New-onset autoimmune hepatitis following mRNA COVID-19 vaccination in a 36-year-old woman with primary sclerosing cholangitis – should we be more vigilant?
Authors: Taotao Zhou, Florian Fronhoffs, Leona Dold, Christian P. Strassburg, Tobias J. Weismüller
Journal: Journal of Hepatology (2021)

Recently, colleagues from different institutions reported in this Journal on 5 cases of newly diagnosed autoimmune hepatitis (AIH) following COVID-19-vaccination with the Pfizer/BioNTech1Bril 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,2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casualty.J Hepatol. 2021; 75: 728-729Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar or the Moderna mRNA-vaccine.3McShane C. Kiat C. Rigby J. Crosbie O. The mRNA COVID-19 vaccine - a rare trigger of autoimmune hepatitis?.J Hepatol. 2021; 75: 1252-1254Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 4Tan 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: 1250-1252Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 5Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar The patients were all female and between 35 and 80 years of age; liver-specific symptoms occurred between 43McShane C. Kiat C. Rigby J. Crosbie O. The mRNA COVID-19 vaccine - a rare trigger of autoimmune hepatitis?.J Hepatol. 2021; 75: 1252-1254Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and 35 days4Tan 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: 1250-1252Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar after the 1st vaccination, or 7 days after the 2nd vaccination.2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casualty.J Hepatol. 2021; 75: 728-729Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,5Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Two patients had possibly confounding risk factors for AIH development, namely recent pregnancy1Bril 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 autoimmune thyroiditis.2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casualty.J Hepatol. 2021; 75: 728-729Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The 5 cases have stirred up discussion about whether mRNA vaccines could trigger hepatic autoimmune reactions through molecular mimicry or bystander activation of dormant autoreactive T-helper cells.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. 2021; 75: 994-995Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Herein, we add another case to this discussion: the first case of a patient with pre-existing primary sclerosing cholangitis (PSC) diagnosed with AIH after mRNA-COVID-vaccination. PSC is a chronic progressive cholestatic liver disease characterized by multi-focal biliary strictures. A subgroup of patients with PSC have biochemical, serological, and/or histological features that overlap with those of AIH;7Boberg K.M. Chapman R.W. Hirschfield G.M. Lohse A.W. Manns M.P. Schrumpf E. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar in the largest international PSC cohort study, 8.1% of the 2,454 female and 5.8% of the 4,661 male patients were diagnosed with the PSC/AIH variant.8Weismuller T.J. Trivedi P.J. Bergquist A. Imam M. Lenzen H. Ponsioen C.Y. et al.Patient Age, sex, and inflammatory bowel disease phenotype Associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152 (1975-1984 e1978)Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar Our patient (female, 36 years-old) was diagnosed with ulcerative colitis and PSC at the age of 33. Diagnosis was made after exclusion of viral or metabolic hepatopathy due to a typical cholangiogram and highly elevated alkaline phosphatase (AP, 1,077 U/L) and gamma glutamyltransferase (GGT, 757 U/L), while aspartate aminotransferase (AST, 117 U/L), alanine aminotransferase (ALT, 193 U/L) and Immunoglobulin G (IgG, 16.9g/L) were only slightly elevated. Following treatment with ursodeoxycholic acid (1,000 mg/day) and endoscopic biliary intervention, AP and GGT initially decreased and ALT and AST normalized. However, after 1 year, the patient presented with cholangitis and pruritus and had multiple high-grade intra- and extrahepatic strictures on endoscopic retrograde cholangiography (Fig. S1). Due to recurrent episodes of purulent cholangitis and refractory strictures scheduled balloon dilatations had to be performed regularly every 3 months. During episodes of cholangitis, aminotransferases were also elevated but less than AP/GGT (Fig. 1). The patient received her first dose of Moderna mRNA-1273 vaccine on May 20th. Except for minor muscle aches the patient was without further symptoms. On May 31st she was hospitalized