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Winn M, Karra P, Haaland B, Doherty JA, Summers SA, Litchman ML, Gunter MJ, Playdon MC, Hardikar S. Metabolic dysfunction and obesity-related cancer: Results from the cross-sectional National Health and Nutrition Examination Survey. Cancer Med 2023; 12:606-618. [PMID: 35719035 PMCID: PMC9844618 DOI: 10.1002/cam4.4912] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/02/2022] [Accepted: 05/25/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Metabolic syndrome (MetS), a group of risk factors that define metabolic dysfunction in adults, is strongly associated with obesity and is an emerging risk factor for cancer. However, the association of MetS and degree of metabolic dysfunction with obesity-related cancer is unknown. METHODS Using National Health and Nutrition Examination Survey data from 1999 to 2018, we identified 528 obesity-related cancer cases and 18,972 cancer-free participants. MetS was defined as the presence of or treatment for ≥3 of hyperglycemia, hypertension, hypertriglyceridemia, low HDL-cholesterol, and abdominal obesity. A metabolic syndrome score (MSS) was computed as the total number of abnormal MetS parameters to determine the severity of metabolic dysfunction. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models, adjusting for sociodemographic and lifestyle factors. RESULTS About 45.7% of obesity-related cancer cases were classified as having MetS compared with only 33.0% of cancer-free participants. Overall, MetS and MSS were not associated with obesity-related cancer. However, MSS was associated with higher obesity-related cancer risk among participants under 50 years of age (OR [95% CI] = 1.28 [1.08-1.52]). When evaluating MSS categorically, compared with healthy participants with no abnormal MetS parameters (MSS = 0), participants with one or two abnormal parameters had a statistically significant higher risk of obesity-related cancer (OR [95% CI] = 1.73 [1.06-2.83]). CONCLUSIONS Metabolic dysfunction is associated with a higher risk of obesity-related cancer, particularly in young adults under 50 years of age, and among participants with one or two abnormal metabolic parameters. A more accurate indicator of metabolic dysfunction, beyond metabolic syndrome, is needed to better assist in stratifying individuals for obesity-related cancer risk.
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Affiliation(s)
- Maci Winn
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
| | - Prasoona Karra
- Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
- Department of Nutrition and Integrative PhysiologyUniversity of UtahSalt Lake CityUtahUSA
| | - Benjamin Haaland
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
| | - Jennifer A. Doherty
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
| | - Scott A. Summers
- Department of Nutrition and Integrative PhysiologyUniversity of UtahSalt Lake CityUtahUSA
| | | | - Marc J. Gunter
- Nutrition and Metabolism BranchInternational Agency for Research on CancerLyonFrance
| | - Mary C. Playdon
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Department of Nutrition and Integrative PhysiologyUniversity of UtahSalt Lake CityUtahUSA
| | - Sheetal Hardikar
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
- Fred Hutchinson Cancer Research CenterSeattleWashingtonUSA
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Kim RG, Kramer-Feldman J, Bacchetti P, Grimes B, Burchard E, Eng C, Hu D, Hellerstein M, Khalili M. Disentangling the impact of alcohol use and hepatitis C on insulin action in Latino individuals. Alcohol Clin Exp Res 2022; 46:87-99. [PMID: 34773280 PMCID: PMC8799492 DOI: 10.1111/acer.14743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/18/2021] [Accepted: 11/09/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Alcohol, insulin resistance (IR), and hepatitis C (HCV) are all significant contributors to adverse outcomes of chronic liver disease. Latinos are disproportionately affected by these risk factors. We investigated the relationship between alcohol use and insulin action in a prospective cohort of Latino individuals with and without HCV. METHODS One hundred fifty-three nondiabetic Latino individuals (60 HCV+, 93 HCV-) underwent clinical evaluation and metabolic testing; 56 had repeat testing over a median follow-up of 1.5 years. Peripheral IR and hepatic IR were measured via steady-state plasma glucose (SSPG) and endogenous glucose production during a two-step, 240-min insulin suppression test. Insulin secretion (IS) was measured using the graded glucose infusion test. Alcohol use was categorized as none, moderate (≤1 drink/day for women and ≤2 drinks/day for men), and heavy (>moderate). Multivariable models including HCV status assessed associations of alcohol use with baseline SSPG, hepatic IR and IS, and changes in these parameters over time. RESULTS Overall, the median age was 44 years, 63.4% were male, 66.7% overweight/ obese, and 31.9% had heavy lifetime alcohol use while 60.4% had moderate lifetime alcohol use. SSPG and IS were similar by levels of alcohol use at baseline and alcohol use was not statistically significantly associated with change in these measures over time. However, lifetime daily heavy alcohol use (vs. not heavy, coef 2.4 μU-mg/kg-min-ml, p = 0.04) and HCV status (coef 4.4 μU-mg/kg-min-ml, p = 0.0003) were independently associated with higher baseline hepatic IR, and current heavy alcohol use was associated with greater change in hepatic IR in follow-up (coef 5.8 μU-mg/kg-min-ml, p = 0.03). CONCLUSIONS In this cohort of Latino individuals, lifetime and current heavy alcohol use influenced hepatic IR and its change over time. Strategies to decrease rates of heavy alcohol use or increase abstinence along with lifestyle modification and anti-HCV therapy to reduce metabolic risk are critical to prevent adverse liver and metabolic outcomes in Latino individuals.
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Affiliation(s)
- Rebecca G Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA
| | - Jonathan Kramer-Feldman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Barbara Grimes
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Esteban Burchard
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Celeste Eng
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Donglei Hu
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Marc Hellerstein
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA
| | - Mandana Khalili
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
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Khalili M, King WC, Kleiner DE, Jain MK, Chung RT, Sulkowski M, Lisker-Melman M, Wong DK, Ghany M, Sanyal A, Sterling RK. Fatty Liver Disease in a Prospective North American Cohort of Adults With Human Immunodeficiency Virus and Hepatitis B Virus Coinfection. Clin Infect Dis 2021; 73:e3275-e3285. [PMID: 32869840 PMCID: PMC8563226 DOI: 10.1093/cid/ciaa1303] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) and fatty liver disease (FLD) are common in human immunodeficiency virus (HIV). Correlates of FLD and its relationship with alanine aminotransferase (ALT) were examined longitudinally in HIV-HBV coinfection. METHODS From 28/4/2014-7/11/2018, 114 HIV-HBV adults had liver biopsy and were followed for a median of 3 years (ancillary study of Hepatitis B Research Network). Steatohepatitis was based on presence of steatosis, ballooning, and perisinusoidal fibrosis. FLD was defined as ≥5% steatosis and/or steatohepatitis. RESULTS Median age was 49 years, 93% were male, 51% black, 93% had HIV RNA <400 copies/mL and 83% HBV DNA <1000 IU/mL. Thirty percent had FLD (20% steatosis, 10% steatohepatitis). Those with FLD had higher median triglyceride (171 vs 100 mg/dL, P < .01) and small, dense LDL (44 vs 29 mg/dL, P < .01) and lower HDL-2-C (9 vs 12 mg/dL, P = .001). After adjusting for age, sex, and alcohol use, white and other versus black race (ORs, 8.49 and 16.54, respectively), ALT (OR, 3.13/doubling), hypertension (OR, 10.93), hyperlipidemia (OR, 4.36), and diabetes family history (OR, 5.38) were associated with having FLD (all P < .05). Steatohepatitis or steatosis alone (vs none) was associated with higher ALT over time (1.93 and 1.34 times higher, respectively; P < .001), with adjustment for age, sex, and HBV DNA. CONCLUSIONS About 30% with HIV-HBV coinfection had FLD including 10% with steatohepatitis. FLD was associated with non-black race, metabolic risks, an atherogenic lipid profile, and elevated ALT over time. Thus, identification of FLD and management of adverse metabolic profiles are critically important in HIV-HBV coinfection. Clinical Trial Registration. NCT01924455.
