mRNA-loaded lipid nanoparticles (LNPs) have emerged as a potent and versatile platform that underpins the success of mRNA vaccines, but guidelines for designing safe and effective formulations with minimal off-target effects remain unclear. In this study, we focused on a rational design for a novel ionizable lipid library that is based on ionizable tri-oleoyl-tris (iTOT) compounds with a high yield via a simple 2-step synthesis. To further enhance the efficacy and safety of this potent library for vaccine applications, we identified the optimal composition for a vaccine by focusing on the molar ratio of specific lipid excipients in the formulation. This composition brought about a shift in delivery to the spleen, and the LNP formulation, which contained 15 mol% DSPC (15%DSPC-LNPs), was thoroughly taken up by both B cells and other splenic immune cells. This formulation requires neither additional lipid components nor targeting ligand modifications, and it is accompanied by antigen-specific cytotoxic T lymphocyte responses. The rigid, hydrophobic, and charge-neutral surface of 15%DSPC-LNPs minimizes apolipoprotein E-dependent hepatic uptake and maximizes complement receptor-mediated B-cell targeting. Furthermore, as an intramuscularly administered vaccine, 15%DSPC-LNPs induce antigen-specific immune responses and, importantly, results in significantly lower levels of hepatotoxicity compared with that of the mRNA vaccine formulations currently being marketed. In summary, this study demonstrated how the passive targeting of mRNA-LNPs to organs and cells could be regulated by designing novel ionizable lipids combined with adjusting the relative proportions of lipid components. The results of this study also emphasize how selective mRNA delivery to the spleen could avoid the liver, which highlights a promising strategy for the development of safe and effective vaccines.

Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported.

To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury.

Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed.

All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy, except one patient who developed autoimmune hepatitis.

Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition.

Since the remarkable breakthrough of COVID-19 mRNA vaccines, lipid nanoparticles (LNPs) have gained substantial attention as the most cutting-edge clinical formulations for mRNA delivery. PEGylated lipid (PEG-lipid) has been regarded as an essential constituent of LNPs that helps to prolong their systemic circulation by preventing particle aggregation in the blood and sequestration by the mononuclear phagocyte system. Herein, we synthesized a series of mRNA-loaded nanoparticles by replacing ALC-0159 (a PEG-lipid used in the Comirnaty formulation) with amphiphilic PEG-polycarbonate diblock copolymers (PC-HNPs). Interestingly, variations of polycarbonate block length and structure significantly influenced mRNA encapsulation efficiency, transfection potency, colloidal stability, and PEG shedding rate of PC-HNPs. In vivo and ex vivo bioluminescence imaging revealed that upon subcutaneous administration in mice, the leading candidate PC3-HNP achieved lymph node accumulation comparable to that of the conventional ALC-0159-based LNP formulation while avoiding undesirable liver accumulation. Our findings may provide valuable information for the construction of next-generation nanocarriers for effective mRNA delivery.

Immune checkpoint inhibitors (ICIs) have been widely used in various types of cancer, but they have also led to a significant number of adverse events, including ICI-induced immune-mediated hepatitis (IMH). This study aimed to explore the risk factors for IMH in patients treated with ICIs and to develop and validate a new nomogram model to predict the risk of IMH. Detailed information was collected between January 1, 2020, and December 31, 2023. Univariate logistic regression analysis was used to assess the impact of each clinical variable on the occurrence of IMH, followed by stepwise multivariate logistic regression analysis to determine independent risk factors for IMH. A nomogram model was constructed based on the results of the multivariate analysis. The performance of the nomogram model was evaluated via the area under the receiver operating characteristic curve (AUC), calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC) analysis. A total of 216 (8.82%) patients developed IMH. According to stepwise multivariate logistic analysis, hepatic metastasis, the TNM stage, the WBC count, LYM, ALT, TBIL, ALB, GLB, and ADA were identified as risk factors for IMH. The AUC for the nomogram model was 0.817 in the training set and 0.737 in the validation set. The calibration curves, DCA results, and CIC results indicated that the nomogram model had good predictive accuracy and clinical utility. The nomogram model is intuitive and straightforward, making it highly suitable for rapid assessment of the risk of IMH in patients receiving ICI therapy in clinical practice. Implementing this model enables early adoption of preventive and therapeutic strategies, ultimately reducing the likelihood of immune-related adverse events (IRAEs), and especially IMH.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

The development of ionizable mRNA-lipid nanoparticle (mRNA-LNP) nucleic acid carriers facilitated the clinical translation of the Coronavirus 2019 (COVID-19) mRNA vaccines BNT162b2 and mRNA-1273. Here, we discuss insights into rational improvements to mRNA vaccines, focusing on LNP modifications for mRNA-LNP biodistribution control, miRNA-based biodistribution control of encoded transcripts, and precision adjuvantation strategies.

