[98]2014Egypt392Non DMHOMA-IRMultivariateYesAllOR of virological response: 0.19 [0.1, 0.38]; P = 0.0001
Grasso et al[99]2009Italy90Non DM, G1HOMA-IRMultivariateNoG1NS
Fattovich et al[100]2010Italy412HOMA-IRMultivariateNoNoNS
Khattab et al[76]2012Egypt107G4HOMA-IRMultivariateNoG4NS
Brandman et al[101]2012United States23Non DMIGT, FGP, SSGPUnivariateNoNoNS
Aghemo et al[102]2012Italy339HOMA-IRUnivariateNoNoNS
Fattovich et al[100]2012Italy124Non DMHOMA-IRMultivariateNoNoNS
Serfaty et al[103]2012France1611G4HOMA-IRMultivariateNoG4NS
Alfaleh et al[78]2013Saudi Arabia157DMMultivariateNoNoNS
Younossi et al[104]2013United States5781G1HOMA-IRUnivariate adjustedNoG1NS
Jung et al[105]2014Soutk Korea60HOMA-IRUnivariateNoNoNS
What is the impact of interferon alfa-based treatment on glucose abnormalities?

Twenty studies assessed the impact of interferon-based antiviral treatment on DM/IR, either as an improvement of GA after treatment or as the occurrence of GA after antiviral treatment (Table 4).

Table 4 Glucose abnormalities after interferon alpha based treatment.
Ref.YearCountryNumber of HCV patientsPatient profileGlucose metabolism parameterStatistical methodSignificant association or differenceGenotypesStatistics
Improvement of glucose abnormalities after HCV treatment
Konrad et al[42]2000United States13FPG and FIUnivariateYesAllP < 0.05 and P < 0.01
Romero-Gomez et al[86]2005Spain50HOMA-IRUnivariateYesAllIn SVR; P < 0.05
Kawaguchi et al[106]2007Japan89HOMA-IRUnivariateYesAllIn SVR; P < 0.01
Chehadeh et al[107]2009Kuwait181G4FPGUnivariateYesG4In SVR; P < 0.001
Kim et al[108]2009Korea28G1, G2HOMA-IRMultivariateYesG1, G2In SVR, OR of decreased IR 50 [3.74, 668.35]; P = 0.003
Conjeevaram et al[75]2011United States341G1HOMA-IRUnivariateYesG1In SVR; P < 0.001
Khattab et al[76]2012Egypt107G4, non cirrhoticHOMA-IRUnivariateYesG4In SVR ; P = 0.001
Thompson et al[13]2012United States1038HOMA-IRMultivariate1YesAllIn G1 SVR; P = 0.007
Serfaty et al[103]2012France161G1, non cirrhoticHOMA-IRUnivariateYesG1In SVR ; P < 0.05
Ziada et al[77]2012Egypt140Non DM, non cirrhoticHOMA-IRUnivariateYesAllP = 0.009
Chan et al[109]2013Australia86Non DMHOMA-IRUnivariateYesAllIn SVR; P = 0.04
Jung et al[105]2014South Korea60HOMA-IRUnivariateYesAllIn SVR; P = 0.036
Mello et al[110]2006Brazil30G1, G3HOMA-IRUnivariateNoAllNS
Kawaguchi et al[111]2009Japan72Non DM, non cirrhoticHOMA-IR, SI and ISIUnivariate1NoNoHOMA-IR: NS In SVR, SI P = 0.002 and ISI P = 0.009
Brandman et al[101]2012United States23Non cirrhoticSSGPUnivariateNoNoNS
Occurrence of glucose abnormalities after HCV treatment
Simó et al[112]2006Spain234Non DMDM or IGTMultivariate1YesAllIn SVR, OR = 0.48 [0.24, 0.48]; P = 0.04
Romero-Gomez et al[91]2008Spain1059DM or IGTMultivariate1YesAllIn SVR, OR = 0.44 [0.2, 0.97]; P = 0.04
Arase et al[113]2009Japan2842DMMultivariate1YesAllIn SVR, HR = 0.36 [0.24; 0.56]
Aghemo et al[102]2012Italy339Non DMHOMA-IRMultivariate1YesAllIn SVR, OR = 0.36 [0.18, 0.72]; P = 0.004
Giordanino et al[114]2008Italy202Non DMDM or IGTMultivariate1NoNoNS

Improvement of GA after antiviral treatment was analysed in fifteen surveys that included 13 to 1038 HCV treated patients. Most of these studies performed univariate analyses. A significant decreased prevalence of GA was noted in 12 out of 15 studies. Eleven of these 12 studies reported a significant change of IR only in patients who achieved a SVR. One survey found a significant change of IR after antiviral treatment only in genotype 1 patients[13].

Five studies evaluated the risk of GA occurrence according to antiviral treatment response. They included 202 to 2842 HCV treated patients, and all performed multivariate analyses. Four out of five studies showed a significant association between GA occurrence and the absence of SVR.

Do glucose abnormalities increase the risk of HCC in HCV infected patients?

Sixteen studies assessed the association between HCC and DM/IR in HCV infected patients (Table 5). These studies included from 120 to 5186 HCV patients, both treated and non-treated. Most of them (10/16) included Asian patients, and all but one performed multivariate analyses.