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Affiliation(s)
- Mandana Khalili
- University of California San Francisco, San Francisco, California, USA
| | - Wendy C King
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | | | - Mamta K Jain
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | | | | | | | - Marc Ghany
- National Institutes of Health, Bethesda, Maryland, USA
| | - Arun Sanyal
- Virginia Commonwealth University, Richmond, Virginia, USA
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Álvarez-Nava F, Bastidas D, Racines-Orbe M, Guarderas J. Insulin Sensitivity and Pancreatic β-Cell Function in Ecuadorian Women With Turner Syndrome. Front Endocrinol (Lausanne) 2020; 11:482. [PMID: 32849275 PMCID: PMC7427507 DOI: 10.3389/fendo.2020.00482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Objective: To assess insulin sensitivity and pancreatic β-cell function in an adult population of Ecuadorian individuals with Turner syndrome (TS). Design and Methods: This was a cross-sectional correlational study conducted in TS subjects (>20 years old; n = 38). A standard 2-h oral glucose tolerance test was performed in both women with TS and the reference group. Glucose, lipids, insulin, and C-peptide concentrations were measured. Homeostasis Model Assessment (HOMA) of Insulin Resistance, Quantitative Insulin Sensitivity Check Index, McAuley, Matsuda, and Belfiore indices were calculated to evaluate the degree of insulin resistance (IR). The pancreatic β-cell function was assessed using HOMA-β, basal C-Peptide Index (CPI), and CPII at 120'. Results: A higher prevalence of impaired glucose tolerance was found in TS subjects compared with the reference group. Although significant differences were found for glucose concentrations at 60' and 120' (but not at 0'), only the baseline insulin concentrations differed significantly between the two groups. The values of the IR indices were statistically different between study and reference groups. A significant number of TS subjects diagnosed with IR were differently classified according to the index applied. The concentrations of C-peptide at 0' and 120' of TS subjects were similar to those of the control group. In contrast, the CPI and CPII values in the study group were significantly lower than those in the control group. Conclusion: It is impossible to select the best surrogate method for the assessment of IR in women with TS. The CPI and CPII values could be preferable to other indices to assess the pancreatic β-cell function in TS subjects. Our findings suggest that IR and pancreatic β-cell dysfunction could be independent events in women with TS, and both conditions seem to be caused by the disease per se. Our results imply that early screening and intervention for TS would be therapeutic for TS women.
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Affiliation(s)
- Francisco Álvarez-Nava
- Faculty of Biological Sciences, Biological Sciences School, Central University of Ecuador, Quito, Ecuador
- *Correspondence: Francisco Álvarez-Nava
| | - Daniela Bastidas
- Faculty of Biological Sciences, Biological Sciences School, Central University of Ecuador, Quito, Ecuador
| | - Marcia Racines-Orbe
- Institute of Biomedicine Research, Central University of Ecuador, Quito, Ecuador
| | - Jéssica Guarderas
- Faculty of Biological Sciences, Biological Sciences School, Central University of Ecuador, Quito, Ecuador
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Cito G, Coccia ME, Fucci R, Picone R, Cocci A, Sessa M, Sessa F, Rizzello F, Micelli E, Trotta M, Badolato L, Campi R, Criscuoli L, Serni S, Carini M, Natali A. Hepatitis B Surface Antigen Seropositive Men in Serodiscordant Couples: Effects on the Assisted Reproductive Outcomes. World J Mens Health 2019; 39:99-106. [PMID: 32009315 PMCID: PMC7752521 DOI: 10.5534/wjmh.190121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/23/2019] [Accepted: 11/15/2019] [Indexed: 11/18/2022] Open
Abstract
Purpose To evaluate the influence of hepatitis B virus (HBV) infection in men of serodiscordant couples on the reproductive outcomes. Materials and Methods A total of 134 infertile couples were included in this retrospective single-center cohort study. Sixty-six couples had hepatitis B surface antigen (HBsAg)-seropositive men and seronegative partners, while 68 couples were controls with both seronegative men and women. Overall, 134 fresh in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments were performed. As the main outcome measures, on the day of the fresh IVF/ICSI cycle, we assessed seminal parameters Before and after sperm preparation techniques. Two-pronuclear (2PN) fertilization, 1-2-3PN fertilization, cleavage, miscarriage, pregnancy and live birth rates were collected. Results No significant differences were found between groups in terms of oocytes retrieved, oocytes injected and embryos obtained (p=0.64, p=0.97, and p=0.40, respectively). The 2PN fertilization rate (FR) was comparable among groups (p=0.51). The 1-2-3PN FR was significantly lower in the HBsAg group than in the control group (66.6% vs. 69.7%, respectively). The clinical pregnancy per cycle, implantation, miscarriage and live birth rate were comparable between the HBsAg group and the control group. The median sperm concentration/ml and total sperm count, measured at baseline and after sperm preparation, was comparable between groups (p>0.05). There was a trend toward significant lower progressive motility (35.0% vs. 55.0%; p<0.05) in the HBsAg group at baseline and after sperm preparation (p<0.05). Conclusions HBV infected men have the same chance to became father, compared to seronegative patients.
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Affiliation(s)
- Gianmartin Cito
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy.
| | - Maria Elisabetta Coccia
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Rossella Fucci
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Rita Picone
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Andrea Cocci
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Maurizio Sessa
- Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Francesco Sessa
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Francesca Rizzello
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Elisabetta Micelli
- Department of Gynecology and Obstetrics, St. Claire Hospital, University of Pisa, Pisa, Italy
| | - Michele Trotta
- Department of Critical Care Medicine and Surgery, Infectious Disease Unit, Careggi Hospital, University of Florence, Florence, Italy
| | - Laura Badolato
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Riccardo Campi
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Luciana Criscuoli
- Assisted Reproductive Technology Centre, Careggi Hospital, University of Florence, Florence, Italy
| | - Sergio Serni
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Marco Carini
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
| | - Alessandro Natali
- Department of Urology, Careggi Hospital, University of Florence, Florence, Italy
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Comparisons of the Incidence and Critical Risk Factors of Metabolic Syndrome in Patients With a Rheumatic Disease or Gout. Orthop Nurs 2019; 38:201-208. [PMID: 31124872 DOI: 10.1097/nor.0000000000000557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Rheumatic disease and gout are particularly known to be associated with metabolic syndrome. PURPOSE To compare incidence, physiological indices, and risk factors of metabolic syndrome in patients with rheumatic diseases or gout. METHODS Data were collected from medical records of 220 patients with rheumatic disease or gout. RESULTS The incidence rate and most physiological indices of metabolic syndrome (body mass index, blood pressure, serum triglyceride, and fasting blood glucose levels) were significantly higher in the gout group than in the rheumatic disease group. In terms of risk factors of metabolic syndrome, age, gender, and steroid use were significant in the rheumatic disease group, whereas smoking and gout duration were significant in the gout group. CONCLUSIONS Men with a rheumatic disease taking steroids warrant additional attention regarding metabolic syndrome development. Special supports are also needed for people with gout who are smokers and who have suffered from gout for a longer duration.
