The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or "immune paralysis" caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.

A rise in paediatric cases of acute hepatitis of unknown origin (AHUO) was observed in 2022, some requiring liver transplantation. A link to adeno-associated virus 2 infection and CD4+T-cell mediated disease was reported in cohorts in the UK and USA but does not explain all cases.

To determine the intrahepatic immune cell interactions in the inflamed liver and a possible contribution of SARS-CoV-2 infection.

Patients with acute non-A non-E hepatitis (10/12 AHUO, 2/12 subacute) during February 2022-December 2022 undergoing liver biopsy were recruited in a European patient cohort. Hepatological, virological, histopathological and highly multiplexed spatial and single-cell analyses of liver biopsies were performed.

Patients were negative for adenoviral and SARS-CoV-2 PCR. Three patients had a positive adenoviral serology and 10/12 patients had a history or serological evidence of SARS-CoV-2 infection. Imaging mass cytometry identified significant intrahepatic immune infiltration with an enrichment of CD8+T-cells. The highest CD8 infiltration and concomitant peripheral immune activation were observed in patients with the most severe hepatitis. CD8+T-cell infiltration was connected to histomorphological interface hepatitis and bridging necrosis. Cellular neighbourhood analysis indicated disease-associated microanatomic interactions between CX3CR1+ endothelial and myeloid cell populations, interacting with effector CD8+T-cells suggesting a pathogenic cellular triad. Of note, we detected intrahepatic SARS-CoV-2 antigens in ACE2-expressing cells in the areas with significant pathology in 11/12 samples using several different detection methods. 10/12 patients were treated with corticosteroid therapy and no liver transplantation was required.

We identified a possible manifestation of an immune-mediated postacute sequel to COVID-19 associated with a characteristic immune infiltrate in children with AHUO. COVID-19 testing should be considered in paediatric AHUO.

Steatotic liver diseases (SLD) have become more prevalent over the last decade and are associated not only with cardiometabolic diseases but also with psychological symptoms (depression, fatigue). These symptoms are also common in post-COVID syndrome (PCS). Therefore, the aim of the study was to analyze the burden of SLD in PCS patients.

We systematically screened all PCS patients from our post-COVID outpatient clinic using transient elastography, structured questionnaires for neurocognitive evaluation and blood sample analysis. Controls without PCS and without known liver diseases were also recruited and assessed with the same approach.

560 PCS patients and 103 healthy controls were included. The overall prevalence of SLD was high in both cohorts (57 vs. 53%). PCS patients with SLD were more frequently male (41 vs. 24%), older (52 vs. 44 years) and had more cardiometabolic diseases (87.0 vs. 46.4%). Cognitive impairment was more related to SLD in PCS patients than in the no-SLD group (OR: 1.68, CI: 1.14-2.46, p = 0.008). The presence of SLD was related to severe COVID-19 with hospitalization (OR: 2.91, CI: 1.85-4.56, p < 0.001). Within 1 year of the follow-up, 152 of 289 patients described a resolution in PCS irrespective of the presence or absence of SLD (log-rank p = 0.96).

SLD is associated with severe COVID-19 and cognitive dysfunction in PCS. Longitudinal studies are needed to assess the role of hepatic steatosis, development of post-acute infection regulation (e.g., SARS-CoV-2) and to differentiate between SLD-associated symptoms and PCS.

Abnormalities in liver biochemistry are common in COVID-19 patients. Hepatic vein Doppler waveform, typically triphasic, may become biphasic or monophasic in cirrhosis, correlating with liver dysfunction, fibrosis, inflammation, and portal hypertension. This study investigates liver ultrasound (US) features in COVID-19 patients, correlating hepatic vein Doppler waveform and portal vein velocity (PVV) with inflammatory indexes and clinical outcomes.

Fifty-seven patients with SARS-CoV-2 infection participated in a crosssectional study. Bedside upper abdomen US evaluations, including B-mode and Doppler, were conducted using a convex probe. Hepatic vein Doppler waveforms were classified as triphasic, biphasic, or monophasic, and the hepatic vein waveform index (HVWI) was calculated. PVV was measured over three cardiac cycles. Tracings were blindly analyzed by three operators to ensure consistency.

Low HVWI and high PVV correlated with elevated LDH, ALT, D-dimer, and ferritin (p < 0.05). HVWI showed significant negative correlations with ferritin, D-dimer, and ALT (p < 0.05). D-Dimer and ferritin were higher in patients with biphasic/monophasic waveforms (p < 0.05). High PVV and larger spleen diameters predicted worse respiratory outcomes, including CPAP and tracheal intubation (p < 0.05). Optimal cut-off values for PVV (21.7 cm/s) and spleen diameter (9.84 cm) maximized sensitivity and specificity for predicting these outcomes. FIB-4 scores did not correlate with respiratory outcomes or hepatic hemodynamics (p > 0.05). Hemodynamic alterations were not significantly influenced by the presence of SLD (Steatotic Liver Disease).

