The mRNA COVID-19 vaccine – A rare trigger of autoimmune hepatitis?
Authors: Cathy McShane, Clifford Kiat, Jonathan Rigby, Órla Crosbie
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 letters "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 and "Autoimmune hepatitis following SARS-CoV-2 vaccine: May not be a casuality" by Rocco et al.2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casuality.J Hepatol. 2021; 75: 728-729https://doi.org/10.1016/j.jhep.2021.05.038Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar which highlight the hypothesis that COVID-19 mRNA-based vaccines might increase the risk of developing autoimmune diseases. There are growing reports of autoimmune diseases developing after SARS-CoV-2 infection, including Guillain-Barré syndrome and primary biliary cholangitis.3Bartoli A. Gitto S. Sighinolfi P. Cursaro C. Andreone P. Primary biliary cholangitis associated with SARS-CoV-2 infection.J Hepatol. 2021; 74: 1245-1246https://doi.org/10.1016/j.jhep.2021.02.006Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar It is speculated that SARS-CoV-2 can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells and that the COVID-19 mRNA vaccines may trigger the same response.4Lui Y. Sawalha A.H. Lu Q. COVID-19 and autoimmune diseases.Curr Opin Rheumatol. March 1 2021; https://doi.org/10.1097/BOR.0000000000000776Crossref Scopus (312) Google Scholar,5Velikova T. Georgiev T. SARS-CoV-2 vaccines and autoimmune diseases amidst the COVID-19 crisis.Rheumatol Int. January 30 2021; https://doi.org/10.1007/s00296-021-04792-9Crossref PubMed Scopus (113) Google Scholar We report a further case of autoimmune hepatitis (AIH) following COVID-19 mRNA vaccination. Our patient is a 71-year-old Caucasian female. Background history was significant for cholecystectomy 20 years previously, left total hip replacement and osteoarthritis of the knees. There were no risk factors for autoimmune disease. She was on no regular medications or supplements. She received the Moderna mRNA vaccine on the 16th of April 2021. During the 24-hour period around vaccination she took 2 g of paracetamol. Four days post vaccination she noticed jaundice. She attended her primary carer on the 26th of April (+10 days post vaccination). Laboratory results were markedly abnormal (bilirubin 270 μmol/L, alkaline phosphatase 217 U/L, alanine aminotransferase 1,067 U/L). She was promptly referred to our hepatology services. On physical examination she was jaundiced. Laboratory results were negative for hepatitis B, C, and E, Epstein-Barr virus, cytomegalovirus and HIV. Hepatitis A IgG was positive with a negative IgM. Smooth muscle antibody was strongly positive with a titre of 2,560 and an anti-actin pattern. Total IgG was markedly raised at 21.77 g/L. Liver ultrasound, magnetic resonance cholangiopancreatography and computer tomography pancreas protocol showed distal common bile duct dilation of 1.4 cm consistent with prior cholecystectomy. On receipt of positive autoantibodies and a rising liver profile (bilirubin 332 μmol/L, alanine aminotransferase 1,143 U/L, aspartate aminotransferase 1,469 U/L, alkaline phosphatase 237 U/L and international normalized ratio 1.4), steroids were commenced on the 4th of May and liver biopsy was performed the following day. Up to 20 portal tracts were present, each expanded with a marked polymorphous inflammatory cell infiltrate of plasma cells, lymphocytes, eosinophils, neutrophils and PASD-positive ceroid laden macrophages; interface hepatitis was present and continuous in most tracts, with portal-portal and portal-central bridging necrosis (Fig. 1A–C). The findings were compatible with AIH, however drugs, toxins or infections could not be ruled out as aetiological agents. Since discharge from hospital our patient remains well and liver biochemistry has continued to improve on a tapering course of prednisolone (Fig. 1D). There are a number of similarities between the previously described cases and our own. Firstly, there was a short interval between vaccination and symptom onset in all cases. In response to the first case, Capecchi et al.6Capecchi P.L. Lazzerini P.E. Brillanti S. Comment on "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) Vaccine: causality or casualty?".J Hepatol. May 2021; 75: 994-995https://doi.org/10.1016/j.jhep.2021.04.039Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar questioned whether this was too short an interval to develop the necessary immune activation. It is indeed short when compared to established causatives agents of drug-induced autoimmune liver disease such as immune checkpoint inhibitors where a latency period of 2 to 24 weeks has been described.7Regev A. Avigan M. Kiazand A. Vierling J. Lewis J. Omokaro S. et al.Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.J Autoimmun. 2020; 114https://doi.org/10.1016/j.jaut.2020.102514Crossref PubMed Scopus (31) Google Scholar However, a much shorter latency period is described for other vaccine-induced autoimmune conditions such as Guillain-Barré syndrome (median onset 13 days).8Haber P. DeStefano F. Angulo F.J. Iskander J. Shadomy S.V. Weintraub E. et al.Guillain-barré syndrome following influenza vaccination.JAMA. 2004; 292: 2478-2481https://doi.org/10.1001/jama.292.20.2478Crossref PubMed Scopus (219) Google Scholar Secondly, histological appearances are similar between our case and that described by Bril et al. Both cases had an eosinophil infiltration which is more typical of a drug-induced liver injury. This raises the possibility that this is a vaccine-related drug-induced liver injury with features of AIH rather than the vaccine causing immune dysregulation. Unlike the other cases, our patient had no confounding risk factors for developing autoimmune liver disease such as other autoimmune conditions or recent pregnancy and she received a different mRNA vaccine, Moderna rather than Pfizer-BioNTech. These findings raise the question as to whether COVID-19 mRNA vaccination can, through activation of the innate immune system and subsequent non-specific activation of autoreactive lymphocytes, lead to the development of autoimmune diseases including AIH or trigger a drug-induced liver injury with features of AIH. The trigger, if any, may become more apparent over time, especially following withdrawal of immunosuppression. As with other autoimmune diseases associated with vaccines the causality or casualty factor will prove difficult to tease apart and should not distract from the overwhelming benefits of mass COVID-19 vaccination. But it does beg the question of whether or not these individuals should receive the second dose of an mRNA COVID-19 vaccine. The authors received no financial support to produce this manuscript. Dr Cathy McShane, Dr Clifford Kiat & Dr Órla Crosbie - involved in clinical care of patient and writing of manuscript. Dr Jonathan Rigby – interpreted histology and involved with writing of manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.23 MB) Help with pdf files Multimedia component 1