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Salomone F, Catania M, Montineri A, Bertino G, Godos J, Rizzo L, Magrì G, Li Volti G. Hepatitis C virus eradication by direct antiviral agents improves glucose tolerance and reduces post-load insulin resistance in nondiabetic patients with genotype 1. Liver Int 2018; 38:1206-1211. [PMID: 29265719 DOI: 10.1111/liv.13669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 12/11/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Genotype 1 chronic hepatitis C is associated with an impairment of glucose homoeostasis, especially in the advanced stages of the disease. Glucose tolerance is an independent predictor of liver-related mortality in patients with cirrhosis because of chronic hepatitis C. However, no study has demonstrated so far weather hepatitis C virus clearance affects glucose tolerance. METHODS To this aim, we performed a prospective study assessing the effects of direct antiviral agents treatment in nondiabetic cirrhotic patients with genotypes 1a/1b and impaired glucose tolerance based on a 75-g oral glucose tolerance test. Impaired glucose tolerance was diagnosed by a 2-hour plasma glucose between 140 and 199 mg/dL. Insulin resistance was estimated by the oral glucose insulin sensitivity index, an oral glucose tolerance test-derived measure. RESULTS After meeting the inclusion criteria, the study population included 32 outpatients (26/6 genotypes 1b/1a; age 62 ± 7.4 years; 18 males) with compensated Child-A cirrhosis. All patients achieved a sustained virological response following direct antiviral agents treatment. After viral eradication, we did not observe change in fasting plasma glucose (103.5 ± 7.1 vs 102.8 ± 7.2 mg/dL, P = .15) but 2-hour plasma glucose was reduced (165.2 ± 22.7 vs 138.5 ± 21.3 mg/dL, P < .001). Hepatitis C virus eradication led also to a significant reduction in HbA1c (6.1 ± 0.2% vs 5.7 ± 0.3%, P < .001) and post-load insulin resistance as assessed by the oral glucose insulin sensitivity index (6.92 ± 1.56 vs 9.52 ± 1.39 mg/kg/min, P < .001). These effects were observed despite no change in body mass index from baseline to follow-up (25.6 ± 4.3 vs 25.8 ± 4.4, P > .5). CONCLUSIONS Our results indicate that hepatitis C virus eradication may early improve glucose tolerance in patients with hepatitis C virus-related cirrhosis.
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Affiliation(s)
- Federico Salomone
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Maurizio Catania
- Division of Laboratory Medicine, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Arturo Montineri
- Division of Infectious Diseases, Ospedale "Ferrarotto", Catania, Italy
| | - Gaetano Bertino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Justyna Godos
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | | | - Giovanni Magrì
- Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Influence of insulin resistance on the development of hepatocellular carcinoma after antiviral treatment for non-cirrhotic patients with chronic hepatitis C. Infect Agent Cancer 2016; 11:9. [PMID: 26913058 PMCID: PMC4765113 DOI: 10.1186/s13027-016-0056-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Background Insulin resistance is considered to be an important factor in the progression of fibrosis and the enhancement of the risk of hepatocellular carcinoma (HCC) for chronic hepatitis C patients. The aim of this study was to assess the effect of insulin resistance on the development of HCC by non-cirrhotic chronic hepatitis C patients treated with pegylated interferon alpha-2b (PEG-IFNα2b) and ribavirin. Methods This retrospective study consisted of 474 Japanese non-cirrhotic patients with chronic hepatitis C. The cumulative incidence of HCC was estimated using the Kaplan-Meier method, according to insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) and treatment outcome. Results The overall sustained virological response (SVR) rate was 45.1 % (214/474, genotype 1: 35.4 % [129/364] and genotype 2: 77.3 % [85/110]). Twenty-one (4.4 %) patients developed HCC during the follow-up period. The 5-year cumulative incidence of HCC of the SVR group (2.6 %) was significantly lower than that of the non-SVR group (9.7 %) (log-rank test: P = 0.025). In multivariable logistic regression analysis, HOMA-IR (≥2.5) (hazard ratio [HR] 12.8, P = 0.0006), fibrosis status (F3) (HR 8.85, P < 0.0001), and post-treatment alanine aminotransferase (ALT) level (≥40 U/L) (HR 4.33, P = 0.036) were independently correlated to the development of HCC. Receiver operating characteristic analysis to determine the optimal threshold value of HOMA-IR for predicting the development of HCC in the non-SVR group showed that the areas under the curve was high (0.80, cutoff value: 3.0). Only three patients (1.4 %) who achieved SVR developed HCC. Two of them had severe insulin resistance and did not show improvement in HOMA-IR after achieving SVR. Conclusions Insulin resistance has a strong impact on the development of HCC by non-cirrhotic patients who have PEG-IFNα2b and ribavirin treatment failure.
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Knobler H, Malnick S. Hepatitis C and insulin action: An intimate relationship. World J Hepatol 2016; 8:131-138. [PMID: 26807209 PMCID: PMC4716529 DOI: 10.4254/wjh.v8.i2.131] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 12/10/2015] [Accepted: 12/29/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection has been shown to be linked to a higher prevalence of type 2 diabetes compared with the general population or with patients with chronic hepatitis B infection and diabetes is the most common extra-hepatic manifestation of HCV. The HCV-diabetes association is due to insulin resistance (IR) that occurs early in the course of the disease even in patients without or with minimal fibrosis. The mechanisms for HCV-induced IR are only partly understood and include a direct inhibitory effect of HCV on insulin signaling pathway. IR in chronic HCV results in an increased progression rate of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Some but not all studies found that IR reduces the response rate to interferon/ribavirin therapy. Whether IR affects the response to the new direct-acting antiviral treatments is still unknown.
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Affiliation(s)
- Hilla Knobler
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
| | - Stephen Malnick
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
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10
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Diugan F, Mota M. Elevated 1 Hour Glucose During Oral Glucose Tolerance Test- A New Parameter of Impaired Metabolism. ROMANIAN JOURNAL OF DIABETES NUTRITION AND METABOLIC DISEASES 2016. [DOI: 10.1515/rjdnmd-2016-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Shah SC, Kornak J, Khalili M. Depression is not associated with peripheral insulin resistance in patients with chronic hepatitis C infection. J Viral Hepat 2015; 22:272-80. [PMID: 25196736 PMCID: PMC4386832 DOI: 10.1111/jvh.12306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Depression is common in individuals infected with hepatitis C virus (HCV), and both depression and HCV infection are independently associated with insulin resistance (IR). To evaluate the relationship between depression and IR, among other factors, in an HCV-infected cohort. In this cross-sectional analysis, seventy-four non-type 2 diabetic, noncirrhotic, HCV-infected patients underwent comprehensive clinical, histologic and metabolic evaluation. IR was assessed directly with an insulin suppression test by measuring steady-state plasma glucose (SSPG) levels during continuous infusions of octreotide, glucose and insulin. Logistic regression modelling was used to evaluate predictors associated with depression. Thirty-nine (53%) patients were depressed, and 21 (54%) depressed patients were on at least one antidepressant. A higher estimated proportion of depressed patients were Caucasian (51% vs 20%, P = 0.005), unemployed (69% vs 49%, P = 0.07), heavier smokers (18 pack-years vs 13 pack-years, P = 0.07), on substance abuse therapy (16% vs 3%, P = 0.06) and had lower HDL levels (1.2 mmol/L vs 1.4 mmol/L, P = 0.01). The mean SSPG levels in depressed and nondepressed patients were 7.3 and 8.3 mmol/L (P = 0.45), respectively. In multipredictor adjusted analysis, only Caucasian race (OR 4.19, 95% CI 1.42-12.35, P = 0.009) and lower HDL (OR 0.95, 95% CI 0.89-0.99, P = 0.046) were associated with depression. In conclusion, although prevalent, depression was not associated with peripheral IR in this HCV-infected cohort. Attention to other modifiable factors associated with depression in the HCV-infected population is warranted.
