Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: One or even several swallows do not make a summer
Authors: Fernando Bril
Journal: Journal of Hepatology (2021)

Another case of autoimmune hepatitis after SARS-CoV-2 vaccination – still casualty?Journal of HepatologyVol. 75Issue 5PreviewWe read with interest the letter entitled "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?" by Bril et al.1 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). Full-Text PDF Autoimmune hepatitis following COVID-19 vaccination: True causality or mere association?Journal of HepatologyVol. 75Issue 5PreviewThe COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, as many vaccines were granted expedited approval, safety still remains a concern.1 In light of this, we read with great interest a recent article by Bril et. al.2 They described a case of autoimmune hepatitis (AIH) possibly triggered by COVID-19 vaccination. However, as the patient was 3-months post-partum a true causal relationship is difficult to determine. Full-Text PDF An unusual case of acute cholestatic hepatitis after m-RNABNT162b2 (Comirnaty) SARS-CoV-2 vaccine: Coincidence, autoimmunity or drug-related liver injuryJournal of HepatologyVol. 75Issue 5PreviewWe read with interest the article "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?" by Bril et al. recently published in Journal of Hepatology.1 In this case, autoimmune hepatitis had some atypical features such as the absence of immunoglobulin G elevation and the presence of eosinophils on liver histology. Full-Text PDF Autoimmune hepatitis developing after the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccineJournal of HepatologyVol. 75Issue 5PreviewWe read with interest the recent letter published by Bril et al. recently published in Journal of Hepatology.1 The authors describe a possible case of COVID-19 vaccine-associated autoimmune hepatitis (AIH) in a 35-year-old woman 3 months post-partum. The patient presented with pruritis and jaundice 13 days after receiving a BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine, which may be the first report of COVID-19 vaccine-associated liver injury. As vaccination programs are being rolled out globally,2 many clinically significant side effects are starting to be identified, such as vaccine-induced immune thrombotic thrombocytopenia. Full-Text PDF The mRNA COVID-19 vaccine – A rare trigger of autoimmune hepatitis?Journal of HepatologyVol. 75Issue 5PreviewWe read with interest the letters "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) Vaccine: Causality or casualty?" by Bril et al.1 and "Autoimmune hepatitis following SARS-CoV-2 vaccine: May not be a casuality" by Rocco et al.2 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. Full-Text PDF 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 I read with interest the comments to our letter by Londoño et al.,1Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249https://doi.org/10.1016/j.jhep.2021.06.004Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Clayton-Chubb et al.,2Clayton-Chubb D. Schneider D. Freeman E. Kemp W. Roberts S.K. Autoimmune hepatitis developing after the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine.J Hepatol. 2021; 75: 1249-1250https://doi.org/10.1016/j.jhep.2021.06.014Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Tan et al.,3Tan C.K. Wong Y.J. Wang L.M. Ang T.L. Kumar R. Autoimmune hepatitis following COVID-19 Vaccination: true causality or mere association?.J Hepatol. 2021; 75: 1250-1252https://doi.org/10.1016/j.jhep.2021.06.009Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar McShane et al.,4McShane C. Kiat C. Rigby J. Crosbie O. The mRNA COVID-19 vaccine - a rare trigger of Autoimmune Hepatitis?.J Hepatol. 2021; 75: 1252-1254https://doi.org/10.1016/j.jhep.2021.06.044Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and Lodato et al.,5Lodato F. Larocca A. D'Errico A. Cennamo V. An anusual case of acute cholestatic hepatitis after m-RNABNT162b2 (comirnaty) SARS-COV-2 vaccine: coincidence, autoimmunity or drug related liver injury?.J Hepatol. 2021; 75: 1254-1256https://doi.org/10.1016/j.jhep.2021.07.005Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar 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.,5Lodato F. Larocca A. D'Errico A. Cennamo V. An anusual case of acute cholestatic hepatitis after m-RNABNT162b2 (comirnaty) SARS-COV-2 vaccine: coincidence, autoimmunity or drug related liver injury?.J Hepatol. 2021; 75: 1254-1256https://doi.org/10.1016/j.jhep.2021.07.005Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar who actually described a case of acute liver injury with some features of autoimmunity. First of all, I was glad to see the repercussions of our manuscript, as it triggered the publication of many similar cases. Only by sharing experiences we will be able to learn more about COVID-19 infection and the effects of its vaccines. Our observation was evidently not an isolated finding, and similar presentations were observed worldwide. Capecchi et al.6Capecchi P.L. Lazzerini P.E. Brillanti S. Comment to the letter of Bril F et al. "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) Vaccine: causality or casualty?