Clinical update on risks and efficacy of anti-SARS-CoV-2 vaccines in patients with autoimmune hepatitis and summary of reports on post-vaccination liver injury

Authors: Ana Lleo 1Nora Cazzagon 2Cristina Rigamonti 3Giuseppe Cabibbo 4Quirino Lai 5Luigi Muratori 6Marco Carbone 7Italian Association for the Study of the LiverAffiliations expand PMID: 35410851 PMCID: PMC8958090DOI: 10.1016/j.dld.2022.03.014 Published:March 27, 2022DOI:https://doi.org/10.1016/j.dld.2022.03.014

Abstract

Patients with liver diseases, especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 and therefore anti-SARS-CoV-2 vaccine has been recommended by leading Scientific Associations for all patients with chronic liver diseases. However, previous reports have shown a reduced antibody response following the full course of vaccination in immunosuppressed patients, including liver transplant recipients and several rheumatic diseases.This document, drafted by an expert panel of hepatologists appointed by the Italian Association for the Study of the Liver (AISF), aims to present the updated scientific data on the safety and efficacy of anti-SARS-CoV-2 mRNA vaccines in patients with autoimmune hepatitis (AIH). Furthermore, given the recent reports of sporadic cases of AIH-like cases following anti-SARS-CoV-2 mRNA vaccines, we summarize available data. Finally, we provide experts recommendations based on the limited data available.

1. 2022 AISF recommendation on anti-SARS-CoV-2 vaccines for patients with known autoimmune hepatitis

Patients with chronic liver diseases (CLD), especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 [[1]]. One of the largest international studies currently available, showed an observed mortality of 32% in patients with cirrhosis compared to 8% in those without [[2]]. Therefore, the European Association for the Study of the Liver (EASL) has recommended vaccination against SARS-CoV-2 for all patients with CLD [[3]]. Although contrasting data have been published, patients with AIH with or without cirrhosis under immunosuppressive therapy represent an at-risk category of developing severe COVID-19 when infected [[4],[5]]. Therefore, based on the data available, the benefit of anti-SARS-CoV-2 vaccination outweighs the potential risk for disease exacerbation in AIH.Although the registration trials of mRNA vaccines enrolled patients with CLD (217 patients in Pfizer trial and 196 patients in Moderna trial), subjects under immunosuppressive therapy were excluded. A recent study by Thuluvath and colleagues found that 75% of patients with CLD without cirrhosis and 77% of patients with cirrhosis had adequate antibody response to anti-SARS-CoV2 vaccines [[6]]. The authors included 233 patients with CLD with 61 being affected by immune mediated liver diseases, including AIH, primary biliary cholangitis, and primary sclerosing cholangitis. Also 62 patients were liver transplant (LT) recipients, 79 had cirrhosis, and 92 had CLD without cirrhosis. Antibody levels were undetectable in 11 patients who had LT, 3 with cirrhosis, and 4 without liver cirrhosis. LT and treatment with two or more immunosuppressive drugs were associated with poor antibody responses. However, only 3 patients out of 18 with undetectable antibody were AIH patients on immunosuppression (2 on prednisone plus mycophenolate mofetil (MMF) and 1 on prednisone plus azathioprine).Reports have shown a reduced antibody response following the full course of vaccination in liver transplant recipients [[7]]. It has also been formerly demonstrated that specific drugs (i.e. methotrexate, abatacept, and rituximab) reduced the immune response to influenza or pneumococcal vaccines in a number of different rheumatic diseases [8910]. The efficacy of anti-SARS-CoV-2 vaccination in preventing COVID-19 in patients with AIH on immunosuppressive therapies [[11],[12]], as well as the risk of disease reactivation after anti-SARS-CoV-2 vaccination, have been poorly investigated. Similarly, cellular immunity to SARS-CoV-2 in AIH patients has not been studied.The American College of Rheumatology (ACR) has recently proposed a guidance [[13]] suggesting a short-term withdrawal of methotrexate, JAK inhibitors, abatacept, and MMF, and deferral of rituximab and cyclophosphamide infusion if possible before anti SARS-Cov-2 vaccination, according to rheumatic disease activity. However, there is no solid evidence as to whether it is appropriate or not to suspend or reduce the dose of immunosuppressive drugs immediately before or following the administration of the vaccine in AIH patients. Importantly, this strategy may be potentially associated with an increased risk of AIH reactivation particularly dangerous in patients with cirrhosis. Of interest, high doses of MMF and rituximab remain independent predictors of failure to develop an antibody response after vaccination in rheumatic diseases [[14]]; however, no data are available in AIH. At the present time, the available data do not justify withdraw or reduction of immunosuppression before or immediately after vaccination in patients with AIH.Finally, no clear evidence of reactivation of AIH after anti-SARS-CoV-2 vaccination has been reported in the literature. Interestingly, the presence of significant fibrosis at the liver histology of a small number of newly diagnosed AIH following anti-SARS-CoV-2 vaccination might suggest the possibility of disease reactivation [151617]. However, until new multicenter studies are available there is no current indication for routine testing of transaminases levels in AIH patients after vaccination.