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Affiliation(s)
- S. C. Shah
- Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
| | - J. Kornak
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - M. Khalili
- Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA,Liver Center, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
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Burman BE, Bacchetti P, Ayala CE, Gelman N, Melgar J, Khalili M. Liver inflammation is a risk factor for prediabetes in at-risk latinos with and without hepatitis C infection. Liver Int 2015; 35:101-7. [PMID: 25156890 PMCID: PMC4293255 DOI: 10.1111/liv.12676] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 08/19/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Early recognition of prediabetes can lead to timely clinical interventions to prevent type 2 diabetes. Both Latino ethnicity and chronic hepatitis C (HCV) have been identified as diabetic risk factors. We aimed to investigate predictors of impaired fasting glucose (IFG), a common prediabetic state, among Latinos with and without HCV. METHODS One hundred Latino adults with no history of diabetes or cirrhosis underwent clinical, laboratory, and metabolic evaluation, including oral glucose tolerance testing (OGTT) and insulin suppression testing to quantify directly measured insulin resistance (IR). Isolated IFG was defined as fasting glucose ≥100 mg/dl and <140 mg/dl at 2 h during normal glucose tolerance during OGTT. RESULTS Overall subject characteristics included median age 44 years, 64% male, 40% HCV-positive and 32% with isolated IFG. Factors associated with isolated IFG included subject age (OR 2.42 per decade, 95%CI 1.40-3.90, P = 0.001), HCV infection (OR 4.0, 95%CI 1.71-9.72, P = 0.002) and alanine aminotransferase (ALT) (OR 2.35 per doubling, 95%CI 1.46-3.77, P < 0.0001). Multipredictor logistic regression analysis identified ALT (OR 2.05 per doubling, P = 0.005, 95% CI 1.24-3.40) and age (OR 2.20 per 10 years, P = 0.005, 95%CI 1.27-3.80) as factors independently associated with IFG. While HCV was associated with 4-fold higher odds of IFG, this entire effect was mediated by ALT. CONCLUSIONS We found strong evidence that liver inflammation is a risk factor for prediabetes among Latinos with and without HCV. Among HCV-infected individuals, early antiviral therapy could mitigate the effect of inflammation and represent an important intervention to prevent diabetes in this at-risk population.
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Affiliation(s)
- Blaire E Burman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Claudia E. Ayala
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Nicholas Gelman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jennifer Melgar
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Mandana Khalili
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA,Liver Center, University of California San Francisco, San Francisco, CA, USA
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13
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Ruhl CE, Menke A, Cowie CC, Everhart JE. Relationship of hepatitis C virus infection with diabetes in the U.S. population. Hepatology 2014; 60:1139-49. [PMID: 24500979 PMCID: PMC4122643 DOI: 10.1002/hep.27047] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 01/31/2014] [Indexed: 12/16/2022]
Abstract
UNLABELLED An association of hepatitis C virus (HCV) infection with diabetes has been reported in many studies, but few have been population based and applied standard criteria for diabetes diagnosis. We examined this relationship using recent population-based data from the U.S. National Health and Nutrition Examination Survey. Adult participants (15,128) in the 1999-2010 surveys had data on diabetes status and serum HCV antibody (anti-HCV) or HCV RNA. Using American Diabetes Association criteria, diabetes was defined as a health care provider diagnosis, serum hemoglobin A1C (A1C) ≥6.5%, or fasting plasma glucose (FPG) ≥126 mg/dL, prediabetes as A1C 5.7%-<6.5% or FPG 100-<126 mg/dL, and normal glucose as A1C <5.7% and FPG <100 mg/dL. Odds ratios (ORs) for diabetes and prediabetes, comparing persons with HCV infection to those without, were adjusted for demographics, BMI, C-reactive protein, smoking, drinking, and blood transfusion before 1992. Among participants without diabetes, we compared mean insulin resistance (IR), estimated using homeostasis model assessment (HOMA-IR), by HCV status. The overall prevalence of anti-HCV+ was 1.7%, of HCV RNA(+) 1.1%, of diabetes 10.5%, and of prediabetes 32.8%. The prevalence of diabetes and prediabetes did not differ by HCV status. In multivariate-adjusted analysis, diabetes remained unassociated with anti-HCV (OR, 1.0; 95% confidence interval [CI]: 0.6-1.7) or with HCV RNA (OR, 1.1; 95% CI: 0.6-1.9). In contrast, elevated alanine aminotransferase and gamma glutamyltransferase activities were associated with diabetes regardless of HCV status. HOMA-IR was not associated with HCV markers in unadjusted or multivariate-adjusted analyses (P > 0.05). CONCLUSION In the U.S. population, HCV was not associated with diabetes or with IR among persons with normal glucose. Previously reported relationships of HCV with diabetes were possibly attributable to the effect of elevated liver enzymes.
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Affiliation(s)
- Constance E. Ruhl
- Social & Scientific Systems, Inc., 8757 Georgia Avenue, 12floor, Silver Spring, MD 20910, 301-628-3272 (phone), 301-628-3201 (fax)
| | - Andy Menke
- Social & Scientific Systems, Inc., 8757 Georgia Avenue, 12floor, Silver Spring, MD 20910
| | - Catherine C. Cowie
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, 2 Democracy Plaza, Room 691, 6707 Democracy Boulevard MSC 5460, Bethesda, MD 20892-5450
| | - James E. Everhart
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, 2 Democracy Plaza, Room 642F, 6707 Democracy Boulevard MSC 5450, Bethesda, MD 20892-5450
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14
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Bu Z, Kong H, Li J, Wang F, Guo Y, Su Y, Zhai J, Sun Y. Effect of male hepatitis B virus infection on outcomes of in vitro fertilization and embryo transfer treatment: insights from couples undergoing oocyte donation. Int J Clin Exp Med 2014; 7:1860-1866. [PMID: 25126191 PMCID: PMC4132155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/28/2014] [Indexed: 06/03/2023]
Abstract
It is common to see HBV infected couple seeking fertility treatment in reproductive medical centers. However, it is still unclear whether HBV infection has any relationship with IVF outcome. To assess the impact of male HVB infection on the outcomes of IVF, we retrospectively analyzed data from two hundred and seventy-seven subfertile couples undergoing oocyte donation cycles in our center. Twenty men (7.2%) were HBV seropositive in 277 couples. 20 couples with seropositive husbands had similar semen parameters and fertilization rate when compared with their controls. Among the 215 couples undergoing their first oocyte donation cycles, 19 couples with seropositive husbands/seronegative wives had lower implantation rate (26.7% vs. 40.6%; P > 0.05), and lower clinical pregnancy rate (42.1% vs. 63.8%; P > 0.05), but the difference was not statistically significant. In binary regression model, male HBV infection had no association with clinical pregnancy. Our study shows that male HBV infection has little impact on IVF outcomes.
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Affiliation(s)
- Zhiqin Bu
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Huijuan Kong
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Jing Li
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Fang Wang
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Yihong Guo
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Yingchun Su
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Jun Zhai
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
| | - Yingpu Sun
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, People's Republic of China
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15
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Milner KL, Jenkins AB, Trenell M, Tid-Ang J, Samocha-Bonet D, Weltman M, Xu A, George J, Chisholm DJ. Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots. J Viral Hepat 2014; 21:325-32. [PMID: 24716635 DOI: 10.1111/jvh.12143] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 06/17/2013] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic-euglycaemic clamp with [6,6-(2) H2 ] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.
