Sato K. Liver injury after COVID-19 vaccination: Current status and future perspectives. World J Hepatol 2026; 18(5): 116542 [DOI: 10.4254/wjh.v18.i5.116542]
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Ken Sato, MD, PhD, Professor, Department of Healthcare Informatics, Takasaki University of Health and Welfare, 37-1 Nakaorui-machi, Takasaki 370-0033, Japan. satoken@gunma-u.ac.jp
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Sato K. Liver injury after COVID-19 vaccination: Current status and future perspectives. World J Hepatol 2026; 18(5): 116542 [DOI: 10.4254/wjh.v18.i5.116542]
Author contributions: Sato K designed the overall concept and contributed to the writing, editing, and revision of the manuscript, illustrations, and literature review.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Ken Sato, MD, PhD, Professor, Department of Healthcare Informatics, Takasaki University of Health and Welfare, 37-1 Nakaorui-machi, Takasaki 370-0033, Japan. satoken@gunma-u.ac.jp
Received: November 17, 2025 Revised: January 18, 2026 Accepted: March 12, 2026 Published online: May 27, 2026 Processing time: 191 Days and 19.1 Hours
Abstract
Coronavirus disease 2019 (COVID-19) vaccination has reduced the morbidity and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has resulted in many benefits for humans. Conversely, although not frequent, hepatic injury, such as autoimmune hepatitis and drug-induced liver injury due to COVID-19 vaccination, has been observed in scattered cases. Furthermore, recent increases in the number of case series publications have progressively contributed to the understanding of the pathophysiological mechanisms, clinical management strategies, and prognostic implications associated with post-COVID-19 liver injury. Nonetheless, several critical aspects remain to be elucidated, including the optimal timing for initiating therapeutic interventions, the criteria for their discontinuation, and the clinical appropriateness of vaccine rechallenge. Here, I comprehensively review the literature concerning liver injury after COVID-19 vaccination and discuss possible measures to help prevent unexpected liver injury after COVID-19 vaccination considering the expected continued future occurrence of SARS-CoV-2 infection.
Core Tip: Liver injury following coronavirus disease 2019 vaccination presents with heterogeneous phenotypes, including new-onset autoimmune hepatitis, drug-induced autoimmune-like hepatitis, drug-induced liver injury, and secondary hepatic manifestations linked to comorbidities such as hemophagocytic lymphohistiocytosis. Vaccine-type differences in liver injury remain inconclusive. Prognosis varies by etiology; although many cases resolve spontaneously or respond to immunosuppressive therapy, some progress to acute liver failure necessitating transplantation or resulting in death. Vaccine rechallenge may not be contraindicated, but switching vaccine platforms is advised. The pathogenesis likely involves multifactorial mechanisms, such as genetic predispositions and immunological cross-reactivity between viral-specific antigens and host self-proteins.
Citation: Sato K. Liver injury after COVID-19 vaccination: Current status and future perspectives. World J Hepatol 2026; 18(5): 116542
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative virus of coronavirus disease 2019 (COVID-19) and has a high capacity for transmission, starting with the first case of COVID-19 diagnosed in Wuhan, Hubei Province, China, in December 2019, which caused a chain of infection not only within China but also worldwide. The World Health Organization (WHO) declared a Public Health Emergency of International Concern against the threat of its diseases on January 30, 2020, and finally judged it as a pandemic on March 11, 2020. Although the number of reported cases and deaths (cumulative total) has generally declined since 2024, more than 779 million cases and 7.10 million deaths have been reported as of September 2025 according to the WHO[1,2]. While a number of therapeutic agents have been developed to treat COVID-19, the development of vaccines has been aimed at reducing the number of severe cases, hospitalizations, and deaths, and this goal is being fulfilled. COVID-19 vaccines fall into several categories that will be detailed later, some of which have been approved for emergency administration and have been put into use. In December 2020, the WHO issued its first emergency use validation for a COVID-19 vaccine and emphasized the need for equitable global access[3]. Subsequently, other countries also approved vaccinations; for example, Japan first began vaccinating healthcare workers in February 2021[4]. Thirteen billion vaccinations have been administered worldwide as of December 2023[5].
A systematic review and meta-analysis of controlled and randomized clinical trials[6] that evaluated the safety and efficacy of COVID-19 vaccines revealed that the overall efficacy of the approved vaccines, including mRNA vaccines, non-replicating viral vector vaccines, protein subunit-based vaccines, and inactivated vaccines was confirmed, with the mRNA-based vaccine showing the greatest efficacy after the first dose and the inactive vaccine after the second dose[6]. As a result, comparative analyses indicate that mRNA-based vaccines elicit more robust immune protection against SARS-CoV-2 than do alternative platform technologies[6]. In fact, a recent modeling study assessing the impact of vaccination on COVID-19-related mortality in Japan under various counterfactual scenarios of vaccine rollout timing and coverage estimated that, when accounting for both direct and indirect effects of immunization, approximately 30117 deaths could have been prevented in 2021[4]. This systematic review and meta-analysis revealed that all four vaccines demonstrated a favorable safety profile, with only minimal local and systemic adverse reactions observed. Unexpected serious adverse events were exceedingly rare[6]. Pain at the injection site, fever, fatigue, and headache were the most common adverse reactions, accounting for 54.5% of the total among the four vaccine platforms[6].
However, more serious adverse reactions, although extremely rare, have been reported. Adverse reactions, including anaphylaxis, myocarditis/pericarditis, vaccine-induced immune thrombocytopenia, Miller Fisher syndrome, myasthenia gravis, Guillain–Barré syndrome, demyelinating diseases, Bell’s palsy, autoimmune encephalitis, and small-fiber neuropathy, have been reported[7]. These adverse reactions were reported to be predominantly associated with mRNA and viral vector vaccines[7]. The authors proposed that the principal immunopathogenic mechanisms underlying COVID-19 vaccine-associated adverse immune responses include molecular mimicry, the induction of specific autoantibodies, and immunomodulatory effects mediated by certain vaccine adjuvants[7]. Another review suggested that vaccine-induced autoimmunity in the context of COVID-19 may be attributable to immunological cross-reactivity between viral-specific antigens and host self-proteins via molecular mimicry, as well as to nonspecific bystander activation of non-target antigen-independent immune pathways elicited by vaccine components[8]. Liver injuries associated with COVID-19 vaccination, though extremely rare, have been increasingly reported and recognized[9,10]. These injuries may involve various mechanisms, including liver damage resembling autoimmune hepatitis (AIH)[9,10], an autoimmune disease as previously mentioned. The WHO reported that the number of reported potential adverse drug reactions (ADRs) after the COVID-19 vaccine as of October 5, 2025 was approximately 5.8 million, while the frequency of hepatobiliary disorders was approximately 13 thousand, or 0.23% of ADRs[11].
I reviewed articles concerning the current status of liver injury after COVID-19 vaccination and discussed plausible mechanisms and potential risk factors and possible measures that can be taken against unexpected liver injury after COVID-19 vaccination considering the anticipated continued existence of SARS-CoV-2 infection in the future. Relevant publications indexed in PubMed through August 2025 were systematically reviewed.
TYPES AND CHARACTERISTICS OF COVID-19 VACCINES
COVID-19 vaccines encompass a broad range of platforms, including traditional whole-virus vaccines, nucleic acid–based vaccines (such as mRNA and DNA vaccines), protein subunit vaccines, viral vector vaccines, and virus-like particle (VLP) vaccines[7,12].
