Significance of Anti-Nuclear Antibodies and Cryoglobulins in Patients with Acute and Chronic HEV Infection

Abstract

Background: Hepatitis E virus (HEV) has been associated with immunological phenomena. Their clinical significance, however, still needs to be clarified, that is, whether cryoglobulins or autoantibodies impact overt disease in HEV-infected individuals. To better understand, we analyzed these different immune phenomena in three cohorts, each representing different types of HEV infection. Methods: The cohorts included: (i) immunocompetent patients with acute hepatitis E, (ii) immunosuppressed patients with chronic hepatitis E, and (iii) individuals with asymptomatic HEV infection. Together, they consisted of 57 individuals and were studied retrospectively for the presence of anti-nuclear antibodies (ANAs), cryoglobulins, and serum total IgG. They were then compared with a control cohort of 17 untreated patients with chronic hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. Results: Thirteen (23%) were immunocompetent patients with acute hepatitis E (median alanine aminotransferase (ALT) = 872 U/L), 15 (26%) were immunosuppressed patients with chronic hepatitis E (median ALT = 137 U/L), and 29 (51%) were blood donors with asymptomatic HEV infection (median ALT = 35 U/L). Overall, 24% tested positive for elevated ANA titers of >1:160, and 11% presented with a specific ANA pattern. ANA detection was not associated with the type of HEV infection, IgG levels, sex, or age. All individuals tested negative for anti-mitochondrial antibodies, anti-neutrophil cytoplasmic antibodies, liver-kidney microsomal antibodies, anti-myeloperoxidase-, and anti-proteinase-3 antibodies. Five patients (9%) tested positive for cryoglobulins. Notably, cryoglobulinemia was present in overt hepatitis E (Groups (i) and (ii); one acute and four chronic HEV infections), but was not present in any of the asymptomatic blood donors (p = 0.02). The frequency of cryoglobulins and elevated ANAs did not differ significantly between HEV and HBV/HCV patients. Conclusion: In line with findings on HBV and HCV infections, we frequently observed detection of ANAs (24%) and cryoglobulins (9%) in association with HEV infections. The presence of cryoglobulins was limited to patients with overt hepatitis E. We add to the findings on the immune phenomena of hepatitis E.

Acute Hepatitis E Virus Infection Triggering Autoimmune Hepatitis in a Patient With Chronic Liver Disease: Case Report and the Review of the Literature

“…Cryoglobulinemia is also associated with HEV infections. It is present in around 7-27% of patients with HEV infections but without any clinical manifestations except neurological involvement [11]. Autoimmune liver diseases are often associated with circulating antibodies including immunoglobulin G-4, which can be found in acute viral hepatitis as well [12,13].…”

Non-organ-specific autoantibodies with unspecific patterns are a frequent para-infectious feature of chronic hepatitis D

“…Further studies should assess the prevalence of additional clinical symptoms (arthralgias, sicca symptom) and autoantibodies typical of other autoimmune diseases. For example, anti-SSA and anti-SSB in Sjögren’s syndrome, and cryoglobulins have been repeatedly found in patients with chronic hepatitis B, C, and E infection ( 34 ).…”

“…HEp-2 Cells (human epithelioma cells) and tissue slides (Euroimmun, Lübeck, Germany) were incubated in accordance with the manufacturer’s instructions, and interpretation was performed manually using the Eurostar microscope (Euroimmun, Lübeck Germany). SLA was tested by ELISA using enzyme immunoassays from Euroimmun, Germany ( 11 , 34 ). According to our internal laboratory criteria, we regarded ANA, SMA, and LKM-1 as positive at a titer of >1:80, AMA as positive at titers of ≥1:40, and SLA/LP as positive if ≥20 U/mL.…”

Similarities, differences, and possible interactions between hepatitis E and hepatitis C viruses: Relevance for research and clinical practice

“…Both acute and chronic hepatitis E infections are associated with antinuclear antibodies and cryoglobulinemia in the serum of patients that is similar to untreated HCV infection. The cryoglobulin concentration correlates with the viral load rather than with the degree of inflammation[ 73 ]. Serum cryoglobulins in the serum of patients affected by HCV infection are associated with a worse degree of steatosis and fibrosis, and it is not known if the same can happen in HEV infection[ 74 ].…”