Table 5 Glucose abnormalities and hepatocellular carcinoma in hepatitis C virus-infected patients.
Ref.YearCountryPatient numberPatient profileAssociationStatistical methodAssociation DM and HCCStatistics
Diabetes mellitus/insulin resistance in HCV-related HCC
K-Kutala et al[15]2014France162HCC, not treated for HCVDM and HCCMultivariateYes3HR = 3.13 [1.17, 8.38]; P = 0.0223
Hung et al[115]2010Taiwan18859 HCC; 129 non-HCCDM and HCCMultivariateYesOR = 11.6 [2.500, 53.800]; P = 0.002
Hung et al[115]2010Taiwan18859 HCC; 129 non-HCCHOMA-IR and HCCMultivariateYesOR = 2.0 [1.35, 3]; P = 0.001
Khattab et al[116]2012Egypt294147 HCC; 147 non-HCCHOMA-IR and HCCMultivariateYesOR = 2.5 [1.7, 3.69]; P = 0.001
Mohamed et al[73]2011Egypt10050 HCC; 50 non-HCC; 20 non HCVHOMA-IR and HCCUnivariateNoNS
Diabetes mellitus/insulin resistance and development of HCC in HCV-infected patients
Chen et al[117]2008Taiwan1095-DM and HCCMultivariateYesOR = 3.52 [1.29, 9.24]
Veldt et al[16]2008Europe541DM and HCCMultivariateYes3OR = 3.28 [1.35, 7.97]; P = 0.0093
Konishi et al[118]2009Japan197Non DM, treated for HCVDM1 and HCCMultivariateYesHR = 4.63 [1.677, 12.766]; P = 0.003
Hung et al[14]2010Taiwan1470Treated for HCVDM and HCCMultivariateYes2HR = 4.32 [1.23, 15.25]; P = 0.0232
Nkontchou et al[119]2010France248CirrhoticsHOMA-IR and HCCMultivariateYesHR = 1.10 [1.01, 1.21]; P = 0.026
Takahashi et al[120]2011Japan203Non DM, treated for HCVDM1 and HCCMultivariateYesHR = 6.9 [1.7, 28.4]; P < 0.05
Arase et al[121]2013Japan4302Non treated for HCVDM and HCCMultivariateYesHR = 1.73 [1.3, 2.3]; P < 0.001
Elkrief et al[45]2014France348CirrhoticsDMMultivariateYesHR = 1.938 [1.129 , 3.328]; P = 0.016
Toyoda et al[122]2015Japan522Patients with SVRDM and HCCMultivariateYesHR = 2.08 [1.0170, 4.0133]; P = 0.045
Lai et al[123]2006Taiwan2141-DM and HCCMultivariateNoNS
Chen et al[124]2013Taiwan5186-DM and HCCMultivariateNoNS

Five studies looked for the presence of DM/IR in HCV infected patients with HCC compared with HCV patients without HCC. Four out of five studies found a significant association between DM/IR and HCC (as compared with non-HCC) (OR from 2.0 to 11.6).

Nine out of eleven other studies found a significant association between the presence of DM/IR and the development of HCC in the follow-up of HCV infected patients (HR from 1.10 to 6.9). One study found a higher risk of HCC in diabetic patients only with SVR and without cirrhosis[14], while 2 others reported an increased risk of HCC only in diabetic patients with advanced fibrosis[15,16].

DISCUSSION

Many studies have evaluated the association between HCV chronic infection, insulin-resistance and diabetes mellitus. The abnormalities of carbohydrate metabolism, including hyperinsulinemia and IR, known to be per se related to chronic hepatic diseases, were the rationale for speculation on this relationship. Insulin-resistance is an often undetected condition, commonly coexisting with obesity and metabolic syndrome, and possibly progressing to type 2 diabetes. HCV-related type 2 diabetes mellitus may arise from a complex interaction between IR, steatosis and inflammatory processes. Epidemiologic studies supporting the association between type 2 diabetes and HCV infection were first published in the early 1990s. More recently, larger epidemiologic studies gave more in-depth analyses of the relationship between HCV chronic infection and glucose abnormalities and were included in the present analysis.

HCV infection is associated with increased rates of glucose abnormalities, including diabetes mellitus and insulin resistance

In the present analysis, most studies found a significant association between HCV infection (whether active HCV RNA positive, or not i.e., HCV Ab positive) and diabetes mellitus or insulin resistance. This tight association was confirmed in both directions by the increased rates of HCV infection markers in DM/IR patients and the high rates of glucose abnormalities in HCV infected patients. The consistency of this association was supported by the confirmation of such results compared with different control groups, such as healthy volunteers or HBV carriers[6,8,12,17-34]. The variability of HOMA-IR cut-offs used (between 1.8 and 2.5 generally) may explain the heterogeneous results reported in the literature. Confounding factors might have also led to significant bias. Indeed, some studies comparing HCV patients with healthy volunteers did not perform multivariate analysis or adjust for confounding factors. However, seven out of ten multivariate analyses found a significant increased risk of DM/IR in HCV patients (OR = 1.2-3.7), after adjusting for confounding variables such as age, gender, BMI, ethnicity and education level.

How are we able to explain the increased risk of DM in HCV infected patients? Some authors have suggested that diabetic patients might have been infected by HCV due to injections or nosocomial transmission. The association of HCV infection with IR and the widespread use of universal precautions nowadays in hospitals to avoid virus transmission probably disqualify this hypothesis. There are a variety of other possible mechanisms of increased risk of DM/IR in HCV patients. As shown in this study, glucose abnormalities in HCV patients are associated with liver fibrosis severity. Severe liver fibrosis and cirrhosis are well-known conditions that are able to induce glucose metabolism impairment. However, studies with other liver diseases, including cirrhosis, still showed an excess of risk in HCV patients compared with HBV patients[6,12,17,31-34]. The ability of HCV, particularly genotype 3 viruses, to induce liver steatosis on its own, which might in turn increase the risk of DM/IR, has also been suggested in previous studies[35,36]. Other underlying mechanisms may involve HCV per se. Experimental data suggest the role of inflammation. Increased HOMA-IR has been correlated with soluble Tumor Necrosis Factor Receptor1 (sTNFR1) and sTNFR2 levels[37]. Increased abnormal HOMA-IR was not associated with elevated serum levels of TNFα, IL6 and adiponectin in another study[38]. Other studies have also suggested an impairment of glucose uptake in HCV-infected patients. Glucose uptake and the surface expression of Glucose Transporters (GLUT1 and 2) were suppressed in cells infected by HCV compared with controls[39]. Interferon alfa restored glucose uptake, GLUT2 surface expression, mRNA expression and GLUT2 promoter activities. HCV has also been shown to impair glucose uptake and to promote IR by increasing suppressor of cytokine signalling 3 (SOC3), which inhibits insulin phosphorylation of AKT and phosphoinositide 3-kinase (PI3K)[40]. HCV may be involved in the regulation of phosphorylation of insulin receptor substrate 1 (ISR-1), implicated in the insulin pathway[41]. In HCV core transgenic mice, the viral protein was able to induce increasing TNFα levels in the liver, which in turn promoted the induction of IR. The high levels of TNFα inhibited the ISR-1, causing IR and its possible progression to diabetes. A decreased expression of ISR-1 and ISR-2 mediated by ubiquitination was observed and was inversely proportional to the liver fibrosis stage.