Whole-virus vaccines include inactivated vaccines, which are rendered non-infectious through chemical or physical treatments, and live-attenuated vaccines, which use weakened viral strains[7,12]. Examples such as Covaxin (Bharat Biotech, Hyderabad, India), Covilo (Sinopharm, Beijing, China), and Coronavac (Sinovac, Beijing, China) have been widely approved and listed for emergency use by the WHO[7].
Nucleic acid–based vaccines consist of DNA and RNA vaccines[7,12]. DNA vaccines use plasmid DNA encoding antigenic proteins that are expressed within host cells[7,12], although their clinical application faces challenges such as limited antigen trafficking and theoretical risks of genomic integration[12]. ZyCoV-D (Zydus Cadila, Ahmedabad, India) is an example approved for long-term prophylaxis[7]. RNA vaccines, which do not require nuclear entry, include non-replicating mRNA vaccines and self-amplifying mRNA vaccines. The latter contain replicase machinery enabling intracellular RNA amplification[12]. Widely used mRNA vaccines such as Comirnaty (Pfizer, New York, NY, United States; BioNTech, Mainz, Germany) and mRNA-1273 (Moderna, Cambridge, MA, United States) received WHO emergency authorization in 2020-2021[7].
Protein subunit vaccines use purified viral components, such as the spike protein, to induce immunity with a favorable safety profile[7,12]. Nuvaxovid (Novovax, Gaithersburg, MD, United States) and COVOVAX (Serum Institute of India, Pune, India) are representative examples added to the WHO emergency use list in 2021[7].
Viral vector vaccines utilize genetically engineered viruses to deliver antigen-encoding genes[12]. They may be replication-competent or replication-deficient, with the former offering stronger immunogenicity but lower safety[7]. Adenoviral vector vaccines, including Ad26.COV2.S (Janssen, Beerse, Belgium) and ChAdOx1-S (Oxford University, Oxford, United Kingdom-AstraZeneca, Cambridge, England) have been widely used[7]. However, pre-existing immunity to human adenoviruses can reduce vaccine efficacy, prompting the use of rare or non-human serotypes[12].
VLP vaccines consist of self-assembled viral proteins that mimic the structure of authentic viruses without containing genetic material, making them non-infectious[12]. They induce both T-cell and B-cell responses, but generally require adjuvants due to low inherent immunogenicity[12]. Several VLP vaccines have undergone clinical evaluation, and one has been authorized for long-term prevention of SARS-CoV-2 infection[13].
Overall, the diversity of COVID-19 vaccine platforms reflects advances in biotechnology and the need for rapid, scalable, and safe immunization strategies during the global pandemic[7,12,13].
AN OVERVIEW OF CLINICAL CHARACTERISTICS OF LIVER INJURY AFTER COVID-19 VACCINATION
As mentioned above, mRNA-based vaccines can be rapidly and massively produced against COVID-19, a pandemic. In the randomized clinical trial of BNT162b2 (NCT04368728)[14], 21720 participants received the vaccine and 21728 received the placebo. In the trial of mRNA-1273 (NCT04470427)[15], 15210 participants received the vaccine and the same number received the placebo. In both studies, no adverse events, such as elevated liver enzymes or liver injury, were reported. However, as vaccination progressed worldwide, case reports and case series began to be reported, beginning with a case report[16] of a woman who developed AIH after receiving the Pfizer-BioNTech COVID-19 vaccine, followed by subsequent case reports and case series reported worldwide. Here, I reviewed case series (Supplementary Table 1)[17-27] on COVID-19 vaccine-associated liver injury regardless of AIH involving more than 5 subjects to date. Additionally, I investigated case series of 5 or more patients[28-31], which focused on new-onset AIH associated with COVID-19 vaccination (Tables 1 and 2). In this section, I discuss the clinical characteristics of liver injury following COVID-19 vaccination, focusing primarily on these case series.
Table 1 Case series focused on new-onset autoimmune hepatitis associated with coronavirus disease 2019 vaccination, n (%)/median (range).
Ref.
n
Demographics: Age, M/F
Pre-exisiting other autoimmune disorders
Pre-exisiting liver diseases
COVID-19 survivor
Vaccine
Injury after 1st/2nd/3rd/4th dose (%)
Pattern of injury (hep/chol/mixed) (%)
The median (range) time from last vacine dose to onset of liver injury (days)
TOTAL INCIDENCE OF COVID-19 VACCINE-ASSOCIATED LIVER INJURY
Using data from the Indiana University Health Enterprise Data Warehouse, Guardiola et al[18] reported that among 470274 patients who received the COVID-19 vaccine from December 2020 to October 2021, 177 (0.038%) patients developed liver injury. In contrast, liver injury was significantly more frequent in response to the influenza virus vaccine (0.069%) than in response to the COVID-19 vaccine (0.038%) (P = 0.04)[18]. In a modified self-controlled case series analysis, 2343288 patients received the mRNA vaccine (BNT162b2) and the inactivated vaccine (CoronaVac) between February 2021 and September 2021[17]. A total of 4677 patients (0.20%) developed acute liver injury within 56 days after the first or second dose of either vaccination[17]. In contrast, the number of cases of acute liver injury within 56 days of SARS-CoV-2 infection was 32997 per 100000 person-years[17]. The 56-day incidence of acute liver injury was significantly lower among vaccinated individuals than among patients with confirmed SARS-CoV-2 infection on the basis of propensity score weighting[17]. There was no increased risk of acute liver injury after COVID-19 vaccination compared with that in the non-exposure period[17]. However, the contradictory results revealed that there were no differences in cumulative incidence at 90 days of new-onset liver enzyme test alteration between the COVID-19 vaccine group [4.7 per 1000 (95%CI: 4.0-5.5)] and the influenza vaccine group [5.1 per 1000 (95%CI: 4.3-6.1)][32].
NEW-ONSET AIH CASES AFTER COVID-19 VACCINATION
COVID-19-associated liver injury includes new-onset AIH. Three studies[28,30,33] have investigated the frequency of AIH after COVID-19 vaccination. Rüther et al[33] reported that the COVID-19 vaccine did not increase the risk of developing AIH on the basis of a systematic retrospective analysis, although this study was a single-center and non-population-based analysis[33]. However, as the authors also mentioned, it is possible that AIH was missed because of the extremely low frequency or that it was associated with a reduced opportunity to be detected during a pandemic. A population-based study conducted in Singapore[30] reported no significant increase in the incidence of acute presentations of AIH within 21 and 42 days of COVID-19 vaccination. By disproportionality analysis, Chen et al[28] reported that the frequency of COVID-19 vaccine-associated AIH was 0.21 (95%CI: 0.16-0.27) per million people and concluded that mRNA and viral vector vaccines did not increase the risk of AIH. Notably, the diagnosis of AIH may be overlooked even by hepatologists, since some patients improve with spontaneous remission or temporary immunosuppressive drugs. Therefore, epidemiological studies and case series are useful and should continue to accumulate more cases.
AGE AND SEX
The age range is widely distributed from 14 to 92 years. There are currently no case series that summarize a large number of cases in children and young adults. The median patient age ranges from those in their late 40s to early 60s, including new-onset AIH-focused case series (Tables 1 and 2 and Supplementary Table 1). Excluding case series with fewer than 10 patients[26,27], most studies report that female patients are more frequently observed among those exhibiting liver dysfunction (Supplementary Table 1). In two articles[28,29] of new-onset AIH-focused case series with more than 10 patients, there were equal numbers of men and women in one study[29] but more women in the other study[28].
