Another case of autoimmune hepatitis after SARS-CoV-2 vaccination – still casualty?
Authors: Maria-Carlota Londoño, Jordi Gratacós-Ginès, Joaquín Sáez-Peñataro
Journal: Journal of Hepatology (2021)

Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?Journal of HepatologyVol. 75Issue 1PreviewSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with the development of autoimmune processes.1–4 Molecular mimicry has been suggested as a potential mechanism for these associations.1 In an in vitro study, Vojdani et al.5 showed that antibodies against the spike protein S1 of SARS-CoV-2 had high affinity against the following human tissue proteins: transglutaminase 3, transglutaminase 2, anti-extractable nuclear antigen, nuclear antigen, and myelin basic protein. Full-Text PDF Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: One or even several swallows do not make a summerJournal of HepatologyVol. 75Issue 5PreviewI read with interest the comments to our letter by Londoño et al.,1 Clayton-Chubb et al.,2 Tan et al.,3 McShane et al.,4 and Lodato et al.,5 and I appreciate their contribution. All these authors presented similar cases of autoimmune hepatitis (AIH) that developed after coronavirus disease 2019 (COVID-19) vaccine, with the exception of Lodato et al.,5 who actually described a case of acute liver injury with some features of autoimmunity. Full-Text PDF We read with interest the letter entitled "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?" by Bril et al.1Bril F. Al Diffalha S. Dean M. Fettig D.M. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty?.J Hepatol. 2021; 75: 222-224https://doi.org/10.1016/j.jhep.2021.04.003Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar recently published in Journal of Hepatology. We had a similar case which strengthens the message of SARS-CoV-2 vaccines as a potential trigger for autoimmune hepatitis (AIH). The patient is a 41-year-old female with a past medical history of premature ovarian failure undergoing substitutive hormonal therapy with no side effects. After receiving the first dose of SARS-CoV-2 Moderna vaccine (mRNA-1273) the patient presented epigastric pain, nausea and vomiting. These symptoms lasted for 3 weeks and then decreased in intensity. Seven days after the second dose, symptoms reappeared with higher intensity and were associated with choluria and jaundice. Liver tests showed aspartate aminotransferase 993 IU/L, alanine aminotransferase 1,312 IU/L, total bilirubin 2.3 mg/dl (peak of 8.5 mg/dl), gamma-glutamyltransferase 209 IU/L, alkaline phosphatase 190 IU/L. Laboratory results were negative for hepatitis A, B, C, E, cytomegalovirus, Epstein-Bar virus, herpes simplex virus type 1 and 2, and herpes 6 virus. Antinuclear antibody (1:80), anti-smooth muscle antibody (1:40), anti-soluble liver antigen (anti-SLA), anti-liver cytosol were positive. IgG levels were elevated (20.8 g/L). Liver ultrasound was normal. The liver biopsy (2.5 cm, 19 portal tracts) showed a marked expansion of the portal tracts with a dense inflammatory infiltrate composed of lymphocytes and plasma cells, severe interface hepatitis and lobular inflammation with disperse necroinflammatory foci, apoptotic bodies and hepatocyte ballooning. Masson's trichrome staining showed no signs of parenchymal or perisinusoidal fibrosis. The score of simplified diagnostic criteria of the International Autoimmune Hepatitis Group was 8 (definite diagnosis of AIH) and the patient was diagnosed with SARS-CoV-2 vaccine induced-AIH. Corticosteroid treatment with high-dose prednisone (1 mg/kg) was started with rapid normalization of liver enzymes. The patient was followed by the Liver Unit in collaboration with the active surveillance program established by the Technical Pharmacovigilance Committee of the Hospital. Specific environmental factors, including viruses, drugs and herbal products can trigger the loss of self-tolerance to liver autoantigens. Several reports have shown that vaccination against influenza and hepatitis A viruses can trigger AIH.2Sasaki T. Suzuki Y. Ishida K. Kakisaka K. Abe H. Sugai T. et al.Autoimmune hepatitis following influenza virus vaccination: two case reports.Med (United States). 