Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis.

Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.

COVID-19 vaccine and autoimmune hepatitis.

We would like to correspond and share ideas on the publication "SARS-CoV-2 vaccine, a new autoimmune hepatitis trigger?." López Romero-Salazar reported a case of autoimmune hepatitis (AIH) after receiving SARS-COV2 vaccine. López Romero-Salazar et al noted that "vaccination can induce the development of autoimmune pathology in patients at risk." The possibility of a link between AIH and the SARS-CoV2 vaccine is explored. We agree that the COVID-19 vaccination has the potential to create clinical problems. The aberrant immune response could lead to a variety of health issues, including hepatitis. The vaccine recipient in this case had hepatitis, but there is no information about his or her health or liver function prior to inoculation. Other probable causes of hepatitis should be considered.

Postvaccination immune-mediated hepatitis: what do we really know?

Tweetable abstract The percentage of patients with immune-mediated vaccine-associated hepatitis is minimal compared with the number of patients vaccinated worldwide.

Autoimmune liver diseases and SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry. Here we summarise the current knowledge about auto-immune liver diseases (AILDs) and SARS-CoV-2, focusing on: (1) The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs; (2) the role of SARS-CoV-2 in inducing liver damage and triggering AILDs; and (3) the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver. Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine. Although SARS-CoV-2 infection can lead to the development of several autoimmune diseases, few reports correlate it to the appearance of de novo manifestation of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or AIH/PBC overlap syndrome. Different case series of an AIH-like syndrome with a good prognosis after SARS-CoV-2 vaccination have been described. Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established, these reports suggest that this association could be more than coincidental.

Insights into new-onset autoimmune diseases after COVID-19 vaccination.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 670 million infections and almost 7 million deaths globally. The emergence of numerous SARS-CoV-2 has heightened public concern regarding the future course of the epidemic. Currently, the SARS-CoV-2 Omicron variant has rapidly become globally dominant in the COVID-19 pandemic due to its high infectivity and immune evasion. Consequently, vaccination implementation is critically significant. However, growing evidence suggests that COVID-19 vaccination may cause new-onset autoimmune diseases, including autoimmune glomerulonephritis, autoimmune rheumatic diseases, and autoimmune hepatitis. Nevertheless, the causal relationship between COVID-19 vaccines and these autoimmune diseases remains to be demonstrated. In this review, we provide evidence that vaccination induces autoimmunity and summarize possible mechanisms of action, such as molecular mimicry, activation by bystanders, and adjuvants. Our objective is not to refute the importance of vaccines, but to raise awareness about the potential risks of COVID-19 vaccination. In fact, we believe that the benefits of vaccination far outweigh the possible risks and encourage people to get vaccinated.

COVID-19 Hospitalizations with and without Psoriasis (preprint)

Background: Psoriasis is an autoimmune chronic skin condition and as suggested by some recent studies, the inflammatory condition might be exacerbated with COVID-19. However, the relationship between psoriasis and COVID-19 infection needs to be investigated further. In our retrospective cohort study, we have attempted to delineate clinical outcomes in COVID-19 hospitalized patients with psoriasis. Methods: Using the 2020 National Inpatient Sample (NIS), we obtained demographic and clinical data and analyzed a total of 1050040 primary COVID-19 adult hospitalizations in the US. We used weighted logistic and linear regression models to determine the association of psoriasis with various clinical outcomes. The models were adjusted for age, sex, race, comorbidities, and hospital characteristics. Using Stata 16.1 (StataCorp, College Station, TX), we accounted for survey design complexity by incorporating sampling weights, primary sampling units, and strata. Results: The psoriasis cohort comprised 5365 (0.511%) patients. For our primary outcome, there was no significant difference between hospital mortality in hospitalized COVID-19 patients with and without psoriasis (11.18% in non-psoriasis patients vs 9.98% in the psoriasis patients, adjusted odds ratio: [aOR]; 0.93; 95% CI: 0.75 -1.16, p=0.54). Some clinical outcomes were worse for psoriasis patients, and these also had a higher resource utilization. Conclusion: Overall, COVID-19 outcomes do not differ significantly for hospitalized patients with psoriasis than those without. However, psoriatic patients’ trajectory might be affected more owing to higher comorbidities, indicating severe illness.

Autoimmune hepatitis after COVID-19 vaccination.

Vaccination is one of the most vigorous ways to intervene in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Cases of autoimmune hepatitis (AIH) after coronavirus disease (COVID-19) vaccination have been increasingly reported. Twenty-seven cases of AIH are summarized in this study, providing emerging evidence of autoimmune reactions in response to various COVID-19 vaccines, including in patients with special disease backgrounds such as primary sclerosing cholangitis (PSC), liver transplantation, and previous hepatitis C virus (HCV) treatment. Molecular mimicry, adjuvants, epitope spreading, bystander activation, X chromosome, and sceptical hepatotropism of SARS-CoV-2 may account for, to some extent, such autoimmune phenomena. Immunosuppressive corticosteroids perform well with or without azathioprine in such post-COVID-19-vaccination AIH. However, determination of the exact mechanism and establishment of causality require further confirmation.

New-onset and relapsed liver diseases following COVID-19 vaccination: a systematic review.