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Affiliation(s)
- K-L Milner
- Garvan Institute of Medical Research, University of New South Wales, Sydney, NSW, Australia; Department of Endocrinology, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia
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16
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Romero-Gómez M, Del Campo JA. Insulin resistance, telaprevir, and virological response in hepatitis C: the debate must go on. Hepatology 2013; 58:1874-6. [PMID: 23913755 DOI: 10.1002/hep.26642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 07/01/2013] [Accepted: 07/16/2013] [Indexed: 12/07/2022]
Affiliation(s)
- Manuel Romero-Gómez
- UCM Digestive Diseases and CIBERehd, Valme University Hospital, University of Seville, Sevilla, Spain
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17
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Mukhtar NA, Bacchetti P, Ayala CE, Melgar J, Christensen S, Maher JJ, Khalili M. Insulin sensitivity and variability in hepatitis C virus infection using direct measurement. Dig Dis Sci 2013; 58:1141-8. [PMID: 23086116 PMCID: PMC3566265 DOI: 10.1007/s10620-012-2438-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Accepted: 09/26/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement. METHODS One hundred two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. RESULTS Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95 % CI 37-96), BMI (Coef 19 per 5 kg/m(2), 95 % CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95 % CI 0.2-2.5), male gender (Coef -48, 95 % CI -80 to -16), and HDL (Coef -16, 95 % CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95 % CI 19-90), steatosis (Coef -44, 95 % CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m(2), 95 % CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95 % CI 0.3-6.7) predicted change in SSPG. CONCLUSIONS There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.
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Affiliation(s)
- Nizar A. Mukhtar
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA
| | - Claudia E Ayala
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Jennifer Melgar
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Spencer Christensen
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Jacquelyn J. Maher
- Department of Medicine, University of California San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
| | - Mandana Khalili
- Department of Medicine, University of California San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
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18
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Pascarella S, Clément S, Dill MT, Conzelmann S, Lagging M, Missale G, Neumann AU, Pawlotsky JM, Zeuzem S, Rubbia-Brandt L, Bochud PY, Negro F. Intrahepatic mRNA levels of SOCS1 and SOCS3 are associated with cirrhosis but do not predict virological response to therapy in chronic hepatitis C. Liver Int 2013; 33:94-103. [PMID: 23164156 DOI: 10.1111/liv.12031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 10/04/2012] [Indexed: 02/13/2023]
Abstract
BACKGROUND Antiviral treatment of chronic hepatitis C is not invariably successful, costly and associated with serious side-effects, and therefore should be indicated only when the chances of benefitting patients exceed the potential risks. The suppressor of cytokine signalling (SOCS) family members have been suggested to affect the rate of virological response to therapy, but the published evidence is conflicting. METHODS We measured the intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels in 107 chronic hepatitis C patients and assessed their clinical and histological correlates with the virological response to therapy and with some factors known for affecting treatment outcome. RESULTS By multivariate analysis, SOCS1, SOCS3 and SOCS7 mRNA levels were not associated with rapid or sustained virological response. Similarly, no association was found between the levels of any intrahepatic SOCS mRNA and those of the homeostasis model assessment of insulin resistance. Conversely, SOCS1 (OR 2.185, 95% CI 1.223-3.906, P=0.0083) and SOCS3 (OR 40.601, 95% CI 2.357-699.25, P=0.0108) mRNA level (but not SOCS7), together with age (OR 1.156, 95% CI 1.049-1.275, P=0.0036), were independently associated with cirrhosis. CONCLUSIONS Intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels do not predict virological response to therapy in chronic hepatitis C. The association between SOCS1, SOCS3 and cirrhosis warrants further study.
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Affiliation(s)
- Stéphanie Pascarella
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
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19
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Ogawa E, Furusyo N, Murata M, Ikezaki H, Ihara T, Hayashi T, Toyoda K, Taniai H, Okada K, Kainuma M, Hayashi J. Insulin resistance undermines the advantages of IL28B polymorphism in the pegylated interferon alpha-2b and ribavirin treatment of chronic hepatitis C patients with genotype 1. J Hepatol 2012; 57:534-40. [PMID: 22613000 DOI: 10.1016/j.jhep.2012.04.027] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 04/20/2012] [Accepted: 04/23/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Recent studies have suggested that insulin resistance exerts a strong influence on chronic hepatitis C virus (HCV) infection. We analyzed pretreatment factors useful for predicting sustained virological response (SVR), especially interleukin (IL) 28B polymorphism and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). METHODS This cohort study consisted of 328 chronic hepatitis C patients with HCV genotype 1 who were treated for 48 weeks with pegylated interferon (PegIFN) α-2b and ribavirin (RBV). Genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on DNA collected from each patient. RESULTS No significant difference in IL28B genotype distribution was found according to HOMA-IR. Multivariate analysis identified the IL28B TT genotype (OR=5.97, 95% CI 2.15-16.55, p=0.0006) and the baseline HOMA-IR (OR=0.65, 95% CI 0.48-0.87, p=0.0044) as significant, independent pretreatment predictors of SVR. Receiver operating characteristic analyses to determine the optimal threshold values of HOMA-IR for predicting SVR showed that the areas under the curve (AUC) were high for both IL28B TT (AUC=0.774, HOMA-IR cut-off value: 2.45) and IL28B TG/GG genotypes (AUC=0.772, HOMA-IR cut-off value: 1.55). CONCLUSIONS For HCV genotype 1, both IL28B and baseline HOMA-IR are independent pretreatment predictors of SVR in patients treated with PegIFNα-2b and RBV. Insulin resistance undermines the advantages of IL28B polymorphism to obtain SVR.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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20
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Chung WJ. [Chronic hepatitis C and insulin resistance]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:268-74. [PMID: 22544023 DOI: 10.4166/kjg.2012.59.4.268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Insulin resistance is frequently associated with chronic liver disease, and the interaction between hepatitis C virus (HCV) infection and insulin resistance is a major public health issue, bound to increase in the near term. Because of their potential synergism on liver disease severity, a better understanding of the clinical consequences of the relationship between HCV infection and insulin resistance is needed. This translates into accelerated liver disease progression, reduced response to anti-viral agents and, in susceptible individuals, increased risk of developing 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. Little is known regarding the effect of anti-diabetic agents on HCV infection, and a possible association between use of exogenous insulin or a sulfonylurea agents and the development of hepatocellular carcinoma has recently been reported. Thus, modified lifestyle and pharmacological modalities are urgently warranted in chronic hepatitis C with metabolic alterations.