2. 2022 aisf recommendation on autoimmune hepatitis like onset following anti-SARS-CoV-2 vaccination

The COVID-19 pandemics has necessitated the development and registration of several vaccines in record time. The monitoring for safety, side effect and efficacy is ongoing in the post-marketing surveillance. Recent reports inform on the possible occurrence of immune mediated hepatitis or AIH-like disease in predisposed individuals. Autoimmunity is widely accepted to develop in genetically predisposed individuals and some polymorphisms have been identified in AIH [[18]]; unfortunately, they are not yet of clinical use and cannot be of help to identify individuals at risk.Considering that 58% of the world population has received at least one dose of anti-SARS-CoV-2 vaccine, with 9.2 billion doses been administered globally, it is unclear whether this is a pure coincidence rather than a causality.The fact that someone developed immune-mediated acute hepatitis after vaccination does not necessarily mean that this was caused by the vaccine.The European Medicine Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) has recently started an assessment following the very small number of cases reported after vaccination with Spikevax and Comirnaty (known as Moderna and Pfizer vaccines, respectively) in the medical literature and EudraVigilance (www.ema.europa.eu). Further data and analyses have been requested from the marketing authorization holder to support the ongoing assessment by PRAC. Given the small number of cases currently reported, the issue seems to be rare; however, specific studies should be performed to define the number and severity of cases.At the time these recommendations are drafted, 17 reports have been published in the medical literature that overall include 31 cases of suspected AIH-like triggered by the vaccine (Table 1). Patients were more often women (F:M 21:10), age ranging from 32 to 89 years old (median 58 years). In eleven cases a pre-existent autoimmune condition (i.e., seven Hashimoto thyroiditis, one primary biliary cholangitis, two rheumatoid arthritis, one systemic lupus erythematosus) is reported. Two patients had experienced COVID-19 infection before the vaccine. All except four presented with an acute onset of AIH-like with jaundice. All patients underwent liver biopsy and in six of them fibrosis was already present, which might suggest that they had a previous liver disease, possibly an undiagnosed AIH. All were treated with steroid therapy, and all improved the liver function tests (LFTs), although details on the biochemical response are not thoroughly reported.Table 1Cases of suspected AIH triggered by the vaccine reported in the literature.