COVID-19 patients exhibit altered intrahepatic hemodynamics, with hepatic vein waveform abnormalities potentially reflecting liver inflammation and fibrosis. PVV and spleen diameter may serve as non-invasive predictors of respiratory outcomes.

Despite azvudine being prioritized for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, its effectiveness and safety remain inadequately substantiated in hospitalized SARS-CoV-2 infected patients with liver diseases. A retrospective nine-center cohort study along with an independent validation cohort is conducted to examine the efficacy of azvudine (Clinical Trial Registration Number: NCT06349655). The primary outcome is all-cause mortality and the secondary outcome is composite disease progression. Efficacy is assessed via Kaplan-Meier analysis and Cox regression, with subgroup and sensitivity analyses for further validation. Among 32 864 hospitalized SARS-CoV-2 infected patients, 1022 eligible azvudine recipients, and 1022 controls are included through propensity score match. Kaplan-Meier analysis reveals that azvudine treatment is associated with a lower risk of all-cause mortality and composite disease progression (both p<0.0001). Cox regression analysis suggests azvudine recipients could have a 39% lower risk of all-cause mortality than controls (95% confidence interval [CI]: 0.468-0.795, p<0.001), but with no notable significance in composite disease progression (hazard ratio: 0.85, 95% CI: 0.686-1.061, p = 0.154). Subgroup analysis suggests that azvudine has a greater benefit for both all-cause mortality and composite disease progression in patients with kidney diseases or without autoimmune diseases. Three sensitivity analyses and validation cohorts confirm the robustness of the findings. Safety analysis observes few adverse events in azvudine recipients. Within 15 days after azvudine administration, no significant difference in liver function indexes and kidney function indexes is observed between the two groups except for a few time points. These findings demonstrate that azvudine shows potential clinical efficacy in improving all-cause mortality in hospitalized SARS-CoV-2 infected patients with liver diseases, with acceptable adverse effects.

Multi-society experts proposed the adoption of new terminology, metabolic dysfunctionassociated steatotic liver disease (MASLD) and steatotic liver disease (SLD). We studied the current prevalence of SLD and its subcategories in the US.

Using the recent National Health and Nutrition Examination Survey from 2017 to 2023, we analyzed data from 12,199 participants (≥18 years) who completed transient elastography. SLD and its subcategories, including MASLD, metabolic and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD), were categorized according to consensus nomenclature.

The age-adjusted prevalence of SLD (cut-off: 285 dB/m) was 35.0% (95% confidence interval [CI] 33.4-36.7). Within this category, the age-adjusted prevalence for MASLD was 31.9% (95% CI 30.4-33.4), MetALD 2.2% (95% CI 1.8-2.6), and ALD 0.8% (95% CI 0.6-1.1). The prevalence of SLD and MASLD showed a statistically insignificant decrease during COVID-19, while ALD increased without significance. In contrast, the prevalence of advanced fibrosis in SLD was significantly higher during the COVID-19 era, at 9.8% for 285 dB/m and 7.8% for 263 dB/m, compared to 7.4% (P=0.039) and 6% (P=0.041) in the pre-COVID-19 era. The proportion of advanced fibrosis and cirrhosis in individuals with ALD was two-fold higher than MASLD and MetALD, largely due to increases during the COVID-19 era.

While the prevalence of SLD and its subcategories remained stable, there was a significant increase in advanced fibrosis among SLD individuals during the COVID-19 era, with ALD having a proportion of advanced fibrosis and cirrhosis that was twice as high as MASLD and MetALD.

The molecular underpinnings of organ dysfunction in severe COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we perform single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents.

We identify hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells, and a central role in a pro-fibrotic TGFβ signaling cell-cell communications network. Integrated analysis and comparisons with healthy controls reveal extensive changes in the cellular composition and expression states in COVID-19 liver, providing the underpinning of hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis characteristic of COVID-19 cholangiopathy. We also observe Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition is dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells.

Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.

During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).

After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501YMA30) intranasally at 3 × 102, 1 × 103, 3 × 103, and 1 × 104 plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated.

A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 102 group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 103 or 1 × 104 PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 104 PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine.

SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.