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Affiliation(s)
- Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
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21
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Mukhtar NA, Ayala C, Maher JJ, Khalili M. Assessment of factors associated with pre-diabetes in HCV infection including direct and dynamic measurements of insulin action. J Viral Hepat 2012; 19:480-7. [PMID: 22676360 PMCID: PMC3375865 DOI: 10.1111/j.1365-2893.2011.01568.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although hepatitis C (HCV) is associated with diabetes, few studies have examined pre-diabetes in this population. We aimed to evaluate factors associated with pre-diabetes in HCV-infected patients, including direct measurement of insulin action. Ninety-seven non-cirrhotic, non-diabetic and HCV-infected patients underwent clinical evaluation and oral glucose tolerance testing (OGTT). Insulin sensitivity was measured directly by steady-state plasma glucose (SSPG) concentration during insulin suppression test. Early phase and total insulin secretion were determined using OGTT. Rates of pre-diabetes were as follows: 21% impaired fasting glucose (IFG), 7% impaired glucose tolerance (IGT) and 9% combined IFG/IGT. Twelve percent of Caucasians, 50% of African Americans and 70% of Latinos had pre-diabetes (P = 0.002). Patient characteristics among the glucose metabolism categories were similar except those with combined IFG/IGT had a higher body mass index (BMI) vs normal glucose tolerance (NGT) (30 vs 26 kg/m(2), P = 0.007) and lower LDL vs NGT and IGT (74, 104 and 112 mg/dL, respectively, P ≤ 0.01). On multivariable analysis, non-Caucasian race (OR 23.1, P = 0.003), BMI (OR 3.4, P = 0.02) and greater liver inflammation (OR 7.9, P = 0.03) predicted IFG, whereas non-Caucasian race (OR 14.8, P = 0.01) and SSPG (OR 1.1 per 10 units, P = 0.01) predicted IGT. Early and total insulin secretion adjusted for the degree of insulin resistance was decreased in pre-diabetes compared with NGT (P = 0.01 and P = 0.02, respectively). Pre-diabetes is highly prevalent among HCV-infected patients, and in some instances, coincides with host responses to the virus. In most cases, however, factors that are associated with pre-diabetes in HCV-infected patients are similar to those observed in the non-HCV population.
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Affiliation(s)
- Nizar A. Mukhtar
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Claudia Ayala
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Jacquelyn J. Maher
- Department of Medicine, University of California San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
| | - Mandana Khalili
- Department of Medicine, University of California San Francisco, San Francisco, CA,Liver Center, University of California San Francisco, San Francisco, CA
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22
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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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23
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Fattovich G, Baroni GS, Pasino M, Pierantonelli I, Covolo L, Ieluzzi D, Passigato N, Tonon A, Faraci MG, Guido M, Negro F. Post-load insulin resistance does not predict virological response to treatment of chronic hepatitis C patients without the metabolic syndrome. Dig Liver Dis 2012; 44:419-25. [PMID: 22277808 DOI: 10.1016/j.dld.2011.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 11/06/2011] [Accepted: 12/09/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM The role of insulin resistance in predicting virological response to therapy of chronic hepatitis C is debated. We assessed the association between basal (defined as homeostasis model assessment of insulin resistance (HOMA-IR)>2) and post-load insulin resistance (as oral glucose insulin sensitivity index<9.8 mg/kg/min) with the rapid and sustained virological responses in chronic hepatitis C. METHODS Observational prospective study of 124 treatment-naïve patients with chronic hepatitis C not fulfilling the metabolic syndrome criteria, adherent to a standard treatment with pegylated interferon alpha plus ribavirin. RESULTS Insulin resistance was detected in 50% (by HOMA-IR) and 29% (by oral glucose insulin sensitivity index) of patients. Independent predictors of rapid virologic response were hepatitis C virus (HCV) genotype 2 (odds ratio 5.66; 95% confidence interval 1.88-17.01), HCV genotype 3 (odds ratio 5.23; 95% confidence interval 1.84-14.84) and lower basal ferritin levels (odds ratio 0.99; 95% confidence interval 0.993-0.998). Independent predictors of sustained virologic response were HCV genotype 2 (odds ratio 19.54; 95% confidence interval 2.29-166.41) and HCV genotype 3 (odds ratio 3.24; 95% confidence interval 1.10-9.58). Rapid virologic response was by itself predictive of sustained virologic response (odds ratio 40.90; 95% confidence interval 5.37-311.53). CONCLUSIONS Insulin resistance, measured by both static and dynamic methods, does not predict rapid or sustained virologic response in chronic hepatitis C patients without the metabolic syndrome.
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24
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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; 35:1090-4. [PMID: 22399695 PMCID: PMC3329815 DOI: 10.2337/dc11-1837] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Insulin resistance, as measured by surrogate markers, is associated with lower response to hepatitis C virus (HCV) therapy and may improve with HCV eradication. We prospectively evaluated the impact of directly measured insulin resistance and abnormal glucose metabolism on achieving sustained virologic response (SVR) with HCV therapy and assessed whether SVR results in improved insulin sensitivity and fasting glucose. RESEARCH DESIGN AND METHODS A total of 50 noncirrhotic, nondiabetic, HCV-infected patients (27 untreated, 23 treated with pegylated interferon/ribavirin, nonrandomized) underwent clinical and histologic evaluation and 75-g oral glucose tolerance test. Insulin sensitivity was assessed directly with insulin suppression test by measuring steady-state plasma glucose (SSPG) concentration during a 240-min infusion of octreotide, glucose, and insulin. Of the subjects, 43 had at least one follow-up evaluation. RESULTS Patient characteristics were median age 48, 57% male, and 52% white. SVR was achieved in 61% (14 of 23) of treated subjects. SVR was independently associated with HCV genotypes 2 and 3 (odds ratio 8.8 [95% CI 1.2-61.7]) but was not strongly associated with insulin sensitivity. When controlling for elapsed time between measurements, being on interferon, and BMI, SSPG decreased by 36 mg/dL (-88 to 16) in those with SVR and decreased by 28 mg/dL (-93 to 38) in those without SVR, compared with the untreated group. BMI (coefficient 9.1 per 5 units; 95% CI 5.3-12.9) and interferon use (coefficient 56; 95% CI 6.8-105) were associated with SSPG. CONCLUSIONS Insulin resistance does not appear to be strongly associated with SVR. HCV therapy may improve insulin resistance regardless of virologic response; however, BMI and interferon use were clearly associated with insulin resistance.
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Affiliation(s)
- Danielle Brandman
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
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25
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García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ, Reyes-Cabello E, González-González JA, Muñoz-Espinosa LE, Vázquez-Elizondo G, Villarreal-Pérez JZ, Maldonado-Garza HJ. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012; 11:240-248. [PMID: 22345342 DOI: 10.1016/s1665-2681(19)31030-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIMS To define the prevalence and clinical characteristics of glucose metabolism disorders (GMD) in patients with compensated liver cirrhosis (LC). MATERIAL AND METHODS Fasting plasma glucose (FPG) levels were measured to 130 patients with clinically stable LC. Oral glucose tolerance tests (OGTT) and fasting plasma insulin determinations were performed to patients with normal FPG. Insulin resistance (IR) was calculated with HOMA2-IR index. GMD were classified according to FPG and OGTT tests results and to the chronologic relation between diagnosis of diabetes mellitus (DM) and LC as follows: type-2 DM (T2DM), hepatogenous diabetes (HD) and impaired glucose tolerance. Patients from all groups were compared. RESULTS The prevalence of GMD were as follows: T2DM in 25 patients (19.2%, 95% CI 12.5-25.9), HD in 28 (21.5%, 95% CI 14.5-28.5) and IGT in 36 (38.5%, 95% CI 30.1-46.7). The total of patients with GMD was 79.2% (95% CI 72.3-86.1). In 41% of cases GMD were subclinical and 48.7% of patients had IR. Patients with T2DM had a higher number of variables with significant differences compared with the other groups (more marked compared to the patients without GMD). The only differences between the patients with T2DM and HD were hypercreatininemia: 1.14 ± 0.53 vs. 0.84 ± 0.22 mg/dL (p = 0.005) and family history of DM: 8 (32%) vs. 2 (7%) (p = 0.02). CONCLUSION Almost 80% of patients with compensated LC had GMD. Half of them were subclinical. The patients with T2DM had marked clinical differences compared to patients from the other groups, particularly renal impairment.
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Affiliation(s)
- Diego García-Compeán
- Gastroenterology Service and Department of Internal Medicine, University Hospital Dr. José E. González and Medical School, Universidad Autónoma de Nuevo León, Monterrey, Mexico.