Autoimmune hepatitis (AIH) is a rare immune-mediated chronic liver disease that is diagnosed based on a combination of biochemical, immunologic, and histologic features and the exclusion of other causes of liver disease. According to the new consensus criteria of the International Autoimmune Hepatitis Pathology Group (IAIHPG), the likely histologic features include a chronic hepatitis pattern of injury with a lymphoplasmacytic portal infiltrate, interface activity, and portal-based fibrosis. More than mild lobular hepatitis with any of the above features can also be diagnosed as likely AIH in the absence of features of another liver disease. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation may represent an acute-onset disease and indicate possible AIH in the absence of concurrent liver disease. Kupffer cell hyaline bodies and portal lymphocyte apoptosis are significantly associated with AIH, whereas emperipolesis and hepatocellular rosette formation are nonspecific features indicative of disease severity. Liver histology is an integral part of the clinical diagnostic scoring system and is required to confirm or support AIH diagnosis. Substitution of the histologic component of the simplified AIH scoring system with the consensus IAIHPG criteria has been proposed to optimize clinical diagnosis. This review explores the significant role of histopathology in AIH by analyzing its main features and current histologic diagnostic criteria, different AIH presentations, differential diagnosis, assessment of concurrent liver disease, and identification of AIH variants with primary cholangiopathy.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.

Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.

Luspatercept, approved for treating beta thalassemia, myelodysplastic syndromes (MDS) associated anemia, and MDS with ring sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis associated anemia, has uncertain long-term safety in large populations. This study analyzed adverse events (AEs) linked to luspatercept using data from the FDA Adverse Event Reporting System (FAERS) with data mining techniques.

We collected and analyzed luspatercept-related reports from the FAERS database from the first quarter of 2022 through the first quarter of 2024. Disproportionality analysis was used in data mining to quantify luspatercept-related AE signals.

A total of 46 AE signals were detected in 13 SOCs (system organ classes). In addition to the AEs identified during the clinical trial stage, this study also identified some unexpected and important AEs, such as product preparation error, prescribed overdose, product preparation issue, prescribed underdose, and acute hepatitis.

Our study provides a comprehensive description of the post-marketing safety of luspatercept and identifies new potential AEs. Healthcare workers must be vigilant in avoiding product preparation errors, an adverse event that highlights the need for enhanced training and the participation of pharmacists in assessing medication utilization scenarios.

Vaccines are the most effective tool against COVID-19 and are generally safe. Very rare and heterogeneous cases of acute liver injury associated to all types of SARS-CoV-2 vaccines have been reported, mostly with autoimmune features. Epidemiological studies used heterogeneous diagnostic criteria and included different populations. Immunological studies in selected cases of acute liver injury linked to mRNA SARS-CoV-2 vaccines suggest that it has a unique pathophysiology, the vaccine-encoded spike protein playing a central role in triggering the aberrant immune response. In most series, liver injury was observed more often following the second vaccine dose. Latency from vaccination to the diagnosis of hepatitis was 1-147 days after the last vaccine dose. Raised immunoglobulin G levels and positive anti-nuclear and/or anti-smooth muscle antibodies are frequent. The vast majority of reported cases have been treated with corticosteroids, mostly associated with azathioprine. Outcome is generally favourable, but cases requiring liver transplantation or causing death have been reported. The heterogeneous clinical entity of acute liver injury linked to SARS-CoV-2 vaccines includes patients requiring long-term immunosuppression, similarly to autoimmune hepatitis, and patients with self-limiting liver damage, possibly representing a unique form of autoimmune-like hepatitis, which we suggest being referred to as SARS-CoV-2 vaccine-associated liver injury (SVALI). Further studies are needed to investigate the pathogenic mechanisms related to the immune response to the spike viral protein in the liver.

DNA technology has emerged as a promising route to accelerated manufacture of sequence agnostic vaccines. For activity, DNA vaccines must be protected and delivered to the correct antigen presenting cells. However, the physicochemical properties of the vector must be carefully tuned to enhance interaction with immune cells and generate sufficient immune response for disease protection. In this study, we have engineered a range of polymer-based nanocarriers based on the poly(beta-amino ester) (PBAE) polycation platform to investigate the role that surface poly(ethylene glycol) (PEG) density has on pDNA encapsulation, formulation properties and gene transfectability both in vitro and in vivo. We achieved this by synthesising a non-PEGylated and PEGylated PBAE and produced formulations containing these PBAEs, and mixed polyplexes to tune surface PEG density. All polymers and co-formulations produced small polyplex nanoparticles with almost complete encapsulation of the cargo in all cases. Despite high gene transfection in HEK293T cells, only the fully PEGylated and mixed formulations displayed significantly higher expression of the reporter gene than the negative control in dendritic cells. Further in vivo studies with a bivalent SARS-CoV-2 pDNA vaccine revealed that only the mixed formulation led to strong antigen specific T-cell responses, however this did not translate into the presence of serum antibodies indicating the need for further studies into improving immunisation with polymer delivery systems.

mRNA vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection have been associated with immune-related adverse reactions. We aimed at investigating whether SARS-CoV-2 vaccines may worsen autoimmune reactions in patients with autoimmune liver diseases.

We centrally tested a large panel of liver- and non-liver-related autoantibodies in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and in healthcare workers (HW) before and after SARS-CoV-2 mRNA vaccines.

49 PBC, 35 AIH, 9 PSC and 38 HW were included. The proportion of subjects with at least one autoantibody positivization after vaccination was 11 % for HW, 37 % for AIH, 35 % for PBC and 56 % for PSC patients, patients having a significantly higher frequency of positivization as compared to HW. The proportion of seropositive subjects before vaccination who had at least one autoantibody negativization was 25 % for HW, 57 % for AIH, 40 % for PBC and 50 % for PSC, AIH patients having a significantly higher frequency of negativization as compared to HW. In the AIH group, the number of autoantibody negativizations was higher than the number of positivizations. The BNT162b2 vaccine was associated with a higher risk of developing new autoantibodies as compared to the mRNA-1273 vaccine. No new-onset autoimmune disease was observed after one year. One AIH patient had a relapse after vaccination.

mRNA SARS-CoV-2 vaccines do not induce short-term worsening of autoimmunity in patients with autoimmune liver diseases.

This review explores the mechanisms, diagnostic approaches, and management strategies for COVID-19-induced liver injury, with a focus on its impact on patients with pre-existing liver conditions, liver cancer, and those undergoing liver transplantation.

A comprehensive literature review included studies on clinical manifestations of liver injury due to COVID-19. Key areas examined were direct viral effects, drug-induced liver injury, cytokine storms, and impacts on individuals with chronic liver diseases, liver transplants, and the role of vaccination. Data were collected from clinical trials, observational studies, case reports, and review literature.

COVID-19 can cause a spectrum of liver injuries, from mild enzyme elevations to severe hepatic dysfunction. Injury mechanisms include direct viral invasion, immune response alterations, drug toxicity, and hypoxia-reperfusion injury. Patients with chronic liver conditions (such as alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma) face increased risks of severe outcomes. The pandemic has worsened pre-existing liver conditions, disrupted cancer treatments, and complicated liver transplantation. Vaccination remains crucial for reducing severe disease, particularly in chronic liver patients and transplant recipients. Telemedicine has been beneficial in managing patients and reducing cross-infection risks.

This review discusses the importance of improved diagnostic methods and management strategies for liver injury caused by COVID-19. It emphasizes the need for close monitoring and customized treatment for high-risk groups, advocating for future research to explore long-term effects, novel therapies, and evidence-based approaches to improve liver health during and after the pandemic.

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in long COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.

The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of lives, leading to significant morbidity and mortality. With >772 million cases and nearly seven million deaths reported worldwide to date, the development of vaccines has been a critical step in mitigating the impact of COVID-19. However, concerns have arisen regarding the potential for SARS-CoV-2 mRNA vaccination to trigger autoimmune diseases, including autoimmune hepatitis (AIH). The present single-center, retrospective study aimed to compare the clinical and pathological features of AIH in patients with or without a history of SARS-CoV-2 mRNA vaccination. A total of 72 patients with AIH were examined. Among them, 10 had received the SARS-CoV-2 mRNA vaccination prior to AIH onset. These patients exhibited more pronounced CD4+ T cell infiltration into the liver tissue compared with those who were unvaccinated. No significant differences in the levels of other liver enzymes, autoimmune antibodies, or CD8+ T cell infiltration were observed between the groups. Moreover, the AIH patients with a history of SARS-CoV-2 mRNA vaccination had more extensive CD4+ T cell infiltration in their liver tissues than the unvaccinated patients. These findings suggested that the immune response to SARS-CoV-2 mRNA vaccination may influence the pathogenesis of AIH, highlighting the need for further research into the relationship between SARS-CoV-2 mRNA vaccination and autoimmune liver diseases. Such studies will also help clarify the distinction between vaccine-induced liver injury and traditional AIH.

The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination.

Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform.

Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively).

Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

SARS-CoV-2 spread rapidly across the globe, contributing to the death of millions of individuals from 2019 to 2023, and has continued to be a major cause of morbidity and mortality after the pandemic. At the start of the pandemic, no vaccines or anti-viral treatments were available to reduce the burden of disease associated with this virus, as it was a novel SARS coronavirus. Because of the tremendous need, the development of vaccines to protect against COVID-19 was critically important. The flexibility and ease of manufacture of nucleic acid-based vaccines, specifically mRNA-based products, allowed the accelerated development of COVID-19 vaccines. Although mRNA-based vaccines and therapeutics had been in clinical trials for over a decade, there were no licensed mRNA vaccines on the market at the start of the pandemic. The rapid development of mRNA-based COVID-19 vaccines reduced serious complications and death from the virus but also engendered significant public concerns, which continue now, years after emergency-use authorization and subsequent licensure of these vaccines. This article summarizes and addresses some of the safety concerns that continue to be expressed about these vaccines and their underlying technology.

