Comment on “Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?”
Authors: Pier Leopoldo Capecchi, Pietro Enea Lazzerini, Stefano Brillanti
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 Reply to: "Comment on "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?""Journal of HepatologyVol. 75Issue 4PreviewWe read with interest the comment by Capecchi et al.1 regarding our Letter to the Editor describing a case of autoimmune hepatitis (AIH) developing after COVID-19 vaccination.2 We thank the authors for their interest in our manuscript and for their thoughtful insight, which complemented our report. Full-Text PDF Autoimmune hepatitis following SARS-CoV-2 vaccine: May not be a casualityJournal of HepatologyVol. 75Issue 3PreviewWe read with interest the article: "Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) Vaccine: Causality or casualty?ˮ by Bril F. et al.1 and the comment to the letter by Capecchi L. et al. recently published in J Hepatol.2 Full-Text PDF We read with great interest the article by Bril F. et al. recently published in the Journal of Hepatology.[1]Bril 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 (142) Google Scholar In our opinion, several considerations increase the possibility that the described association is indeed coincidental, as also acknowledged by the authors. The patient was a 35-year-old Caucasian female on her 3rd month postpartum under treatment with labetalol for gestational hypertension. Symptoms developed 6 days after vaccination. The presence of eosinophils at liver histology seems to preferentially support the possibility of a drug- or toxin-induced liver injury, even if the marked lymphoplasmacytic infiltrate is more common in immune-mediated liver diseases. While immune reactions to vaccines are rather common, the association with the onset of autoimmune diseases is a matter of debate and most of the studies are inconclusive.[2]Segal Y. Shoenfeld Y. Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction.Cellular Mol Immunol. 2018; 15: 586-594Crossref PubMed Scopus (234) Google Scholar,[3]Vadalà M. Poddighes D. Laurino C. Palmieri B. Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?.EPMA J. 2017; 8: 295-311https://doi.org/10.1007/s13167-017-0101-yCrossref PubMed Scopus (92) Google Scholar Putative mechanisms should include molecular mimicry or bystander activation of dormant autoreactive T-helper cells for both tissue-specific and systemic reactions.[2]Segal Y. Shoenfeld Y. Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction.Cellular Mol Immunol. 2018; 15: 586-594Crossref PubMed Scopus (234) Google Scholar,[3]Vadalà M. Poddighes D. Laurino C. Palmieri B. Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?.EPMA J. 2017; 8: 295-311https://doi.org/10.1007/s13167-017-0101-yCrossref PubMed Scopus (92) Google Scholar It is also debated whether vaccines may be the causative agent of autoimmunity or whether they rather represent the trigger of a latent autoimmunity that would have occurred later in any case.[2]Segal Y. Shoenfeld Y. Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction.Cellular Mol Immunol. 2018; 15: 586-594Crossref PubMed Scopus (234) Google Scholar,[3]Vadalà M. Poddighes D. Laurino C. Palmieri B. Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?.EPMA J. 2017; 8: 295-311https://doi.org/10.1007/s13167-017-0101-yCrossref PubMed Scopus (92) Google Scholar Moreover, a period of time as short as 6 days from vaccine administration to the development of symptoms seems frankly poorly consistent with the time course of the putatively involved immunopathologic reaction, as indeed the same authors recognize. Conversely, autoimmune diseases are rather commonly observed to present in the postpartum period,[4]Somers E.C. Pregnancy and autoimmune diseases.Clin J Gastroenterol. 2020; 64: 3-10https://doi.org/10.1007/s1232802001092wCrossref Google Scholar,[5]Marder W. Littlejohn E.A. Somers E.C. Pregnancy and autoimmune connective tissue diseases.Best Pract Res Clin Rheumatol. 2016; 30: 63-80Crossref PubMed Scopus (51) Google Scholar particularly tyroiditis[6]Nguyen C.T. Mestman J.H. Postpartum thyroiditis.Clin Obstet Gynecol. 2019; 62: 359-364https://doi.org/10.1097/GRF.0000000000000430Crossref PubMed Scopus (18) Google Scholar and rheumatoid arthritis.[4]Somers E.C. Pregnancy and autoimmune diseases.Clin J Gastroenterol. 2020; 64: 3-10https://doi.org/10.1007/s1232802001092wCrossref Google Scholar Nevertheless several cases of autoimmune hepatitis (AIH) have also been reported7Efe C. Batibay E. Acute seronegative autoimmune hepatitis in the post-partum period.Clin J Gastroenterol. 2020; 13: 632-633https://doi.org/10.1007/s12328-020-01121-8Crossref PubMed Scopus (1) Google Scholar, 8Saito M. Akutsu N. Numata Y. Ishigami K. Sasaki S. Nakase H. Development of anti-centromere antibody-positive autoimmune hepatitis after childbirth.Clin J Gastroenterol. 2020; 13: 855-859https://doi.org/10.1007/s1232802001092wCrossref PubMed Scopus (0) Google Scholar, 9Samuel D. Riordan S. Strasser S. Kurtovic J. Singh-Grewel I. Koorey D. Severe autoimmune hepatitis first presenting in the early post partum period.Clin Gastroenterol Hepatol. 2004; 2: 622-624Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and the addition of such a disease to the list of autoimmune conditions that may first present after pregnancy has been suggested.[9]Samuel D. Riordan S. Strasser S. Kurtovic J. Singh-Grewel I. Koorey D. Severe autoimmune hepatitis first presenting in the early post partum period.Clin Gastroenterol Hepatol. 2004; 2: 622-624Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Thus, we wonder whether in the case report of Bril et al., the recent pregnancy rather than the administration of the COVID-19 vaccine is the event associated with the development of AIH. In favour of such a hypothesis also stands the time of latency before clinical presentation which is more consistent with pregnancy as the causative event. In fact, symptoms of postpartum AIH have been reported to occur from a few days to 1 year after delivery, usually within 4 months,[9]Samuel D. Riordan S. Strasser S. Kurtovic J. Singh-Grewel I. Koorey D. Severe autoimmune hepatitis first presenting in the early post partum period.Clin Gastroenterol Hepatol. 2004; 2: 622-624Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,[10]Izumi Y. Kaneko A. Oku K. Kimura M. Tanaka S. Tada H. et al.Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases.J Intern Med. 2002; 252: 361-367Crossref PubMed Scopus (22) Google Scholar but cases with early appearance are often difficult to differentiate from non-autoimmune pregnancy-associated liver damage.[10]Izumi Y. Kaneko A. Oku K. Kimura M. Tanaka S. Tada H. et al.Development of liver dysfunction after delivery is possibly due to postpartum autoimmune hepatitis. A report of three cases.J Intern Med. 2002; 252: 361-367Crossref PubMed Scopus (22) Google Scholar In this sense, we agree with the authors that in terms of pharmacovigilance the case can be appropriately reported as AIH as a possible expression of a vaccine-related adverse event/reaction. However, the concomitant history of a recent pregnancy represents a tremendous confounding factor. No financial support was obtained for this letter to the editor. Pier Leopoldo Capecchi: conceived and wrote the letter to the Editor. Pietro Enea Lazzerini: made critical revision of the letter to the Editor for important intellectual content. Stefano Brillanti: made critical revision of the letter to the Editor for important intellectual content. The authors declare no conflict of interest. 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