ReferenceVaccinePatient’s characteristicsClinical presentation and laboratory dataTherapyOutcome
Age, genderAutoimmune comorbiditiesPrevious COVID-19 infectionOther comorbidities
Avci & Abasiyanik [15]mRNAPfizer/BioNTech,1 month before61, FHashimoto thyroiditisYes, mild, 8 months beforeHypertensionAcute icteric ANA, ASMA, hyper-IgG, fibrosis F2,Prednisolone + azathioprine add-on35 days follow-up, mild transaminases and bilirubin
Bril et al. [16]mRNAPfizer/BioNTech,7 days before35, FNot reportedNoGestational hypertension and cesarian section 3 months beforeAcute icteric, normal IgG, no fibrosisPrednisone 20 mg/day50 days follow-up, transaminases normalization
Cao et al. [17]Inactivated whole-virion SARS-CoV2 (Coronavac)57, FNot reportedNoNot reportedAcute icteric, pruritus IgG slight elevation, ANA+, Fibrosis F2Methylprednisolone, UDCA + azathioprine add-on5 months follow-up, no relapse
Clayton-Chubb et al. [23]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 26 days before36, MNoNoHypertension, laser eye surgery 2 weeks beforeAcute, sub-icteric, asymptomatic, ANA+, normal IgG, no fibrosisPrednisolone 60 mg/day24 days, normalization of bilirubin, marked reduction of ALT
Garrido et al. [24]mRNA Moderna, 2 weeks before65, FNoNoPolycythemia vera under PEG-IFNAcute icteric severe, ANA, hyper-IgG, no fibrosisPrednisolone 60 mg/day1 month, improvement of LFTs and IgG normalization
Ghielmetti et al. [25]mRNA-1273, 7 days before63, MNoNo, unknown but anti-cardiolipin+Type 2 diabetes, ischemic heart diseaseAcute icteric, hyper-IgG, ANA+, AMA+ (different from PBC) APCA+, no fibrosisPrednisone 40 mg/day, rapidly tapered14 days follow-up
Goulas et al. [26]mRNA Moderna, 2 weeks before52, FNoNoAcute icteric, ANA+, ASMA+, hyper-IgG, no fibrosis reportedPrednisolone 50 mg/day, azathioprine add-onUnknown
Londono et al. [27]mRNA Moderna, 7 days after the II dose41, FNot reportedNoHormonal therapy for premature ovarian failureAcute icteric, ANA, ASMA, anti-SLA/LC+, hyper-IgG, no fibrosisPrednisone 1 mg/KgNormalization of LFTs
Palla et al. [28]mRNAPfizer/BioNTech 1 month after II dose40, FSarcoidosisTransaminases 3–4 x ULN fluctuation, ANA+, hyper-IgG, active hepatitis, fibrosis with septaPrednisolone 40 mg/dayTransaminases decline after 7 days of prednisolone
Rela et al. [29]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 20 days before38, FNo (hypothyroidism?)NoHypothyroidismAcute icteric, ANA+, IgG mildly elevated, multiacinar hepatic necrosis, no fibrosisPrednisolone 30 mg/day and tapering after 4 weeks1 month of follow-up normal LFTs
ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 16 days before62, M2 episodes of jaundice resolved with native medicationAcute severe AIH, autoantibodies negative, mild fibrosisPrednisolone 30 mg/day + plasma exchange 5 cyclesPersistent cholestasis → death in 21 days for economic constraints regarding liver transplantation
Rocco et al. [30]Pfizer/BioNTech 1 week before (II dose)89, FHashimoto thyroiditisNoPrevious acute glomerulonephritis, pravastatin and low-dose aspirin for primary preventionAcute icteric, ANA+, hyper-IgG, no fibrosisPrednisone 1 mg/Kg/day and tapering3 months of follow-up, progressive improvement
Tan et al. [31]mRNA Moderna, 6 weeks before56, FNot reportedNoRosuvastatinAcute icteric, ANA+, ASMA+, hyper-IgG, also eosinophil, early fibrosisBudesonide1 week of follow-up
Tun et al. [32]mRNA Moderna, 3 days before (I dose) and 2 days before (II dose)47, MNot reportedNoNot reportedAcute icteric, ANA+ hyper-IgG, rapidly resolved and then reappeared 2 days after the II dose, minimal fibrosisPrednisolone 40 mg/day2 weeks of follow-up PT normalized
Vuille-Lessard et al. [33]mRNA Moderna, 3 days before76, FHashimoto thyroiditisYes, 3 months before (mild disease)Prior urothelial carcinomaAcute icteric, hyper-IgG, ANA+, ASMA+, ANCA+, steatosis, active AIH, fibrosis not evaluablePrednisolone 40 mg/day + azathioprine add-on 2 weeks after4 months follow-up: LFTs normalization after 4 weeks, stop azathioprine and 6 weeks after no relapse
Suzuki Y et al. [34]mRNA Pfizer/BioNTech 10 days before (II dose)80, FNot reportedNot reportedGastroesophageal reflux esophagitisAcute icteric, ANA+, hyper-IgGPrednisone at an initial dose of 0.8 mg/kg/day, then tapered to 10 mg/week50 days of follow-up: transaminases normalization
mRNA Pfizer/BioNTech 4 days before (II dose)75, FNot reportedNot reportedDyslipidemiaAcute icteric, ANA+, AMA +, hyper-IgGPrednisone at an initial dose of 1 mg/kg/day, then tapered to 10 mg/week105 days of follow-up: transaminases normalization
mRNA Pfizer/BioNTech 7 days before (I dose)78, FPrimary biliary cholangitisNot reportedNoAcute, ANA+, AMA+, hyper IgGPrednisone at an initial dose of 0.6 mg/kg/day, then tapered to 10 mg/week103 days of follow-up: transaminases normalization
Torrente et al. [35]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 3 weeks before49, FHypothyroidism (?), ANA+NoHypothyroidism treated with levothyroxineAcute AIH, ANA+, hyper-IgG, no fibrosisPrednisone 30 mg/day then tapering and azathioprine add-onTransaminases decrease after 2 weeks
Rigamonti C et al. [36]mRNAPfizer/BioNTech, 7 patientsmRNA Moderna, 2 patientsChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca),3 patientsmedian age 62 years (range 32–80)6 F, 6 M3 thyroiditis,2 rheumatoid arthritis,1 systemic lupus erythematosus10 acute onset,8 jaundice,8 positive autoantibodies (6 ANA, 1 SMA, 1 LKM-1)Prednisone / prednisolone +/- azathioprinemedian follow-up 3 months: 58% complete biochemical response
Efe C et al. [37]mRNAPfizer/BioNTech, 1 patient53, MNoneNot reportedNoneAcute icteric hepatitis, no ANA, hyper-IgG, no fibrosisprednisolone (40 mg/day) and plasma exchangeLiver transplantation