COVID-19 has affected millions worldwide, causing significant morbidity and mortality. While predominantly involving the respiratory tract, SARS-CoV-2 has also caused systemic illnesses involving other sites. Liver injury due to COVID-19 has been variably reported in observational studies. It has been postulated that liver damage may be due to direct damage by the SARS-CoV-2 virus or multifactorial secondary to hepatotoxic therapeutic options, as well as cytokine release syndrome and sepsis-induced multiorgan dysfunction. The approach to a COVID-19 patient with liver injury requires a thorough evaluation of the pattern of hepatocellular injury, along with the presence of underlying chronic liver disease and concurrent medications which may cause drug-induced liver injury. While studies have shown uneventful recovery in the majority of mildly affected patients, severe COVID-19 associated liver injury has been associated with higher mortality, prolonged hospitalization, and greater morbidity in survivors. Furthermore, its impact on long-term outcomes remains to be ascertained as recent studies report an association with metabolic-fatty liver disease. This present review provides insight into the subject by describing the postulated mechanism of liver injury, its impact in the presence of pre-existing liver disease, and its short- and long-term clinical implications.

Although previous studies have focused on hepatobiliary and gastrointestinal adverse drug reactions (ADRs) associated with COVID-19 vaccines, literature on such ADRs with other vaccines is limited, particularly on a global scale. Therefore, we aimed to investigate the global burden of vaccine-associated hepatobiliary and gastrointestinal ADRs and identify the vaccines implicated in these occurrences. This study utilized data from the World Health Organization (WHO) international pharmacovigilance database to extract reports of vaccine-associated hepatobiliary and gastrointestinal ADRs from 1967 to 2023 (total reports = 131 255 418). Through global reporting counts, reported odds ratios (ROR) with 95% confidence interval (CI), and information components (IC) with IC0.25, the study examined the association between 16 vaccines and the incidence of hepatobiliary and gastrointestinal ADRs across 156 countries. Of the 6 842 303 reports in the vaccine-associated ADRs, 10 786 reports of liver injury, 927 870 reports of gastrointestinal symptoms, 2978 reports of pancreas and bile duct injury, and 96 reports of intra-abdominal hemorrhage between 1967 and 2023 were identified. Most hepatobiliary and gastrointestinal ADRs surged after 2020, with the majority of reports attributed to COVID-19 messenger RNA (mRNA) vaccines. Hepatitis A vaccines exhibited the highest association with liver injury (ROR [95% CI]: 10.30 [9.65-10.99]; IC [IC0.25]: 3.33 [3.22]), followed by hepatitis B, typhoid, and rotavirus. Specifically, ischemic hepatitis had a significant association with both Ad5-vectored and mRNA COVID-19 vaccines. Gastrointestinal symptoms were associated with all vaccines except for tuberculosis vaccines, particularly with rotavirus (11.62 [11.45-11.80]; 3.05 [3.03]) and typhoid (11.02 [10.66-11.39]; 3.00 [2.96]). Pancreas and bile duct injury were associated with COVID-19 mRNA (1.99 [1.89-2.09]; 0.90 [0.83]), MMR (measles, mumps, and rubella), and papillomavirus vaccines. For intra-abdominal hemorrhage, inactivated whole-virus COVID-19 vaccines (3.93 [1.86-8.27]; 1.71 [0.41]) had the highest association, followed by COVID-19 mRNA (1.81 [1.42-2.29]; 0.77 [0.39]). Most of these ADRs had a short time to onset, within 1 day, and low mortality rate. Through a global scale database, the majority of ADRs occurred within 1 day, emphasizing the importance of healthcare workers' vigilant monitoring and timely management.

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.

Different patterns of liver injury have been reported in association with the SARS-CoV-2 vaccines. The aim of this study was to describe a nationwide cohort of patients with SARS CoV-2 vaccine-induced liver injury, focusing on treatment and the evolution after further booster administration.

multicentre, retrospective-prospective study, including subjects who developed abnormal liver tests within 90 days after administration of SARS-CoV-2 vaccination.

47 cases were collected: 17 after prime dose and 30 after booster. Age was 57 years, 30 (63.8 %) were female, and 7 (14.9 %) had a history of prior autoimmune hepatitis (AIH). Most cases were non-severe, though 9 (19.1 %) developed acute liver injury or failure (ALF). Liver injury tended to be more severe in those presenting after a booster (p=0.084). Pattern of liver injury was hepatocellular (80.9 %), mixed (12.8 %) and 3 (6.4 %) cholestatic. Liver biopsy was performed on 33 patients; 29 showed findings of AIH. Forty-one (87.2 %) patients received immunosuppressants, mostly corticosteroids (35/41). One required liver transplantation and another died due to ALF. Immunosuppression was discontinued in 6/41 patients without later rebound. Twenty-five subjects received at least one booster and 7 (28.0 %) relapsed from the liver injury, but all were non-severe. Recurrence was less frequent among patients on immunosuppressants at booster administration (28.6 % vs. 88.9 %, p=0.007).

SARS CoV-2 vaccine-induced liver injury is heterogeneous but mostly immune-mediated. Relapse of liver injury after re-exposure to vaccine is frequent (28.0 %) but mild. Immunosuppression at booster administration is associated with a lower risk of liver injury.

The rapid rollout and uptake of novel coronavirus disease 2019 (COVID-19) vaccines has been accompanied by a small yet noticeable accumulation of reports of liver injury occurring after vaccination. This review describes the present evidence surrounding COVID-19 vaccine-induced liver injury (VILI).

Liver injury occurring after the COVID-19 vaccine often presents clinically similar to autoimmune hepatitis, with positive autoantibodies and a portal and lobular inflammatory infiltrate and varying degrees of necrosis on biopsy. The overwhelming majority of patients recover, often spontaneously or with a limited course of immunosuppression. The overall incidence of this phenomenon appears to be exceedingly low.

Providers should remain vigilant for ongoing reports of VILI after COVID-19 and yet feel reassured by the low incidence and high likelihood of recovery. Ongoing genetic and histological study, as well as longer-term follow-up of presently identified cases, will shed further light on the clinical entity of VILI.

Antibiotics are among the most common causes of drug-induced liver injury worldwide. Amoxicillin/clavulanic acid and nitrofurantoin are the most common culprits while tetracyclines are a rare cause of liver injury. Among tetracyclines, minocycline has been reported more frequently than doxycycline, which is an extremely rare cause of drug-induced liver injury. We present a healthy 28-year-old male patient from rural United States who was taking doxycycline for Lyme disease. After five days of therapy, he developed nausea, vomiting, fatigue, and significant transaminitis consistent with a hepatocellular pattern of liver injury. After a thorough workup which ruled out other causes such as infection, autoimmune diseases, liver malignancy, and vascular, structural, and metabolic disorders, his liver injury was attributed to doxycycline. We reached the diagnosis also by demonstrating a consistent temporal association between doxycycline intake and liver injury and the patient recovered completely with the cessation of doxycycline. Recognition of doxycycline as a cause of drug-induced liver injury should be considered in patients utilizing this antibiotic. Doxycycline, unlike minocycline, has a short latency period. Early recognition and discontinuation of doxycycline in our patient resulted in the complete resolution of symptoms and transaminitis preventing further morbidity and mortality.

Soluble liver antigen/liver pancreas antibodies (anti-SLA/LP) are specific markers for autoimmune hepatitis (AIH) that have been associated with a distinct clinical phenotype and a more aggressive form of AIH. We prospectively evaluated the frequency and clinical significance of anti-SLA/LP in Turkish patients with AIH.

We prospectively included patients diagnosed with AIH between January 2018 and May 2023. Autoantibodies were detected using by immunofluorescence and immunoblot.

We included 61 (80%, female) AIH patients with a median age of 31 years (15-78) at the time of diagnosis. Anti-SLA/LP was detected in 20% ( n  = 12) of the patients. Baseline characteristics, treatment responses and outcomes were similar among anti-SLA/LP-positive and anti-SLA/LP-negative AIH patients. Anti-SLA/LP-positive patients had significantly higher biochemical response rates after 4 weeks (100 vs. 67%, P  = 0.027), 3 months (100 vs. 39%, P  < 0.001), 6 months (100 vs. 69%, P  = 0.041) of therapy but not after 12 months (100 vs. 76%, P  = 0.103) and at the end of follow-up (100 vs. 91%, P  = 0.328). Relapse rates following treatment response were similar in patients with and without anti-SLA/LP (22 vs. 23%, P  = 0.956). Second-line therapies (tacrolimus and mycophenolate mofetil) were given to seven (11%) patients, all were anti-SLA/LP-negative. Two of these progressed into end-stage liver disease and both underwent liver transplantation.

Our study results suggest that anti-SLA/LP positivity does not entail clinically distinct or severe features in AIH. In our cohort, anti-SLA/LP-positive patients showed a quicker response to immunosuppressive therapy.

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality. Spike messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 may contribute to immune-mediated injuries. Here we present a case of a previously healthy 47-year-old man, who developed progressive jaundice 2 weeks after receiving his 3rd COVID-19 vaccination (1st mRNA-based vaccine). Apart from elevated serum total bilirubin levels (peaked at >70 mg/dL), deteriorating renal (blood urea nitrogen: peak, 108.5 mg/dL; creatinine: peak, 6 mg/dL) and exocrine pancreas (amylase: peak, 1717 U/L; lipase: peak, 5784 U/L) profiles were also seen. Vanishing bile duct syndrome characterized by ductopenia and cholangiocyte vacuolation, positive C4d deposition, and high titer of anti-angiotensin II type 1 receptor antibody consistently explain the overall antibody-mediated pathogenesis resembling antibody-mediated "rejection" in the solid organ transplant setting. Corticosteroids and plasmapheresis were administered, leading to gradual resolution of the symptoms, and the jaundice completely resolved 2 months later. In conclusion, we reported a case of antibody-mediated multiorgan injury after an mRNA COVID-19 vaccine, characterized by severe cholangiopathy. The patient recovered with corticosteroids and plasmapheresis, and long-term follow-up is necessary.

