Autoimmune hepatitis following COVID-19 vaccination: True causality or mere association?
Authors: Chin Kimg Tan, Yu Jun Wong, Lai Mun Wang, Tiing Leong Ang, Rahul Kumar
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 The 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.1Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6728) Google Scholar In light of this, we read with great interest a recent article by Bril et. al.2Bril 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: 222-224Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar 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.3Capecchi 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?".J Hepatol. 2021; 75: 994-995Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar We hereby describe a case of severe AIH in a pre-morbidly well patient after the first dose of Moderna-COVID-19 vaccine (mRNA-1273). A 56-year-old woman received her first dose of Moderna-COVID-19 vaccine (mRNA-1273) on 14-April 2021. She developed intense malaise and flu-like symptoms the next day, owing to which she later decided against receiving the recommended second dose. Six weeks after vaccination, she presented with a 1-week history of jaundice, feeling unwell and persistent anorexia. Apart from her regular medication (rosuvastatin 10 mg daily) started 9 years ago, she was not on any other prescription or traditional medication/supplements. Prior to admission, her last liver function test was performed in 2019 and was normal. On the day of presentation, her physical examination was normal except for scleral icterus. The initial laboratory studies showed that she had hepatocellular injury (albumin 46 g/L, bilirubin 102 μmol/L, alkaline phosphatase 298 U/L, alanine aminotransferase [ALT] 1,701 U/L, aspartate aminotransferase 1,124 U/L, international normalized ratio 1.0) fulfilling Hy's law.4Robles-Diaz M. Lucena M.I. Kaplowitz N. Stephens C. Medina-Cáliz I. González-Jimenez A. et al.Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.Gastroenterology. 2014; 147: 109-118Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Acute viral hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis E, cytomegalovirus, Epstein-Barr virus, herpes simplex virus) was excluded and cross-sectional abdominal imaging was unremarkable. Antinuclear antibody and anti-smooth muscle antibody were positive and serum IgG level was raised (32.6 G/L). The trend in bilirubin and ALT levels is illustrated in Fig. 1A. Liver biopsy demonstrated portal inflammation with interface hepatitis, accompanied by conspicuous lobular inflammation with the presence of plasma cell aggregates, rosette formation and apoptotic hepatocytes (Fig. 1B–D). The histological features are in-keeping with an AIH-type pattern. Eosinophils were also identified, raising the possibility of drug association. Early young fibrosis is noted in the portal regions and would be compatible with recent subacute injury (Fig. 1E). The details of lab work are presented in Table S1 and S2. The pre-treatment revised original AIH score5Alvarez F. Berg P.A. Bianchi F.B. Bianchi L. Burroughs A.K. Cancado E.L. et al.International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (2640) Google Scholar was 16. The patient was started on budesonide which led to rapid clinical and biochemical improvement (Fig. 1A). COVID-19 infection is not known to impact outcomes of patients with AIH, but little is known about the relationship between COVID-19 vaccines and AIH.6Marjot T. Buescher G. Sebode M. Barnes E. Barritt A.S. Armstrong M.J. et al.SARS-CoV-2 infection in patients with autoimmune hepatitis.J Hepatol. 2021; 74: 1335-1343Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Drug-induced AIH (DI-AIH) is often a diagnostic challenge.7Mack C.L. Adams D. Assis D.N. Kerkar N. Manns M.P. Mayo M.J. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.Hepatology. 2020 Aug; 72: 671-722Crossref PubMed Scopus (448) Google Scholar,8European Association for the Study of the LiverElectronic address: [email protected]; clinical practice guideline panel: chair; panel members; EASL governing board representative: EASL clinical practice guidelines: drug-induced liver injury.J Hepatol. 2019 Jun; 70: 1222-1261Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar Features favouring DI-AIH include history of recent drug exposure, absence of advanced fibrosis on liver histology and lack of relapse after stopping immunosuppressants.5Alvarez F. Berg P.A. Bianchi F.B. Bianchi L. Burroughs A.K. Cancado E.L. et al.International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.J Hepatol. 1999; 31: 929-938Abstract Full Text Full Text PDF PubMed Scopus (2640) Google Scholar,6Marjot T. Buescher G. Sebode M. Barnes E. Barritt A.S. Armstrong M.J. et al.SARS-CoV-2 infection in patients with autoimmune hepatitis.J Hepatol. 2021; 74: 1335-1343Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar While our patient is still undergoing steroid therapy, other features are suggestive of DI-AIH. However, a few considerations require particular attention. Although statins are well known to cause DI-AIH, the median latency in statin-induced AIH is around 150 days.9Russo M.W. Hoofnagle J.H. Gu J. Fontana R.J. Barnhart H. Kleiner D.E. et al.Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.Hepatology. 2014; 60: 679-686Crossref PubMed Scopus (181) Google Scholar Given the temporal sequence, results of biochemistry, immunological assays (Table S1) and typical histological changes on liver biopsy, diagnosis of DI-AIH due to the COVID19 vaccine is most plausible. While DI-AIH is rare,10Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1174) Google Scholar the diagnosis of vaccine-related DI-AIH carries 2 important clinical implications. First, the re-exposure to a second dose of COVID-19 vaccine might trigger a fulminant AIH flare and second, prolonged immunosuppression may not be required. Thus, an accurate diagnosis and being aware of this rare complication of COVID mRNA vaccines is vital. DI-AIH after COVID-19 vaccination has rarely been reported to date (2), which might be due to either minimal awareness of this condition or the fact that patients without icteric disease do not usually present to hospitals. Our report differs from that of Bril et. al.2Bril 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: 222-224Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar in a few important domains. Firstly, our patient is not post-partum, which could be seen as a confounder3Capecchi 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?".J Hepatol. 2021; 75: 994-995Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar emphasizing that DI-AIH post COVID-19 vaccination might have been a causal relationship rather than just an association. Secondly, our patient was inoculated with the Moderna-COVID-19 vaccine (mRNA-1273) and not the Pfizer-BioNTech vaccine. However, both are mRNA vaccines. The mechanism by which the mRNA vaccines could cause DI-AIH is explained by Bril et al. in their report2Bril 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: 222-224Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar and we hold the same view that molecular mimicry might be the potential mechanism underlying these mRNA vaccine-induced autoimmune conditions. In conclusion, we would like to emphasize that clinicians need to remain vigilant and should consider DI-AIH secondary to mRNA vaccines in patients with similar presentation. However, this rare complication of the Moderna-COVID-19 vaccine (mRNA-1273) should not deter people from getting vaccinated. All the authors have no financial support statement to make. Concept: CKT, RK; Data Collection: CKT,LMW; Manuscript Writing: CKT, YJW; LWM; RK; Critical Reviewing: All. Guarantor of article and data interpretation: LWM, RK. All authors do not have any potential conflict of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. The following is the supplementary data to this article: Download .pdf (.14 MB) Help with pdf files Multimedia component 1 Download .pdf (.23 MB) Help with pdf files Multimedia component 2