ASSOCIATION WITH BACKGROUND AUTOIMMUNE DISEASES OTHER THAN LIVER DISEASE
In three case series with more than 10 cases of COVID-19 vaccine-associated liver injury[19-21], the prevalence of pre-existing autoimmune diseases other than liver disease ranged from 26%-31%. Conversely, the frequency of autoimmune diseases varied between 1.9% and 50% in two studies[28,29] that focused on COVID-19 vaccine-associated new-onset AIH cases with more than 10 subjects. In a population-based cohort study in the United Kingdom, the prevalence of 19 autoimmune diseases increased progressively from 7.7% (n = 697236) during 2000-2002 to 11.0% (n = 1050995) in 2017-2019, corresponding to a relative risk of 1.41 (95%CI: 1.37-1.44) for the latter period compared with the former[34]. However, the complication rate of autoimmune diseases in patients who developed liver disorders tended to be relatively high (26%-50%) in case series with more than 10 cases of COVID-19 vaccine-associated liver injury[19-21,29], with the exception of one study[28] (Tables 1 and 2 and Supplementary Table 1).
ASSOCIATION WITH PRE-EXISTING LIVER DISEASES
In case series of COVID-19 vaccine-associated liver injury with more than 10 subjects, six studies[17,19,23-25,28] reported complication rates for pre-existing liver diseases ranging from 3.1%-50%. In case series of COVID-19 vaccine-associated liver injury with more than 10 subjects, where the complication rate of AIH could also be determined[19,21-23,25], the rates varied from 2.3%-31%.
COVID-19 INFECTION AND VACCINE-ASSOCIATED LIVER INJURY
In case series of COVID-19 vaccine-associated liver injury with more than 10 subjects, regarding the relationship between COVID-19 infection and vaccine-associated liver injury, the percentage of patients with previous COVID-19 infection varied from approximately 8.5% of those who developed COVID-19 vaccine-related liver injury in two studies[20,21] to less than 1% in one study[17]. However, Bernasconi et al[26] reported that one out of seven patients developed liver injury following both COVID-19 infection and vaccination. Thus, although the frequency of COVID-19 vaccine-associated liver injury is assumed to be quite low, it may be worthwhile to keep in mind that if liver injury is observed in COVID-19 infection, it might also occur during vaccination. The reverse might also apply.
TYPES OF VACCINES
When analyzed by the type of vaccine administered, the incidence of COVID-19 vaccine-associated liver injury has been reported for mRNA, vector, and inactivated vaccines (Tables 1 and 2 and Supplementary Table 1). Wong et al[17] reported the number of cases of acute liver injury within 56 days after COVID-19 vaccination. The number of liver injuries after receiving the BNT162b2 vaccine compared with CoronaVac was 335 and 334 vs 358 and 403 per 100000 person-years for the first and second doses, respectively[17]. In addition, there were no significant differences in disease severity defined by the Drug Induced Liver Injury Network scale, peak alanine aminotransferase (ALT) level, peak aspartate aminotransferase (AST) level, AST: ALT ratio, hospitalization rate, or intensive care unit admission between the two groups of vaccine recipients[17]. Guardiola et al[18] reported that there was no significant difference in the frequency of liver injury after COVID-19 vaccination between mRNA (0.038%) and viral vector (0.024%) vaccines (P = 0.26). Efe et al[19] described that comparable proportions of individuals who experienced liver injury following administration of the Pfizer-BioNTech (mRNA), Oxford-AstraZeneca (viral vector), and Moderna (mRNA) vaccines exhibited immune-mediated phenotypes (59.6%, 55.6%, and 50.0%, respectively; P = 0.81). In general, mRNA vaccines were more frequently reported in case series, but this phenomenon might be a reflection of the relatively large number of inoculations of mRNA vaccines. The frequency of mRNA vaccine use was high (60%-100%) in the case series focused on new-onset AIH associated with COVID-19 vaccination (Tables 1 and 2). Currently, no definitive differences in the incidence or severity of vaccine-associated liver injury have been established across vaccine platforms.
LIVER INJURY ASSOCIATED WITH THE NUMBER OF VACCINATIONS
With respect to the frequency of liver injury due to the number of vaccinations, there are some exceptions[24,27,30], but in general, more cases of liver injury occurred after the second dose than after the first dose. The number of reported studies on the third dose was only six[20-22,25,28,30], and the relative vaccination population is assumed to be small, making it difficult to compare the third dose with the first and second doses at this time (Tables 1 and 2 and SupplementaryTable 1).
CLASSIFICATIONS OF LIVER INJURY
The patterns of liver injury that were based on the Roussel Uclaf Causality Assessment Method (RUCAM) classification[35] used in many studies were divided into hepatocellular, cholestatic, and mixed injury, of which the hepatocellular injury was the most common in studies consisting of more than 10 cases regardless of AIH (Supplementary Table 1). The mixed injury was the second most common except in the studies[18,24]. None of the studies on the development of newly diagnosed AIH mentioned the classification (Tables 1 and 2).
TIME FROM VACCINATION TO ONSET OF LIVER INJURY, SYMPTOMS, OR DIAGNOSIS
In case series of COVID-19 vaccine-associated liver injury containing more than 10 subjects, the number of days from the most recent vaccination to the onset of liver injury, symptoms, or diagnosis could be evaluated[17-22,25,28,29]. In seven studies[17,19-22,25,28], the median duration was 8-24 days; in one study[18], the average duration was 29 days for the first vaccine and 45 days for the second vaccine; and in one study[29], the median duration was 48 days for the first vaccine and 10 days for the second vaccine. Thus, approximately half of the patients had a high incidence of liver injury within approximately one month of COVID-19 vaccination.
CLINICAL PRESENTATION
The clinical presentation of COVID-19 vaccine-associated liver injury varied across studies (Tables 1 and 2 and Supplementary Table 1). Thus, reported studies encompassed a spectrum of clinical outcomes, ranging from cases progressing to acute liver failure with fatal consequences to cohorts without such progression. According to the report by Efe et al[19], 22% of the study population developed grade 3-4 liver injury, and one patient (1.1%) required liver transplantation (LT) due to acute liver failure, as assessed by the drug-induced liver injury (DILI) severity index[36]. One study[20] assessed the clinical severity of liver injury on the basis of the original and revised Hy’s laws[37] and revealed that one patient (1.7%) required LT due to acute liver failure. Another study[21] utilized the European Association for the Study of the Liver (EASL) Clinical Practical Guidelines on the management of acute (fulminant) liver failure[38] and reported that 6.4% of the cohort developed acute liver failure. Marked jaundice was observed in a notable subset of cases. One investigation[17] revealed no statistically significant difference in the incidence of a peak ALT value > 20 × the upper limit of normal between recipients of mRNA and inactivated vaccines.
DATA RELATED TO AUTOIMMUNE LIVER DISEASE
In case series with more than 10 cases of COVID-19 vaccine-associated liver injury, the frequencies of antinuclear antibodies and anti-smooth muscle antibodies varied from 27% to 74% and from 8.3% to 37%, respectively (Tables 1 and 2 and Supplementary Table 1). If the number of subjects was disregarded, in the studies regarding newly diagnosed AIH patients after COVID-19 vaccination, the frequency of antinuclear antibodies ranged from 50%-100% (Tables 1 and 2). Evaluation of IgG was difficult because the evaluation criteria varied from study to study. However, in studies consisting of more than 10 cases regardless of AIH, high IgG levels were found in 13% of the cases in one study[22], but in 50%-68% of the cases in other studies where IgG could be evaluated (Supplementary Table 1). If the number of subjects was disregarded, in the studies regarding newly diagnosed AIH patients after COVID-19 vaccination, the median IgG level was 1.2 times the upper limit of normal in one study[29] and IgG levels were elevated in all cases in two other study[30,31] (Tables 1 and 2).
