Relationship Between Steatosis, Inflammation, and Fibrosis in Chronic Hepatitis C: A Meta-Analysis of Individual Patient Data
2006; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2006.03.014
ISSN1528-0012
AutoresGioacchino Leandro, Alessandra Mangia, Jason M. Hui, Paolo Fabris, Laura Rubbia‐Brandt, Guido Colloredo, Luigi Elio Adinolfi, Tarik Asselah, Julie R. Jonsson, Antonina Smedile, Norah A. Terrault, Valerio Pazienza, Maria Teresa Giordani, Emiliano Giostra, Aurelio Sonzogni, Giuseppe Ruggiero, Patrick Marcellin, Elizabeth E. Powell, Jacob George, Francesco Negro,
Tópico(s)Hepatitis B Virus Studies
ResumoBackground & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC. Background & Aims: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. Methods: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. Results: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. Conclusions: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC. Chronic hepatitis C (CHC) affects more than 150 million individuals worldwide.1Niederau C. Lange S. Heintges T. Erhardt A. Buschkamp M. Hurter D. et al.Prognosis of chronic hepatitis C results of a large, prospective cohort study.Hepatology. 1998; 28: 1687-1695Google Scholar Up to 20% of patients will develop long-term sequelae, such as cirrhosis and hepatocellular carcinoma, over a period of 20 years. However, disease progression is highly variable. Several factors have been acknowledged to influence the rate of disease progression in CHC. These include age at infection,2Poynard T. Bedossa P. Opolon P. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsNatural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997; 349: 825-832Google Scholar, 3Seeff L.B. Buskell-Bales Z. Wright E.C. Durako S.J. Alter H.J. Iber F.L. et al.Long-term mortality after transfusion-associated non-A, non-B hepatitis.N Engl J Med. 1992; 327: 1906-1911Google Scholar, 4Vogt M. Lang T. Frosner G. Klingler C. Sendl A.F. Zeller A. et al.Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.N Engl J Med. 1999; 341: 866-870Google Scholar, 5Kenny-Walsh E. Irish Hepatology Research GroupClinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.N Engl J Med. 1999; 340: 1228-1233Google Scholar, 6Wiese M. Berr F. Lafrenz M. Porst H. Oesen U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany a 20-year multicenter study.Hepatology. 2000; 32: 91-96Google Scholar sex,2Poynard T. Bedossa P. Opolon P. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsNatural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997; 349: 825-832Google Scholar, 3Seeff L.B. Buskell-Bales Z. Wright E.C. Durako S.J. Alter H.J. Iber F.L. et al.Long-term mortality after transfusion-associated non-A, non-B hepatitis.N Engl J Med. 1992; 327: 1906-1911Google Scholar, 5Kenny-Walsh E. Irish Hepatology Research GroupClinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.N Engl J Med. 1999; 340: 1228-1233Google Scholar, 6Wiese M. Berr F. Lafrenz M. Porst H. Oesen U. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany a 20-year multicenter study.Hepatology. 2000; 32: 91-96Google Scholar prolonged alcohol abuse,2Poynard T. Bedossa P. Opolon P. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsNatural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997; 349: 825-832Google Scholar, 5Kenny-Walsh E. Irish Hepatology Research GroupClinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.N Engl J Med. 1999; 340: 1228-1233Google Scholar, 7Ostapowicz G. Watson K.J. Locarnini S.A. Desmond P.V. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.Hepatology. 1998; 27: 1730-1735Google Scholar and co-infections with the hepatitis B virus8Mathurin P. Thibault V. Kadidja K. Ganne-Carrie N. Moussalli J. El Younsi M. et al.Replication status and histological features of patients with triple (B, C, D) and dual (B, C) hepatic infections.J Viral Hepat. 2000; 7: 15-22Google Scholar or the human immunodeficiency virus.9Benhamou Y. Bochet M. Di Martino V. Charlotte F. Azria F. Coutellier A. et al.The Multivirc GroupLiver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients.Hepatology. 1999; 30: 1054-1058Google Scholar Furthermore, liver steatosis may influence fibrogenesis in CHC, although some uncertainty exists as to whether this effect is significant in all10Hourigan L.F. Macdonald G.A. Purdie D. Whitehall V.H. Shorthouse C. Clouston A. et al.Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.Hepatology. 1999; 29: 1215-1219Google Scholar, 11Rubbia-Brandt L. Quadri R. Abid K. Giostra E. Male P.J. Mentha G. et al.Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3.J Hepatol. 2000; 33: 106-115Google Scholar, 12Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Google Scholar or only some subgroups of patients, such as those infected with genotype 313Castera L. Hezode C. Roudot-Thoraval F. Bastie A. Zafrani E.S. Pawlotsky J.M. et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.Gut. 2003; 52: 288-292Google Scholar, 14Westin J. Nordlinder H. Lagging M. Norkrans G. Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients.J Hepatol. 2002; 37: 837-842Google Scholar, 15Rubbia-Brandt L. Fabris P. Paganin S. Leandro G. Male P.-J. Giostra E. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Google Scholar or 1.16Patton H. Patel K. Behling C. Bylund D. Blatt L.M. Vallée M. et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.J Hepatol. 2004; 40: 484-490Google Scholar However, the discordant results reported in the literature may be explained by differences in the clinical features of the population under study, patients’ recruitment biases, varying inclusion/exclusion criteria, or ethnic factors. To understand whether steatosis may affect liver disease progression in CHC, we performed a multivariable, stepwise logistic regression analysis on all individual patient data included in 10 databases from different countries. To identify associations that were independent of local selection factors, we included the center as a covariate in the analysis. Collection of CHC patient data was performed at 10 centers from Italy, Switzerland, France, Australia, and the United States. Patients were recruited consecutively for clinical management of their hepatitis C virus (HCV) infection, including the assessment of the indication to antiviral therapy, but were not involved primarily in clinical treatment trials. To be included in the HCV Meta-Analysis (on) Individual patients’ Data Study Group database, patients had to fulfill the following basic criteria: HCV infection (ie, detectable HCV-RNA level in serum by qualitative polymerase chain reaction assay) documented for at least 6 months, available liver biopsy specimen, completeness of clinical records (see later for data selection), and age older than 18 years. The following data were collected at the time of the liver biopsy examination: sex, age, notion of ongoing alcohol abuse (>40 g/day at the time of liver biopsy examination or within the 6 months preceding the liver biopsy examination, based on self-reporting) or of past alcohol abuse (>40 g/day for >5 years, again based on self-reporting), history of diabetes (according to the American Diabetes Association definition),17Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1997; 20: 1183-1197Google Scholar HCV genotype, and complete liver histologic records with activity, fibrosis, and steatosis scores (see later). Patients with HCV genotype 5 or 6 (because of their scarcity), or with simultaneous infection with the hepatitis B virus (hepatitis B surface antigen–positive in serum), the immunodeficiency virus, or those who were immunosuppressed were excluded from the study. All data available at the different centers first were collected in Excel (Excel 2000; Microsoft Corporation, Redmond, WA) files with standardized entries and then entered in a centralized database. The ethnic background was collected initially but later was excluded from the analysis because 93% of subjects were Caucasian. The serum HCV-RNA level was not included because collection procedures at the various centers were too different and because there are no data clearly suggesting an association between viral load and fibrosis stage. The estimated duration of HCV infection was not included either because there was no sufficient consistency between centers on how these data were collected and at some of the centers—mostly in Italy—as many as 50% of patients had no identifiable event at history that plausibly could account for infection with HCV. This study was approved by all local ethics committees and was conducted in conformity with the Helsinki declaration. Assays were performed on plasma or serum samples collected by venipuncture after overnight fasting. HCV genotyping was performed with a second-generation reverse-hybridization line probe assay (Inno-Lipa HCV II; Innogenetics, Zwijndrecht, Belgium). A liver biopsy specimen was obtained from all patients for diagnostic purposes. Liver specimens were formalin-fixed and paraffin-embedded for histologic evaluation. Histologic diagnoses were established according to internationally accepted criteria18Scheuer P.J. Classification of chronic viral hepatitis a need for reassessment.J Hepatol. 1991; 13: 372-374Google Scholar, 19Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Google Scholar, 20Bedossa P. Poynard T. The METAVIR Cooperative Study GroupAn algorithm for the grading of activity in chronic hepatitis C.Hepatology. 1996; 24: 289-293Google Scholar by experienced pathologists. Because the necroinflammatory activity and fibrosis were not scored uniformly at the various centers (except when scored as absent or present), we considered activity and fibrosis as binary variables (ie, either absent or present). This also eliminated potential flaws associated with direct conversion of scores evaluated by the most frequently used grading and staging methods in which a different emphasis often is put on different histologic features. This approach significantly reduced the need for a centralized rereading of the liver biopsy specimens, which would have been compulsory if we had used a more detailed categorization. For this same reason, histologic features peculiar to nonalcoholic steatohepatitis were not considered in this analysis. Thus, activity was scored as absent in the following situations: (1) grade 0 or 1 of necroinflammatory activity according to Scheuer’s18Scheuer P.J. Classification of chronic viral hepatitis a need for reassessment.J Hepatol. 1991; 13: 372-374Google Scholar scoring system; (2) absent (A0) or mild (A1) periportal/periseptal hepatitis, absence of confluent necrosis (B0), absence (C0) or presence of 1 focus or less (per 10× objective) of focal (C1) necrosis/focal inflammation/apoptosis independently of the presence/severity of periportal inflammation, according to the scoring system of Ishak et al19Ishak K. Baptista A. Bianchi L. Callea F. De Groote J. Gudat F. et al.Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699Google Scholar; or (3) score A0 according to the Metavir system.20Bedossa P. Poynard T. The METAVIR Cooperative Study GroupAn algorithm for the grading of activity in chronic hepatitis C.Hepatology. 1996; 24: 289-293Google Scholar Fibrosis was scored as absent in case of stage 0 according to the 3 scoring systems mentioned previously. Steatosis was graded as absent or minimal when affecting less than 5% of hepatocytes, and present when involving more than 5%. Univariate analysis was by the χ2 test for frequencies and by the Mann–Whitney rank-sum test for means. For multivariable analysis, when steatosis was used as the dependent variable (ie, absence vs presence of steatosis independent of its severity), we considered as possibly independent variables: sex, age, body mass index (BMI), ongoing alcohol use, history of diabetes, HCV genotype (individually considered), histologic activity (absent/minimal vs present), and fibrosis (absent vs present). When fibrosis was used as the dependent variable (ie, absent or present), we considered as independent variables: sex, age, BMI, past alcohol abuse, HCV genotype (individually considered), histologic activity (absent/minimal vs present), and steatosis (absent/minimal vs present). Both age and BMI were treated as continuous variables, with the odds ratios expressed as units per year and units per 1 kg/m2, respectively. In all multivariable analyses, the center was entered into the model. The maximum likelihood method was used for entering or removing variables at each step. All the parameters taken into account were the default parameters of the statistical software package (Bio Medical Data Processing, Dynamic version 7.0; Los Angeles, CA) used for the calculations. In particular, this software uses a P value of less than .10 for entering and a P value of greater than .15 for removing variables. The baseline characteristics of the 3068 patients included in the study population are shown in Table 1. There were 1999 men (65.2%) with a mean age of 44.7 ± 11.8 years, and an average BMI of 25.4 ± 3.9 kg/m2. According to the previously described definitions, alcohol abuse at the time of liver biopsy examination was reported by 370 persons (12.1%), whereas 737 (24.0%) had a history of long-lasting excess alcohol drinking in the past. Diabetes was present in 194 patients (6.3%). Overall, HCV genotype was 1 in 1694 subjects (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). There were 1561 (50.9%) patients