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Immune-mediated liver injury represented as overlap syndrome after SARS-CoV-2 vaccination

  • Soon Kyu Lee
    Correspondence
    Corresponding authors. Addresses: Department of Internal Medicine, Incheon St. Mary's Hospital, #56 Dongsu-ro, Bupyeong-gu, Incheon, Republic of Korea; Tel.: +82-31-280-5018; fax. +82-2-3481-4025 (S.K. Lee)
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
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  • Jung Hyun Kwon
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
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  • Nara Yoon
    Affiliations
    Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
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  • Sung Hak Lee
    Affiliations
    Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
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  • Pil Soo Sung
    Correspondence
    Department of Internal Medicine, Seoul St. Mary's Hospital, #222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea; Tel. +82-2-2258-2073; fax. +82-2-3481-4025 (P.S. Sung).
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Republic of Korea
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      • SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis
        Journal of HepatologyVol. 77Issue 3
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          Autoimmune hepatitis episodes have been described following SARS-CoV-2 infection and vaccination but their pathophysiology remains unclear. Herein, we report the case of a 52-year-old male, presenting with bimodal episodes of acute hepatitis, each occurring 2-3 weeks after BNT162b2 mRNA vaccination. We sought to identify the underlying immune correlates. The patient received oral budesonide, relapsed, but achieved remission under systemic steroids.
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      To the Editor:
      We read an interesting article entitled “SARS-CoV-2 vaccination can elicit a CD8+ T-cell dominant hepatitis” by Boettler et al.,
      • Boettler T.
      • Csernalabics B.
      • Salié H.
      • Luxenburger H.
      • Wischer L.
      • Alizei E.S.
      • et al.
      SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis.
      recently published in the Journal of Hepatology, demonstrating SARS-CoV-2-specific T-cell-dominant immune-mediated hepatitis after vaccination. This phenomenon may account for the association between SARS-CoV-2 vaccination and autoimmune hepatitis (AIH)-like conditions including overlap syndrome. Herein, we describe a case of overlap syndrome after SARS-CoV-2 vaccination.
      Case: A 57-year-old woman without a history of medical diseases and taking hepatotoxic drugs or alcohol was referred to the clinic for general weakness. She used to have normal liver function tests in a routine medical check-up. Two weeks after the first dose of SARS-CoV-2 Pfizer/BioNTech BNT162b2 mRNA vaccine, she started developing fatigue and general weakness. Her physical examination was normal; however, laboratory tests were significant for total bilirubin, 1.2 mg/dl; aspartate aminotransferase, 635 U/L; alanine aminotransferase, 870 U/L; alkaline phosphatase, 250 U/L; gamma-glutamyl transferase, 210 U/L; and international normalized ratio, 1.02. Laboratory results were negative for hepatitis A, B, C, and E, Epstein-Barr virus (EBV), cytomegalovirus, and herpes simplex virus (HSV) types 1 and 2. Autoantibody tests were positive for antinuclear antibody (ANA, 1:160; homogeneous pattern) and anti-mitochondrial M2 antibody (AMA-M2), while the test for anti-smooth muscle antibody was negative. The immunoglobulin G level was 1,532 mg/dl (normal range: 800–1,800 mg/dl). Abdominal ultrasound findings were normal, without evidence of abnormal findings in the biliary tract and liver. A percutaneous liver biopsy was performed, revealing moderate portal inflammation with CD3+ T-cell-dominant infiltration along with CD38+ cells suggesting plasma cells, interface hepatitis, rosette formation, and piecemeal necrosis. Moreover, nonsuppurative and granulomatous cholangitis with destruction and proliferation of the bile duct, was also noted, which was compatible with the findings of overlap syndrome (Fig. 1A).
      EASL Clinical Practice Guidelines
      The diagnosis and management of patients with primary biliary cholangitis.
      ,
      • Lindor K.D.
      • Bowlus C.L.
      • Boyer J.
      • Levy C.
      • Mayo M.
      Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases.
      Taken together, the revised original score for AIH was 13 (results ≥10 suggest probable AIH) and the Paris criteria for AIH-primary biliary cholangitis (PBC) overlap syndrome was satisfied.
      • Alvarez 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.
      ,