ˮ.J Hepatol. 2021; 75: 994-995https://doi.org/10.1016/j.jhep.2021.04.039Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar suggested that a period of time of 6 days after vaccine administration, as seen in our case,7Bril 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 seemed inconsistent with an immunopathologic reaction. However, among these 5 other cases, the latency period was similarly short and ranged from only 4 to 35 days. With some small variations, the cases also shared similar biochemical, immunological, and histological characteristics (Table 1). Indeed, a peculiarity among all these cases was a histology with characteristics of an immune process with features of drug-induced toxicity. Moreover, the rate and speed of improvement with glucocorticoids appeared to be similar in all the cases, and no relapses have been observed thus far. Only a longer follow-up will help us assess the risk of relapses in these cases. Further supporting a link between the vaccines and AIH, some of the authors even observed worsening of the symptoms after the second dose of the vaccine.1Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249https://doi.org/10.1016/j.jhep.2021.06.004Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,5Lodato F. Larocca A. D'Errico A. Cennamo V. An anusual case of acute cholestatic hepatitis after m-RNABNT162b2 (comirnaty) SARS-COV-2 vaccine: coincidence, autoimmunity or drug related liver injury?.J Hepatol. 2021; 75: 1254-1256https://doi.org/10.1016/j.jhep.2021.07.005Abstract Full Text Full Text PDF PubMed Scopus (45) Google ScholarTable 1Characteristics of patients with autoimmune hepatitis after COVID-19 vaccination.StudyPatient's characteristicsVaccineLatency period (days)AST/ALT at presentation (U/L)Bilirubin at presentation (mg/dl)AbIgGBiopsy consistent with AIHBril et al.Female, 35Pfizer (1st dose)13754/2,0014.8ANANYesds-DNALondoño et al.Female, 41Moderna (2nd dose)7993/1,3122.3ANA↑YesSMASLALC1Clayton-Chubb et al.Male, 36Oxford-AstraZeneca (1st dose)26633/1,7741.0ANANYesTan et al.Female, 56Moderna (1st dose)351,124/1,7016.0ANA↑YesSMAMcShane et al.Female, 71Moderna (unknown)4?/1,06712.1SMA↑YesLodato et al.Female, 43Pfizer (1st dose)1551/5217.5-NYesALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, aspartate aminotransferase; ds-DNA, double-stranded DNA antibodies; LC1, liver cytosol antibodies; SLA, soluble liver antigen antibodies; SMA, smooth muscle antibodies. Open table in a new tab ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, aspartate aminotransferase; ds-DNA, double-stranded DNA antibodies; LC1, liver cytosol antibodies; SLA, soluble liver antigen antibodies; SMA, smooth muscle antibodies. However, while the resemblance of all these cases suggests a potential causal link between the vaccine and AIH, as the title of this article suggests, this cannot be taken as proof that this link really exists. Considering an annual incidence of 1 case per 100,000 habitants as previously reported,8Ben-Ari Z. Czaja A.J. Autoimmune hepatitis and its variant syndromes.Gut. 2001; 49: 589-594https://doi.org/10.1136/gut.49.4.589Crossref PubMed Scopus (100) Google Scholar and assuming an even distribution during the 12 months, we can estimate 1 monthly case per 1,200,000 habitants. Based on CDC data, during the first month of the US COVID-19 vaccination program, approximately 13,000,000 people received at least 1 dose of the vaccine (available at https://covid.cdc.gov/covid-data-tracker/#vaccinations). Based on AIH incidence, we can therefore roughly estimate that ~10 people from this vaccinated cohort would have developed AIH within a month of getting the vaccine. Thus, it should not be surprising that we will all continue to see these cases as we continue with our vaccination efforts. Epidemiological studies assessing changes in AIH incidence may be able to shed some light on this uncertainty. Only if we observe a true increment of AIH incidence after COVID-19 vaccination, can we make the case for a potential relationship. Until then, primary care providers and hepatologists are encouraged to keep their eyes open and maximize adverse event reporting to the appropriate authorities. In summary, we need to remain vigilant and stay open to the idea that SARS-CoV-2 infection and its vaccines may induce autoimmune processes, including AIH. However, we do not have any solid proof of a causal relationship. And even if there was a relationship, it is probably the result of cross-reactivity to the viral spike protein9Ehrenfeld M. Tincani A. Andreoli L. Cattalini M. Greenbaum A. Kanduc D. et al.Covid-19 and autoimmunity.Autoimmun Rev. 2020; 19: 102597https://doi.org/10.1016/j.autrev.2020.102597Crossref PubMed Scopus (376) Google Scholar and likely to be much worse after COVID-19 infection than vaccination. Writing from Alabama, a US state with one of the lowest vaccination rates, I am witnessing first-hand the consequences of low vaccination rates. Therefore, it is crucial that we continue to promote widespread vaccination. Only with this strategy will we be able to ultimately defeat COVID-19. The authors received no financial support to produce this manuscript. 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