with any degree of liver steatosis, whereas 2688 had fibrosis (87.6%).Table 1Baseline Clinical and Virologic Features of 3068 CHC Patients (by Center)CenternAge (x ± SD)% malesBMI% current alcohol abuse% past alcohol abuse% diabetesHCV genotype (%)1234San Giovanni Rotondo60549.9 ± 12.860.326.6 ± 3.027.420.87.4331 (54.7)185 (30.6)65 (10.7)24 (4.0)Naples28247.3 ± 11.863.525.3 ± 3.01.815.23.2180 (63.8)70 (24.8)29 (10.3)3 (1.1)Bergamo30044.6 ± 12.368.725.0 ± 3.716.724.07.0145 (48.3)96 (32.0)57 (19.0)2 (.7)Vicenza35139.6 ± 12.376.623.6 ± 3.15.721.73.4169 (48.1)77 (21.9)90 (25.6)15 (4.3)Torino19846.0 ± 11.664.624.7 ± 2.77.615.21.5121 (61.1)26 (13.1)34 (17.2)17 (8.6)Genève30345.8 ± 11.168.324.3 ± 3.59.627.412.5159 (52.5)39 (12.9)80 (26.4)25 (8.3)Paris26643.5 ± 10.150.424.1 ± 3.614.712.810.2160 (60.2)22 (8.3)53 (19.9)31 (11.7)Sydney37941.3 ± 9.668.326.8 ± 5.04.035.46.9180 (47.5)25 (6.6)151 (39.8)23 (6.1)Brisbane25239.2 ± 8.169.825.7 ± 4.311.941.72.8139 (55.2)10 (4.0)101 (40.1)2 (.8)San Francisco13247.8 ± 8.157.627.6 ± 5.6.825.84.5110 (83.3)13 (9.8)9 (6.8)0Total306844.7 ± 11.865.225.4 ± 3.912.124.06.31694 (55.2)563 (18.4)669 (21.8)142 (4.6) Open table in a new tab Table 2 reports the results of the univariate analysis using steatosis and fibrosis, respectively, as dependent variables.Table 2Univariate Analysis of the Factors Associated With Liver Steatosis or Fibrosis in 3068 CHC PatientsVariableAbsentPresentPaMann–Whitney rank-sum test of Pearson χ2 test as appropriate.Steatosis Sex (male)9381061.009 Mean age (± SD)44.3 ± 12.445.1 ± 11.2.0998 Mean BMI (± SD)24.9 ± 3.526.0 ± 4.2<.001 Ongoing alcohol abuse (%)179 (5.8)191 (6.2).7661 History of alcohol abuse (%)382 (25.3)455 (29.1).0187 History of diabetes (%)68 (4.5)126 (8.1)<.001 HCV genotype (%) 1944 (62.6)750 (48.0) 2298 (19.8)265 (17.0)<.001 3195 (12.9)474 (30.4) 470 (4.6)72 (4.6) Histologic activity (%) Absent/minimal451 (29.9)333 (21.3) Present1056 (70.1)1228 (78.7)<.001 Fibrosis (%) Absent246 (16.3)134 (8.6) Present1261 (83.7)1427 (91.4)<.001Fibrosis Sex (male)232 (61.1)1767 (65.7).07 Mean age (± SD)39.0 ± 11.145.5 ± 11.7<.001 Mean BMI (± SD)24.6 ± 4.125.5 ± 3.9<.001 Ongoing alcohol abuse (%)27 (7.1)343 (12.8).0015 History of alcohol abuse (%)81 (21.3)756 (28.1).0052 History of diabetes (%)10 (2.6)184 (6.8).0016 HCV genotype (%) 1199 (52.4)1495 (55.6) 267 (17.6)496 (18.5).2479 390 (23.7)579 (21.5) 424 (6.3)118 (4.4) Histologic activity (%) Absent/minimal204 (53.7)580 (21.6) Present176 (46.3)2108 (78.4)<.001 Steatosis (%)134 (35.3)1427 (53.1)<.001NOTE. Steatosis was absent in 1507 patients and present in 1561 patients. Fibrosis was absent in 380 patients and present in 2688 patients.a Mann–Whitney rank-sum test of Pearson χ2 test as appropriate. Open table in a new tab NOTE. Steatosis was absent in 1507 patients and present in 1561 patients. Fibrosis was absent in 380 patients and present in 2688 patients. Patients with liver steatosis were more likely to be men (P = .009), have a higher BMI (P < .001), a history of past alcohol use (P = .0187), diabetes (P < .001), infection with HCV genotype 3 (P < .001), liver inflammation (P < .001), and fibrosis (P < .001). Fibrosis was associated with age (P < .001), BMI (P < .001), alcohol use both ongoing (P = .0015) and past (P = .0052), a history of diabetes (P = .0016), liver inflammation (P < .001), and steatosis (P < .001). Table 3 shows the results of multivariable logistic regression performed on all 3068 patients. Steatosis was associated with HCV genotype 3 (P < .001), fibrosis (P < .001), diabetes (P = .007), hepatic inflammation (P = .001), ongoing alcohol abuse (P = .009), a high BMI (P < .001), and older age (P < .001) (Table 4).Table 3Multivariate Analysis of the Factors Independently Associated With Liver Steatosis or Fibrosis in 3068 CHC PatientsOdds ratio95% Confidence intervalPLiver steatosis Genotype 34.243.38–5.34<.001 Fibrosis1.651.26–2.16<.001 Diabetes1.621.15–2.3.007 Activity1.411.15–1.72.001 Alcohol abuse1.411.09–1.83.009 BMI1.121.10–1.15<.001 Age1.021.01–1.03<.001Fibrosis Activity5.334.02–7.08<.001 Male sex1.921.48–2.49.001 Steatosis1.661.27–2.18<.001 Age1.041.02–1.05<.001 Genotype 2.688.483–.981.083 Open table in a new tab Table 4Multivariate Analysis of the Factors Independently Associated With Liver Steatosis or Fibrosis in 1694 CHC Patients Infected with Genotype 1Odds ratio95% confidence intervalPLiver steatosis Fibrosis1.701.17–2.48<.001 Activity1.551.18–2.03.001 BMI1.121.09–1.16<.001 Age1.021.01–1.03<.001Fibrosis Activity4.352.96–6.41<.001 Diabetes4.521.07–19.1.011 Male sex1.791.27–2.53.002 Steatosis1.721.19–2.51.001 Age1.041.03–1.06<.001 Open table in a new tab When hepatic fibrosis was considered as the dependent variable its presence was associated with greater histologic activity (P < .001), male sex (P = .001), the presence of steatosis (P < .001), and older age (P < .001), whereas a negative association was observed for infection with HCV genotype 2 (odds ratio, .688; 95% confidence interval, .483–.981; P = .083). All associations then were evaluated after stratification according to viral genotype. In genotype 1–infected patients (n = 1694), steatosis was associated with a higher BMI (P < .001), older age (P < .001), greater fibrosis (P < .001), and histologic activity (P = .001) (Table 4), whereas fibrosis was associated with histologic activity (P < .001), older age (P < .001), hepatic steatosis (P = .001), male sex (P = .002), and diabetes (P = .011) (Table 4). In genotype 2–infected patients (n = 563), steatosis was associated with older age (P < .001), a higher BMI (P < .001), and diabetes (P = .022), whereas fibrosis was associated only with the presence of significant histologic activity (P < .001) (Table 5).Table 5Multivariate Analysis of the Factors Independently Associated With Liver Steatosis or Fibrosis in 563 CHC Patients Infected With Genotype 2Odds ratio95% confidence intervalPLiver steatosis Diabetes2.451.13–5.32.022 BMI1.121.05–1.19<.001 Age1.031.01–1.05<.001Fibrosis Activity4.522.23–9.18<.001 Open table in a new tab In genotype 3–infected patients (n = 1694), steatosis was associated with age (P = .053), a high BMI (P < .001), and current alcohol abuse (P = .026), whereas fibrosis was associated with histologic activity (P < .001) and age (P = .003) (Table 6).Table 6Multivariate Analysis of the Factors Independently Associated With Liver Steatosis or Fibrosis in 669 CHC Patients Infected With Genotype 3Odds ratio95% confidence intervalPLiver steatosis Alcohol abuse1.921.04–3.53.026 BMI1.141.07–1.21<.001 Age1.021.00–1.05.053Fibrosis Activity11.15.98–20.7<.001 Age1.051.01–1.09.003 Open table in a new tab Finally, in genotype 4–infected patients (n = 142), no factors were associated independently with steatosis, whereas fibrosis was associated with histologic activity (odds ratio, 4.11; 95% confidence interval, 1.06 – 16.0; P = .015). Patients then were divided according to BMI into 3 categories: lean persons (ie, having a BMI 30 kg/m2). The results of the multivariable analyses performed on these 3 subgroups are presented in Tables 7–9. In lean patients (n = 1481), steatosis was associated with HCV genotype 3 (P < .001), older age (P < .001), histologic activity (P < .001), current alcohol abuse (P < .001), fibrosis (P < .001), diabetes (P = .011), and a greater BMI (P = .048). In this subgroup, fibrosis was associated with histologic activity (P < .001), steatosis (P < .001), older age (P = .008), and male sex (P = .015) (Table 7). In nonobese overweight patients (n = 1287), steatosis was associated with HCV genotype 3 (P < .001), older age (P < .001), and a higher BMI (P = .001), whereas fibrosis was associated with histologic activity (P < .001), older age (P = .008), and male sex (P = .015) (Table 8). Finally, in obese patients (n = 300), steatosis was associated with HCV genotype 3 (P = .002) and a higher BMI (P = .006), whereas fibrosis was associated with older age (P < .001) (Table 9).Table 7Multivariate Analysis of the Factors Associated Independently With Liver Steatosis or Fibrosis in 1481 Lean (BMI < 25) CHC PatientsOdds ratio95% confidence intervalPLiver steatosis Genotype 34.563.38–6.16<.001 Fibrosis1.691.16–2.47<.001 Diabetes2.091.15–3.82.011 Activity1.691.16–2.47<.001 Alcohol abuse2.321.53–3.53<.001 BMI1.071.00–1.15.048 Age1.021.01–1.04<.001Fibrosis Activity6.494.35–9.68<.001 Male sex1.911.34–2.71.015 Steatosis1.611.10–2.34<.001 Age1.021.01–1.04.008 Open table in a new tab Table 8Multivariate Analysis of the Factors Associated Independently With Liver Steatosis or Fibrosis in 1287 Nonobese, Overweight (BMI 25–30) CHC PatientsOdds ratio95% confidence intervalPLiver steatosis Genotype 33.942.65–5.86<.001 BMI1.161.06–1.27.001 Age1.021.01–1.04<.001Fibrosis Activity4.903.08–7.79<.001 Male sex1.911.19–3.06.073 Past alcohol abuse1.691.05–2.73.012 Age1.051.03–1.07<.001 Open table in a new tab Table 9Multivariate Analysis of the Factors Associated Independently With Liver Steatosis or Fibrosis in 300 Obese (BMI > 30) CHC PatientsOdds ratio95% confidence intervalPLiver steatosis Genotype 35.941.94–18.2.002 BMI1.141.03–1.26.006Fibrosis Age1.081.08–1.08<.001 Open table in a new tab Progression of CHC depends significantly on host and environmental factors. Given that currently available antiviral regimens induce a sustained virologic response in only approximately 60% of patients, and that individuals with advanced liver disease may not benefit from therapy, medical interventions often are limited to correcting cofactors associated with liver-related morbidity. Steatosis has been suggested as an important cofactor for liver fibrosis. However, there is not a clear consensus on the relationship between steatosis and fibrosis. Some studies have reported an independent association between steatosis and fibrosis for all patients with CHC, whereas others have provided evidence that this relationship holds only for certain subgroups (ie, those infected with HCV genotype 116Patton H. Patel K. Behling C. Bylund D. Blatt L.M. Vallée M. et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.J Hepatol. 2004; 40: 484-490Google Scholar or 313Castera L. Hezode C. Roudot-Thoraval F. Bastie A. Zafrani E.S. Pawlotsky J.M. et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.Gut. 2003; 52: 288-292Google Scholar, 14Westin J. Nordlinder H. Lagging M. Norkrans G. Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients.J Hepatol. 2002; 37: 837-842Google Scholar, 15Rubbia-Brandt L. Fabris P. Paganin S. Leandro G. Male P.-J. Giostra E. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Google Scholar, 16Patton H. Patel K. Behling C. Bylund D. Blatt L.M. Vallée M. et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.J Hepatol. 2004; 40: 484-490Google Scholar). A few reports have failed to confirm any association between steatosis and hepatic fibrosis.21Asselah T. Boyer N. Guimont M.C. Cazals-Hatem D. Tubach F. Nahon K. et al.Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C.Gut. 2003; 52: 1638-1643Google Scholar, 22Hui J.M. Sud A. Farrell G.C. Bandara P. Byth K. Kench J.G. et al.Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression.Gastroenterology. 2003; 125: 1695-1705Google Scholar Because these conflicting conclusions may depend on the varying baseline features of individual patients (inclusion and exclusion criteria, age and viral genotype distribution, proportion of cirrhotic patients), we pooled patients’ data from 10 databases from various centers around the world (many of whom were involved in the aforementioned studies) and conducted a meta-analysis of individual patient data. We are well aware of the limitations inherent in this kind of analysis, for example, the impossibility of properly converting the varying activity and fibrosis scores into a uniform scoring system, the lack of homogeneous data on viral load, or of the full appreciation of the impact of disease duration. Despite these limitations, our multivariate regression identified steatosis as associated with fibrosis, and this effect was independent of the participating center. The association also held for some large subgroups of patients, that is, those with genotype 1 or with a BMI less than 25 kg/m2. The conclusions, although partly conflicting with those obtained by similar analyses performed at the level of single centers (including some considered in the present study15Rubbia-Brandt L. Fabris P. Paganin S. Leandro G. Male P.-J. Giostra E. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Google Scholar, 21Asselah T. Boyer N. Guimont M.C. Cazals-Hatem D. Tubach F. Nahon K. et al.Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C.Gut. 2003; 52: 1638-1643Google Scholar, 23Fabris P. Floreani A. Carlotto A. Giordani M.T. Baldo V. Stecca C. et al.Alcohol is an important co-factor for both steatosis and fibrosis in Northern Italian patients with chronic hepatitis C.J Hepatol. 2004; 41: 644-651Abstract Full Text Full Text PDF Scopus (22) Google Scholar), are not necessarily incompatible with one another. Our large dataset, however, allowed us to enter the center as a variable into the analyses, the conclusions of which are therefore independent of the population characteristics at each participating location. Some other results worthy of comment include (1) the strong association between steatosis and genotype 3 (observed in all subgroups including the 300 obese patients and confirming previous work)11Rubbia-Brandt L. Quadri R. Abid K. Giostra E. Male P.J. Mentha G. et al.Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3.J Hepatol. 2000; 33: 106-115Google Scholar, 12Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Google Scholar, 13Castera L. Hezode C. Roudot-Thoraval F. Bastie A. Zafrani E.S. Pawlotsky J.M. et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.Gut. 2003; 52: 288-292Google Scholar, 14Westin J. Nordlinder H. Lagging M. Norkrans G. Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients.J Hepatol. 2002; 37: 837-842Google Scholar, 15Rubbia-Brandt L. Fabris P. Paganin S. Leandro G. Male P.-J. Giostra E. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Google Scholar, 16Patton H. Patel K. Behling C. Bylund D. Blatt L.M. Vallée M. et al.The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.J Hepatol. 2004; 40: 484-490Google Scholar; (2) the association between fibrosis and histologic activity in all 4 viral genotypes examined (see later); and (3) the observation that patients with genotype 2 had less fibrosis. Although the latter was not found in the univariate analysis (ie, presence and level of activity in these patients were not different from those found in patients with other genotypes), suggesting a possible statistical artifact, we consider that it may be worth further study because a possible association between genotype 2 and slower disease progression was suggested in an earlier report.24Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G. Bergami N. et al.Histological and virological features and follow-up of hepatitis C virus carriers with normal aminotransferase levels the Italian prospective study of the asymptomatic C carriers (ISACC).J Hepatol. 2002; 37: 117-123Google Scholar Assuming that the steatosis/fibrosis association entails a causative link between fatty liver and fibrogenesis, proper clinical management should address the pathogenesis of a fatty liver and/or the mechanisms that make steatosis a fibrogenic risk factor. According to our data the association holds essentially for genotype 1–infected patients, in whom fat accumulation is not determined by HCV replication, as shown by the total or partial lack of a response to antivirals.25Kumar D. Farrell G.C. Fung C. George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes reversal of hepatic steatosis after sustained therapeutic response.Hepatology. 2002; 36: 1266-1272Google Scholar, 26Poynard T. Ratziu V. McHutchison J. Manns M. Goodman Z. Zeuzem S. et al.Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C.Hepatology. 2003; 38: 75-85Google Scholar Conversely, in these same persons, a correlation has been established between the severity of steatosis and metabolic features such as BMI,12Adinolfi L.E. Gambardella M. Andreana A. Tripodi M.F. Utili R. Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity.Hepatology. 2001; 33: 1358-1364Google Scholar and such an association was confirmed by our analysis. Thus, correction of an increased BMI should be advised strongly in patients with CHC, especially those with advanced fibrosis. The beneficial effect of body-weight reduction and physical fitness on liver disease activity already has been reported27Hickman I.J. Jonsson J.R. Prins J.B. Ash S. Purdie D.M. Clouston A.D. et al.Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life.Gut. 2004; 53: 413-419Google Scholar, 28Hickman I.J. Clouston A.D. Macdonald G.A. Purdie D.M. Prins J.B. Ash S. et al.Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C.Gut. 2002; 51: 89-94Google Scholar in persons with CHC. Likewise, other cofactors including alcohol consumption2Poynard T. Bedossa P. Opolon P. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groupsNatural history of liver fibrosis progression in patients with chronic hepatitis C.Lancet. 1997; 349: 825-832Google Scholar and possibly cigarette smoking29Pessione F. Ramond M.J. Njapoum C. Duchatelle V. Degott C. Erlinger S. et al.Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.Hepatology. 