      • Chazouillères O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      After treatment with high-dose ursodeoxycholic acid (13 mg/kg), her laboratory findings normalized in 2 weeks (Fig. 1B).
      Figure thumbnail gr1
      Fig. 1Histopathological findings and clinical course of the patient.
      (A) On H&E staining, moderate-to-severe portal inflammation, piecemeal necrosis, interface hepatitis (left upper, yellow arrows), and rosette formation (right upper, yellow arrowhead) was noted. CD3+ T-cell-dominant infiltration (left middle, black arrows) along with CD38+ cells (right middle, black arrowhead) were also identified. Nonsuppurative and granulomatous cholangitis with destruction and proliferation of the bile duct was also noted on CK-19 (left lower, black arrowhead) and CD68 (right lower, black arrows) staining. (B) The patient was treated with high-dose UDCA (13 mg/kg), and laboratory findings normalized in 2 weeks. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; UDCA, ursodeoxycholic acid. (This figure appears in color on the web.)
      Several reports have documented the possibility of an association between the development of AIH and SARS-CoV-2 vaccination or infection.
      • Bril F.
      • Al Diffalha S.
      • Dean M.
      • Fettig D.M.
      Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty?.
      ,
      • Marjot T.
      • Buescher G.
      • Sebode M.
      • Barnes E.
      • Barritt ASt
      • Armstrong M.J.
      • et al.
      SARS-CoV-2 infection in patients with autoimmune hepatitis.
      This association has been thought to be attributable to molecular mimicry between the spike protein S1 of SARS-CoV-2, a viral protein coded by the mRNA vaccine, and human tissue proteins.
      • Vojdani A.
      • Kharrazian D.
      Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases.
      ,
      • Kanduc D.
      • Shoenfeld Y.
      Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.
      Finally, Boettler et al.
      • Boettler T.
      • Csernalabics B.
      • Salié H.
      • Luxenburger H.
      • Wischer L.
      • Alizei E.S.
      • et al.
      SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis.
      successfully demonstrated that AIH-like conditions could be caused by activated CD8+ T cells, including vaccine-induced spike-specific CD8+ T cells. These novel findings provide insights into the strong association between the development of AIH-like hepatitis and SARS-CoV-2 vaccination, which can also be applied to our case.
      In our patient, CD3+ T cells were also dominant among the infiltrating inflammatory cells of the portal area. Although virus-specific CD8+ T cells were not identified in our case, most of the infiltrated T cells might be SARS-CoV-2 specific CD8+ T cells according to the results of Boettler et al.,
      • Boettler T.
      • Csernalabics B.
      • Salié H.
      • Luxenburger H.
      • Wischer L.
      • Alizei E.S.
      • et al.
      SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis.
      which could be attributable to the development of overlap syndrome in our case. Interestingly, in our patient, non-suppurative and granulomatous cholangitis with destruction and proliferation of the bile ducts was identified, suggesting the presence of combined PBC.
      EASL Clinical Practice Guidelines
      The diagnosis and management of patients with primary biliary cholangitis.
      ,
      • Lindor K.D.
      • Bowlus C.L.
      • Boyer J.
      • Levy C.
      • Mayo M.
      Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases.
      ,
      • Tanaka A.
      Current understanding of primary biliary cholangitis.
      As PBC also develops with the interaction of immune and biliary pathways, including recruited CD4+ and CD8+ T cells,
      • Tanaka A.
      Current understanding of primary biliary cholangitis.
      SARS-CoV-2-specific CD8+ T cells might have contributed to the development of overlap syndrome in our patient following SARS-CoV-2 vaccination. In conclusion, our case supports the notion that SARS-CoV-2-specific T cells can cause AIH-like conditions, including overlap syndrome, after SARS-CoV-2 vaccination.

      Financial support

      This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (No. 2021R1I1A1A01050954; S.K.L.). This work was also principally supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2020R1A2C3011569; P.S.S.).

      Authors’ contributions

      Soon Kyu Lee: Study concept and design, data acquisition and interpretation, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Jung Hyun Kwon: Acquisition of data. Nara Yoon and Sung Hak Lee: Analysis and interpretation of data. Pil Soo Sung: Study concept and design and critical revision of the manuscript for important intellectual content.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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