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26
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Eslam M, Aparcero R, Mousa YI, Grande L, Shaker Y, Ali A, Del Campo JA, Khattab MA, Romero-Gomez M. Insulin resistance impairs viral dynamics independently of ethnicity or genotypes. J Clin Gastroenterol 2012; 46:228-234. [PMID: 22298085 DOI: 10.1097/mcg.0b013e31822a2dc6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Data concerning the influence of insulin resistance (IR) and ethnicity on early phases of viral kinetics after initiation of peginterferon plus ribavirin in treatment-naive, chronic hepatitis C (CHC) patients are limited. METHODS A total of 263 nondiabetic CHC patients treated with peginterferon plus ribavirin were enrolled for analysis from an Egyptian and Spanish center. IR was evaluated by homeostasis model assessment (HOMA)-IR. Hepatitis C virus (HCV) RNA levels were measured at baseline, 48 hours, 2, 4, and 12 weeks after treatment initiation. Sustained virological response (SVR) was examined 24 weeks after therapy discontinuation. RESULTS Baseline HOMA-IR strongly influenced 48 hours viral dynamics. HCV-RNA decay observed at 48 hours after the first injection of peginterferon was significantly lower (0.91±0.51 log) in patients with HOMA ≥2 compared with those with HOMA <2 (1.8±0.95 log, P=0.005) this effect was independent of stage of liver fibrosis, HCV genotype, and ethnicity. These differences remained with several cutoffs such as HOMA >3 or HOMA >4. Multivariate analysis identified baseline insulin levels as the main independent variable affecting the 48-hour response in addition to baseline HCV-RNA. The difference in early viral kinetics between patients with HOMA ≥2 or <2 is associated with a significant difference in the percentage of patients achieving both rapid virological response and SVR. CONCLUSIONS IR is a major determinant of the early viral kinetic response to peginterferon plus ribavirin, which has a great impact on subsequent rapid virological response and SVR in CHC patients. This suggests that strategies to improve IR may have a positive effect on SVR and may be early monitored.
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Affiliation(s)
- Mohammed Eslam
- Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Ctra de Cadiz s/n, Sevilla, Spain
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27
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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; 55:1187-94. [PMID: 21703195 DOI: 10.1016/j.jhep.2011.03.010] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 02/16/2011] [Accepted: 03/03/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Recent studies suggested that SVR rates might be lower in HCV patients with insulin resistance (IR) than in patients without IR, but the extent of the impact of IR on treatment response has not been established. We aimed to confirm the role of IR assessed by the homoeostasis model assessment (HOMA-IR) on SVR and to determine its magnitude. METHODS We performed meta-analysis of studies evaluating the impact of IR in HCV patients treated with pegylated interferon and ribavirin. RESULTS Fourteen studies involving 2732 patients were included. SVR was less frequent in patients with IR than in patients without IR (mean difference: -19.6%, 95% CI: -29.9% to -9.4%, p<0.001). In sensitivity analyses according to HCV-1 patients, patients with IR also less frequently attained a SVR than patients without IR (mean difference: -13.0%, 95% CI: -22.6% to -3.4%, p=0.008). In addition, the baseline HOMA-IR index was lower in responders than in non-responders (mean difference: -0.92, 95% CI: -1.53 to -0.32, p<0.001). In sensitivity analyses restricted to HCV-1 patients, the baseline HOMA-IR index remained lower in responders than in non-responders (mean difference: -0.63, 95% CI: -1.13 to -0.14, p<0.001). CONCLUSIONS HCV patients with IR have a 20% lower SVR than patients without IR. The baseline HOMA-IR index is a major determinant of SVR.
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Affiliation(s)
- Pierre Deltenre
- Service d'Hépato-Gastroentérologie, Hôpital Huriez, CHRU Lille, Lille, France
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28
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Eslam M, López-Cortés LF, Romero-Gomez M. The role of insulin resistance in HIV/hepatitis C virus-coinfected patients. Curr Opin HIV AIDS 2011; 6:553-558. [PMID: 21934619 DOI: 10.1097/coh.0b013e32834bd21d] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW Insulin resistance, HIV, antiviral drugs and hepatitis C virus (HCV) infection contribute to a complex interaction involving the metabolic syndrome. The objective of this review was to explore the meaning of insulin resistance in HIV-HCV-coinfected patients and how it may impact on sustained virological response (SVR) and disease progression. RECENT FINDINGS In the HIV/HCV coinfection setting, insulin resistance seems to be associated with a reduction in rapid virological response and SVR to pegylated interferon and ribavirin, both in naive and treatment experienced patients. A recent meta-analysis demonstrated insulin resistance impairs SVR rate with an odds ratio 0.47 (95% confidence interval 0.31-0.71). However, many confounding factors may promote contradictory results. Prevalence of insulin resistance depends on surrogate markers of insulin resistance and the threshold for defining impaired insulin sensitivity. For example, homeostasis model for the assessment of insulin resistance may be influenced by both methods of insulin measurement and interpretation. Insulin sensitizers, lifestyle changes and improvement in the use of protease inhibitors should be evaluated in the management of coinfected patients. SUMMARY Insulin resistance is common finding in patients with HIV/HCV coinfection, with wide clinical consequences including progression of hepatic fibrosis and reduction in the response to antiviral treatment. Our understanding of this relationship continues to improve. More prospective studies are required to improve future management.
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Affiliation(s)
- Mohammed Eslam
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Ctra de Cadiz s/n, Spain
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29
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Abstract
Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent manner and contributes to steatosis, progression of fibrosis and resistance to interferon plus ribavirin therapy. Our understanding of HCV-induced IR has improved considerably over the years, but certain aspects concerning its evaluation still remain elusive to clinical researchers. One of the most important issues is elucidating the ideal method for assessment of IR in the setting of hepatitis C. The hyperinsulinaemic euglycaemic clamp is the gold standard method for determining insulin sensitivity, but is impractical as it is labour intensive and time-consuming. To date, all human studies except for four where IR was evaluated in the HCV setting, an estimation of IR has been used rather than direct measurements of insulin-mediated glucose uptake. The most commonly used estimation in the HCV population is the homeostasis model assessment of insulin resistance (HOMA-IR) which is calculated from a single measurement of fasting insulin and glucose. In this article, we review the use and reporting of HOMA in the literature and provide guidance on its appropriate as well as inappropriate use in the hepatitis setting.
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Affiliation(s)
- M Eslam
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
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30
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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. [PMID: 21623851 DOI: 10.1111/j.1365-2036.2011.04716.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND A higher baseline homeostasis model assessment of insulin resistance (HOMA-IR) score has sometimes predicted a poorer sustained virological response (SVR) rate to peginterferon/ribavirin therapy in treatment-naïve chronic hepatitis C patients. AIM To perform a meta-analysis to evaluate the impact of HOMA-IR on SVR in hepatitis C. METHODS Relevant studies were identified by searching Medline and EMBASE. We identified 17 publications that addressed the influence of insulin resistance on SVR. The random effect model of Der Simonian and Laird method were used for heterogeneous studies using the Meta-Disc software 1.4, Madrid, Spain. RESULTS Normal insulin sensitivity was associated with a higher rate of SVR [odds ratio (OR) 2.86 (95%CI: 1.97-4.16)] in comparison with insulin resistance. Moreover, in separate analysis by genotype selecting studies that used HOMA-IR > 2 as cut-off defining insulin resistance, SVR was higher in patients with HOMA-IR < 2 in all genotypes: HCV-1 [OR: 2.16 (95%CI: 1.51-3.08)], HCV-2&3 [OR: 3.06 (95%CI: 1.06-8.82)] and HCV-4 [OR: 6.65(95%CI: 2.51-17.61)]. Studies reporting no association between HOMA and SVR included easy-to-cure cohorts, analysed variables strongly related with insulin resistance like body mass index, steatosis, hyper γGT, age and fibrosis and reported differences in handling and interpretation of HOMA-IR. CONCLUSION Elevated HOMA-IR was associated with a lower cure rate of patients with hepatitis C treated with Peg-IFN-α/ribavirin irrespective of genotype, and the more difficult-to-treat cohort, the better the HOMA-IR prediction. HOMA-IR is, as a surrogate marker of insulin resistance, susceptible to some biases derived from both handling and interpretation.