BACKGROUND: Liver diseases post-COVID-19 vaccination is extremely rare but can occur. A growing body of evidence has indicated that portal vein thrombosis, autoimmune hepatitis, raised liver enzymes and liver injuries, etc., may be potential consequence of COVID-19 vaccines. OBJECTIVES: To describe the results of a systematic review for new-onset and relapsed liver disease following COVID-19 vaccination. METHODS: For this systematic review, we searched Proquest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses PRISMA guideline for studies on the incidence of new onset or relapsed liver diseases post-COVID-19 vaccination, published from December 1, 2020 to July 31, 2022, with English language restriction. RESULTS: Two hundred seventy-five cases from one hundred and eighteen articles were included in the qualitative synthesis of this systematic review. Autoimmune hepatitis (138 cases) was the most frequent pathology observed post-COVID-19 vaccination, followed by portal vein thrombosis (52 cases), raised liver enzymes (26 cases) and liver injury (21 cases). Other cases include splanchnic vein thrombosis, acute cellular rejection of the liver, jaundice, hepatomegaly, acute hepatic failure and hepatic porphyria. Mortality was reported in any of the included cases for acute hepatic failure (n = 4, 50%), portal vein thrombosis (n = 25, 48.1%), splanchnic vein thrombosis (n = 6, 42.8%), jaundice (n = 1, 12.5%), raised liver enzymes (n = 2, 7.7%), and autoimmune hepatitis (n = 3, 2.2%). Most patients were easily treated without any serious complications, recovered and did not require long-term hepatic therapy. CONCLUSION: Reported evidence of liver diseases post-COIVD-19 vaccination should not discourage vaccination against this worldwide pandemic. The number of reported cases is relatively very small in relation to the hundreds of millions of vaccinations that have occurred and the protective benefits offered by COVID-19 vaccination far outweigh the risks.

SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis.

BACKGROUND: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. PATIENTS AND METHODS: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. RESULTS: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17-85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10-0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11-0.35). CONCLUSIONS: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.

Autoimmune Hepatitis-Like Syndrome Following COVID-19 Vaccination: A Systematic Review of the Literature.

OBJECTIVES: During the summer of 2021, case reports began to emerge documenting a small number of individuals who developed autoimmune hepatitis (AIH) following COVID-19 vaccination. These cases are rare and novel, and very little is known. In our systematic review, we analyzed every published case of AIH and reviewed their characteristic findings, treatment, and outcomes. METHODS: We searched PubMed, Embase, and Web of Science from December 1, 2019, to November 1, 2021. Two researchers independently extracted information from the articles about vaccine type, patient history, laboratory values, histology results, treatment regimens, and disease course. RESULTS: Thirty-two patients developed AIH-like syndromes after receiving a COVID-19 vaccine. Jaundice was the most frequently reported symptom (81%), and 19% of patients were initially asymptomatic and presented with elevated liver enzymes found during routine bloodwork. Mean alanine transaminase, aspartate transaminase, and total bilirubin were 1231 U/L, 921 U/L, and 14 mg/dL, respectively. Anti-nuclear antibody was positive in 56%, and anti-smooth muscle antibody in 28% of patients. Steroids were used in 75% of patients. Improvement or complete resolution was seen in 97% of patients. One patient died despite aggressive steroid treatment. CONCLUSION: COVID-19 vaccine-induced AIH is an uncommon association with just 32 documented cases in the literature. Clinicians should be vigilant for AIH in patients who present with liver injury following vaccination. These new findings should under not deter individuals from getting vaccinated, as the benefits of vaccination far outweigh the risks. Fortunately, COVID-19 vaccine-induced AIH appears amendable to corticosteroid therapy and appears to have a favorable outcome.

Editorial: Acute Hepatitis of Unknown Origin in Children. Is Autoimmunity at Play?

A recent global outbreak of cases of acute hepatitis of unknown origin in children has raised health alerts. Increasing numbers of cases are being reported in most countries, mainly in the United Kingdom (UK). Although the cause remains unknown, several viruses have been isolated from affected children, including adenovirus, severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), Epstein-Barr virus (EBV), and rhinovirus. Notably, the cause is not from common hepatitis viruses, as serology for hepatitis viruses A, B, C, D, and E has been negative. Current causal hypotheses include possible infection with a new adenovirus variant that affects immunocompetent children, a new pediatric manifestation of COVID-19, or coinfection with enteric adenovirus type F41. This Editorial aims to present current hypotheses regarding the etiology of acute hepatitis of unknown origin in children, including the role of autoimmune hepatitis secondary to viral infection.

Autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination: case report and literature review.

Although vaccines have been effective against the worldwide pandemic of Coronavirus Disease 19 (COVID-19), some case reports have described autoimmune hepatitis triggered by COVID-19 vaccination. Meanwhile, hepatitis C virus (HCV) is known to be related to autoimmune diseases. Here, we report a case of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination. An 82-year-old woman was referred to our hospital for severe liver injury. She had received a COVID-19 vaccination 7 days prior. She had a history of HCV treatment with direct-acting antivirals 7 years previously. In her blood data, despite HCV antibody positivity, she was negative for HCV RNA by real-time RT-PCR. Anti-nuclear antibody was positive and IgG was elevated. Interface hepatitis and plasma cell infiltration were confirmed pathologically. She was diagnosed as autoimmune hepatitis and her liver injury quickly improved after initiation of steroid administration. This is a first case report of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination.