The impact of hepatic steatosis on the natural history of chronic hepatitis C infection T. J. S. Cross, 1 A. Quaglia, 2 S. Hughes, 2 D. Joshi 2 and P. M. Harrison 3 1 Hepatology Department, Derriford Hospital, Plymouth, UK; 2 Institute of Liver Studies, KingÕs College Hospital, London, UK; and 3 Division of Gene and Cell-based Therapy, Department of Liver Studies and Transplantation, KingÕs College London, London, UK Received July 2008; accepted for publication December 2008 SUMMARY. Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39–51 years), who had two liver biopsies performed (median biopsy interval 50, 34–74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5–33% = S1, 33–66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n= 59), declined therapy (n= 48), or had co-existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3–16.7, P= 0.02). Twenty-three patients (21%) had disease pro- gression on the second biopsy, defined as an increase in Ishak score by ‡1 stage. On univariate analysis, fibrosis progression was associated with older age (P= 0.004), higher AST (P= 0.04), and steatosis (P= 0.005) but on multivariate analysis, only baseline steatosis was signifi- cant, odds ratio 14.3 (2.1–111.1, P= 0.006). Kaplan- Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak ‡F3) and cirrhosis (Ishak F5-6) (P= 0.001 and P= 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome. Keywords: cirrhosis, fibrosis, hepatitis C, steatosis, natural history. INTRODUCTION The severity of hepatic fibrosis in chronic hepatitis C (CHC) infection is a good indicator of long-term outcome [1,2] with cirrhosis occurring at a median time of 30 years from infection [3]. Several factors influence the rate at which fibrosis evolves [3] including: male sex, age at infection, excessive alcohol intake, elevated alanine aminotransferase level (ALT) [3,4], smoking [5] and HIV co-infection [6]. Interestingly, hepatic fibrosis can occur in the absence of these characteristics, suggesting that other factors contrib- ute to fibrogenesis. Hepatic steatosis is the hallmark of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steato-hepatitis (NASH). Risk factors include obesity, type 2 diabetes mellitus, and dyslipidaemia [7–9]. Steatosis is also observed in patients with CHC, with reported prevalence rates between 30% and 70%, compared to 10% in the general population [10–12], suggesting a link between hepatitis C virus (HCV) infection and steatosis development. Furthermore, a number of studies have demonstrated that steatosis may be associated with fibrosis progression in patients with CHC infection [13–16]. The aim of this study was to assess the factors that influence fibrosis progression in untreated patients with CHC, in particular the effect of baseline hepatic steatosis, using paired liver biopsies. Patients were excluded if there was co-existent liver disease or if they had previously received anti-viral therapy leading to a sustained virological response (SVR). J V H 1 0 9 8 B Dispatch: 27.1.09 Journal: JVH CE: Sittanand Journal Name Manuscript No. Author Received: No. of pages: 8 PE: Prasanna Abbreviations: cGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; ALT, alanine aminotransferase level; CHC, chronic hepatitis C; GGT, gamma-glutamyl transferase; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steato-hepatitis; SVR, sustained virological response. Correspondence: Dr Phil Harrison PhD, MD, FRCP, Senior Lecturer/ Consultant Hepatologist, Division of Gene and Cell-Based Therapy, Department of Liver Studies and Transplantation, KingÕs College London, Denmark Hill Campus, Bessemer Road, London SE5 9PJ, UK. E-mail: phillip.harrison@kcl.ac.uk Journal of Viral Hepatitis, 2009 doi:10.1111/j.1365-2893.2009.01098.x Ó 2009 The Authors Journal compilation Ó 2009 Blackwell Publishing Ltd 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55