Interferon alfa use might lead to glucose metabolism impairment and is a potential bias. However, increased DM/IR rates have been also reported in HCV patients not taking interferon alfa[20,22-25,34]. Many studies found a decreased rate of glucose abnormalities in HCV patients who showed a SVR after interferon alfa-based therapy, and even in non virological responders in one study[42]. This strongly suggests a direct/indirect role of HCV on glucose metabolism impairment. As eradication of HCV seems to be effective in decreasing the occurrence rate of DM/IR, it will very be interesting to analyse the impact of new direct antiviral agents (DAAs) for preventing DM/IR and eventually cardiovascular disorders. Indeed, in a recent study, IFN-free antiviral regimen resulted in rapid changes in serum lipid profiles and intrahepatic expression of lipid-related genes in G1 patients[43].

Presence of glucose abnormalities in HCV infected patients, including diabetes mellitus and insulin resistance, is associated with negative liver-related outcomes

Severe liver fibrosis, the absence of SVR after interferon alfa-based treatment, and the development of HCC are the main negative outcomes of chronic HCV infection. Interestingly, the presence of DM or IR in HCV patients showed a pejorative impact on each of these end points. Most studies found an independent association of glucose abnormalities with advanced liver fibrosis, absence of SVR after antiviral treatment and HCC occurrence. Only few studies did not confirm such associations. This might be explained by the small size cohort of such studies, the heterogeneity of criteria for DM or HOMA-IR and the very high prevalence of other metabolic risk factors (such as elevated BMI) which may underestimates the impact of DM/IR. Our data is consistent with recent studies that demonstrated that DM increases cumulative incidence of decompensated cirrhosis[44]. In another recent survey, diabetes was independently associated with transplantation-free survival, development of ascites, renal dysfunction, bacterial infections, and HCC during the follow-up[45].

Experimental data suggest that increased insulin levels after hyperglycaemia leads to interferon signalling impairment. Insulin may inhibit the ability of interferon alfa to block HCV replication due to the activation of PI3K by insulin, thus leading to inhibition of STAT-1, which is involved in the interferon alfa pathway[40].

The impact of glucose abnormalities on virological response needs to be further evaluated with new DAA, interferon-free combinations. To date, there is very few data on the impact of GA on virological response to new DAA. Preliminary results suggest that the presence of diabetes does not appear to be predictive of treatment failure in G1 patients[46,47]. Further studies are needed to confirm these data and to evaluate the impact of DM on SVR in patients without poor prognostic factors.

Should glucose abnormalities be corrected to increase SVR rates?

A prospective study, including 155 HCV genotype 1 patients with IR, showed no difference in SVR rates after peginterferon alfa and ribavirin were given, regardless of whether or not patients had received pioglitazone, an antidiabetic drug[48]. Of note, most glycemic control indexes improved significantly in the pioglitazone group except for HbA1c. Another study found higher SVR rates in G4 patients treated with pioglitazone[49]. Pioglitazone may alter NK cell functions and thus impair clearance of infected hepatocytes[48]. A retrospective cohort from Taiwan (19349 diabetic patients, 1.7% HCV positive) showed that patients taking metformin and thiazolidinediones had the lowest risk of HCC (HR 0.49 and 0.56, respectively) after adjusting for age, gender and comorbidities[50]. Consistently, in a prospective cohort of 100 HCV patients with ongoing cirrhosis, metformin treatment was independently associated with a decrease of HCC occurrence and liver-related death or transplantation[51]. In a two-year prospective follow-up of 85 patients with HCV-related HCC, HCC recurrence-free survival was increased in diabetics taking pioglitazone vs non-treated diabetics (44.2% vs 36.5%, respectively, P = 0.37)[52]. A significant decrease in HCC recurrence was observed in the pioglitazone group for patients with a BMI > 24.

We acknowledge some limitations of this study. Although we tried to include all published studies, we may have missed others in non-English literature or data only presented at meetings. Some studies were done with a limited number of patients. For some studies included in the present analysis, it is possible that there are some remaining bias and residual confounding factors. Despite multivariate analyses, the association between glucose abnormalities improvement and improved outcome may have been influenced by unmeasured confounding factors. Such final confirmation should arise from controlled clinical trials with long-term follow-up.

In conclusion, HCV chronic infection is associated with an increased risk of DM or IR, by a likely direct effect on glucose metabolism. In such patients, DM and IR are associated with a pejorative liver-related prognosis, as shown by increased rates of severe liver fibrosis, HCC occurrence, and decreased SVR rates after interferon-based therapy. This tight relationship between DM/IR and HCV infection needs to be further analysed with new DAAs, interferon-free combinations, with special attention to improvement in glucose abnormalities and long-term follow-up.

COMMENTS
Background

During hepatitis C virus (HCV) infection, extra-hepatic disorders are very frequent and polymorphous. Studies that have evaluated the link between glucose metabolism impairment and HCV reported heterogeneous data.