Efficient translation mediated by the 5' untranslated region (5' UTR) is essential for the robust efficacy of mRNA vaccines. However, the N1-methyl-pseudouridine (m1Ψ) modification of mRNA can impact the translation efficiency of the 5' UTR. We discovered that the optimal 5' UTR for m1Ψ-modified mRNA (m1Ψ-5' UTR) differs significantly from its unmodified counterpart, highlighting the need for a specialized tool for designing m1Ψ-5' UTRs rather than directly utilizing high-expression endogenous gene 5' UTRs. In response, we developed a novel machine learning-based tool, Smart5UTR, which employs a deep generative model to identify superior m1Ψ-5' UTRs in silico. The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models. As a result, Smart5UTR can successfully design superior 5' UTRs, greatly benefiting mRNA vaccine development. Notably, Smart5UTR-designed superior 5' UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2, surpassing the performance of vaccines using high-expression endogenous gene 5' UTRs.

Glycyrrhizic acid (GA), one of the major active components derived from licorice root, exerts liver-protecting activity. Its molecular mechanisms of action, however, remain not completely understood. The angiotensin (Ang) converting enzyme (ACE) 2/Ang-(1-7)/Mas axis, regulated by ACE2 through converting Ang II into Ang-(1-7) to activate Mas receptor, counteracts the pro-inflammatory and pro-steatotic effects of the ACE/Ang II/Ang II receptor type 1 (AT1) axis. Here, it was found that pretreatment with GA suppressed LPS/D-galactosamine-induced serum hyperactivities of alanine aminotransferase and aspartate aminotransferase, hepatomegaly, pathological changes, and over-accumulation of triglycerides and fatty droplets in the liver of mice. GA also diminished LPS/free fatty acid-induced inflammation and steatosis in cultured hepatocytes. Mechanistically, GA restored hepatic protein hypoexpression of ACE2 and Mas receptor, and the decrease in hepatic Ang-(1-7) content. Hepatic overexpression of angiotensin II and AT1 was also suppressed. However, GA did not alter hepatic protein expression of renin and ACE. In addition, GA inhibited hepatic protein over-phosphorylation of the p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor κB at Ser536. Hepatic overexpression of tumor necrosis factor α, interleukin 6, interleukin 1β, sterol regulatory element-binding protein 1c, and fatty acid synthase was also inhibited. GA-elicited recovery of ACE2 and Mas protein hypoexpression was further confirmed in the hepatocyte. Thus, the present results demonstrate that GA restores the downregulated hepatic ACE2-mediated anti-inflammatory and anti-steatotic signaling in the amelioration of steatohepatitis. We suggest that GA may protect the liver from injury by regulating the hepatic ACE2-mediated signaling.

During recent years, there have been major insight into the pathogenesis, diagnosis and treatment of autoimmune hepatitis (AIH). We aim to evaluate modifications of the clinical-epidemiological phenotype of AIH patients from 1980 to our days.

Single-centre, tertiary care retrospective study on 507 consecutive Italian patients with AIH. Patients were divided into four subgroups according to the decade of diagnosis: 1981-1990, 1991-2000, 2001-2010 and 2011-2020. We assessed clinical, laboratory and histological features at diagnosis, response to treatment and clinical outcomes. Acute presentation is defined as transaminase levels >10-fold the upper limit and/or bilirubin >5 mg/dL. Complete response is defined as the normalization of transaminases and IgG after 12 months. Clinical progression is defined as the development of cirrhosis in non-cirrhotic patients and hepatic decompensation/hepatocellular carcinoma development in compensated cirrhosis.

Median age at diagnosis increased across decades (24, 31, 39, 52 years, p < .001). Acute onset became more common (39.6%, 44.4%, 47.7%, 59.5%, p = .019), while cirrhosis at diagnosis became less frequent (36.5%, 16.3%, 10.8%, 8.7%, p < .001). Complete response rates rose (11.1%, 49.4%, 72.7% 76.2%, p < .001) and clinical progression during follow-up decreased (54.3%, 29.9%, 16.9%, 11.2%, p < .001). Anti-nuclear antibodies positivity increased (40.7%, 52.0%, 73.7%, 79.3%, p < .001), while IgG levels/upper limit progressively decreased (1.546, 1.515, 1.252, 1.120, p < .001). Liver-related death and liver transplantation reduced from 17.1% to 2.1% (p < .001).

In the new millennium, the typical AIH patient in Italy is older at diagnosis, more often presents with acute hepatitis, cirrhosis is less frequent and response to treatment is more favourable.

SARS-CoV-2 vaccines-associated autoimmune liver diseases have been reported in several case reports. However, the safety and immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in patients with autoimmune liver diseases (AILD) is still unknown.

