Molecular mechanisms underlying SARS-CoV-2 hepatotropism and liver damage

In coronavirus disease 2019(COVID-19),severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)primarily targets the respiratory system,but evidence suggests extrapulmonary organ involvement,notably in the liver.Viral RNA has been detected in hepatic tissues,and in situ hybridization revealed virions in blood vessels and endothelial cells.Electron microscopy confirmed viral particles in hepatocytes,emphasizing the need for understanding hepatotropism and direct cytopathic effects in COVID-19-related liver injury.Various factors contribute to liver injury,including direct cytotoxicity,vascular changes,inflammatory responses,immune reactions from COVID-19 and vaccinations,and druginduced liver injury.Although a typical hepatitis presentation is not widely documented,elevated liver biochemical markers are common in hospitalized COVID-19 patients,primarily showing a hepatocellular pattern of elevation.Long-term studies suggest progressive cholestasis may affect 20%of patients with chronic liver disease post-SARS-CoV-2 infection.The molecular mechanisms underlying SARS-CoV-2 infection in the liver and the resulting liver damage are complex.This“Editorial”highlights the expression of the Angiotensin-converting enzyme-2 receptor in liver cells,the role of inflammatory responses,the impact of hypoxia,the involvement of the liver's vascular system,the infection of bile duct epithelial cells,the activation of hepatic stellate cells,and the contribution of monocyte-derived macrophages.It also mentions that pre-existing liver conditions can worsen the outcomes of COVID-19.Understanding the interaction of SARS-CoV-2 with the liver is still evolving,and further research is required.

COVID-19-induced liver injury in adult patients:A brief overview

Coronavirus disease has spread worldwide since 2019,causing important pandemic issues and various social health problems to date.Little is known about the origin of this virus and the effects it has on extra-pulmonary organs.The different mechanisms of the virus and the influence it has on humans are still being studied,with hopes of finding a cure for the disease and the pathologies associated with the infection.Liver damage caused by coronavirus disease 2019(COVID-19)is sometimes underestimated and has been of important clinical interest in the past few years.Hepatic dysfunctions can manifest in different forms which can sometimes be mild and without specific signs and symptoms or be severe with important clinical implications.There are several studies that have tried to explain the mechanism of entry(hepatotropism)of the virus into hepatocytes and the effects the virus has on this important organ.What clearly emerges from the current literature is that hepatic injury represents an important clinical aspect in the management of patients infected with COVID-19,especially in frail patients and those with comorbidities.The aim of our brief overview is to summarize the current literature regarding the forms of hepatic damage,complications,mechanisms of pathology,clinical features of liver injury,influence of comorbidities and clinical management in patients with COVID-19 infection.

Hepatotropic growth factors protect hepatocytes during inflammation by upregulation of antioxidative systems

AIM:To investigate effects of hepatotropic growth factors on radical production in rat hepatocytes during sepsis.METHODS:Rat hepatocytes,isolated by collagenase perfusion,were incubated with a lipopolysaccharide(LPS)-containing cytokine mixture of interleukin-1β,tumor necrosis factor-α and interferon-γ to simulate sepsis and either co-incubated or pre-incubated with hepatotropic growth factors,e.g.hepatocyte growth factor,epidermal growth factor and/or transforming growth factor-α.Cells were analyzed for glutathione levels.Culture supernatants were assayed for produc-tion of reactive oxygen intermediates(ROIs) as well as NO2-,NO3-and S-nitrosothiols.To determine cellular damage,release of aspartate aminotransferase(AST) into the culture medium was analyzed.Activation of nuclear factor(NF)-κB was measured by electrophoretic mobility shift assay.RESULTS:Rat hepatocytes treated with the LPS-containing cytokine mixture showed a significant increase in ROI and nitrogen oxide intermediate formation.AST leakage was not significantly increased in cells treated with the LPS-containing cytokine mixture,independent of growth-factor co-stimulation.However,pretreatment with growth factors significantly reduced AST leakage and ROI formation while increasing cellular glutathione.Application of growth factors did not result in increased NF-κB activation.Pretreatment with growth factors further increased formation of NO2-,NO3-and S-nitrosothiols in hepatocytes stimulated with LPS-containing cytokine mixture.Thus,we propose that,together with an increase in glutathione increased NO2-,NO3-formation might shift their metabolism towards non-toxic products.CONCLUSION:Our data suggest that hepatotropic growth factors positively influence sepsis-induced hepatocellular injury by reducing cytotoxic ROI formation via induction of the cellular protective antioxidative systems.

Newer developments in viral hepatitis:Looking beyond hepatotropic viruses

Viral hepatitis in the entirety of its clinical spectrum is vast and most discussion are often restricted to hepatotropic viral infections,including hepatitis virus(A to E).With the advent of more advanced diagnostic techniques,it has now become possible to diagnose patients with non-hepatotropic viral infection in patients with hepatitis.Majority of these viruses belong to the Herpes family,with characteristic feature of latency.With the increase in the rate of liver transplantation globally,especially for the indication of acute hepatitis,it becomes even more relevant to identify non hepatotropic viral infection as the primary hepatic insult.Immunosuppression post-transplant is an established cause of reactivation of a number of viral infections that could then indirectly cause hepatic injury.Antiviral agents may be utilized for treatment of most of these infections,although data supporting their role is derived primarily from case reports.There are no current guidelines to manage patients suspected to have viral hepatitis secondary to non-hepatotropic viral infection,a gap that needs to be addressed.In this review article,the authors analyze the common non hepatotropic viral infections contributing to viral hepatitis,with emphasis on recent advances on diagnosis,management and role of liver transplantation.