Research frontiers

Further studies are needed to evaluate the impact of glucose abnormalities in patients treated with interferon-free antiviral therapies. The effects of correction of glucose abnormalities in reducing liver event rates also need to be further studied.

Innovations and breakthroughs

This systematic review allows clarifying the close relationship between glucose abnormalities, HCV infection and poor liver outcomes. HCV infection is associated with increased rates of glucose abnormalities, including diabetes mellitus and insulin resistance. The presence of glucose abnormalities in HCV infected patients, including diabetes mellitus and insulin resistance, is associated with negative liver-related outcomes (i.e., severe liver fibrosis, decreased response to antivirals, and increased occurrence of hepatocellular carcinoma).

Applications

These data strongly encourage clinicians to systematically screen HCV-infected patients for the presence of glucose abnormalities. Considering the impact of glucose abnormalities on liver-related outcomes in HCV infected patients, antiviral treatment should also be considered in HCV-infected patients with metabolic syndrome.

Peer-review

This review talks about the relationship between HCV infection and glucose abnormalities. There are already lots of articles about the topic. This review summarizes those articles published from January 2000 to April 2015 in PubMed and gives us a conclusion about the topic.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: France

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): 0

Grade C (Good): C, C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Wang K, Zheng SS S- Editor: Gong ZM L- Editor: A E- Editor: Liu WX