PATHOLOGICAL FINDINGS
To summarize the case series, liver biopsy findings revealed that the majority of liver fibrosis, if present, was mild (Tables 1 and 2 and Supplementary Table 1). Although the diagnostic criteria for AIH and DILI used varied from study to study, the number of cases with more than compatible AIH ranged from 46% to 92%, with 9.1% of the cases reported to have featured DILI in one study[21] in studies consisting of more than 10 cases regardless of AIH (SupplementaryTable 1). In the studies regarding newly diagnosed AIH patients after COVID-19 vaccination, the pathology revealed typical and compatible AIH in more than 91% of the patients in one study[29]. One study regarding the development of newly diagnosed AIH[31] revealed that the simplified criteria score of the International AIH group[39] was 7 or 8. Another study on the occurrence of newly diagnosed AIH revealed that 50% of 4 patients who underwent liver biopsy had fibrosis[30]. The literature cited in Supplementary Table 1 was used for pathological diagnosis and for scoring the diagnosis of AIH and DILI[39-44].
GENETIC BACKGROUND FACTORS OF NOTE
In the context of COVID-19 vaccine-associated liver injury, some patients presented with liver dysfunction similar to that associated with AIH, prompting the investigation of HLA genes as genetic background factors. Among the studies introduced in Tables 1 and 2 and Supplementary Table 1, three[22,26,31] examined HLA genes, and one[22] also examined variants and haplotypes of endoplasmic reticulum endopeptidases (ERAPs). These genetic background factors will be discussed in detail later with other references.
TREATMENTS
With respect to the cases that required treatment, the use of immunosuppressive drugs was the main focus of case series of COVID-19 vaccine-associated liver injury regardless of AIH (Supplementary Table 1). Specifically, steroids were the most common immunosuppressive agents, and azathioprine and mycophenolate mofetil were used, as well as intravenous immunoglobulin (Supplementary Table 1). Three studies[19-21] reported cases of LT due to acute liver failure. Among the three studies[29-31] concerning newly diagnosed AIH patients after COVID-19 vaccination (Tables 1 and 2), one used immunosuppressive treatment (the details were unknown)[29], and the others used steroids with or without azathioprine therapy[30,31].
OUTCOMES
There were cases that required treatment, such as immunosuppressive medications, while 8.5%-47% of the cases healed spontaneously with no treatment in case series with more than 10 cases of COVID-19 vaccine-associated liver injury regardless of AIH (Supplementary Table 1). I also observed a case of spontaneous remission[31] among studies regarding newly diagnosed AIH patients after COVID-19 vaccination. However, relapse after spontaneous remission was observed in one study[20]. While some patients were able to discontinue immunosuppressive drugs, others whose liver function improved but did not normalize and continued the drugs during the observation period were observed (Tables 1 and 2 and Supplementary Table 1). There were also cases of relapse after the discontinuation of immunosuppressive drugs[20]. Acute liver failure-related death[21] has also been reported. Overall, the prognosis of COVID-19 vaccine-associated liver injury was relatively good in most studies, although scattered cases did not lead to remission. Notably, two cases resulted in (likely) liver-related death due to COVID-19 vaccine-associated liver injury[21,28].
RECHALLENGE
In case series with COVID-19 vaccine-associated liver injury regardless of the number of subjects, six studies[19-22,26,31] reported on rechallenge. If the vaccine used as a rechallenge was the same vaccine or the same vaccine platform as the previous vaccine, the relapse rate might be higher than that in the differential vaccine platform, and LT has been reported in cases in which the same vaccine or the same vaccine platform was used in two studies[19,20]. However, importantly, the same vaccine or same vaccine platform did not necessarily cause a relapse. If possible, different vaccine platforms might be considered desirable when vaccines are administered as a rechallenge. Notably, in a study[21] in which the vaccine was administered as a rechallenge, patients who had been receiving immunosuppressants experienced significantly fewer recurrences. Thus, it is recommended that patients at high risk for COVID-19 infection who have developed COVID-19 vaccine-associated liver injury be given a different vaccine platform from that used as the prior dose. If the next dose of vaccine is to be considered and if the patient has experienced liver damage from the previous vaccination and has been on immunosuppressive therapy, vaccination without discontinuation of immunosuppressive drugs is one strategy to reduce relapse of COVID-19 vaccine-associated liver injury.
SPECIFIC COVID-19 VACCINE-ASSOCIATED LIVER INJURY
Table 3 summarizes case reports of a special type of COVID-19 vaccine-associated hepatic injury[45-55]. A male patient with type 1 diabetes mellitus presented with hepatic injury with mild hepatomegaly accompanied by glycemic excursions and Raynaud's phenomenon. Liver function improved to some extent. The cause of liver injury was speculated to be an immunological mechanism[45]. One reported female case was associated with IgG4-related hepatopathy and multiple lymphadenopathy after vaccination in a patient with a history of IgG4-related disease[46]. The disease resolved spontaneously without treatment and did not recur during the observation time[46]. Kishimoto et al[47] reported that a patient with lifestyle-related diseases such as fatty liver and hypercholesterolemia as background diseases developed liver injury with subacute thyroiditis after receiving a COVID-19 mRNA vaccination. All but γGTP improved with corticosteroid administration[47]. On the basis of laboratory findings, AIH or viral hepatitis were unlikely[47]. Given that improvement after steroid therapy and/or amelioration of thyrotoxicosis, COVID-19 mRNA vaccine-associated liver injury in addition to thyrotoxicosis-associated liver injury with subacute thyroiditis may be involved in this pathophysiology[47]. The other eight cases[48-55] were summarized as cases of hemophagocytic lymphohistiocytosis (HLH) secondary to COVID-19 vaccination, in which liver injury was thought to have developed as part of the syndrome. COVID-19 vaccine-associated HLH has been reported relatively frequently and does not necessarily result in liver injury; however, reports of vaccine-associated secondary HLH cases with liver injury are shown in Table 3. Two of the eight cases[53,55] were found to have Epstein-Barr virus (EBV) infection, and the involvement of the COVID-19 vaccine and EBV as a cause of HLH was also considered. On the basis of these specific reports of COVID-19 vaccine-associated liver injury, I believe that the possibility of this specific liver injury should be kept in mind for patients with liver injury after COVID-19 vaccination, even if the frequency is extremely rare. In addition, since HLH is likely to occur in patients with persistent EBV infection, it is advisable to investigate the presence of EBV infection whenever COVID-19 vaccine-associated liver injury with certain symptoms of HLH develops. Treatment methods and outcomes varied depending on the status of the underlying disease. Furthermore, in cases of secondary HLH, unfortunate outcomes such as multiple organ failure may occur[51].
Table 3 Case reports of specific liver injury associated with coronavirus disease 2019 vaccination.
