Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

• Published in: Gut Vol. 55; no. 4; pp. 529 - 535
• Main Authors: Walsh, M J, Jonsson, J R, Richardson, M M, Lipka, G M, Purdie, D M, Clouston, A D, Powell, E E
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.04.2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - therapeutic use; antiviral therapy; Biological and medical sciences; BMI; body mass index; Drug Therapy, Combination; Fatty Liver - complications; Female; GAPDH; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; glyceraldehyde-3-phosphate dehydrogenase; HCV; Hepacivirus - genetics; Hepatitis; hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; HOMA; homeostasis model of assessment; Humans; IFN-R1; IFN-α; Immunohistochemistry - methods; Insulin resistance; Insulin Resistance - physiology; Interferon; interferon receptor 1; interferon α; Interferon-alpha - therapeutic use; Liver; Liver - chemistry; Male; Medical sciences; Metabolic diseases; Middle Aged; non-response to antiviral treatment; Obesity; Obesity - complications; PEPCK; Pharmacology. Drug treatments; phosphoenolpyruvate carboxy kinase; Phosphoenolpyruvate Carboxykinase (GTP) - analysis; Polyethylene Glycols - therapeutic use; real time-polymerase chain reaction; Recombinant Proteins; RES; response to antiviral treatment; Retrospective Studies; Ribavirin - therapeutic use; Rodents; RT-PCR; signal transducer and activator of transcription; Signal Transduction; SOCS; STAT; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - analysis; suppressor of cytokine signalling; sustained virological response; SVR; TNF-α; Treatment Outcome; tumour necrosis factor; tumour necrosis factor α; Human; Obesity; Typing; Nutrition disorder; Cytokine; Hepatic disease; Genotype; Non response; Signalling; Infection; Microbiological investigation; Treatment; Viral disease; Gastroenterology; Digestive diseases; Antiviral; Suppressor; Nutritional status; Viral hepatitis C
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.069674

Background: Interferon α (IFN-α) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-α therapy and to determine hepatic expression of factors inhibiting IFN-α signalling in obese and non-obese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-α or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p<0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index ⩾ 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-α.