for a scheduled endoscopic balloon dilatation of the strictures. On admission, highly elevated ALT (588 U/L) and AST (581 U/L) were noticed with a rise in serum bilirubin (1.4 mg/dl) and international normalized ratio (INR, 1.2), while AP and GGT were only slightly elevated (Fig. 1). Serology was negative for acute viral infections (hepatitis A, B, C, E, cytomegalovirus, Epstein-Barr-Virus, herpes virus). Total IgG was elevated up to 24.75 g/L (upper limit of normal: 16 g/L) and antinuclear antibody (ANA, 1:2,560; homogeneous pattern) and anti-double-stranded DNA antibodies (186.8 IU/L; ULN: 100 IU/L) were positive. Anti-mitochondrial-, anti-smooth-muscle- and antineutrophil cytoplasmic antibodies were negative. Liver histology showed a dense lymphoplasmacellular portal infiltrate with involvement of the adjacent lobular parenchyma (interface hepatitis) and discrete presence of rosette formation and apoptotic hepatocytes (Fig. 1). Besides lymphocytes and plasma cells, few eosinophils and small bile ducts with associated neutrophilic granulocytes (ductular reaction) were observed. Hence, we diagnosed AIH and started treatment with prednisone (50 mg) on June 10th with rapidly decreasing liver enzymes. Since the SARS-CoV2-antibody-titer 2 weeks after the 1st vaccination was only weak, we decided to vaccinate a 2nd time on June 19th while the patient was still treated with 50 mg prednisone. Nonetheless, we recorded a further decline of liver enzymes and normalization of INR, bilirubin and of total IgG (14.6 g/L), while prednisone was slowly tapered down and azathioprine (75 mg) was added July 1st. The SARS-CoV2-IgG-antibody-response 2 weeks after the 2nd vaccination was sufficient with >384 BAU/ml. Our case has some unique features when compared to the previous cases. Due to PSC, liver enzymes were well documented before vaccination, leaving no doubt about the temporal coincidence between vaccination and increase of aminotransferases. Although we interpreted the elevated aminotransferases prior to vaccination as a concomitant periductular hepatitis during severe cholangitis, we cannot exclude that a latent AIH may already have existed, which was accelerated by the vaccination. Of note, our patient was without liver-specific symptoms when we diagnosed AIH during routine liver enzyme tests. Since classical AIH takes an asymptomatic subclinical course in about half of cases,9European Association for the Study of the LEASL clinical practice guidelines: autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar this raises the question of whether the 5 symptomatic cases1Bril 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, 2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casualty.J Hepatol. 2021; 75: 728-729Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 3McShane C. Kiat C. Rigby J. Crosbie O. The mRNA COVID-19 vaccine - a rare trigger of autoimmune hepatitis?.J Hepatol. 2021; 75: 1252-1254Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 4Tan 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: 1250-1252Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 5Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar documented so far represent just the tip of the iceberg of mRNA-vaccine triggered AIH. One can speculate whether in the 2 cases that were diagnosed after the 2nd vaccination,2Rocco A. Sgamato C. Compare D. Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casualty.J Hepatol. 2021; 75: 728-729Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,5Londono M.C. Gratacos-Gines J. Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination. Still casualty?.J Hepatol. 2021; 75: 1248-1249Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar a subclinical AIH was already induced after the 1st vaccination and – without treatment - exacerbated after the 2nd vaccination. In our patient, the 2nd vaccination was well tolerated under concomitant therapy with prednisone and induced a sufficient antibody response. In summary, the question arises whether we should be more vigilant, at least in female patients with pre-existing predisposition to autoimmune diseases, and routinely check aminotransferases 2-4 weeks after COVID-19-vaccination. The authors received no financial support to produce this manuscript. TZ and TJW wrote the letter to the editor. TZ, LD, CPS and TJW were involved in the patient's clinical care. FF performed the pathology examination and interpreted the histology. All authors reviewed the final version of the 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 (.38 MB) Help with pdf files Multimedia component 1