References
1.  Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, Opolon P. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum. 1999;42:2204-2212.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia Vasculitis. Am J Med. 2015;128:950-955.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 186]  [Cited by in F6Publishing: 165]  [Article Influence: 18.3]  [Reference Citation Analysis (0)]
3.  Cacoub P, Gragnani L, Comarmond C, Zignego AL. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46 Suppl 5:S165-S173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 190]  [Article Influence: 19.0]  [Reference Citation Analysis (0)]
4.  Sangiorgio L, Attardo T, Gangemi R, Rubino C, Barone M, Lunetta M. Increased frequency of HCV and HBV infection in type 2 diabetic patients. Diabetes Res Clin Pract. 2000;48:147-151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 59]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
5.  Chen HF, Li CY, Chen P, See TT, Lee HY. Seroprevalence of hepatitis B and C in type 2 diabetic patients. J Chin Med Assoc. 2006;69:146-152.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 44]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
6.  Huang JF, Dai CY, Hwang SJ, Ho CK, Hsiao PJ, Hsieh MY, Lee LP, Lin ZY, Chen SC, Hsieh MY. Hepatitis C viremia increases the association with type 2 diabetes mellitus in a hepatitis B and C endemic area: an epidemiological link with virological implication. Am J Gastroenterol. 2007;102:1237-1243.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 93]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
7.  Jadoon NA, Shahzad MA, Yaqoob R, Hussain M, Ali N. Seroprevalence of hepatitis C in type 2 diabetes: evidence for a positive association. Virol J. 2010;7:304.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 41]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
8.  Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592-599.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 495]  [Cited by in F6Publishing: 474]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
9.  Montenegro L, De Michina A, Misciagna G, Guerra V, Di Leo A. Virus C hepatitis and type 2 diabetes: a cohort study in southern Italy. Am J Gastroenterol. 2013;108:1108-1111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 43]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
10.  Mehta SH, Brancati FL, Strathdee SA, Pankow JS, Netski D, Coresh J, Szklo M, Thomas DL. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50-56.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 288]  [Cited by in F6Publishing: 283]  [Article Influence: 13.5]  [Reference Citation Analysis (0)]
11.  Stepanova M, Lam B, Younossi Y, Srishord MK, Younossi ZM. Association of hepatitis C with insulin resistance and type 2 diabetes in US general population: the impact of the epidemic of obesity. J Viral Hepat. 2012;19:341-345.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 42]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
12.  White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49:831-844.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 299]  [Cited by in F6Publishing: 296]  [Article Influence: 18.5]  [Reference Citation Analysis (0)]
13.  Thompson AJ, Patel K, Chuang WL, Lawitz EJ, Rodriguez-Torres M, Rustgi VK, Flisiak R, Pianko S, Diago M, Arora S. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut. 2012;61:128-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 65]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
14.  Hung CH, Lee CM, Wang JH, Hu TH, Chen CH, Lin CY, Lu SN. Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy. Int J Cancer. 2011;128:2344-2352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 79]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
15.  K-Kutala B, Bedossa P, Guedj J, Asselah T, Martinot-Peignoux M, Duval X, Marcellin P. Patients with chronic hepatitis C without advanced fibrosis and hepatocellular carcinoma: a retrospective clinical-pathological study. Dig Liver Dis. 2015;47:296-302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
16.  Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology. 2008;47:1856-1862.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 210]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
17.  Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc. 2000;75:355-359.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 202]  [Cited by in F6Publishing: 189]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
18.  Marzouk D, Sass J, Bakr I, El Hosseiny M, Abdel-Hamid M, Rekacewicz C, Chaturvedi N, Mohamed MK, Fontanet A. Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt. Gut. 2007;56:1105-1110.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 74]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
19.  Shaheen M, Echeverry D, Oblad MG, Montoya MI, Teklehaimanot S, Akhtar AJ. Hepatitis C, metabolic syndrome, and inflammatory markers: results from the Third National Health and Nutrition Examination Survey [NHANES III]. Diabetes Res Clin Pract. 2007;75:320-326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 67]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
20.  Park SK, Cho YK, Park JH, Kim HJ, Park DI, Sohn CI, Jeon WK, Kim BI. Change of insulin sensitivity in hepatitis C patients with normal insulin sensitivity: a 5-year prospective follow-up study variation of insulin sensitivity in HCV patients. Intern Med J. 2010;40:503-511.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 7]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
21.  Huang JF, Yu ML, Dai CY, Hsieh MY, Hwang SJ, Hsiao PJ, Lee LP, Lin ZY, Chen SC, Hsieh MY. Reappraisal of the characteristics of glucose abnormalities in patients with chronic hepatitis C infection. Am J Gastroenterol. 2008;103:1933-1940.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 38]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
22.  Mohamed HR, Abdel-Azziz MY, Zalata KR, Abdel-Razik AM. Relation of insulin resistance and liver fibrosis progression in patients with chronic hepatitis C virus infection. Int J Health Sci (Qassim). 2009;3:177-186.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Duseja A, Dhiman RK, Chawla Y, Thumburu KK, Kumar A, Das A, Bhadada S, Bhansali A. Insulin resistance is common in patients with predominantly genotype 3 chronic hepatitis C. Dig Dis Sci. 2009;54:1778-1782.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 13]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
24.  Lonardo A, Ballestri S, Adinolfi LE, Violi E, Carulli L, Lombardini S, Scaglioni F, Ricchi M, Ruggiero G, Loria P. Hepatitis C virus-infected patients are 'spared' from the metabolic syndrome but not from insulin resistance. A comparative study of nonalcoholic fatty liver disease and hepatitis C virus-related steatosis. Can J Gastroenterol. 2009;23:273-278.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 21]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
25.  Huang JF, Chuang WL, Yu ML, Yu SH, Huang CF, Huang CI, Yeh ML, Hsieh MH, Yang JF, Lin ZY. Hepatitis C virus infection and metabolic syndrome---a community-based study in an endemic area of Taiwan. Kaohsiung J Med Sci. 2009;25:299-305.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 28]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
26.  Mostafa A, Mohamed MK, Saeed M, Hasan A, Fontanet A, Godsland I, Coady E, Esmat G, El-Hoseiny M, Abdul-Hamid M. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59:1135-1140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 85]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
27.  Miyajima I, Kawaguchi T, Fukami A, Nagao Y, Adachi H, Sasaki S, Imaizumi T, Sata M. Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area. J Gastroenterol. 2013;48:93-100.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 34]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
28.  Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37:647-652.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 118]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
29.  Pothineni NV, Delongchamp R, Vallurupalli S, Ding Z, Dai Y, Hagedorn CH, Mehta JL. Impact of hepatitis C seropositivity on the risk of coronary heart disease events. Am J Cardiol. 2014;114:1841-1845.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 60]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
30.  Dai CY, Yeh ML, Huang CF, Hou CH, Hsieh MY, Huang JF, Lin IL, Lin ZY, Chen SC, Wang LY. Chronic hepatitis C infection is associated with insulin resistance and lipid profiles. J Gastroenterol Hepatol. 2015;30:879-884.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 34]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
31.  Ryu JK, Lee SB, Hong SJ, Lee S. Association of chronic hepatitis C virus infection and diabetes mellitus in Korean patients. Korean J Intern Med. 2001;16:18-23.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 34]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
