Human Herpesviruses Increase the Severity of Hepatitis

Abstract

Acute and chronic liver diseases are a major global public health problem; nevertheless, the etiology of 12-30% of cases remains obscure. The purpose of this research was to study the incidence of human herpesviruses (HHVs) cytomegalovirus, Epstein-Barr virus (EBV), and HHV-6 in patients with hepatitis and to examine the effect of HHV on the disease severity. We studied the clinical materials of 259 patients with hepatitis treated in Infectious Clinic n.1 (Moscow) and the archived materials of 118 patients with hepatitis C. HHV DNA was detected in the whole blood in 13.5% of patients with hepatitis B or C and in 10.1% of patients with hepatitis of unspecified etiology. EBV demonstrated the highest incidence (58.1%). Cirrhosis was diagnosed in 50% of patients with HHV and in 15.6% of patients without HHV. In patients with hepatitis C, the frequency of HHV was higher in liver biopsy (38.7%) compared to blood. The clinical and virological indicators of hepatitis were considerably higher in patients with coinfection. Conclusion: HHV detected in patients with viral hepatitis has been associated with a significant effect on the severity of the disease, and we suggest monitoring HHV DNA in patients with severe hepatitis and/or poor response to antiviral drugs.

Keywords: HCV RNA; disease severity; hepatitis C virus; herpesviruses; liver cirrhosis; unspecified hepatitis; viral DNA; viral hepatitis.

Figure 1

Clinical and laboratory signs (a) and clinical condition (b) in patients with viral hepatitis and hepatitis of unspecified etiology in coinfection with herpesviruses (group 1, n = 8) and without it (n = 77, group 2). Values are the detection rates, %. * p < 0.05 between groups according χ2 and Fisher’s exact tests. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Figure 2

Virological data of patients with chronic hepatitis C depending on the detection of herpesvirus DNA. (a) HCV genotype, HCV RNA plus-strand (genomic) and minus-strand (replicative) were detected in peripheral blood and liver by RT-PCR. (b) Concentrations of HCV core in sera were estimated by ELISA using original monoclonal antibodies (mAbs). (c) The presence of anti-HCV antibodies to viral proteins was determined by indirect ELISA. Group 1 (n = 30): patients with CHC and coinfection with HHV; group 2 (n = 67): only CHC without HHV. Values are the detection rates (a, c) or means ± SEM (b), * p < 0.05 between groups.

Figure 3

Comparative analysis of HCV proteins in hepatocytes of patients with chronic hepatitis C coinfected or not infected with herpesviruses. (a) Immunohistochemical detection of HCV proteins in cryostat liver sections using a mixture of mAbs to the core, NS3, NS4A/B, and NS5A proteins (A–D, F); E—mAb to HBsAg (negative control). A–E: patients with CHC, F: patient with steatohepatitis (negative control). Note more intensive cytoplasmic staining (brown) in group 1—HHV detected (A, B) compared with group 2—HHV not detected (C, D). No immunoreactivity was observed in the controls (E, F). The cell nuclei were stained with hematoxylin (blue). Magnification, × 400. (b) The relative number of HCV-containing liver cells in patients with CHC, depending on the detection of herpesviruses. Values are the means ± SEM (b), * p < 0.05 between groups.