Adverse effects of the vaccine are possible, and abnormal liver function tests following vaccination represent an important clinical issue. AIH is a relatively rare, chronic immune-mediated liver disease, which develops in genetically predisposed individuals following environmental triggers; viral infections and drug exposures have been suggested to trigger the disease, but not definitive evidence is available [[19],[20]]. AIH-like onset after vaccination – other than anti-SARS-CoV-2 – has been also previously reported [[21]]. However, even if it can be speculated that the vaccines can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells, it might be hard to definitively state that AIH is induced by a vaccine. Considering the reported AIH-like cases following SARS-CoV-2 vaccination, timing of occurrence of acute hepatitis from vaccination in some of them is very short (less than 7 days), suggesting that a dysregulation of immune system has already occurred before vaccination in those cases. So far, given the availability of only observational literature without a structured collection of AIH-like cases after anti-SARS-CoV-2 vaccines, no definitive conclusions can be drawn. There is a need for population-based studies to gather data on the incidence, severity, and clinical features of anti-SARS-Cov-2 vaccination-induced AIH under the umbrella of the national and European Scientific Societies.In the meantime, while intensive vaccination against SARS-CoV-2 continues, healthcare providers should include the diagnosis of AIH triggered by vaccines in the differential diagnosis in cases of acute hepatitis of unexplained etiology and manage them as drug-induced AIH or AIH-like liver injury as recommended by current guidelines [[22]].

3. RECOMMENDATIONS

*These recommendations will be reviewed periodically as further information becomes available.

  • •AIH patients should receive anti-SARS-CoV-2 vaccination consistent with the age restriction of the local approval. In Italy, as recommended by the Italian Ministry of Health for all immunosuppressed patients, mRNA vaccines should be used. Based on the data for the mRNA vaccines available, there is no preference for one vaccine over another.
  • Patients with AIH are suggested to undergo vaccination when the disease activity is controlled by immunosuppressive therapy. To date there are no data available to establish variations on the interval between doses of anti-SARS-Cov2 vaccine.
  • There is no current evidence to recommend suspension or reduction of immunosuppressive drugs in AIH patients before or immediately after anti-SARS-CoV-2 vaccination.
  • The risk of AIH flare or disease worsening following anti-SARS-Cov-2 vaccination has not been assessed to date and specific studies are required before defining a line of recommendation. Based on available data routine testing of transaminases levels in AIH patients after vaccination could be suggested in selected patients although the timing needs to be defined.
  • •Testing of antibody levels for IgM and/or IgG to spike or nucleocapsid proteins to assess immunity to SARS-Cov2 after vaccination in AIH patients is not recommended, nor to assess the need for vaccination in an unvaccinated AIH patients.
  • Patients with new acute onset of liver injury following anti-SARS-Cov-2 vaccine should be managed as suggested by current guidelines and known clinical algorithms, including the indication to liver biopsy. Considering the lack of evidence currently available to exclude drug induced AIH in this setting, immunosuppressive therapy should be carefully considered and used if AIH diagnosis is confirmed; long-term immunosuppressive therapy needs to be assessed on a patient-by-patient basis.
  • Patients with newly diagnosed AIH or AIH flare after anti-SARS-Cov-2 vaccine should be consider for vaccine booster; however, the timing of the booster could be personalised based on the disease activity and ongoing therapy and discussed case-by-case with an expert center in autoimmune liver diseases.
  • Given the limited number of cases compared to the number of vaccinated subjects, extended testing of transaminases level after vaccination in the general population is not sustainable nor suggested.
  • EMA’s PRAC encourages all healthcare professionals and patients to report any cases of autoimmune hepatitis and other adverse events in people after vaccination.