Eighty-four patients with AILD were prospectively followed up after the second dose (primary) of inactivated SARS-CoV-2 vaccine. Some of them received the third dose (booster) of inactivated vaccine. Adverse events (AEs), autoimmune activation, and liver inflammation exacerbation after primary and booster vaccination were recorded. Meanwhile, dynamics of antireceptor-binding-domain IgG (anti-RBD-IgG), neutralizing antibodies (NAbs) and RBD-specific B cells responses were evaluated.

The overall AEs in AILD patients after primary and booster vaccination were 26.2% and 13.3%, respectively. The decrease of C3 level and increase of immunoglobulin light chain κ and λ levels were observed in AILD patients after primary vaccination, however, liver inflammation was not exacerbated, even after booster vaccination. Both the seroprevalence and titers of anti-RBD-IgG and NAbs were decreased over time in AILD patients after primary vaccination. Notably, the antibody titers were significantly elevated after booster vaccination (10-fold in anti-RBD-IgG and 7.4-fold in NAbs, respectively), which was as high as in healthy controls. Unfortunately, the inferior antibody response was not enhanced after booster vaccination in patients with immunosuppressants. Changes of atypical memory B cells were inversely related to antibody levels, which indicate that the impaired immune memory was partially restored partly by the booster vaccination.

The well tolerability and enhanced humoral immune response of inactivated vaccine supports an additional booster vaccination in AILD patients without immunosuppressants.

The pandemic period due to coronavirus disease 2019 (COVID-19) revolutionized all possible areas of global health. Significant consequences were also related to diverse extrapulmonary manifestations of this pathology. The liver was found to be a relatively common organ, beyond the respiratory tract, affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple studies revealed the essential role of chronic liver disease (CLD) in the general outcome of coronavirus infection. Present concerns in this field are related to the direct hepatic consequences caused by COVID-19 and pre-existing liver disorders as risk factors for the severe course of the infection. Which mechanism has a key role in this phenomenon-previously existing hepatic disorder or acute liver failure due to SARS-CoV-2-is still not fully clarified. Alcoholic liver disease (ALD) constitutes another not fully elucidated context of coronavirus infection. Should the toxic effects of ethanol or already developed liver cirrhosis and its consequences be perceived as a causative or triggering factor of hepatic impairment in COVID-19 patients? In the face of these discrepancies, we decided to summarize the role of the liver in the whole picture of coronavirus infection, paying special attention to ALD and focusing on the pathological pathways related to COVID-19, ethanol toxicity and liver cirrhosis.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may trigger autoimmune disease (AD) through initial innate immune activation with subsequent aberrations in adaptive immune cells leading to AD. While there are multiple reports of incident AD diagnosed after COVID-19, the risk in the context of key circulating strains is unknown.

TriNetX, a global, federated, health research network providing access to electronic medical records across 74 healthcare organizations, was utilized to define an adult cohort between January 1, 2020, and March 3, 2023. Exposure was defined as COVID-19 diagnosis (ICD-10 code or positive laboratory test). Age- and sex-propensity score-matched controls never had COVID-19 diagnosed. Outcomes were assessed 1 month to 1 year after the index date. Patients with AD prior to or within 1 month after the index date were excluded from the primary analysis. Incidence and risk ratios of each AD were assessed.

A total of 3,908,592 patients were included. Of 24 AD patients assessed, adjusted risk ratios for eight AD patients who had COVID-19 were higher compared to those who had no COVID-19. Cutaneous vasculitis (adjusted hazard ratio (aHR): 1.82; 95% CI 1.55-2.13), polyarteritis nodosa (aHR: 1.76; 95% CI 1.15-2.70), and hypersensitivity angiitis (aHR: 1.64; 95% CI 1.12-2.38) had the highest risk ratios. Overall, psoriasis (0.15%), rheumatoid arthritis (0.14%), and type 1 diabetes (0.13%) had the highest incidence during the study period, and of these, psoriasis and diabetes were more likely after COVID-19. The risk of any AD was lower if COVID-19 was diagnosed when Omicron variants were the predominant circulating strains. A positive antinuclear antibody was more likely and predictive of AD after COVID-19.

SARS-CoV-2 may be a potential trigger for some AD, but the risk for AD may decrease with time given the apparent lower risk after infection with Omicron variants.

Coronavirus disease 2019 (COVID-19) vaccines were rapidly implemented globally and vaccine-associated immune-related hepatitis was recently reported. We aim to investigate its impact in regions endemic of chronic hepatitis B (CHB).

We retrospectively collected patients who developed hepatitis within 90 days after COVID-19 vaccination in Taiwan. The mechanisms of hepatitis included vaccine induced liver injury (VILI) and immune-related hepatitis, which are direct liver injuries defined as aspartate or alanine aminotransferase (AST or ALT) increased ≥ 5-fold upper limit of normal (ULN) and/or AST or ALT ≥ 3-fold of ULN with concurrent total bilirubin ≥ 2-fold of ULN. Indirect liver injury due to HBV reactivation was defined as HBsAg reverse seroconversion or significant rise in HBV DNA level. The demographics, clinical data, and course of hepatitis were compared statistically.