VACCINATION UNDER SPECIAL LIVER DISEASE CONDITIONS
In a multicenter case series involving 7745 pregnant Chinese women, Zhao et al[56] found no adverse effects on maternal liver function in early pregnancy when inactivated COVID-19 vaccination was administered more than three months before conception. In contrast, vaccination within three months prior to conception was associated with a significantly increased risk of elevated serum total bile acid levels compared with unvaccinated individuals. Cao et al[57] reported that the administration of two doses of inactivated COVID-19 vaccine to 643 patients with chronic hepatitis B was generally well tolerated, regardless of the presence of cirrhosis. In the study cohort, 16% of patients exhibited mild hepatic dysfunction, and 42.9% of these patients resolved spontaneously within six months without any additional treatment[57]. The study showed that 528 patients had intractable hepatobiliary diseases (220 AIH, 251 primary biliary cholangitis, 6 AIH-primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction)[58]. In this study, the incidence of postvaccine adverse events was similar to that reported in the general population[58]. In this disease population, 83 cases (16%) of postvaccine liver injury were classified as grade 1 or higher, whereas only 6 cases (1.1%) were classified as grade 2 or 3[58]. There were no cases of liver injury resembling AIH that required therapeutic intervention[58]. However, the incidence of COVID-19 vaccine-associated liver injury remains exceedingly low, and recurrence following vaccine rechallenge in patients maintained on immunosuppressive therapy has been infrequent[21]. Given the limited number of reported cases and the confounding influence of ongoing immunosuppression, such events may be underrecognized. To increase diagnostic accuracy and clarify the true incidence, large-scale international cohort studies are warranted.
MECHANISMS OF COVID-19 VACCINE-ASSOCIATED LIVER INJURY
Given the wide range of liver injury patterns, the mechanisms of COVID-19 vaccine-associated liver injury are thought to result from diverse causes. In terms of vaccine-induced autoimmunity, representative causes include molecular mimicry, bystander activation, adjuvant-induced tissue damage, and genetic background[8,9,59-61].
The concept of molecular mimicry involves shared epitopic features between endogenous proteins and exogenous antigens present in vaccine formulations[62]. This structural homology has the potential to induce immunological cross-reactivity[62]. Such molecular similarity can elicit cross-reactive immune mechanisms, resulting in collateral damage to self-antigens and promoting autoimmune disease onset[62]. In other words, antigen-specific immune responses elicited by COVID-19 vaccination may play a role in the pathogenesis of acquired autoimmunity[8]. For example, Mizuno et al[63] demonstrated that among many potentially risky short constituent sequences (cSCSs) in the spike protein, which were identified bioinformatically, anti-EPLDVL antibody demonstrated a high binding affinity to the SARS-CoV-2 spike protein and exhibited cross-reactivity with EPLDVL-containing peptide sequences derived from the human UNC-80 homolog protein. Furthermore, western blot analysis revealed that this antibody exhibited cross-reactivity with multiple human proteins predominantly expressed in the small intestine, ovarian tissue, and stomach, indicating that cSCSs containing EPLDVL represent a high risk[63].
The immune system’s ability to discriminate between self and non-self enables the targeted elimination of cells presenting diverse foreign antigens, including those derived from microbial sources, thereby safeguarding host integrity[64]. The immune response is involved in the release of a broad array of soluble mediators, including cytokines and chemokines[64]. These soluble mediators facilitate the elimination of infected host cells and concurrently promote the activation of T cells lacking specificity for the initiating cognate antigen[64]. This cytokine-dependent, nonspecific T-cell activation is commonly referred to as bystander activation[64]. Bystander activation denotes the antigen-independent activation of autoreactive CD8+ T lymphocytes that is triggered as a secondary effect of antigen-specific immune responses induced by viral vaccination[8]. Consequently, this immunological activation is classified as non-specific[64]. Bystander activation of T cells contributes to host tissue damage via the release of cytotoxic effector molecules and the activation of natural killer cell receptor–ligand pathways[64], thereby triggering autoimmune mechanisms. Moreover, tissue damage facilitates the release of new antigens, thereby promoting epitope spreading-a phenomenon that induces the activation of cross-reactive T lymphocytes, including those originally specific to the initiating antigen, ultimately contributing to the development of autoreactivity[64]. In liver specimens from a patient who presented with probable AIH following mRNA vaccination, panlobular accumulation of activated cytotoxic CD8+ T cells was detected[65]. Among liver-infiltrating T lymphocytes, notable enrichment of SARS-CoV-2-reactive T-cell subsets was observed, which could be implicated in the development of disease pathogenesis[65]. The authors mentioned, however, the possible involvement of other, non-SARS-CoV-2-specific “bystander” CD8+ T-cell populations resulting from broad CD8+ T-cell activation[65].
Additionally, supplements in the cell culture medium contained within vaccine formulations, proteins derived from mammalian cells that contaminate the culture medium, and adjuvants or stabilizers used during the manufacturing process are also considered non-target antigens and may trigger undesirable immune responses[8]. In clinical practice, adjuvants are considered to be principally involved in the onset of autoimmune diseases caused by vaccines[66]. An autoimmune/inflammatory syndrome caused by adjuvants has also been hypothesized[66]. In addition to the possibility of antigen-mediated molecular mimicry, adjuvants promote the up-regulation of co-stimulatory molecules and other inflammatory products, thereby facilitating the polyclonal activation of autoreactive T cells-that is, bystander T-cell activation[66]. This activation is subsequently linked to the initiation of autoimmune reactions[66].
Furthermore, genetic predisposition is also considered important in the mechanism of liver injury caused by COVID-19 vaccines. Although extremely rare, the existence of cases definitively associated with COVID-19 vaccines supports this notion. Indeed, several studies introduced in this article have examined genetic predisposition. In the study by Bernasconi et al[26] cited in Supplementary Table 1, one case judged to likely have liver injury due to COVID-19 infection out of 8 cases was excluded; 4 cases of new-onset AIH and 1 case of AIH relapse carried HLA DRB1 alleles associated with susceptibility to AIH. Among 7 patients, HLA DRB1*03 and HLA DRB1*07 were each present in 3 patients[26]. Furthermore, HLA DRB1*11 was present in 5 patients[26]. Conversely, in the 2 patients whose symptoms resolved spontaneously without immunosuppressive intervention and whose AIH was pathologically atypical, both carried HLA DRB1*11. The authors also mentioned the need to clarify the role of HLA DRB1*11 in COVID-19 vaccine-associated liver injury[26]. Furthermore, in a report by Izagirre et al[31], one of five patients with newly diagnosed AIH following COVID-19 vaccination carried HLA DRB1*11:04. This case did not undergo liver biopsy, resolved spontaneously without immunosuppression, and had a higher Council for International Organizations of Medical Sciences-RUCAM score[35] of 6 than the other four cases, which had scores of 2 or 3. In contrast, Chalasani et al[67] reported that HLA DRB1*11: 04 was significantly more frequent in 78 patients with nitrofurantoin-induced liver injury than in population controls. However, using a very similar cohort of 26 patients to examine HLA risk alleles, Daly et al[68] reported that no individuals carried HLA DRB1*11: 04. Genetic studies recommend replication cohorts to validate the observed associations between genetic variants and phenotypic traits[68,69]. Therefore, to clarify the role of HLA DRB1*11 in COVID-19 vaccine-associated liver injury, investigations using larger replication cohorts are necessary, and careful interpretation is required.
Fontana et al[22] compared 14 high causality cases of liver injury after COVID-19 mRNA vaccination with controls and reported that the frequencies of HLA alleles associated with AIH (DRB1*03: 01, DRB1*04: 01, DR4) did not differ significantly from those observed in the control groups. In contrast, three patients had HLA-DRB1*03: 01, and one patient had DRB1*04, which are associated with AIH, although a total of only five cohorts were included in the study regarding new-onset of AIH[31]. Given the small sample size in these studies, further research with a larger number of patients is necessary.