Autoimmune hepatitis after SARS-CoV-2 vaccine: New-onset or flare-up?

Authors: Enver Avci 1Fatma Abasiyanik 2

Autoimmune 2021 Dec;125: 102745. doi: 10.1016/j.jaut.2021.102745  Epub 2021 Nov 11. PMID:  34781161PMCID: PMC8580815DOI: 10.1016/j.jaut.2021.102745

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported to trigger several autoimmune diseases. There are also recent reports of autoimmune diseases that develop after SARS-CoV-2 vaccines. Autoimmune hepatitis is a polygenic multifactorial disease, which is diagnosed using a scoring system. A 61-year-old woman presented with malaise, fatigue, loss of appetite, nausea and yellow eyes. She had a Pfizer/BioNTech BNT162b2 mRNA vaccine a month ago. Her physical examination revealed jaundice all over the body, especially in the sclera. The laboratory tests showed elevated liver enzymes and bilirubin levels. Antinuclear antibody and anti-smooth muscle antibody were positive and immunoglobulin G was markedly elevated. The liver biopsy revealed histopathological findings consistent with autoimmune hepatitis (AIH). The patient was diagnosed with AIH and initiated on steroid therapy. She rapidly responded to steroid therapy. A few cases of AIH have been reported after the COVID-19 vaccine so far. Although the exact cause of autoimmune reactions is unknown, an abnormal immune response and bystander activation induced by molecular mimicry is considered a potential mechanism, especially in susceptible individuals. As intensive vaccination against SARS-CoV-2 continues, we would like to emphasize that clinicians should be cautious and consider AIH in patients presenting with similar signs and symptoms.