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Affiliation(s)
- M Eslam
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla, Spain
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31
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Patel K, Thompson AJ, Chuang WL, Lee CM, Peng CY, Shanmuganathan G, Thongsawat S, Tanwandee T, Mahachai V, Pramoolsinsap C, Cho M, Han KH, Shah SR, Foster GR, Clark PJ, Pulkstenis E, Subramanian GM, McHutchison JG. Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients. J Gastroenterol Hepatol 2011; 26:1182-8. [PMID: 21410752 DOI: 10.1111/j.1440-1746.2011.06722.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM The role of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C infection (CHC) has yielded conflicting data and few studies have been performed in Asian-region populations. We retrospectively investigated the relationship between host metabolic variables, including IR and hepatic steatosis, to hepatic fibrosis in Asian-region CHC genotype 2/3 patients. METHODS A total of 303 treatment-naïve Asian-region patients with CHC genotype 2/3 were enrolled in a multicenter phase 3 study of albinterferon alfa-2b plus ribavirin for 24 weeks. IR was defined as Homeostasis Model for Assessment of IR (HOMA-IR) > 2. Baseline liver biopsy was evaluated by a single expert histopathologist. Post hoc subgroup logistic regression modeling selected for independent variables associated with significant fibrosis (METAVIR stage F2-F4). RESULTS Insulin resistance was available in 263 non-diabetic Asian-region patients (hepatitis C virus-2 [HCV-2] = 171, HCV-3 = 92), and 433 non-Asian region patients (407 "Caucasian"); METAVIR fibrosis prevalence F0-F1 (minimal fibrosis)= 201 (77%) and F2-F4 (significant fibrosis) = 59 (23%), and steatosis prevalence of grade 0 = 169 (65%), grade 1 = 64 (25%), grade 2/3 = 27 (10%). Median HOMA-IR was 1.8 (interquartile range: 1.2-2.7); 100 (38%) patients had HOMA-IR > 2. Factors independently associated with significant fibrosis included HOMA-IR (odds ratio [OR]= 8.42), necro-inflammatory grade (OR = 3.17), age (OR = 1.07) and serum total cholesterol levels (OR = 0.008). This was similar to non-Asian region patients, but steatosis was not associated with significant fibrosis in either cohort. CONCLUSIONS In this subgroup study of Asian-region HCV genotype 2 or 3 patients, insulin resistance, along with age, cholesterol levels and necro-inflammation, but not steatosis may be associated with significant hepatic fibrosis.
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Affiliation(s)
- Keyur Patel
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.
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Clément S, Peyrou M, Sanchez-Pareja A, Bourgoin L, Ramadori P, Suter D, Vinciguerra M, Guilloux K, Pascarella S, Rubbia-Brandt L, Negro F, Foti M. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology 2011; 54:38-49. [PMID: 21465511 DOI: 10.1002/hep.24340] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) perturbs the host's lipid metabolism and often results in hepatic steatosis. In nonalcoholic fatty liver disease, the intrahepatic down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a critical mechanism leading to steatosis and its progression toward fibrosis and hepatocellular carcinoma. However, whether an HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the livers of patients infected with HCV genotype 1 or 3 with or without steatosis. The role of PTEN in the HCV-induced biogenesis of lipid droplets was further investigated in vitro with hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression was down-regulated at the posttranscriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, down-regulated PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN messenger RNA translation. PTEN down-regulation promoted in turn a reduction of insulin receptor substrate 1 (IRS1) expression. Interestingly, either PTEN or IRS1 overexpression prevented the development of large lipid droplets, and this indicates that the down-regulation of both PTEN and IRS1 is required to affect the biogenesis of lipid droplets. However, IRS1 knockdown per se did not alter the morphology of lipid droplets, and this suggests that other PTEN-dependent mechanisms are involved in this process. CONCLUSION The down-regulation of PTEN and IRS1 is a critical event leading to the HCV genotype 3a-induced formation of large lipid droplets in hepatocytes.
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Affiliation(s)
- Sophie Clément
- Division of Clinical Pathology, University Hospital, Geneva, Switzerland
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Petta S, Di Marco V, Di Stefano R, Cabibi D, Cammà C, Marchesini G, Craxì A. TyG index, HOMA score and viral load in patients with chronic hepatitis C due to genotype 1. J Viral Hepat 2011; 18:e372-80. [PMID: 21692950 DOI: 10.1111/j.1365-2893.2011.01439.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The triglycerides × glucose (TyG) index is a recently proposed surrogate marker of insulin resistance (IR), calculated from fasting plasma triglyceride and glucose concentrations. We tested the host and viral factors associated with Tyg and homeostasis model assessment (HOMA) scores, comparing their associations with histological features and with sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C(G1CHC). Three hundred and forty consecutive patients with G1CHC were considered. All had a liver biopsy scored by one pathologist for staging and grading (Scheuer), and graded for steatosis, which was considered moderate-severe if ≥30%. Anthropometric and metabolic measurements, including IR measured by both HOMA and TyG, were registered. By linear regression analysis, TyG was independently associated with waist circumference (WC), total cholesterol, presence of arterial hypertension, Log10 HCV-RNA and steatosis. Similarly, WC and steatosis were significantly associated with HOMA. Older age (OR, 1.036; 95%CI, 1.004-1.070, P = 0.02), higher WC (1.031; 1.004-1.060; P = 0.02) and higher TyG (11.496; 3.163-41.784; P < 0.001) were linked to moderate-to-severe steatosis (≥30%) by multiple logistic regression analysis. When TyG was replaced by HOMA-IR in the model, the latter remained significantly associated with steatosis ≥30% (1.237; 1.058-1.448; P = 0.008). Receiver operating characteristic curves showed a similar performance of TyG (AUC 0.682) and HOMA-IR (AUC 0.699) in predicting moderate-severe steatosis. No independent associations were found between both TyG and HOMA and fibrosis or SVR. In patients with G1CHC , TyG, an easy-to-calculate and low-cost surrogate marker of IR, is linked to liver steatosis and shows an independent association with viral load.
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Affiliation(s)
- S Petta
- Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Palermo, Italy.
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Fattovich G, Covolo L, Bibert S, Askarieh G, Lagging M, Clément S, Malerba G, Pasino M, Guido M, Puoti M, Gaeta GB, Santantonio T, Raimondo G, Bruno R, Bochud PY, Donato F, Negro F. IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C. Aliment Pharmacol Ther 2011; 33:1162-72. [PMID: 21443535 DOI: 10.1111/j.1365-2036.2011.04635.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. AIM To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC). METHODS Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. RESULTS Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR=0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age <40 years (OR=4.79; 1.50-15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR=6.26; 1.98-19.74) and age <40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67). CONCLUSIONS In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.
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Affiliation(s)
- G Fattovich
- Clinic of Gastroenterology, Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, Verona, Italy.
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