32.  Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166:196-203.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 117]  [Cited by in F6Publishing: 128]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
33.  Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416-423.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 375]  [Cited by in F6Publishing: 360]  [Article Influence: 22.5]  [Reference Citation Analysis (1)]
34.  Rouabhia S, Malek R, Bounecer H, Dekaken A, Bendali Amor F, Sadelaoud M, Benouar A. Prevalence of type 2 diabetes in Algerian patients with hepatitis C virus infection. World J Gastroenterol. 2010;16:3427-3431.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 36]  [Cited by in F6Publishing: 35]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
35.  Lonardo A, Loria P, Adinolfi LE, Carulli N, Ruggiero G. Hepatitis C and steatosis: a reappraisal. J Viral Hepat. 2006;13:73-80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 111]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
36.  Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126:586-597.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 336]  [Cited by in F6Publishing: 325]  [Article Influence: 16.3]  [Reference Citation Analysis (0)]
37.  Lecube A, Hernández C, Genescà J, Simó R. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care. 2006;29:1096-1101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 121]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
38.  Hung CH, Lee CM, Chen CH, Hu TH, Jiang SR, Wang JH, Lu SN, Wang PW. Association of inflammatory and anti-inflammatory cytokines with insulin resistance in chronic hepatitis C. Liver Int. 2009;29:1086-1093.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
39.  Kasai D, Adachi T, Deng L, Nagano-Fujii M, Sada K, Ikeda M, Kato N, Ide YH, Shoji I, Hotta H. HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters. J Hepatol. 2009;50:883-894.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 63]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
40.  Romero-Gómez M. Insulin resistance and hepatitis C. World J Gastroenterol. 2006;12:7075-7080.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 114]  [Cited by in F6Publishing: 108]  [Article Influence: 6.0]  [Reference Citation Analysis (1)]
41.  Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray RB, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol. 2008;82:2606-2612.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 128]  [Cited by in F6Publishing: 138]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
42.  Konrad T, Zeuzem S, Vicini P, Toffolo G, Briem D, Lormann J, Herrmann G, Berger A, Kusterer K, Teuber G. Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon-alpha. Eur J Clin Invest. 2000;30:111-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 72]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
43.  Meissner EG, Lee YJ, Osinusi A, Sims Z, Qin J, Sturdevant D, McHutchison J, Subramanian M, Sampson M, Naggie S. Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology. 2015;61:790-801.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 117]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
44.  Huang YW, Yang SS, Fu SC, Wang TC, Hsu CK, Chen DS, Hu JT, Kao JH. Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study. Hepatology. 2014;60:807-814.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 84]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
45.  Elkrief L, Chouinard P, Bendersky N, Hajage D, Larroque B, Babany G, Kutala B, Francoz C, Boyer N, Moreau R. Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C. Hepatology. 2014;60:823-831.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 122]  [Article Influence: 12.2]  [Reference Citation Analysis (1)]
46.  Backus LI, Belperio PS, Shahoumian TA, Loomis TP, Mole LA. Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans. Aliment Pharmacol Ther. 2015;42:559-573.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 69]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
47.  Butt AA, Yan P, Shaikh OS, Chung RT, Sherman KE. Sofosbuvir-based regimens in clinical practice achieve SVR rates closer to clinical trials: results from ERCHIVES. Liver Int. 2016;36:651-658.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 32]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
48.  Harrison SA, Hamzeh FM, Han J, Pandya PK, Sheikh MY, Vierling JM. Chronic hepatitis C genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin. Hepatology. 2012;56:464-473.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 47]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
49.  Khattab M, Emad M, Abdelaleem A, Eslam M, Atef R, Shaker Y, Hamdy L. Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance. Liver Int. 2010;30:447-454.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 78]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
50.  Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107:46-52.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 232]  [Article Influence: 19.3]  [Reference Citation Analysis (0)]
51.  Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, Ganne-Carrie N, Grando-Lemaire V, Vicaut E, Trinchet JC. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96:2601-2608.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 123]  [Cited by in F6Publishing: 118]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
52.  Sumie S, Kawaguchi T, Kawaguchi A, Kuromatsu R, Nakano M, Satani M, Yamada S, Okamura S, Yonezawa Y, Kakuma T. Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients with hepatitis C virus infection: A prospective study. Mol Clin Oncol. 2015;3:115-120.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 15]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
53.  Balogun WO, Adeleye JO, Akinlade KS, Kuti M, Otegbayo JA. Low prevalence of hepatitis-C viral seropositivity among patients with type-2 diabetes mellitus in a tertiary hospital. J Natl Med Assoc. 2006;98:1805-1808.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Costa LM, Mussi AD, Brianeze MR, Souto FJ. Hepatitis C as a risk factor for diabetes type 2: lack of evidence in a hospital in central-west Brazil. Braz J Infect Dis. 2008;12:24-26.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 19]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
55.  Ruhl CE, Menke A, Cowie CC, Everhart JE. Relationship of hepatitis C virus infection with diabetes in the U.S. population. Hepatology. 2014;60:1139-1149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 65]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
56.  Petta S, Cammà C, Di Marco V, Macaluso FS, Maida M, Pizzolanti G, Belmonte B, Cabibi D, Di Stefano R, Ferraro D. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int. 2011;31:507-515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 61]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
57.  Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28:355-362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 77]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
58.  Tanaka N, Nagaya T, Komatsu M, Horiuchi A, Tsuruta G, Shirakawa H, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K. Insulin resistance and hepatitis C virus: a case-control study of non-obese, non-alcoholic and non-steatotic hepatitis virus carriers with persistently normal serum aminotransferase. Liver Int. 2008;28:1104-1111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 18]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
59.  Mavrogiannaki A, Karamanos B, Manesis EK, Papatheodoridis GV, Koskinas J, Archimandritis AJ. Prevalence of glucose intolerance in patients with chronic hepatitis B or C: a prospective case-control study. J Viral Hepat. 2009;16:430-436.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
60.  Persico M, Masarone M, La Mura V, Persico E, Moschella F, Svelto M, Bruno S, Torella R. Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol. 2009;15:462-466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
61.  Sud A, Hui JM, Farrell GC, Bandara P, Kench JG, Fung C, Lin R, Samarasinghe D, Liddle C, McCaughan GW. Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology. 2004;39:1239-1247.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 140]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
62.  Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, Dufour JF, Helbling B, Hadengue A, Gonvers JJ. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol. 2005;42:41-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 126]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
63.  D'Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005;100:1509-1515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 163]  [Cited by in F6Publishing: 155]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
64.  Taura N, Ichikawa T, Hamasaki K, Nakao K, Nishimura D, Goto T, Fukuta M, Kawashimo H, Fujimoto M, Kusumoto K. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol. 2006;101:2752-2759.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 60]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