References

  1. Liu Y., Sawalha A.H., Lu Q. COVID-19 and autoimmune diseases. Curr. Opin. Rheumatol. 2021;33(2):155–162. doi: 10.1097/BOR.0000000000000776. Mar 1. – DOI – PMC – PubMed
  2. Oldstone M.B. Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclon. Antibodies Immunodiagn. Immunother. 2014;33(3):158–165. doi: 10.1089/mab.2013.0090. – DOI – PMC – PubMed
  3. E Oliver S., Gargano J.W., Marin M., Wallace M., Curran K.G., Chamberland M., et al. The advisory committeeon immunization practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine: United States, December 2020. MMWR Morb. Mortal. Wkly. Rep. 2020;69(50):1922–1924. – PMC – PubMed
  4. Allergic reactions including anaphylaxis After receipt of the first dose of pfizer-BioNTech COVID-19 vaccine – United States, December 14-23, 2020. MMWR Morb. Mortal. Wkly. Rep. 2021;70:46–51. doi: 10.15585/mmwr.mm7002e1. – DOI – PMC – PubMed
  5. Christen U., Hintermann E. Pathogen infection as a possible cause for autoimmune hepatitis. Int. Rev. Immunol. 2014;33:296–313. doi: 10.3109/08830185.2014.921162. – DOI – PubMed
  6. Floreani A., Leung P.S., Gershwin M.E. Environmental basis of autoimmunity. Clin. Rev. Allergy Immunol. 2016;50:287–300. doi: 10.1007/s12016-015-8493-8. – DOI – PubMed
  7. Perumalswami P., Peng L., Odin J.A. Vaccination as a triggering event for autoimmune hepatitis. Semin. Liver Dis. 2009;29:331–334. doi: 10.1055/s-0029-1233537. – DOI – PubMed
  8. 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. 2021:222–224. doi: 10.1016/j.jhep.2021.04.003. – DOI – PMC – PubMed
  9. Tan C.K., Wong Y.J., Wan L.M., Ang T.L., Kumar R. Autoimmune hepatitis following COVID-19 vaccination: true causality or mere association? J. Hepatol. 2021 doi: 10.1016/j.jhep.2021.06.009. – DOI – PMC – PubMed
  10. Mcshane C., Kiat C., Rigby J., Crosbie O. The mRNA Covid-19 vaccine-A rare trigger of autoimmune hepatitis? J. Hepatol. 2021 doi: 10.1016/j.hep.2021.06.044. – DOI – PMC – PubMed
  11. Londono M.C., Gratacos-Gines J., Saez-Penataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination.Still casualty? J. Hepatol. 2021 doi: 10.1016/j.jhep.2021.06.004. – DOI – PMC – PubMed
  12. Clayton-Chubb D., Schneider D., Freeman E., Kemp W., Roberts S.K. 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 doi: 10.1016/j.jhep.2021.06.014. – DOI
  13. Lodato 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 doi: 10.1016/j.jhep.2021.07.005. – DOI – PMC – PubMed
  14. Rocco A., Sgamato C., Compare D., Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casuality. J. Hepatol. 2021:728–729. doi: 10.1016/j.jhep.2021.0538. – DOI – PMC – PubMed
  15. Lessard E.V., Montani M., Bosch J., Semmo N. Autoimmune hepatitis triggered by SARS-CoV-2 vaccination. J. Autoimmun. 2021 doi: 10.1016/j.jaut.2021.102710. – DOI – PMC – PubMed
  16. Rela M., Jothimani D., Vij M., Rajakumar A., Rammohan A. Auto-immune hepatitis following COVID vaccination. J. Autoimmun. 2021 doi: 10.1016/j.jaut.2021.102688. – DOI – PubMed
  17. Ghielmetti M., Schaufelberger H.D., Mieli-Vergani G., Cerny A., Dayer E., Vergani D., Beretta-Piccoli T.B. Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination:A novel clinical entitiy? J. Autoimmun. 2021 doi: 10.1016/j.jaut.2021.102706. – DOI – PMC – PubMed
  18. Perumalswami P., Peng L., Odin J.A. Vaccination as a triggering event for autoimmune hepatitis. Semin. Liver Dis. 2009;29:331–334. doi: 10.1055/s-0029-1233537. – DOI – PubMed
  19. Vadala M., Poddighe D., Laurino C., Palmieri B. Vaccination and autoimmune diseases:is prevention of adverse health effects on the horizon? EPMA J. 2017;8:295–311. doi: 10.1007/s13167-017-0101-y. – DOI – PMC – PubMed
  20. Manns M.P., Czaja A.J., Gorham J.D., Krawitt E.L., Mieli-Vergani G., Vergani D., Vierling J.M. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213. doi: 10.1002/hep.23584. – DOI – PubMed
  21. Czaja A.J. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatoloy. 2008;48:1540–1548. doi: 10.1002/hep.22513. – DOI – PubMed
  22. Kogan J J., Safadi R., Ashur Y., Shouval D., Ilan Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J. Clin. Gastroenterol. 2002;35:75–81. – PubMed
  23. Czaja A.J. Features and consequences of untreated type 1 autoimmune hepatitis. Liver Int. 2009;29:816–823. doi: 10.1111/j.1478-3231.2008.01904.x. – DOI – PubMed

Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Authors: Seong Hee Kang 1 2Moon Young Kim 1 3Mee Yon Cho 4Soon Koo Baik 1 5Affiliations expandPMID: 35437965PMCID: PMC9015903DOI: 10.3346/jkms.2022.37.e116

J Korean Med Sci 2022 Apr 18;37(15):e116. doi: 10.3346/jkms.2022.37.e116.

Abstract

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body’s immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.
Go to:Graphical Abstract

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic, putatively caused by the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in 257,469,528 laboratory-confirmed cases of infection and 5,158,211 deaths globally as of November 28, 2021.1 Rapid vaccine development, however, has significantly mitigated severe COVID-19 illness. Two messenger RNA (mRNA) COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech, New York, NY, USA/Mainz, Germany) and mRNA-1273 (Moderna, Cambridge, MA, USA), were granted emergency use authorization by the United States Food and Drug Administration in December 2020. SARS-CoV-2 infection has been associated with the development of autoimmune processes.2 Because SARS-CoV-2 harbors the same protein motif the mRNA vaccine codes for, it is plausible that these vaccines could trigger autoimmune diseases in predisposed patients.34 Autoimmune hepatitis (AIH) is a polygenic multifactorial disease that may be triggered by specific environmental factors, such as viral infections, resulting in the loss of self-tolerance to autoantigens in genetically susceptible individuals.5