Twenty-five patients were included with a median age of 54. The culprit vaccines were ChAdOx1 nCoV-19 (n = 9), mRNA-1273 (n = 12), and BNT162b2 (n = 4). The characteristics of hepatitis were comparable regardless of vaccine subtypes. The median onset of hepatitis was 25 days post vaccination, with a peak of 10-fold ALT-increase. The etiologies included HBV reactivation (n = 10), VILI (n = 10), and immune-related hepatitis (n = 5). HBV reactivation accounts for 90% of vaccine-induced hepatitis in patients of CHB (n = 10), and two patients died. Patients with initial AST levels >500 U/L increased 27-fold risks of liver injury greater than moderate severity compared with those without.

COVID-19 vaccine induced hepatitis is a clinical significant complication, and HBV reactivation may account for a possible mechanism.

Liver injury after Covid-19 vaccine has been described, although the incidence was not well established. We aimed to compare cumulative incidence of new onset liver test alteration after Covid-19 vaccination, and to compare with an historical control of influenza vaccination.

We conducted a retrospective cohort study which included adults who received at least one dose of Covid-19 vaccine from January 1 to May 30, 2021 and a control group who received a single dose of influenza vaccine during 2019, in a tertiary medical center from Argentina.

We included 29 798 patients in Covid-19 vaccine group and 24 605 in influenza vaccine group. Liver function tests were performed in 7833 (26.9%) in Covid-19 vaccine group and 8459 (34.37%) in influenza vaccine group. Cumulative incidence at 90 days of new onset liver enzyme test alteration was 4.7 per 1000 (95% 4.0-5.5) for Covid-19 group, and 5.1 per 1000 (95% 4.3-6.1) for the influenza vaccine group (p value = 0.489). Two patients in the Covid-19 vaccine group developed immune mediated liver injury.

We found no difference in liver test alteration between groups. These findings support the safety of Covid-19 vaccines. While we have identified two cases that are consistent with immune mediated liver injury following COVID-19 vaccination, we believe that the available data is insufficient to attribute them solely to the vaccination.

There have been massive studies to develop an effective vaccine against SARS-CoV-2 which fortunately led to manage the recent pandemic, COVID-19. According to the quite rapidly developed vaccines in a fast window time, large investigations to assess the probable vaccine-related adverse events are crucially required. COVID-19 vaccines are available of different platforms and the primary clinical trials results presented acceptable safety profile of the approved vaccines. Nevertheless, the long-term assessment of the adverse events or rare conditions need to be investigated. The present systematic review, aimed at classification of probable vaccine-related unsolicited adverse events in Iranian population through the data collection of the published case report studies.The related published case reports were explored via PubMed, Web of Science and Google scholar according to the available published data up to 14th Dec, 2022 using PRISMA guideline. Out of 437 explored studies, the relevant data were fully investigated which totally led to 40 studies, including 64 case reports with a new onset of a problem post-vaccination. The cases were then classified according to the various items, such as the type of adverse event and COVID-19 vaccines.The reported COVID-19 vaccines in the studied cases included BBIBP-CorV, ChAdOx1-S, Sputnik V and COVAXIN. The results showed that the adverse events presented in 8 different categories, including cutaneous involvements in 43.7% (n = 28), neurologic problems (n = 16), blood/vessel involvement (n = 6), cardiovascular involvement (n = 5), ocular disorders (n = 4), liver disorder/failure (n = 2), graft rejection (n = 2) and one metabolic disorder. Notably, almost 60% of the cases had no comorbidities. Moreover, the obtained data revealed nearly half of the incidences occurred after the first dose of injection and the median duration of improvement after the symptom was 10 days (range: 2-120). In addition, 73% of all the cases were either significantly improved or fully recovered. Liver failure following ChAdOx1-S vaccination was the most serious vaccine adverse event which led to death in two individuals with no related medical history.Although the advantages of COVID-19 vaccination is undoubtedly significant, individuals including with a history of serious disease, comorbidities and immunodeficiency conditions should be vaccinated with the utmost caution. This study provides a comprehensive overview and clinical implications of possible vaccine-related adverse events which should be considered in further vaccination strategies. Nevertheless, there might be a bias regarding potential under-reporting and missing data of the case reports included in the present study. Although the reported data are not proven to be the direct vaccination outcomes and could be a possible immune response over stimulation, the people the population with a medium/high risk should be monitored after getting vaccinated against COVID-19 of any platforms. This could be achieved by a carefull attention to the subjects ' medical history and also through consulting with healthcare providers before vaccination.

Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, other organs, such as the liver, are also affected. In this overview, the effects of SARS-CoV-2 infection on the liver in both healthy people and in those with pre-existing liver disease are documented; the relationship between coronavirus disease 19 (COVID-19) vaccination and liver injury is examined; the mechanism of SARS-CoV-2-associated liver injury is explored; and the long-term consequences of COVID-19 are delineated, both in people with and without pre-existing liver disease.