65.  Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130:1636-1642.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 416]  [Cited by in F6Publishing: 394]  [Article Influence: 21.9]  [Reference Citation Analysis (0)]
66.  Bugianesi E, Marchesini G, Gentilcore E, Cua IH, Vanni E, Rizzetto M, George J. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis. Hepatology. 2006;44:1648-1655.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 113]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
67.  Kita Y, Mizukoshi E, Takamura T, Sakurai M, Takata Y, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Impact of diabetes mellitus on prognosis of patients infected with hepatitis C virus. Metabolism. 2007;56:1682-1688.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 34]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
68.  Petta S, Cammà C, Di Marco V, Alessi N, Cabibi D, Caldarella R, Licata A, Massenti F, Tarantino G, Marchesini G. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol. 2008;103:1136-1144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 130]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
69.  Cua IH, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology. 2008;48:723-731.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 89]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
70.  Hsu CS, Liu CH, Liu CJ, Hsu SJ, Chen CL, Hwang JJ, Lai MY, Chen PJ, Chen DS, Kao JH. Association of metabolic profiles with hepatic fibrosis in chronic hepatitis C patients with genotype 1 or 2 infection. J Gastroenterol Hepatol. 2010;25:970-977.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 24]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
71.  Moucari R, Ripault MP, Martinot-Peignoux M, Voitot H, Cardoso AC, Stern C, Boyer N, Maylin S, Nicolas-Chanoine MH, Vidaud M. Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut. 2009;58:1662-1669.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 51]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
72.  Patel K, Thompson AJ, Chuang WL, Lee CM, Peng CY, Shanmuganathan G, Thongsawat S, Tanwandee T, Mahachai V, Pramoolsinsap C. Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients. J Gastroenterol Hepatol. 2011;26:1182-1188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 14]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
73.  Mohamed AA, Loutfy SA, Craik JD, Hashem AG, Siam I. Chronic hepatitis c genotype-4 infection: role of insulin resistance in hepatocellular carcinoma. Virol J. 2011;8:496.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 17]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
74.  Miyaaki H, Ichikawa T, Taura N, Miuma S, Shibata H, Isomoto H, Takeshima F, Nakao K. Predictive value of the fibrosis scores in patients with chronic hepatitis C associated with liver fibrosis and metabolic syndrome. Intern Med. 2011;50:1137-1141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
75.  Conjeevaram HS, Wahed AS, Afdhal N, Howell CD, Everhart JE, Hoofnagle JH. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology. 2011;140:469-477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 59]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
76.  Khattab MA, Eslam M, Shatat M, Abd-Aalhalim H, Mousa YI, Samir F, Aly H, Shaker O, Shaker Y. Changes in adipocytokines and insulin sensitivity during and after antiviral therapy for hepatitis C genotype 4. J Gastrointestin Liver Dis. 2012;21:59-65.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Ziada DH, El Saadany S, Enaba M, Ghazy M, Hasan A. The interaction between insulin resistance, liver fibrosis and early virological response in Egyptian patients with chronic hepatitis C. Can J Gastroenterol. 2012;26:325-329.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 10]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
78.  Alfaleh FZ, Alswat K, Helmy A, Al-hamoudi W, El-sharkawy M, Omar M, Shalaby A, Bedewi MA, Hadad Q, Ali SM. The natural history and long-term outcomes in patients with chronic hepatitis C genotype 4 after interferon-based therapy. Liver Int. 2013;33:871-883.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
79.  Dökmeci A, Ustündağ Y, Hulagu S, Tuncer I, Akdoğan M, Demirsoy H, Köklü S, Güzelbulut F, Doğan I, Demir A. The association between insulin resistance and hepatic fibrosis in patients with chronic hepatitis C: an observational, multicenter study in Turkey. Turk J Gastroenterol. 2014;25:546-552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
80.  Huang CF, Dai CY, Yeh ML, Huang CI, Tai CM, Hsieh MH, Liang PC, Lin YH, Hsieh MY, Yang HL. Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection. J Hepatol. 2015;62:512-518.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 27]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
81.  Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003-1008.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 265]  [Cited by in F6Publishing: 273]  [Article Influence: 14.4]  [Reference Citation Analysis (1)]
82.  Elgouhari HM, Zein CO, Hanouneh I, Feldstein AE, Zein NN. Diabetes mellitus is associated with impaired response to antiviral therapy in chronic hepatitis C infection. Dig Dis Sci. 2009;54:2699-2705.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 31]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
83.  Petta S, Cammà C, DI Marco V, Calvaruso V, Enea M, Bronte F, Butera G, Cabibi D, Craxì A. Insulin resistance is a major determinant of liver stiffness in nondiabetic patients with HCV genotype 1 chronic hepatitis. Aliment Pharmacol Ther. 2009;30:603-613.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 16]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
84.  Rüeger S, Bochud PY, Dufour JF, Müllhaupt B, Semela D, Heim MH, Moradpour D, Cerny A, Malinverni R, Booth DR. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut. 2015;64:1605-1615.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 73]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
85.  Tarantino G, Conca P, Sorrentino P, Ariello M. Metabolic factors involved in the therapeutic response of patients with hepatitis C virus-related chronic hepatitis. J Gastroenterol Hepatol. 2006;21:1266-1268.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 38]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
86.  Romero-Gómez M, Del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, Corpas R, Cruz M, Grande L, Vázquez L. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636-641.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 553]  [Cited by in F6Publishing: 523]  [Article Influence: 27.5]  [Reference Citation Analysis (0)]
87.  Jian Wu Y, Shu Chen L, Gui Qiang W. Effects of fatty liver and related factors on the efficacy of combination antiviral therapy in patients with chronic hepatitis C. Liver Int. 2006;26:166-172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
88.  Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology. 2007;46:37-47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 172]  [Cited by in F6Publishing: 179]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
89.  Conjeevaram HS, Kleiner DE, Everhart JE, Hoofnagle JH, Zacks S, Afdhal NH, Wahed AS. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007;45:80-87.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 133]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
90.  Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, George J. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol. 2008;48:28-34.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 127]  [Cited by in F6Publishing: 129]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
91.  Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, Diago M, Alonso S, Planas R, Solá R, Pons JA, Salmerón J, Barcena R. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48:721-727.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 152]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
92.  Dai CY, Huang JF, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL. Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients. J Hepatol. 2009;50:712-718.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 121]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
93.  Khattab M, Eslam M, Sharwae MA, Shatat M, Ali A, Hamdy L. Insulin resistance predicts rapid virologic response to peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients. Am J Gastroenterol. 2010;105:1970-1977.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 59]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
94.  Deltenre P, Louvet A, Lemoine M, Mourad A, Fartoux L, Moreno C, Henrion J, Mathurin P, Serfaty L. Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis. J Hepatol. 2011;55:1187-1194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 65]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