Go to:CASE DESCRIPTION

We treated a 27-year-old female nurse who developed AIH after COVID-19 vaccination. She had no known history of liver disease and did not use herbal remedies or alcohol. She received a second dose of the Pfizer-BioNTech COVID-19 vaccine on March 30, 2021, and, since April 6, 2021, symptoms of nausea, vomiting, headache, fever, and dark urine continued. Accordingly, she was hospitalized via the emergency room 14 days after COVID-19 vaccination. A COVID-19 polymerase chain reaction test, performed at the local hospital on April 7 and 12, 2021, was negative. The physical examination was unremarkable, except for scleral icterus, jaundice, and palpable hepatomegaly. In the emergency room, laboratory investigations were significant for the following: bilirubin, 8.6 mg/dL; aspartate aminotransferase (AST), 1,004 U/L; alanine aminotransferase (ALT), 1,478 U/L; alkaline phosphatase, 182 U/L, white blood cell count, 6,720/μL (neutrophils, 46.8%); hemoglobin, 13.0 g/dL; platelet count 373,000/μL; blood urea nitrogen/creatinine, < 5.0/0.54 mg/dL (estimated glomerular filtration rate, 145.0 mL/min/1.73 m2); and prothrombin international normalized ratio, 1.1. Laboratory results were negative for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus types 1 and 2, and human immunodeficiency virus. Antinuclear antibody (ANA) was positive (1:80; mixed pattern). Other antibodies (including anti-mitochondrial, anti-smooth muscle, liver-kidney microsomal, and antineutrophil cytoplasmic antibodies) were negative. Total immunoglobulin G (IgG) level was 1,641 mg/dL (normal range, 549–1,584 mg/dL). Ceruloplasmin, transferrin saturation, thyroid function test, and serum protein electrophoresis were all normal. Abdominal ultrasound revealed splenomegaly (12.5 cm) without cirrhosis and gallbladder wall thickening.

Liver dynamic computed tomography revealed no evidence of biliary lithiasis or biliary dilation, and ultrasound-guided transabdominal liver biopsies were obtained. In microscopic examination, 17 portal tracts were identified. Although there was a focal bridging, the overall lobular architecture was preserved in the low magnification. Some portal tracts were widened by moderate inflammation with periportal fibrosis (Fig. 1). The portal inflammation was composed of mainly lymphocytes, clusters of plasma cells and few eosinophils, extending into proto-lobular interface (interface hepatitis) (Fig. 2A). The immunohistochemical staining for plasma cell markers, MUM1 and CD138 confirmed significant plasma cell infiltration in portal tracts as well as in lobules (Fig. 2B). Diffuse moderate necroinflammatory damage in lobules, associated with perivenular hepatocytes degeneration, mild cholestasis with hepatocytic rosettes (Fig. 2C) and sinusoidal inflammation were found. Other than COVID-19 vaccination, no other drug, herbal supplement, or toxin use were reported by the patient. The revised original score for AIH pretreatment was 18 (results > 15 suggest definite AIH). Treatment with oral prednisolone (40 mg daily) was initiated. Plasma ALT, AST, and total bilirubin levels over time, and before and after treatment, are summarized in Fig. 3. After three weeks of treatment, diarrhea and fever developed, and she was transferred to the hospital’s emergency room. Treatment with prednisolone (20 mg daily) was discontinued with the diagnosis of enteritis. Four days after admission, symptoms were relieved, and she was discharged from hospital with steroid discontinuation. Two weeks after stopping therapy, there were biochemical signs of an AIH relapse; therefore, treatment with oral prednisolone (10 mg daily) was restarted. Liver enzyme levels were completely normalized and the patient’s symptoms significantly improved.


Fig. 1
The microphotograph of low magnification of liver biopsy shows portal widening with periportal fibrosis (A) hematoxylin and eosin ×100, (B) Masson trichrome ×100.Click for larger imageDownload as PowerPoint slide

Fig. 2
Histological finding. (A) The porto-lobular interface shows severe inflammation composed of lymphocytes, clausters of plasma cells (circle) and a few eosinophils. Bile ducts (closed arrow) are not damaged (H&E, ×400). (B) The photomicrography of MUM1 immunohistochemical stain demonstrates numerous plasma cell infiltration (×400). (C) The lobules show diffuse degeneration of hepatocytes, mild cholestasis in hepatocytic rosettes (opened arrow) and sinusoidal lymphoplasma cells infiltration (H&E ×400).
H&E = hematoxylin and eosin.Click for larger imageDownload as PowerPoint slide

Fig. 3
Trends of serum ALT, AST and total bilirubin over time.
ALT = alanine aminotransferase, AST = aspartate aminotransferase.Click for larger imageDownload as PowerPoint slide

We described a case of AIH that developed in a patient after vaccination with the Pfizer-BioNTech COVID-19 vaccine, which was resolved with steroid treatment. To date, four cases of AIH have been reported after Pfizer-BioNTech COVID-19 vaccination in the literature (Table 1)678, the first of which was reported by Bril et al.3 The patient was a 35-year-old woman in her third month postpartum who developed AIH after COVID-19 vaccination. In this case, AIH exhibited some atypical features: autoantibodies other than ANA were negative and eosinophils were present on liver histology. Similarly, Lodato et al.6 reported a case of AIH occurring after vaccination, with no development of autoantibodies and eosinophil infiltrate in liver histology. Thereafter, two patients had a history of Hashimoto’s disease, high IgG levels, and typical findings on biopsy, unlike the above cases.78 Although our patient had no autoimmune disease, autoantibodies were positive, and IgG level was high. In addition, our case had typical findings on biopsy and responded well to steroid therapy. It is thought to be a new-onset AIH triggered by COVID-19 vaccination, but periportal fibrosis was observed in histological examination. However, in case with acute onset, there may be minimal fibrosis. Moreover, symptoms developed after the second vaccination in this patient, but there is a possibility that inflammation may have occurred even though there were no symptoms after the first vaccination.


Table 1
Characteristics of patients with autoimmune hepatitis after Pfizer-BioNTech COVID-19 vaccineClick for larger imageClick for full tableDownload as Excel file

Because causality cannot be definitively confirmed, it is possible that this association was coincidental. However, severe cases of SARS-CoV-2 infection are characterized by autoinflammatory dysregulation.9 Because the viral spike protein appears to be responsible, it is plausible that spike-directed antibodies induced by vaccination may also trigger autoimmune conditions in predisposed individuals.10 In support of this, several cases of immune thrombocytopenia have been reported days after COVID-19 vaccination. Vaccines protect the host from the virus by inducing antibody generation against viral peptides.11 Autoimmunity can develop due to cross-reactivity to the generated antibodies. The epitopes used for induction of the host immune system may mimic the structure of self-peptides, and antibodies that develop after vaccination may cause cross-reactivity directed to the self.12

Given the close temporal relationship between vaccination and onset of symptoms, we hypothesized that vaccination against COVID-19 could have triggered the development of AIH in our patient. To the best of our knowledge, this is the first reported episode of AIH that developed post-COVID-19 vaccination in Korea. Whether a causal relationship exists between COVID-19 vaccination and the development of AIH remains to be determined. Nevertheless, it is necessary to raise awareness about potential side effects that will likely emerge as more individuals are vaccinated.

1. World Health Organization. Global surveillance for COVID-19 caused by human infection with COVID-19 virus: interim guidance 2020. [Updated 2020]. [Accessed November 28, 2021].https://apps.who.int/iris/handle/10665/331506.2. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol 2021;33(2):155–162.

3. Bril F, Al Diffalha S, Dean M, Fettig DM. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J Hepatol 2021;75(1):222–224.

4. Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol 2021;96(5):534–537.

5. Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol 2004;20(3):231–240.

6. Lodato F, Larocca A, D’Errico A, Cennamo V. An unusual case of acute cholestatic hepatitis after m-RNABNT162b2 (Comirnaty) SARS-CoV-2 vaccine: coincidence, autoimmunity or drug-related liver injury. J Hepatol 2021;75(5):1254–1256.

7. Rocco A, Sgamato C, Compare D, Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casuality. J Hepatol 2021;75(3):728–729.

8. Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J Autoimmun 2021;125:102745

9. Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. COVID-19 and autoimmunity. Autoimmun Rev 2020;19(8):102597

10. 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. Clin Immunol 2020;217:108480

11. Sadarangani M, Marchant A, Kollmann TR. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat Rev Immunol 2021;21(8):475–484.

12. Malonis RJ, Lai JR, Vergnolle O. Peptide-based vaccines: current progress and future challenges. Chem Rev 2020;120(6):3210–3229.