VV116 is an oral antiviral drug against SARS-CoV-2, known for its favorable efficacy and safety profile. But its application in patients with severe liver dysfunction has not been evaluated. Here, we report a case in which a patient with aplastic anemia and liver impairment (recovery phase of acute liver failure) was infected with SARS-CoV-2. Based on clinical trials and pharmacokinetic analysis about VV116, we initiated a reduced dose of 300 mg every 12 h on day 1, 200 mg every 12 h on days 2-5 for antiviral therapy. Finally, the patient's viral load rapidly dropped to an undetected level, and no drug-related adverse effects were observed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.

The potential effect of ursodeoxycholic acid (UDCA) on the clinical outcomes of SARS-CoV-2 in patients with chronic liver diseases has been a subject of ongoing debate since the onset of the SARS-CoV-2 pandemic in 2019. This study aims to investigate the effect of UDCA on the prognosis of SARS-CoV-2 infection in patients with chronic liver diseases.

A total of 926 patients with chronic liver diseases who contracted their first SARS-CoV-2 infection during December 2022 to January 2023, were included in this study. Participants were divided into two groups based on the use of UDCA: the UDCA cohort (n = 329) and the non-UDCA cohort (n = 597). After performing a 1:1 age-and sex-matching, the analysis proceeded with 309 patients from each group for further evaluation.

In the UDCA-treated cohort, the incidence of asymptomatic SARS-CoV-2 infections was significantly higher, with 30.1% of patients affected, compared to 6.47% in the non-UDCA group (p < 0.0001). Multivariable analysis identified UDCA as a protective factor against symptomatic infections, yielding an odds ratio (OR) of 4.77 (95% CI: 2.70-8.44, p < 0.001). Furthermore, age over 50 was found to be a risk factor for asymptomatic infections in the UDCA cohort, with an adjusted OR of 1.51 (95% CI: 1.01-2.24, p = 0.05).

The study suggests that UDCA therapy may improve clinical outcomes in patients with chronic liver diseases patients who are infected with SARS-CoV-2, highlighting its potential role in improving prognosis within this vulnerable population. However, further research is required to validate these findings and to elucidate the mechanisms underlying UDCA's protective effect.

This study aimed to create a preoperative risk assessment form for COVID-19-positive hepatobiliary patients to guide further prevention of complications after surgery and reduce morbidity and mortality.

Based on the literature, focus groups, and case studies, a multidisciplinary panel of 15 experts conducted three rounds of a Delphi study that resulted in the development of a preoperative risk assessment form to be used by healthcare professionals in the treatment of COVID-19-positive hepatobiliary patients.

A preoperative risk assessment form for health professionals to use among COVID-19-positive hepatobiliary patients was developed based on literature, focus groups, and case studies. A 3-round Delphi study was conducted to validate and revise the risk assessment form using a multidisciplinary panel of 15 experts involved in hepatobiliary surgery.

The experts demonstrated high cooperation and familiarity with the research topic, with positive coefficients ranging from 93.33% to 100% and authority coefficients ranging from 0.83 to 0.86. The coordination coefficients were 0.33, 0.26, and 0.22, respectively, indicating good coordination among expert opinions. The final risk assessment form included 9 primary (first-level) indicators, 38 secondary (second-level) indicators, and 122 tertiary (third-level) indicators.

The preoperative risk assessment form for hepatobiliary surgery patients infected with COVID-19 is scientifically rigorous, reliable, and valid. This screening tool may be used by health providers to identify high-risk patients, prevent postoperative complications, and reduce morbidity and mortality.

Predictors of coronavirus disease 2019 (COVID-19)-related rehospitalization remain underexplored. This study aims to identify the main risk factors associated with rehospitalizations due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections among residents of Lombardy, northern Italy.

A retrospective observational study was conducted using two linked administrative databases covering demographic data, comorbidities, hospital records, and COVID-19 data of Lombardy residents. The study population included patients hospitalized for COVID-19 between February 2020 and August 2021. Rehospitalization was defined as a second COVID-19-related hospitalization occurring at least 90 days after the first admission. The Fine-Gray subdistribution hazard model was used to identify risk factors, accounting for death as a competing risk.

Out of 98,369 patients hospitalized for COVID-19 between February 1, 2020 and August 31, 2021, 72,593 were alive 90 days after admission and 610 of these (0.8%) were rehospitalized. A higher rehospitalization risk was observed in older male patients with multiple comorbidities. Renal failure, liver disease, and use of diuretics were significantly associated with rehospitalization risk, while female biological sex and the use of lipid-lowering drugs were associated with a lower risk.

