COVID-19 and the liver: What do we know so far?

The coronavirus disease 2019(COVID-19) pandemic has caused unprecedented pressure on public health and healthcare. The pandemic surge and resultant lockdown have affected the standard-of-care of many medical conditions and diseases. The initial uncertainty and fear of cross transmission of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) have changed the routine management of patients with pre-existing liver diseases, hepatocellular carcinoma, and patients either listed for or received a liver transplant. COVID-19 is best described as a multisystem disease caused by SARS-CoV-2, and it can cause acute liver injury or decompensation of the pre-existing liver disease. There has been considerable research on the pathophysiology, infection transmission, and treatment of COVID-19 in the last few months. The pathogenesis of liver involvement in COVID-19 includes viral cytotoxicity, the secondary effect of immune dysregulation, hypoxia resulting from respiratory failure, ischemic damage caused by vascular endotheliitis, congestion because of right heart failure, or drug-induced liver injury. Patients with chronic liver diseases, cirrhosis, and hepatocellular carcinoma are at high risk for severe COVID-19 and mortality. The phase Ⅲ trials of recently approved vaccines for SARS-CoV-2 did not include enough patients with pre-existing liver diseases and excluded immunocompromised patients or those on immunomodulators. This article reviews the currently published research on the effect of COVID-19 on the liver and the management of patients with pre-existing liver disease, including SARS-CoV-2 vaccines.     

COVID-19 and liver injury: Pathophysiology,risk factors,outcome and management in special populations

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 is an ongoing health concern. In addition to affecting the respiratory system, COVID-19 can potentially damage other systems in the body, leading to extra-pulmonary manifestations. Hepatic manifestations are among the common consequences of COVID-19. Although the precise mechanism of liver injury is still questionable, several mechanisms have been hypothesized, including direct viral effect, cytokine storm, hypoxic-ischemic injury, hypoxia-reperfusion injury, ferroptosis, and hepatotoxic medications. Risk factors of COVID-19-induced liver injury include severe COVID-19 infection, male gender, advanced age, obesity, and underlying diseases. The presentations of liver involvement comprise abnormalities in liver enzymes and radiologic findings, which can be utilized to predict the prognosis. Increased gamma-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase levels with hypoalbuminemia can indicate severe liver injury and anticipate the need for intensive care units’ hospitalization. In imaging, a lower liver-to-spleen ratio and liver computed tomography attenuation may indicate a more severe illness. Furthermore, chronic liver disease patients are at a higher risk for severe disease and death from COVID-19. Nonalcoholic fatty liver disease had the highest risk of advanced COVID-19 disease and death, followed by metabolic-associated fatty liver disease and cirrhosis. In addition to COVID-19-induced liver injury, the pandemic has also altered the epidemiology and pattern of some hepatic diseases, such as alcoholic liver disease and hepatitis B. Therefore, it warrants special vigilance and awareness by healthcare professionals to screen and treat COVID-19-associated liver injury accordingly.     

Impact of chronic liver disease on SARS-CoV-2 infection outcomes: Roles of stage,etiology and vaccination

Since the first identification in December of 2019 and the fast spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it has represented a dramatic global public health concern. Though affecting mainly the respiratory system, SARS-CoV-2 disease, defined as coronavirus disease 2019 (COVID-19), may have a systemic involvement leading to multiple organ dysfunction. Experimental evidence about the SARS-CoV-2 tropism for the liver and the increasing of hepatic cytolysis enzymes during infection support the presence of a pathophysiological relationship between liver and SARS-CoV-2. On the other side, patients with chronic liver disease have been demonstrated to have a poor prognosis with COVID-19. In particular, patients with liver cirrhosis appear extremely vulnerable to infection. Moreover, the etiology of liver disease and the vaccination status could affect the COVID-19 outcomes. This review analyzes the impact of the disease stage and the related causes on morbidity and mortality, clinical outcomes during SARS-CoV-2 infection, as well as the efficacy of vaccination in patients with chronic liver disease.     

COVID-19 vaccination and liver disease

Various vaccines against severe acute respiratory syndrome coronavirus 2 have been developed in response to the coronavirus disease 2019 (COVID-19) global pandemic, several of which are highly effective in preventing COVID-19 in the general population. Patients with chronic liver diseases (CLDs), particularly those with liver cirrhosis, are considered to be at a high risk for severe COVID-19 and death. Given the increased rates of disease severity and mortality in patients with liver disease, there is an urgent need to understand the efficacy of vaccination in this population. However, the data regarding efficacy and safety of COVID-19 vaccination in patients with CLDs is limited. Indeed, several organ-specific or systemic immune-mediated side effects following COVID-19 vaccination, including liver injury similar to autoimmune hepatitis, have been recently reported. Although the number of cases of vaccine-related liver injury is increasing, its frequency, clinical course, and mechanism remain unclear. Here, we review the current findings on COVID-19 vaccination and liver disease, focusing on: (1) The impact of COVID-19 in patients with CLD; (2) The efficacy, safety, and risk-benefit profiles of COVID-19 vaccines in patients with CLD; and (3) Liver injury following COVID-19 vaccination.     