Moreover, Fontana et al[22] investigated ERAP1 and ERAP2 gene variants in liver injury after COVID-19 mRNA vaccination. The authors reported that the ERAP2 variant (rs1363907) and the ERAP1 Hap6 haplotype were enriched in 14 high causality cases compared with controls[22]. ERAP-1 and ERAP-2 are important components of MHC class I antigen processing and control the renin-angiotensin system (RAS)[70]. Angiotensin-converting enzyme 2 (ACE2) is an endogenous mediator that antagonizes the classical and alternative branches of the RAS, while SARS-CoV-2 utilizes ACE2 as a cellular entry receptor[70]. Furthermore, polymorphisms in ERAP-1 and ERAP-2 have been shown to be associated with autoimmunity, inflammation, hypertension, and malignancies[70]. Impairment of the function of ERAP1 and ERAP2 may potentiate the pathogenic consequences of SARS-CoV-2 infection[70]; thus, the association between ERAP1 and ERAP2 gene variants and COVID-19 vaccine-associated liver injury is intriguing. Furthermore, the association between the risk of DILI due to amoxicillin-clavulanate and reduced hepatic ERAP2 expression has been confirmed in both discovery and validation cohorts[71]. However, the report by Fontana et al[22] involved a small number of cases; the relationship between COVID-19 vaccine-associated liver injury and ERAP variants should be examined in other larger cohorts.
The noteworthiness of the human gut microbiota in liver disease has been acknowledged as dysbiosis and gut-to-liver migration[72]. Distinct gut microbiota patterns have been discovered in liver diseases with different etiologies[72]. For example, reports have indicated that the gut microbiome in the L-tryptophan biosynthesis superpathway is positively correlated with an increased risk of AIH[73]. Reports have documented alterations in the gut microbiota of patients with COVID-19[74,75] as well as following COVID-19 vaccination[76-78]. Although no studies to date have investigated the gut microbiota in relation to COVID-19 vaccine–associated liver injury, gut microbes are well known to play a critical role in the pathogenesis of liver injury. Thus, it is plausible that changes in the gut microbiota may contribute to the development of COVID-19 vaccine–associated liver injury, underscoring the need for further research in this area.
The study by Uzun et al[27] cited in Supplementary Table 1 involved morphological and molecular analyses on a small number of cases to compare COVID-19 vaccine-induced liver injury (VILI) and AIH[27]. (1) Histomorphologically, both disease entities were similar, but centrilobular necrosis was prominent in VILI[27]; (2) Gene expression profiling revealed greater enrichment of mitochondrial metabolism and oxidative stress-associated pathways, whereas the interferon response pathway was less enriched in VILI[27]; (3) Multiplex analysis revealed that inflammation was predominantly mediated by CD8+ effector T cells, as with drug-induced autoimmune-like hepatitis (DI-ALH), which differed from AIH, where inflammation was dominated by CD4+ effector T cells, CD79a+ B cells, and plasma cells[27]; (4) T-cell receptor (TCR) and B-cell receptor sequencing revealed that T- and B-cell clones were more prevalent in VILI than in AIH[27]; (5) Analyses of TCR beta variable-joining gene usage revealed that the use of TRBV6-1 and TRBV7-6 was significantly greater and that the use of TRBV5-1 was significantly lower in VILI than in AIH[27]; and (6) Analyses of IgH variable-joining gene usage revealed that IGHV1-24 was significantly less commonly used in VILI than in AIH[27]. More recently, Uzun et al[79] reported that T-cell repertoire profiling elucidated hyperexpanded clonal populations bearing CDR3 sequences homologous to those of previously characterized SARS-CoV-2 spike-specific T cells. A substantial proportion of these clones expressed cytotoxic effector molecules, including granzymes A, B, and K, in addition to tissue-residency markers such as CXCR6, CD69, and KLRB1[79]. Therefore, the authors inferred that VILI and AIH represent distinct disease entities; however, they could not rule out the possibility that some VILI may trigger latent AIH[27]. Therefore, pathophysiologically, liver injury associated with some COVID-19 vaccines may differ from that associated with AIH. Importantly, as previously discussed, COVID-19 vaccine-associated liver injury presents with diverse outcomes: Some progress to AIH, some improve with transient immunosuppressive therapy, and some resolve spontaneously. It is necessary to clearly distinguish the disease subtypes and subsequently investigate the pathophysiology of each. Furthermore, it is essential to clarify the common pathophysiological features among the different subtypes, such as whether long-term transition to other disease subtypes occurs. Plausible mechanisms of liver injury are shown in Figure 1.
Figure 1 Potential pathophysiological mechanisms underlying coronavirus disease 2019 vaccine-associated liver injury.
The pathogenesis of coronavirus disease 2019 vaccine-associated liver injury is considered multifactorial. One proposed mechanism involves molecular mimicry, wherein structural homology between viral epitopes encoded by the vaccine and host antigens may elicit cross-reactive immune responses. Another mechanism is bystander T-cell activation, characterized by cytokine-mediated, antigen-independent stimulation of T lymphocytes that lack specificity for the initiating antigen. Vaccine adjuvants are hypothesized to contribute to bystander T-cell activation. In addition, increased mitochondrial metabolic activity and activation of oxidative stress pathways have been implicated in hepatocellular injury. A genetic predisposition, particularly that involving human leukocyte antigen alleles and endoplasmic reticulum aminopeptidases, may influence individual susceptibility. Mt: Mitochondrion; HLA: Human leukocyte antigen; ERAPs: Endoplasmic reticulum aminopeptidases.
STANDARDIZED NAMING CONVENTION AND THE LATEST EASL CLINICAL PRACTICE GUIDELINES ON THE MANAGEMENT OF AIH
Various names for COVID-19 vaccine-associated liver injury have been used in many reports and case studies, including AIH, AIH-like syndrome[80] and DILI[81], as well as VILI[9,27] and SARS-CoV-2 vaccine-associated liver injury (SVALI)[10]. As in the case series described above, COVID-19 vaccine-associated liver injury is considered a heterogeneous population, including AIH cases that clearly meet the diagnostic criteria for AIH as well as atypical AIH cases. Efe et al[10] proposed a new term, SVALI, to describe mild cases of COVID-19 vaccine-associated liver injury that show spontaneous resolution or need short-term use of immunosuppressive drugs but do not exhibit relapse. However, the authors[10] reported that all the relevant patients were vaccinated with mRNA vaccines on the basis of immunological studies and clinical observations. However, as shown in Supplementary Table 1, this type of liver injury can also occur with other vaccines. Conversely, the subgroup that differed from SVALI presented a form of disease similar to AIH that required long-term immunosuppressive therapy and relapsed with the discontinuation or dose reduction of immunosuppressive drugs[10]. This condition may be referred to as AIH or “AIH-like” in case series or case reports. In contrast, in the latest EASL Clinical Practice Guidelines on the management of AIH[82], hepatitis with elevated IgG or positive autoantibodies after vaccination or drug intake is considered possible DI-ALH. In addition, if no improvement occurs after the discontinuation of causative substances such as vaccines or drugs, a liver biopsy should be considered. The patient should be: (1) Considered to have likely or possible AIH and initiate corticosteroids; (2) Considered to have unlikely AIH (possible DILI) and monitored with sustained drug withdrawal; or (3) Considered to have other diseases and aligned to specific treatment. In case 1, the diagnosis is confirmed as either definite AIH or DI-ALH, depending on the response to treatment. The position of SVALI in this algorithm seems to include both DI-ALH and unlikely AIH in the EASL Clinical Practice Guidelines on the management of AIH[82]. In addition, this guideline[82] states that the causative agent should be permanently avoided in DI-ALH. As already mentioned, however, there have been not a few cases of COVID-19 vaccine-associated liver injury in which relapse could have been prevented by administering another vaccine platform or even the same platform. Therefore, in cases where there is a high need for vaccination, the decision to readminister the COVID-19 vaccine should be made carefully, weighing the advantages and disadvantages. It does not appear to fall under the contraindications for rechallenge with the COVID-19 vaccine.