This is the first study conducted on regional administrative databases to investigate COVID-19 rehospitalizations. Through the availability of a huge cohort, it provides a groundwork for optimizing care for individuals at higher risk for COVID-19-related rehospitalizations. It underlines the need for patient-management approaches that extend beyond the initial recovery. This stresses the importance of ongoing monitoring and personalized interventions for those at heightened risk not only of SARS-CoV-2 reinfection but also related rehospitalizations.

COVID-19 is a highly contagious viral disease caused by SARS-CoV-2, leading to a tragic global pandemic, where it was ranked in 2020 as the third leading cause of death in the USA, causing approximately 375,000 deaths, following heart disease and cancer. The CDC reports that the risk of death increases with age and preexisting comorbidities such as such as hypertension, diabetes, respiratory system disease, and cardiovascular disease. this report will delineate and analyze the paramount comorbidities and their repercussions on individuals infected with SARS-CoV-2.

SARS-CoV-2 infection is accompanied by elevated liver enzymes, and patients with pre-existing liver conditions experience more severe disease. While it was known that SARS-CoV-2 infects human hepatocytes, our study determines the mechanism of infection, demonstrates viral replication and spread, and highlights direct hepatocyte damage. Viral replication was readily detectable upon infection of primary human hepatocytes and hepatoma cells with the ancestral SARS-CoV-2, Delta, and Omicron variants. Hepatocytes express the SARS-CoV-2 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS-CoV-2 infection. Progeny viruses released from infected hepatocytes showed the typical coronavirus morphology by electron microscopy and proved infectious when transferred to fresh cells, indicating that hepatocytes can contribute to virus spread. Importantly, SARS-CoV-2 infection rapidly induced hepatocyte death in a replication-dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL/6 wild-type mice infected with a mouse-adapted SARS-CoV-2 strain showed high levels of viral RNA in liver and lung tissues. ALT peaked when viral RNA was cleared from the liver. Liver histology revealed profound tissue damage and immune cell infiltration, indicating that direct cytopathic effects of SARS-CoV-2 and immune-mediated killing of infected hepatocytes contribute to liver pathology.

Patients with vascular liver diseases (VLD) are at higher risk of both severe courses of COVID-19 disease and thromboembolic events. The impact of SARS-CoV-2 vaccination in patients with VLD has not been described and represents the aim of our study.

International, multicenter, prospective observational study in patients with VLD analyzing the incidence of COVID-19 infection after vaccination, severity of side effects, occurrence of thromboembolic events and hepatic decompensation. In a subgroup of patients, the humoral and cellular responses to vaccination were also analyzed.

A total of 898 patients from 14 European centers - part of the VALDIG network - were included, 872 (97.1%) patients received two vaccine doses (fully vaccinated), and 674 (75.1%) three doses. Of the total cohort, 151/898 had a COVID-19 infection prior to vaccination, of whom 9/151 (5.9%) were re-infected. Of the 747/898 patients who were not previously infected, 11.2% (84/747) were diagnosed with a COVID-19 infection during the study period. Two infected patients required intensive care unit admission and infection was fatal in two fully vaccinated patients. Adverse effects were reported in around 40% of patients, with local side effects being the most frequent. During the study period, 31 (3.5%) patients had thromboembolic events and 21 (2.3%) hepatic decompensations. No cases of vaccine-induced thrombocytopenia were reported. Vaccine immunogenicity was assessed in 36 patients; seroconversion reached 100% and IFNy T-cell responses significantly increased post two mRNA-1273 vaccine doses.

Patients with VLD seem to have a preserved immune response to SARS-CoV-2 vaccination, which appears to be safe and effective in preventing severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, though the contribution of vaccination as a cofactor in VLD remains to be elucidated.

Patients with vascular liver disease (VLD) are at increased risk of both SARS-CoV-2 infection and severe COVID-19 disease. The potential risks associated with vaccination against this infection need thorough investigation. Our research enhances the understanding of the effects of COVID-19 vaccination in patients with VLD, highlighting its good tolerability. Moreover, patients with VLD appear to have a preserved immune response to SARS-CoV-2 vaccination, providing protection against severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, and no cases of vaccine-induced thrombocytopenia were reported.

The m6A reader insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) is involved in multiple pathophysiological processes through enhanced expression of the proteins encoded by their target mRNAs. However, the functional role of IGF2BP1-mediated m6A in liver fibrosis remains elusive. Here, we report that IGF2BP1 is highly expressed in activated hepatic stellate cells (HSCs), the major driver of fibrogenesis, and TUBB4B is identified as a potential target of IGF2BP1 by re-analysis of the RNA-seq, RIP-seq, and m6A-seq data. The relevant findings were subsequently demonstrated by a series of molecular and cellular evidences. The knockdown of IGF2BP1 or TUBB4B and pharmacological inhibition of TUBB4B by mebendazole treatments significantly suppress the proliferation, migration, and activation of HSCs. Mechanistically, IGF2BP1 upregulates TUBB4B expression through stabilizing TUBB4B in an m6A-dependent manner, and TUBB4B induces liver fibrosis by activating the FAK signaling pathway. Collectively, our results indicate that targeting IGF2BP1/TUBB4B/FAK axis in HSCs could be a promising therapeutic approach for liver fibrosis.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection.

