Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with “Explosive” Immune Response in Course of HCV-Related Liver Cirrhosis

Paolo Conca,Amalia De Renzo,Giovanni Tarantino,Antonio Coppola,Giovanni Cafaro,Ernesto Cimino

doi:10.3390/ijms160614075

Paolo Conca, Amalia De Renzo + Show 4 more

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https://doi.org/10.3390/ijms160614075

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Abstract

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin’s lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.

Highlights

Interaction between Hepatitis C virus (HCV) and the immune system represents a well-known pathogenic mechanism that causes liver and extrahepatic damage in chronically infected patients.Several reports in the literature have confirmed that HCV infection leads to different types of immune disease such as cryoglobulinemia, rheumatoid arthritis, Sjogren’s syndrome, hemolytic anaemia and severe thrombocytopenia, autoimmune hepatitis, thyroid disorders and diabetes mellitus
Infected lymphocytes constitute a reservoir of virus, but on the other hand persistent infection of lymphoid tissue induces a chronic stimulation of the immune system based on various molecular mechanisms, of which the activation of Bcl-2, a proto-oncogene that prolongs lymphocytes survival, and induces a switch of T lymphocytes both in Th2 phenotype and Th1 phenotype, plays a key role
The patient presented with a dysregulated IgM gammopathy showing humoral (RF) and cryoprecipitate activity induced by an amplified HCV replication

Summary

Introduction

Interaction between Hepatitis C virus (HCV) and the immune system represents a well-known pathogenic mechanism that causes liver and extrahepatic damage in chronically infected patients. Several reports in the literature have confirmed that HCV infection leads to different types of immune disease such as cryoglobulinemia, rheumatoid arthritis, Sjogren’s syndrome, hemolytic anaemia and severe thrombocytopenia, autoimmune hepatitis, thyroid disorders and diabetes mellitus. These manifestations, labelled as autoimmune diseases, are reckoned to be caused by the lymphotropism of the virus: the interaction between the E2 glycoprotein of the HCV envelope and the CD81 receptor, expressed by hepatocytes and B lymphocytes, could play a fundamental role. Infected lymphocytes constitute a reservoir of virus, but on the other hand persistent infection of lymphoid tissue induces a chronic stimulation of the immune system based on various molecular mechanisms, of which the activation of Bcl-2, a proto-oncogene that prolongs lymphocytes survival, and induces a switch of T lymphocytes both in Th2 phenotype and Th1 phenotype, plays a key role.

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