PROPOSED ALGORITHM FOR DIAGNOSIS AND TREATMENT OF COVID-19 VACCINE-ASSOCIATED LIVER INJURY
On the basis of a review of the various articles cited above and the latest EASL clinical practice guidelines on the management of AIH[82], I propose the algorithm shown in Figure 2. When liver injury following COVID-19 vaccination is detected and a close causal relationship with the vaccine is suggested, it can be classified as COVID-19 vaccine-associated liver injury. Differential diagnosis is performed by assessing IgG, autoantibodies, and viral markers, among other relevant laboratory parameters. COVID-19 vaccine-associated liver injury has three major outcomes: Spontaneous remission, persistent liver damage, and improvement after treatment intervention. If spontaneous remission is not achieved, a liver biopsy should be considered to differentiate AIH, DI-ALH, DILI, or hepatic manifestation in specific or other diseases. Spontaneous remission may also include DILI or hepatic manifestations in specific or other diseases. If AIH is possible, the patient should be treated with corticosteroids. The diagnosis of DI-ALH or AIH depends on whether long-term remission is achieved or relapse occurs. Subsequently, COVID-19 vaccination rechallenge can be avoided; if necessary, measures such as considering a different vaccine platform can be taken. Whenever possible, it is desirable to monitor cases of spontaneous remission to check for recurrence; however, the duration and frequency of such monitoring remain subjects for future consideration. Cases of spontaneous remission can be considered similar to those of AIH and DI-ALH when COVID-19 vaccines are administered in the future.
Figure 2 Algorithmic approach to the diagnosis and management of coronavirus disease 2019 vaccine-associated liver injury.
In cases where coronavirus disease 2019 (COVID-19) vaccine-associated liver injury is suspected, a comprehensive differential diagnosis should be conducted, including assessments of serum IgG levels, autoantibodies, and viral markers. Liver biopsy should be considered on the basis of the clinical course of hepatic dysfunction, specifically, whether the injury resolves spontaneously, persists, or initially improves with therapeutic intervention but subsequently relapses following dose reduction or discontinuation of the treatment. If autoimmune hepatitis (AIH) is suspected, corticosteroid therapy should be initiated. A clinical biological response achieved through early tapering or cessation of corticosteroids (CSs) may indicate drug-induced autoimmune-like hepatitis. Conversely, relapse upon dose reduction or withdrawal supports a diagnosis of AIH, warranting the resumption of CS therapy. When histopathological findings suggest drug-induced liver injury, management should be tailored according to the clinical trajectory, including either active treatment or continued observation. Cases exhibiting spontaneous remission or persistent liver injury may reflect hepatic manifestations of specific underlying conditions or other systemic diseases. Once a definitive diagnosis is established, appropriate etiological treatment should be initiated, with close monitoring of disease progression. Re-administration of the implicated COVID-19 vaccine should be avoided. If COVID-19 vaccination remains necessary, consideration may be given to using a COVID-19 vaccine from a different platform. AIH: Autoimmune hepatitis; COVID-19: Coronavirus disease 2019; CSs: Cessation of corticosteroids; DI-ALH: Drug-induced autoimmune-like hepatitis; DILI: Drug-induced liver injury.
CONCLUSION
Although acute liver injury is clearly associated with the COVID-19 vaccine, the pathogenesis is diverse and ranges from closely resembling AIH to DILI. As in the guidelines provided by the EASL[82], it is necessary to determine whether the disease resolves spontaneously, improves with short-term immunosuppressive therapy, does not improve, or relapses after discontinuation and to decide on the diagnosis and future interventions, with careful attention paid to the timing of liver biopsy and interpretation of its results. Notably, COVID-19 vaccine-associated liver injury can occur with all vaccines, not just mRNA vaccines. To the best of our knowledge, comparative analyses have not demonstrated significant variation in the frequency or severity of liver injury among different COVID-19 vaccine platforms. Since COVID-19 vaccine-associated liver injury appears regardless of the number of vaccinations and is more common with the second than with the first vaccination, caution should always be exercised when continuing vaccinations after the third vaccination. However, since liver injury is extremely rare with respect to the frequency of COVID-19 vaccine-associated liver injury, I do not believe that liver injury is a reason not to recommend the COVID-19 vaccine, as has been the case with many previous reports. However, patients who develop liver injury after contracting COVID-19 or hepatotoxicity with the COVID-19 vaccine may experience repeated liver injury because of the genetic background and other factors. Notably, liver failure has occurred after rechallenge with the same vaccine or a vaccine of the same platform, necessitating LT in some cases[19,20]. Therefore, although rechallenge should be avoided as much as possible in cases of COVID-19 vaccine–associated liver injury, it may be considered when the potential benefits outweigh the risks, taking into account the patient’s comorbidities and the likelihood of severe disease if infected with COVID-19. In such cases, even with rechallenge using the same vaccine platform, liver damage may not occur. However, I recommend that not only the same vaccine but also vaccines of the same platform should be avoided as much as possible. The prognosis of COVID-19 vaccine-associated liver injury is relatively good but heterogeneous, ranging from spontaneous resolution to death, and some patients continue to receive immunosuppressive drugs. In general, there are many case reports and case series with relatively short observation periods. Whether immunosuppressive agents should be discontinued or continued in the future awaits the accumulation of cases with long-term follow-up. In particular, I believe that there is a future need to verify genetic background factors such as HLADRB1 and ERAP-2 using replication cohorts, identify new causative genes in large cohorts, and develop strategies for safer vaccination, such as vaccination with different vaccine platforms from the previously used one resulting in liver injury.