We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed.

We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome.

We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.

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.

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.

Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.

We assessed chronic liver disease (CLD)-related mortality in the U.S. using death data (2011-2021) obtained from National Vital Statistics System (NVSS). The average annual percentage change (AAPC) from the models selected by Joinpoint regression analysis over the pre-pandemic (2011-2019) and the 2019-2021 were reported because non-linear trend in death rates were observed over the 2011-2021. Liver-specific death was defined as an underlying cause of death and Chronic liver disease (CLD)-related death was defined as any cause of death. During the pre-pandemic, age-standardized HCC- and cirrhosis-specific death rates were annually increased by AAPC = +1.18% (95% confidence interval, 0.34% to 2.03%) and AAPC = +1.95% (1.56% to 2.35%). In contrast, during the 2019-2021, the AAPC in age-standardized cirrhosis-specific death rate (per 100,000) accelerated by up to AAPC +11.25% (15.23 in 2019 to 18.86 in 2021) whereas that in age-standardized HCC-specific death rate slowed to -0.39 (-1.32% to 0.54%) (3.86 in 2019 to 3.84 in 2021). Compared to HCC-specific deaths, cirrhosis-specific deaths were more likely to be non-Hispanic white (72.4% vs. 62.0%) and non-Hispanic American Indian and Alaska native (AIAN) (2.2% vs. 1.1%) and have NAFLD (45.3% vs. 12.5%) and ALD (27.6% vs. 22.0%). During the 2019-2021, the age-standardized HCV- and HBV-related death rate stabilized, whereas the age-standardized NAFLD- and ALD-related deaths rate increased to 20.16 in 2021 (AAPC = +12.13% [7.76% to 16.68%]) and to 14.95 in 2021 (AAPC = +18.30% [13.76% to 23.03%]), which were in contrast to much smaller incremental increases during the pre-pandemic (AAPC = +1.82% [1.29% to 2.35%] and AAPC = +4.54% [3.97% to 5.11%]), respectively). The most pronounced rise in the age-standardized NAFLD-related death rates during the pandemic was observed among AIAN (AAPC = +25.38%), followed by non-Hispanic White female (AAPC = +14.28%), whereas the age-standardized ALD-related death rates during the pandemic were highest among AIAN (AAPC = +40.65%), followed by non-Hispanic Black female (AAPC = +26.79%).

COVID-19 pandemic had a major negative impact on cirrhosis-specific and CLD-related mortality in the U.S. with significant racial and gender disparities.

Conflicting evidence exists regarding the effects of ursodeoxycholic acid (UDCA) on coronavirus disease 2019 (COVID-19). This study investigates the association between UDCA administration and COVID-19 infection and its related outcomes in individuals with chronic liver disease (CLD).

A customized COVID-19 research database (n = 3,485,376) was created by integrating data from the National Health Insurance Service (NHIS) and the Korea Disease Control and Prevention Agency's COVID-19 databases. The study focused on patients diagnosed with COVID-19 in 2021, using the NHIS data from 365 days before diagnosis. To create comparable groups with and without UDCA administration before COVID-19, we used propensity score matching. The primary endpoint was the first confirmed positive result for severe acute respiratory syndrome coronavirus-2. In addition, we identified severe COVID-19-related outcomes. Subgroup analysis were conducted based on the dose of UDCA exposure.

Data from 74,074 individuals with CLD was analyzed. The participants' average age was 57.5 years, and 52.1% (19,277) of those in each group were male. Those with prior UDCA exposure had a significantly lower risk of COVID-19 infection (adjusted OR: 0.80, 95% CI [0.76-0.85]) compared to the non-UDCA group. Additionally, the UDCA group had a lower risk of severe COVID-19 outcomes (adjusted OR: 0.67, 95% CI [0.46-0.98]). Subgroup analyses indicated that there was a decrease in COVID-19 infection and its related outcomes with increasing UDCA exposure dose.

Our large observational study highlights the potential use of readily available UDCA as an adjunctive therapy for COVID-19 in individuals with CLD.

Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups. Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cirrhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy, and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition, we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2, liver health, and broader health management strategies, providing valuable insights for both current clinical practice and future research directions.

Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.