Differential Serum Cytokine Profiles in Patients with Chronic Hepatitis B, C, and Hepatocellular Carcinoma

Jacqueline Estevez,An Le,Yael Rosenberg-Hasson,Ellen T Chang,Biao Li,Vincent L Chen,Mindie H Nguyen,Ondrej Podlaha,Zhaoshi Jiang,Philip Vutien,Anuj Gaggar,Stefan Pflanz,Dongliang Ge

doi:10.1038/s41598-017-11975-7

Abstract

Cytokines play an important role in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC), most cases of which are related to either hepatitis B virus (HBV) or hepatitis C virus (HCV). Prior studies have examined differences in individual cytokine levels in patients with chronic liver disease, but comprehensive cytokine profiling data across different clinical characteristics are lacking. We examined serum cytokine profiles of 411 patients with HCC (n = 102: 32% HBV, 54% HCV, 14% non-viral) and without HCC (n = 309: 39% HBV, 39% HCV, 22% non-viral). Multiplex analysis (Luminex 200 IS) was used to measure serum levels of 51 common cytokines. Random forest machine learning was used to obtain receiver operator characteristic curves and to determine individual cytokine importance using Z scores of mean fluorescence intensity for individual cytokines. Among HCC and non-HCC patients, cytokine profiles differed between HBV and HCV patients (area under curve (AUC) 0.82 for HCC, 0.90 for non-HCC). Cytokine profiles did not distinguish cirrhotic HBV patients with and without HCC (AUC 0.503) or HCV patients with and without HCC (AUC 0.63). In conclusion, patients with HBV or HCV infection, with or without HCC, have distinctly different cytokine profiles, suggesting potential differences in disease pathogenesis and/or disease characteristics.

Highlights

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide[1], with half a million cases diagnosed annually[2]
Falasca et al found that hepatitis B virus (HBV)-infected patients had higher levels of plasma IFN-γ, tumor necrosis factor (TNF)-α, and IL-2 compared to hepatitis C virus (HCV) and healthy control groups
They found that IL-6 and IL-18 were higher in both HBV and HCV groups compared to controls[14]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide[1], with half a million cases diagnosed annually[2]. HCV likely causes HCC through the indirect pathway of chronic inflammation, similar to non-viral etiologies of HCC, and through a more direct pathway involving the interaction of HCV core protein with dendritic cells (DC) This interaction results in reduced interferon (IFN)-α and interleukin (IL)-12 levels, which interrupts the DCs’ function of priming T-cell surveillance potentially leading to HCC carcinogenesis[12,13]. Our aim is to simultaneously study serum levels of 51 immune biomarkers of HCC patients with different viral etiologies and clinical characteristics using multiplex analysis of patient’s serum samples Characterization of these immune profiles provides novel information that may help us understand the mechanistic roles cytokines and chemokines play in HCC pathogenesis in the context of different underlying liver diseases

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Conclusion