Efe C, Kulkarni AV, Terziroli Beretta-Piccoli B, Magro B, Stättermayer A, Cengiz M, Clayton-Chubb D, Lammert C, Bernsmeier C, Gül Ö, la Tijera FH, Anders M, Lytvyak E, Akın M, Purnak T, Liberal R, Peralta M, Ebik B, Duman S, Demir N, Balaban Y, Urzua Á, Contreras F, Venturelli MG, Bilgiç Y, Medina A, Girala M, Günşar F, Londoño MC, Androutsakos T, Kisch A, Yurci A, Güzelbulut F, Çağın YF, Avcı E, Akyıldız M, Dindar-Demiray EK, Harputluoğlu M, Kumar R, Satapathy SK, Mendizabal M, Silva M, Fagiuoli S, Roberts SK, Soylu NK, Idilman R, Yoshida EM, Montano-Loza AJ, Dalekos GN, Ridruejo E, Schiano TD, Wahlin S. Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.Hepatology. 2022;76:1576-1586.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 97][Cited by in RCA: 89][Article Influence: 22.3][Reference Citation Analysis (0)]
Codoni G, Kirchner T, Engel B, Villamil AM, Efe C, Stättermayer AF, Weltzsch JP, Sebode M, Bernsmeier C, Lleo A, Gevers TJ, Kupčinskas L, Castiella A, Pinazo J, De Martin E, Bobis I, Sandahl TD, Pedica F, Invernizzi F, Del Poggio P, Bruns T, Kolev M, Semmo N, Bessone F, Giguet B, Poggi G, Ueno M, Jang H, Elpek GÖ, Soylu NK, Cerny A, Wedemeyer H, Vergani D, Mieli-Vergani G, Lucena MI, Andrade RJ, Zen Y, Taubert R, Terziroli Beretta-Piccoli B. Histological and serological features of acute liver injury after SARS-CoV-2 vaccination.JHEP Rep. 2023;5:100605.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 26][Cited by in RCA: 33][Article Influence: 11.0][Reference Citation Analysis (1)]
Barreira-Díaz A, Riveiro-Barciela M, Fernández-Bonilla EM, Bernal V, Castiella A, Casado-Martín M, Delgado C, Londoño MC, Díaz-González Á, Pérez-Medrano I, Conthe A, Sala M, Mateos B, Gómez-Camarero J, Antón-Conejero D, Pozo-Calzada CD, Cuenca F, Villagrasa-Vilella A, Salcedo M. Outcomes and factors associated with relapse of vaccine-induced liver injury after SARS CoV-2 immunization: A nationwide study.Ann Hepatol. 2024;29:101489.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 4][Reference Citation Analysis (0)]
Bernasconi E, Biagi M, Di Agostino S, Cursaro C, Felicani C, Ronconi E, Franchi E, Costanzo AC, Gabrielli F, Cavicchioli A, Ienopoli G, Marenghi P, Bartoli A, Serra B, Scalabrini D, Sighinolfi P, Andreone P. Investigating Acute Hepatitis after SARS-CoV-2 Vaccination or Infection: A Genetic Case Series.Biomedicines. 2023;11:2848.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 4][Cited by in RCA: 5][Article Influence: 1.7][Reference Citation Analysis (0)]
Ng AJJ, Teo DCH, Dorajoo SR, Yap AJY, Chow WC, Ng NKM, Soh SBL. Acute autoimmune hepatitis following COVID-19 mRNA vaccination: A population-based study using electronic health records in Singapore.Vaccine. 2024;42:126462.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 2][Reference Citation Analysis (0)]
Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, Mason J, Sattar N, McMurray JJV, McInnes IB, Khunti K, Cambridge G. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.Lancet. 2023;401:1878-1890.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 552][Reference Citation Analysis (0)]
Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Cáliz I, González-Jimenez A, Ulzurrun E, Gonzalez AF, Fernandez MC, Romero-Gómez M, Jimenez-Perez M, Bruguera M, Prieto M, Bessone F, Hernandez N, Arrese M, Andrade RJ; Spanish DILI Registry; SLatinDILI Network; Safer and Faster Evidence-based Translation Consortium. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.Gastroenterology. 2014;147:109-118.e5.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 289][Cited by in RCA: 261][Article Influence: 21.8][Reference Citation Analysis (0)]
European Association for the Study of the Liver. Clinical practice guidelines panel, Wendon, J; Panel members, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.J Hepatol. 2017;66:1047-1081.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 816][Cited by in RCA: 693][Article Influence: 77.0][Reference Citation Analysis (4)]
Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, Bianchi FB, Shibata M, Schramm C, Eisenmann de Torres B, Galle PR, McFarlane I, Dienes HP, Lohse AW; International Autoimmune Hepatitis Group. Simplified criteria for the diagnosis of autoimmune hepatitis.Hepatology. 2008;48:169-176.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1606][Cited by in RCA: 1318][Article Influence: 73.2][Reference Citation Analysis (0)]
Lohse AW, Sebode M, Bhathal PS, Clouston AD, Dienes HP, Jain D, Gouw ASH, Guindi M, Kakar S, Kleiner DE, Krech T, Lackner C, Longerich T, Saxena R, Terracciano L, Washington K, Weidemann S, Hübscher SG, Tiniakos D. Consensus recommendations for histological criteria of autoimmune hepatitis from the International AIH Pathology Group: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology.Liver Int. 2022;42:1058-1069.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 110][Cited by in RCA: 107][Article Influence: 26.8][Reference Citation Analysis (2)]
Tanifuji A, Ohfuji S, Matsumoto K, Abe M, Komori A, Takahashi A, Kawata K, Sato K, Joshita S, Umemura T, Ueno M, Nakayama N, Kakisaka K, Arinaga-Hino T, Ito K, Kanai S, Miura R, Arizumi T, Asaoka Y, Ito T, Shimizu T, Yoshida H, Ohta M, Mizuno S, Isayama H, Morimoto Y, Mochida S, Ohira H, Tanaka A. Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.Hepatol Res. 2024;54:706-715.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 1][Reference Citation Analysis (0)]
Mizuno Y, Nakasone W, Nakamura M, Otaki JM. In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development.Vaccines (Basel). 2024;12:539.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 6][Reference Citation Analysis (0)]
Nicoletti P, Dellinger A, Li YJ, Barnhart HX, Chalasani N, Fontana RJ, Odin JA, Serrano J, Stolz A, Etheridge AS, Innocenti F, Govaere O, Grove JI, Stephens C, Aithal GP, Andrade RJ, Bjornsson ES, Daly AK, Lucena MI, Watkins PB; Drug-Induced Liver Injury Network (DILIN); International Drug-Induced Liver Injury Consortium (iDILIC); Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators. Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.Gastroenterology. 2023;164:454-466.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 18][Cited by in RCA: 32][Article Influence: 10.7][Reference Citation Analysis (0)]
Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS, Chow KM, Ng SSS, Li TC, Ng RW, Yip TC, Wong GL, Chan FK, Wong CK, Chan PK, Ng SC. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.Gut. 2021;70:698-706.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 1127][Cited by in RCA: 928][Article Influence: 185.6][Reference Citation Analysis (3)]
Hirota M, Tamai M, Yukawa S, Taira N, Matthews MM, Toma T, Seto Y, Yoshida M, Toguchi S, Miyagi M, Mori T, Tomori H, Tamai O, Kina M, Sakihara E, Yamashiro C, Miyagi M, Tamaki K, Wolf M, Collins MK, Kitano H, Ishikawa H. Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity.Commun Biol. 2023;6:368.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 9][Cited by in RCA: 11][Article Influence: 3.7][Reference Citation Analysis (0)]
Boston RH, Guan R, Kalmar L, Beier S, Horner EC, Beristain-Covarrubias N, Yam-Puc JC, Pereyra Gerber P, Faria L, Kuroshchenkova A, Lindell AE, Blasche S, Correa-Noguera A, Elmer A, Saunders C, Bermperi A, Jose S, Kingston N; CITIID-NIHR COVID-19 BioResource Collaboration, Grigoriadou S, Staples E, Buckland MS, Lear S, Matheson NJ, Benes V, Parkinson C, Thaventhiran JE, Patil KR. Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals.Life Sci Alliance. 2024;7:e202302529.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 2][Cited by in RCA: 11][Article Influence: 5.5][Reference Citation Analysis (0)]
Uzun S, Pant A, Bartoszek E, Gueguen P, Frei S, Heusler H, Arborelli I, Zinner CP, Soylu NK, Terziroli Beretta-Piccoli B, Efe C, Matter MS. Analysis of Hyperexpanded T Cell Clones in SARS-CoV-2 Vaccine-Associated Liver Injury by Spatial Proteomics and Transcriptomics.Liver Int. 2025;45:e70172.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in RCA: 7][Reference Citation Analysis (0)]
Palmer M, Seekins D, Avigan M, Marcinak J, Rockey DC, Regev A, Shastri VK, Lewis JH, Dash A. The Impact of COVID-19 and COVID-19 Vaccination on Detection, Assessment, and Management of Suspected Acute Drug-Induced Liver Injury Occurring during Clinical Trials: Consensus Recommendations from the IQ DILI Initiative.Drug Saf. 2026;49:9-25.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 1][Cited by in RCA: 3][Article Influence: 3.0][Reference Citation Analysis (0)]