2018; 97: e11621https://doi.org/10.1097/MD.0000000000011621Crossref Scopus (31) Google Scholar,3Berry P.A. Smith-Laing G. Hepatitis A vaccine associated with autoimmune hepatitis.World J Gastroenterol. 2007; 13: 2238-2239https://doi.org/10.3748/wjg.v13.i15.2238Crossref PubMed Scopus (48) Google Scholar The mechanism behind the development of vaccine-induced AIH is unknown but it is probably similar to that described for other autoimmune phenomena: genetic susceptibility, exposure to foreign peptides homologous to human peptides (molecular mimicry), and immune system stimulation by vaccine adjuvant.4Segal Y. Shoenfeld Y. Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction.Cell Mol Immunol. 2018; 15: 586-594https://doi.org/10.1038/cmi.2017.151Crossref PubMed Scopus (248) Google Scholar The Moderna vaccine lacks immune adjuvants but the presence of anti-SLA in our patient prompted us to investigate whether there was homology between the SARS-CoV-2 spike protein and soluble liver antigen. Using protein BLAST to align the sequence of these 2 proteins, we found no significant similarity. However, linear sequence matches in amino acid motifs are not the only criteria for molecular mimicry5Sinigaglia F. Hammer J. Defining rules for the peptide-MHC class II interaction.Curr Opin Immunol. 1994; 6: 52-56https://doi.org/10.1016/0952-7915(94)90033-7Crossref PubMed Scopus (77) Google Scholar and we cannot completely rule-out that other factors could have been involved in this case, such as: i) similar native or glycosylated amino acid epitopes shared between the protein expressed in the host after vaccination and soluble liver antigen, and ii) structural similarities between the proteins.6Rojas M. Restrepo-Jiménez P. Monsalve D.M. Pacheco Y. Acosta-Ampudia Y. Ramírez-Santana C. et al.Molecular mimicry and autoimmunity.J Autoimmun. 2018; 95: 100-123https://doi.org/10.1016/j.jaut.2018.10.012Crossref PubMed Scopus (333) Google Scholar It is also possible that other liver autoantigens (different from SLA) share sequence homology with the protein expressed by the host after SARS-CoV-2 vaccination with mRNA vaccines.7Kanduc D. Shoenfeld Y. Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.Immunol Res. 2020; 68: 310-313https://doi.org/10.1007/s12026-020-09152-6Crossref PubMed Scopus (188) Google Scholar Finally, we have to consider the specific features of mRNA vaccines. This approach is based on the synthesis of RNA coding for the desired antigenic protein, but in order to avoid degradation, RNA is encapsulated in nanoparticles or liposomes that deliver their content inside the target cells by endocytosis. Prior to translation, RNA binds to pattern recognition receptors (especially Toll-like receptors) resulting in the activation of several proinflammatory signals including type I interferon response.8Talotta R. Do COVID-19 RNA-based vaccines put at risk of immune-mediated diseases? In reply to "potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases.Clin Immunol. 2021; 224: 108665https://doi.org/10.1016/j.clim.2021.108665Crossref PubMed Scopus (148) Google Scholar The upregulation of these pathways is similar to what has been described in AIH (and other autoimmune diseases) and therefore we believe that more than casualty, the association between SARS-CoV-2 vaccines and AIH is causality. "One swallow does not make summer" and the benefits of vaccination are far higher than the potential risks of the vaccines and therefore the report of these 2 cases should not be used as an argument against vaccination. It should be noted that these reports illustrate a rare adverse event that has only been detected after the administration of millions of doses of mRNA vaccines in a "real-world" setting. Indeed, the coverage of the active surveillance monitoring program established in the hospitals, together with a close collaboration within medical departments, supported the detection of this rare adverse event and its association with previous vaccination. The authors received no financial support to produce this manuscript. MCL detected the case and wrote the letter, JGG and JSP actively participated in the management of the patient and critically reviewed the manuscript. The authors declare not conflict of interests related to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.19 MB) Help with pdf files Multimedia component 1