Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Mar 27, 2015; 7(3): 327-343
Published online Mar 27, 2015. doi: 10.4254/wjh.v7.i3.327
Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin’s lymphoma, and cancer
Clodoveo Ferri, Marco Sebastiani, Dilia Giuggioli, Michele Colaci, Poupak Fallahi, Alessia Piluso, Alessandro Antonelli, Anna Linda Zignego
Clodoveo Ferri, Marco Sebastiani, Dilia Giuggioli, Michele Colaci, Chair and Rheumatology Unit, Medical School, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, 41124 Modena, Italy
Poupak Fallahi, Alessandro Antonelli, Department of Internal Medicine, School of Medicine, University of Pisa, 56126 Pisa, Italy
Alessia Piluso, Anna Linda Zignego, Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy
Author contributions: All authors contributed to this manuscript.
Conflict-of-interest: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Clodoveo Ferri, MD, Professor, Chair and Rheumatology Unit, Medical School, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Via del Pozzo, 71, 41100 Modena, Italy.
Telephone: +39-059-4222279 Fax: +39-059-4223007
Received: August 27, 2014
Peer-review started: August 31, 2014
First decision: November 14, 2014
Revised: December 27, 2014
Accepted: January 9, 2015
Article in press: January 9, 2015
Published online: March 27, 2015

The clinical course of chronic hepatitis C virus (HCV) infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinico-epidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells non-Hodgkin’s lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCV-related thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients’ populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.

Keywords: Hepatitis C virus, Mixed cryoglobulinemia, Thyroid, Diabetes, Lymphoma

Core tip: The proposed definition of hepatitis C virus (HCV) syndrome encompasses the multiform complex of clinico-pathological conditions potentially correlated to chronic HCV infection. The natural history of HCV syndrome is the result of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations, to systemic immune-mediated disorders, and less frequently to overt malignancies. Here we analyze the clinical, epidemiological, and pathogenetic aspects of this multifaceted condition, including the updated results of the world literature.