Date Published: January 13, 2017
Publisher: Public Library of Science
Author(s): Cordelia Manickam, Lynn Wachtman, Amanda J. Martinot, Luis D. Giavedoni, R. Keith Reeves, Gualtiero Alvisi.
Chronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model.
Hepatitis C virus (HCV) causes chronic hepatitis leading to fibrosis, cirrhosis and hepatocellular carcinoma in 80% of infected individuals . About 2.8% of the world’s population is infected with HCV with associated mortality approximating 500,000 deaths per year [2–4]. In addition to liver disease-related mortality, HCV-infected patients are prone to type 2 diabetes and cardiovascular disease [5,6]. A myriad of metabolic aberrations including elevated triglycerides, elevated fasting glucose and abdominal obesity can exacerbate the development of metabolic syndrome, which in turn leads to cardiovascular disease and type 2 diabetes mellitus . Numerous studies have reported the association of HCV and its role in insulin resistance, hepatic steatosis, atherosclerosis and other metabolic aberrations that have been specifically described as HCV-associated dysmetabolic syndrome (HCADS) [8–10]. These metabolic aberrations especially steatosis, have been identified as predictors of poor treatment outcome for interferon-based therapy in chronic HCV infection in the early 2000s [11–14]. In the current era of directly acting antivirals, the impact of metabolic disorders on treatment outcome has not been well studied. A better understanding of the dysmetabolic milieu in HCV-infected patients will be helpful in attaining improved sustained virological response rates followed by successful HCV eradication.
Previous studies including our own observations have shown that GBV-B induces acute hepatitis in marmosets and tamarins with elevated serum enzymes such as ALT, isocitrate dehydrogenase and glutamate dehydrogenase [42,44–46]. However, the hematological, biochemical and metabolic changes over the course of GBV-B infection have not been described in detail. In this study, marmosets infected with GBV-B were assessed for changes in both hematological and serum metabolic parameters from onset of infection until after viral clearance.