2001; 34: 121-125Google Scholar are amenable to medical management, with beneficial effects on liver disease progression. It is noteworthy that steatosis was not associated with fibrosis in patients who were overweight or obese, suggesting that the link may be indirect and conditional on other cofactors. We suggest that, to explain the relationship between steatosis, fibrosis, and metabolic factors, a prominent role is played by liver inflammation. This conclusion is based primarily on the observation that (1) the presence of necroinflammatory activity was associated independently with fibrosis and steatosis, both overall and in the 2 subgroups (ie, patients with genotype 1 and in lean patients [BMI <25 kg/m2]), and that (2) whenever the analysis addressed the factors predicting steatosis, a lack of association with fibrosis was paralleled by a lack of association with activity. We propose that the link between hepatic steatosis and fibrosis is indirect, perhaps through the induction of proinflammatory and hence profibrotic mediators such as tumor necrosis factor, free fatty acids, osteopontin, and interleukin-6. Thus, hepatic (and/or peripheral) steatosis may render the liver more vulnerable to injury, inflammation,30Lonardo A. Adinolfi L.E. Loria P. Carulli N. Ruggiero G. Day C.P. Steatosis and hepatitis C virus mechanisms and significance for hepatic and extrahepatic disease.Gastroenterology. 2004; 126: 586-597Google Scholar and apoptosis.31Walsh M.J. Vanags D.M. Clouston A.D. Richardson M.M. Purdie D.M. Jonsson J.R. et al.Steatosis and liver cell apoptosis in chronic hepatitis C a mechanism for increased liver injury.Hepatology. 2004; 39: 1230-1238Google Scholar In a recent study, CHC without steatosis was not associated with stellate cell activation or fibrosis.31Walsh M.J. Vanags D.M. Clouston A.D. Richardson M.M. Purdie D.M. Jonsson J.R. et al.Steatosis and liver cell apoptosis in chronic hepatitis C a mechanism for increased liver injury.Hepatology. 2004; 39: 1230-1238Google Scholar In contrast, in the presence of steatosis, there was an association with increased apoptosis, stellate cells activation, and fibrosis.31Walsh M.J. Vanags D.M. Clouston A.D. Richardson M.M. Purdie D.M. Jonsson J.R. et al.Steatosis and liver cell apoptosis in chronic hepatitis C a mechanism for increased liver injury.Hepatology. 2004; 39: 1230-1238Google Scholar Thus, liver inflammation would be responsible in part for the steatosis, and amplified by it. Furthermore, the overweight-associated insulin resistance, via free fatty acid overflow to extra-adipose tissues32Browning J.D. Horton J.D. Molecular mediators of hepatic steatosis and liver injury.J Clin Invest. 2004; 114: 147-152Google Scholar and the sustained hyperglycemic/hyperinsulinemic state,22Hui J.M. Sud A. Farrell G.C. Bandara P. Byth K. Kench J.G. et al.Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression.Gastroenterology. 2003; 125: 1695-1705Google Scholar, 33Hickman I.J. Powell E.E. Prins J.B. Clouston A.D. Ash S. Purdie D.M. et al.In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis implications for therapy.J Hepatol. 2003; 39: 1042-1048Google Scholar, 34Ratziu V. Munteanu M. Charlotte F. Bonyhay L. Poynard T. LIDO Study GroupFibrogenic impact of high serum glucose in chronic hepatitis C.J Hepatol. 2003; 39: 1049-1055Google Scholar would contribute further to both hepatic steatosis and fibrosis. In conclusion, we propose that steatosis is associated with fibrosis in CHC via the inflammatory reaction that accompanies steatosis and CHC infection. The simultaneous occurrence of an overweight/insulin resistance syndrome with chronic hepatic inflammation may represent a risky environment for the liver. Because exercise already has been shown to have a beneficial effect on liver disease parameters,30Lonardo A. Adinolfi L.E. Loria P. Carulli N. Ruggiero G. Day C.P. Steatosis and hepatitis C virus mechanisms and significance for hepatic and extrahepatic disease.Gastroenterology. 2004; 126: 586-597Google Scholar strategies aiming to correct being overweight and obese and that encourage physical activity should become a mainstay in the management of patients with CHC.35Powell E.E. Jonsson J.R. Clouston A.D. Steatosis co-factor in other liver diseases.Hepatology. 2005; 42: 5-13Google Scholar The authors thank Elisabetta Bugianesi and Chris Day for helpful discussion and criticism. Other investigators of the hepatitis C virus Meta-Analysis (on) Individual patients’ Data Study Group include Drs P. J. Male, Geneva, Switzerland; J. Kench, Department of Anatomical Pathology, Westmead Hospital, Westmead, New South Wales, Australia; G. C. Farrell (Storr Liver Unit), G. W. McCaughan (AW Morrow Gastroenterology and Liver Center), University of Sydney, Sydney, Australia; A. Andreana and R. Marino, Second University of Naples, Naples, Italy; A. D. Clouston, University of Queensland, Brisbane, Australia; and A. Andriulli, IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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