COVID-19 and liver injury: An ongoing challenge

The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019, in Wuhan, China. The virus was rapidly spread worldwide, causing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is presented, usually, with typical respiratory symptoms (i.e., dyspnea, cough) and fever, extrapulmonary manifestations are also encountered. Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and, even, acute liver failure. The pathogenesis of liver damage is not clearly defined; multiple mechanisms contribute to liver disorder, including direct cytopathic viral effect, cytokine storm and immune-mediated hepatitis, hypoxic injury, and drug-induced liver toxicity. Patients with underlying chronic liver disease (i.e., cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID-19 and further liver deterioration, and, as a consequence, certain issues should be considered during disease management. The aim of this review is to present the prevalence, clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection. Moreover, we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.     

Coronavirus disease 2019 and non-alcoholic fatty liver disease

The coronavirus disease 2019(COVID-19) pandemic may present with a broad range of clinical manifestations, from no or mild symptoms to severe disease. Patients with specific pre-existing comorbidities, such as obesity and type 2 diabetes, are at high risk of coming out with a critical form of COVID-19. Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease, and, because of its frequent association with metabolic alterations including obesity and type 2 diabetes, it has recently been re-named as metabolic-associated fatty liver disease(MAFLD). Several studies and systematic reviews pointed out the increased risk of severe COVID-19 in NAFLD/MAFLD patients. Even though dedicated mechanistic studies are missing, this higher probability may be justified by systemic low-grade chronic inflammation associated with immune dysregulation in NAFLD/MAFLD, which could trigger cytokine storm and hypercoagulable state after severe acute respiratory syndrome coronavirus 2 infection. This review focuses on the predisposing role of NAFLD/MAFLD in favoring severe COVID-19, discussing the available information on specific risk factors, clinical features, outcomes, and pathogenetic mechanisms.     

COVID-19, liver dysfunction and pathophysiology: A conceptual discussion

The intra and extracellular pathways of hepatic injury by coronavirus disease 2019 (COVID-19) are still being studied. Understanding them is important to treat this viral disease and other liver and biliary tract disorders. Thus, this paper aims to present three hypotheses about liver injury caused by COVID-19: (1) The interactions between severe acute respiratory syndrome coronavirus 2 spike protein and membrane receptors in the hepatocyte; (2) The dysbiosis and “gut-liver axis” disruption in patients with serious clinical presentations of COVID-19; and (3) The inflammatory response exacerbated through the production of interleukins such as interleukin-6. However, despite these new perspectives, the pathophysiological process of liver injury caused by COVID-19 is still complex and multifactorial. Thus, understanding all these variables is a challenge to science but also the key to propose individualized and effective patient therapies.     

COVID-19 and the liver: Are footprints still there?

The coronavirus disease 2019(COVID-19) hit the entire world as a global pandemic and soon became the most important concern for all patients with chronic diseases. An early trend in higher mortality in patients with acute respiratory distress attracted all researchers to closely monitor patients for the involvement of other systems. It soon became apparent that patients with chronic liver diseases are at increased risk of mortality given their cirrhosis-associated immune dysfunction. Additionall...     

Association of non-alcoholic fatty liver disease and COVID-19: A literature review of current evidence

The coronavirus disease 2019 (COVID-19) pandemic has swept through nations, crippled economies and caused millions of deaths worldwide. Many people diagnosed with COVID-19 infections are often found to develop liver injury, which, in a small portion of patients, progresses to severe liver disease. Liver injury in the form of elevated transaminases, hyperbilirubinemia and alterations in serum albumin has been observed to be higher in patients with severe forms of the disease. Those who already have insult to the liver from chronic disease, such as nonalcoholic fatty liver disease (NAFLD) may be at the greatest disadvantage. The severity of COVID-19 also seems to be driven by the presence of NAFLD and other co-morbidities. About 25% of the global population has NAFLD. With such a widespread prevalence of NAFLD, understanding the disease progression of COVID-19 and the occurrence of liver injury in this vulnerable population assumes great significance. In this review, we present an overview of COVID-19 infection in patients with NAFLD.     

COVID-19 pandemic: Its impact on liver disease and liver transplantation

Severe pulmonary disease caused by the novel coronavirus [severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)], has devastated many countries around the world.It has overwhelmed the medical system.The priorities of many institutions have changed to manage critically ill corona virus infectious disease-2019(COVID-19) patients,which affected the working style of many departments.Hepatologists and transplant surgeons look after a very sensitive patient group.Patients with liver disease need special attention and continuous follow-up.Similarly,transplant candidates also need special care.Healthcare professionals in the field of hepatology face the overwhelming task of taking care of COVID-19 patients with hepatic complications,liver disease or transplant patients who are SARS-CoV-2 positive,and the patients on routine surveillance who do not have COVID-19.This review will evaluate COVID-19 from the perspective of its effect on the liver and its possible effects on patients with liver disease.Furthermore,the level of care for liver transplant recipients during the pandemic will be discussed.     

Etiology and management of liver injury in patients with COVID-19

The outbreak of novel coronavirus disease 2019(COVID-19) has resulted in global emergence. With the expansion of related research, in addition to respiratory symptoms, digestive system involvement such as nausea, vomiting, and diarrhea have also been reported with COVID-19. Besides, abnormal liver function is also frequent in biochemical tests of COVID-19 patients, which is correlated with the severity and mortality of the disease course. The etiology of liver injury in patients with COVID-19 might include viral immunologic injury, drug-induced liver injury, the systemic inflammatory response, hypoxic hepatitis, and the exacerbation of preexisting liver disease. Although liver injuries in COVID-19 are often transient and reversible, health workers need to pay attention to preexisting liver disease, monitor liver function, strengthen supportive treatment, and reduce the chance of drug-induced liver injury. This article reviews the epidemiological characteristics, etiology, management, and preventive strategies for liver injury in patients with COVID-19.     

Acute-on-chronic liver failure in patients with severe acute respiratory syndrome coronavirus 2 infection

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on the lives of millions of people, especially those with other concomitant diseases, such as chronic liver diseases. To date, seven coronaviruses have been identified to infect humans. The main site of pathological action of these viruses is lung tissue. However, a substantial number of studies have proven that SARS-CoV-2 shows affinity towards several organs, including the gastrointestinal tract and the liver. The current state of evidence points to several proposed mechanisms of liver injury in patients with COVID-19 and their combination. Liver impairment is considered to be the result of the direct effect of the virus on the hepatic tissue cells, a systemic reaction consisting of inflammation, hypoxia and cytokine storm, drug-induced liver injury, with the possible contribution of a perturbed gut-liver axis. Reactivation of chronic hepatic disease could be another factor for liver impairment in patients with SARS-CoV-2 infection. Acute-on-chronic liver failure (ACLF) is a relatively new syndrome that occurs in 10%–30% of all hospitalized patients with chronic liver disease. It is crucial to recognize high-risk patients due to the increased morbidity and mortality in these cases. Several published studies have reported virus infection as a trigger factor for ACLF. However, to date, there are few relevant studies describing the presence of ACLF in patients with acute SARS-CoV-2 infection. In this minireview we summarize the current state of knowledge regarding the relation between ACLF and acute SARS-CoV-2 infection.     

Liver injury in the era of COVID-19

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has undoubtedly revolutionized the whole globe and given a new point of view on respiratory tract infections. Nevertheless, coronavirus disease 2019 (COVID-19) cannot be perceived as a disease limited only to pneumonia with diverse severity. More and more reports have demonstrated a wide range of possible systemic symptoms, including hepatic complications. Liver injury has been observed in a significant proportion of patients, especially in those with a severe or critical illness. COVID-19 might provoke a deterioration of liver function in patients with already diagnosed chronic liver diseases and without pre-existing liver disorders. The deterioration of liver function worsens the prognosis, increases the risk of a severe course of SARS-CoV-2 infection and prolongs the hospital stay. In general, patients who develop liver dysfunction in COVID-19 are mainly males, elderly people, and those with higher body mass index. The underlying mechanisms for hepatic failure in patients infected with SARS-CoV-2 are still unclear, nevertheless liver damage appears to be directly connected with virus-induced cytopathic effects. A liver injury observed during hospitalization might be simultaneously caused by the use of potentially hepatotoxic drugs, mainly antiviral agents. This minireview focuses on a possible relationship between COVID-19 and the liver, potential molecular mechanisms of liver damage, the characteristics of liver injury and suggested factors predisposing to hepatic manifestations in COVID-19 patients.     

Impaired coagulation,liver dysfunction and COVID-19: Discovering an intriguing relationship

Coronavirus disease 2019 (COVID-19) is, at present, one of the most relevant global health problems. In the literature hepatic alterations have been described in COVID-19 patients, and they are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality. Several potential mechanisms used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to cause liver damage have been hypothesized. COVID-19 primary liver injury is less common than secondary liver injury. Most of the available data demonstrate how liver damage in SARS-CoV-2 infection is likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Moreover, liver alterations could be caused by hypoxic injury and drugs (antibiotics and non-steroidal anti-inflammatory drugs, remdesivir, tocilizumab, tofacitinib and dexamethasone). SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by affecting simultaneously cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus triggers an exaggerated immune response, which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis. This leads to a higher incidence of symptomatic and confirmed venous thrombosis and of pulmonary embolisms, especially in central, lobar or segmental pulmonary arteries, in COVID-19. There are currently fewer data for arterial thrombosis, while myocardial injury was identified in 7%-17% of patients hospitalized with SARS-CoV-2 infection and 22%-31% in the intensive care unit setting. Available data also revealed a higher occurrence of stroke and more serious forms of peripheral arterial disease in COVID-19 patients. Hemostasis dysregulation is observed during the COVID-19 course. Lower platelet count, mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARS-CoV-2 infection, described as “COVID-19 associated coagulopathy.” These alterations are correlated to poor outcomes. Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of von Willebrand factor with subsequent ADAMTS13 deficiency and impaired fibrinolysis. Platelet hyperreactivity, hypercoagulability and hypofibrinolysis during SARS-CoV-2 infection induce a pathological state named as “immuno-thromboinflammation.” Finally, liver dysfunction and coagulopathy are often observed at the same time in patients with COVID-19. The hypothesis that liver dysfunction could be mediated by microvascular thrombosis has been supported by post-mortem findings and extensive vascular portal and sinusoidal thrombosis observation. Other evidence has shown a correlation between coagulation and liver damage in COVID-19, underlined by the transaminase association with coagulopathy, identified through laboratory markers such as prothrombin time, international normalized ratio, fibrinogen, D-dimer, fibrin/fibrinogen degradation products and platelet count. Other possible mechanisms like immunogenesis of COVID-19 damage or massive pericyte activation with consequent vessel wall fibrosis have been suggested.     

COVID-19 and liver dysfunction: What nutritionists need to know

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 has brought serious challenges for the medical field. Patients with COVID-19 usually have respiratory symptoms. However, liver dysfunction is not an uncommon presentation. Additionally, the degree of liver dysfunction is associated with the severity and prognosis of COVID-19. Prevention, diagnosis, and treatment of malnutrition should be routinely recommended in the management of patients with COVID-19, especially in those with liver dysfunction. Recently, a large number of studies have reported that nutrition therapy measures, including natural dietary supplements, vitamins, minerals and trace elements, and probiotics, might have potential hepatoprotective effects against COVID-19-related liver dysfunction via their antioxidant, antiviral, anti-inflammatory, and positive immunomodulatory effects. This review mainly focuses on the possible relationship between COVID-19 and liver dysfunction, nutritional and metabolic characteristics, nutritional status assessment, and nutrition therapy to provide a reference for the nutritionists while making evidence-based nutritional decisions during the COVID-19 pandemic.     

Liver and COVID-19:From care of patients with liver diseases to liver injury

The global pandemic of coronavirus disease 2019(COVID-19) changed dramatically all priorities on medical society and created several challenges for clinicians caring for patients with liver diseases. We performed a comprehensive review about how COVID-19 can affect the liver, the influence of liver diseases on the risk of developing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and COVID-19 severity and also some strategies to overcome all the challenges clinicians have to face in the management of patients with liver diseases in a period of time when all the focus turned on COVID-19. We analyze the relationship between COVID-19 and non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, autoimmune liver disease, cirrhosis, hepatocellular carcinoma and liver transplantation, as well as the approach to SARS-CoV-2 vaccination.     

Liver disease in the era of COVID-19: Is the worst yet to come?

The global social, economic and political crises related to coronavirus disease 2019 (COVID-19) presumably had more indirect than direct negative impacts on health systems. Drastic lifestyle changes, social isolation and distancing, and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages, drugs and unhealthy diets. The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease, viral hepatitis, acute alcoholic hepatitis, liver cirrhosis decompensation and ultimately liver-related mortality. The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease (CLD) and has prevented prompt hepatocellular carcinoma detection and treatment. A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation. The indirect, unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined. Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated. Several questions regarding the impact of the COVID-19 pandemic on liver disease remain. The most important question for general CLD patients is: How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients? This article reviews the influence of COVID-19 on patients with liver disease during the pandemic, with particular emphasis on the disease course associated with pandemic resolution.     

Autoimmune liver diseases and SARS-CoV-2

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

Liver diseases in COVID-19:Etiology,treatment and prognosis

In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) was identified in Wuhan, China causing coronavirus disease-2019(COVID-19). Numerous studies have shown varying degrees of liver damage in patients infected with SARS-CoV-2. However, in previous case studies of COVID-19, the exact cause of liver injury has not been clearly elucidated, nor is there clear evidence of the interaction between liver injury and COVID-19. This study will analyze the causes of liver injury in COVID-19 and the influence of liver-related complications on the treatment and prognosis of COVID-19.