95.  Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, Romero-Gomez M. Meta-analysis: insulin resistance and sustained virological response in hepatitis C. Aliment Pharmacol Ther. 2011;34:297-305.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 74]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
96.  Del Campo JA, Ampuero J, Rojas L, Conde M, Rojas A, Maraver M, Millán R, García-Valdecasas M, García-Lozano JR, González-Escribano MF. Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism. Aliment Pharmacol Ther. 2013;37:74-80.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 16]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
97.  Laurito MP, Parise ER. Association between insulin resistance and sustained virologic response in hepatitis C treatment, genotypes 1 versus 2 and 3: systematic literature review and meta-analysis. Braz J Infect Dis. 2013;17:555-563.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 13]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
98.  Abd El-Wahab EW, Mikheal A, Sidkey F, Shatat HZ. Insulin resistance as a predictor of early virologic response to HCV therapy among chronic HCV Egyptian patients. J Med Virol. 2015;87:428-440.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
99.  Grasso A, Malfatti F, De Leo P, Martines H, Fabris P, Toscanini F, Anselmo M, Menardo G. Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin. J Hepatol. 2009;51:984-990.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 78]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
100.  Fattovich G, Covolo L, Pasino M, Perini E, Rossi L, Brocco G, Guido M, Cristofori C, Belotti C, Puoti M. The homeostasis model assessment of the insulin resistance score is not predictive of a sustained virological response in chronic hepatitis C patients. Liver Int. 2011;31:66-74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 29]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
101.  Brandman D, Bacchetti P, Ayala CE, Maher JJ, Khalili M. Impact of insulin resistance on HCV treatment response and impact of HCV treatment on insulin sensitivity using direct measurements of insulin action. Diabetes Care. 2012;35:1090-1094.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 35]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
102.  Aghemo A, Prati GM, Rumi MG, Soffredini R, D'Ambrosio R, Orsi E, De Nicola S, Degasperi E, Grancini V, Colombo M. Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology. 2012;56:1681-1687.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 80]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
103.  Serfaty L, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Lonjon-Domanec I, DeMasi R, Picchio G. Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naive patients infected with HCV genotype 1. Gut. 2012;61:1473-1480.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 60]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
104.  Younossi Z, Negro F, Serfaty L, Pol S, Diago M, Zeuzem S, Andreone P, Lawitz EJ, Roberts S, Focaccia R. Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial. Hepatology. 2013;58:1897-1906.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 21]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
105.  Jung HJ, Kim YS, Kim SG, Lee YN, Jeong SW, Jang JY, Lee SH, Kim HS, Kim BS. The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients. Clin Mol Hepatol. 2014;20:38-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
106.  Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, Nagao Y, Yanagimoto C, Hanada S, Koga H. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570-576.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 187]  [Cited by in F6Publishing: 180]  [Article Influence: 10.6]  [Reference Citation Analysis (0)]
107.  Chehadeh W, Abdella N, Ben-Nakhi A, Al-Arouj M, Al-Nakib W. Risk factors for the development of diabetes mellitus in chronic hepatitis C virus genotype 4 infection. J Gastroenterol Hepatol. 2009;24:42-48.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 32]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
108.  Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI. Clearance of HCV by Combination Therapy of Pegylated Interferon alpha-2a and Ribavirin Improves Insulin Resistance. Gut Liver. 2009;3:108-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 15]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
109.  Chan CH, Hansen RD, Gilliver RS, Jones BE. Sustained virological response following chronic hepatitis C treatment is associated with improvement in insulin resistance. Intern Med J. 2013;43:656-662.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
110.  Mello V, Cruz T, Nuñez G, Simões MT, Ney-Oliveira F, Braga H, Araújo C, Cunha S, Schinoni MI, Cruz M. Peripheral insulin resistance during treatment of chronic hepatitis C with peguilated interferon plus ribavirin. J Med Virol. 2006;78:1406-1410.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 12]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
111.  Kawaguchi Y, Mizuta T, Oza N, Takahashi H, Ario K, Yoshimura T, Eguchi Y, Ozaki I, Hisatomi A, Fujimoto K. Eradication of hepatitis C virus by interferon improves whole-body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C. Liver Int. 2009;29:871-877.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 34]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
112.  Simó R, Lecube A, Genescà J, Esteban JI, Hernández C. Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care. 2006;29:2462-2466.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 98]  [Cited by in F6Publishing: 99]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
113.  Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Hirakawa M. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49:739-744.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 200]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
114.  Giordanino C, Bugianesi E, Smedile A, Ciancio A, Abate ML, Olivero A, Pellicano R, Cassader M, Gambino R, Bo S. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol. 2008;103:2481-2487.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 68]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
115.  Hung CH, Wang JH, Hu TH, Chen CH, Chang KC, Yen YH, Kuo YH, Tsai MC, Lu SN, Lee CM. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J Gastroenterol. 2010;16:2265-2271.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 79]  [Cited by in F6Publishing: 86]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
116.  Khattab MA, Eslam M, Mousa YI, Ela-adawy N, Fathy S, Shatat M, Abd-Aalhalim H, Kamal A, Sharawe MA. Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma. Ann Hepatol. 2012;11:487-494.  [PubMed]  [DOI]  [Cited in This Article: ]
117.  Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, Sun CA, Lu SN, Chen DS. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008;135:111-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 386]  [Cited by in F6Publishing: 410]  [Article Influence: 25.6]  [Reference Citation Analysis (0)]
118.  Konishi I, Hiasa Y, Shigematsu S, Hirooka M, Furukawa S, Abe M, Matsuura B, Michitaka K, Horiike N, Onji M. Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus. Liver Int. 2009;29:1194-1201.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 37]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
119.  Nkontchou G, Bastard JP, Ziol M, Aout M, Cosson E, Ganne-Carrie N, Grando-Lemaire V, Roulot D, Capeau J, Trinchet JC. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol. 2010;53:827-833.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 82]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
120.  Takahashi H, Mizuta T, Eguchi Y, Kawaguchi Y, Kuwashiro T, Oeda S, Isoda H, Oza N, Iwane S, Izumi K. Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C. J Gastroenterol. 2011;46:790-798.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
121.  Arase Y, Kobayashi M, Suzuki F, Suzuki Y, Kawamura Y, Akuta N, Kobayashi M, Sezaki H, Saito S, Hosaka T. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57:964-973.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 140]  [Article Influence: 12.7]  [Reference Citation Analysis (0)]
122.  Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T. Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2015;30:1183-1189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 79]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
123.  Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: A cohort study in high prevalence area of hepatitis virus infection. Hepatology. 2006;43:1295-1302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 145]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
124.  Chen CT, Chen JY, Wang JH, Chang KC, Tseng PL, Kee KM, Chen PF, Tsai LS, Chen SC, Lin SC. Diabetes mellitus, metabolic syndrome and obesity are not significant risk factors for hepatocellular carcinoma in an HBV- and HCV-endemic area of Southern Taiwan. Kaohsiung J Med Sci. 2013;29:451-459.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 25]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]