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.     

COVID-19 and comorbidities of hepatic diseases in a global perspective

The worldwide outbreak of coronavirus disease 2019 (COVID-19) has challenged the priorities of healthcare system in terms of different clinical management and infection transmission, particularly those related to hepatic-disease comorbidities. Epidemiological data evidenced that COVID-19 patients with altered liver function because of hepatitis infection and cholestasis have an adverse prognosis and experience worse health outcomes. COVID-19-associated liver injury is correlated with various liver diseases following a severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infection that can progress during the treatment of COVID-19 patients with or without pre-existing liver disease. SARS-CoV-2 can induce liver injury in a number of ways including direct cytopathic effect of the virus on cholangiocytes/hepatocytes, immune-mediated damage, hypoxia, and sepsis. Indeed, immediate cytopathogenic effects of SARS-CoV-2 via its potential target, the angiotensin-converting enzyme-2 receptor, which is highly expressed in hepatocytes and cholangiocytes, renders the liver as an extra-respiratory organ with increased susceptibility to pathological outcomes. But, underlying COVID-19-linked liver disease pathogenesis with abnormal liver function tests (LFTs) is incompletely understood. Hence, we collated COVID-19-associated liver injuries with increased LFTs at the nexus of pre-existing liver diseases and COVID-19, and defining a plausible pathophysiological triad of COVID-19, hepatocellular damage, and liver disease. This review summarizes recent findings of the exacerbating role of COVID-19 in pre-existing liver disease and vice versa as well as international guidelines of clinical care, management, and treatment recommendations for COVID-19 patients with liver disease.     

Outcomes of COVID-19 among patients with liver disease

Coronavirus disease 2019 (COVID-19) is primarily a respiratory disease with multi-organ involvement, including impaired liver function. It has been noticed that a significant proportion of COVID-19 patients have liver dysfunction, especially those with a more severe disease course. The coronavirus causes direct damage to the liver using the angiotensin-converting enzyme 2, a cell-surface receptor for cellular entry, that is expressed in the liver. According to previous research, liver enzyme abnormalities were observed in a considerable proportion of COVID-19 patients, and elevated liver transaminases were found in about 20% of these patients, alkaline phosphatase in 6.1%, and gamma-glutamyl transferase in 21.1%. COVID-19 might trigger a deterioration of liver function in patients with pre-existing chronic liver diseases (CLDs) and also in those without previous liver disorders. The majority of COVID-19 patients who develop liver injury are men, the elderly, and those with a higher body mass index. Compared to the general population, COVID-19 is associated with significant morbidity and mortality in patients with liver disease (cirrhosis and liver transplantation recipients). However, some studies indicate that CLDs have a lesser role in determining patient progression towards higher disease severity.     

Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier?

The pandemics of coronavirus disease 2019 (COVID-19) and non-alcoholic fatty liver disease (NAFLD) coexist. Elevated liver function tests are frequent in COVID-19 and may influence liver damage in NAFLD, while preexisting liver damage from NAFLD may influence the course of COVID-19. However, the prognostic relevance of this interaction, though, is unclear. Obesity is a risk factor for the presence of NAFLD as well as a severe course of COVID-19. Cohort studies reveal conflicting results regarding the influence of NAFLD presence on COVID-19 illness severity. Striking molecular similarities of cytokine pathways in both diseases, including postacute sequelae of COVID-19, suggest common pathways for chronic low-activity inflammation. This review will summarize existing data regarding the interaction of both diseases and discuss possible mechanisms of the influence of one disease on the other.     

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.     

Liver injury in COVID-19: Clinical features,potential mechanisms,risk factors and clinical treatments

The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to global health for nearly 3 years. In addition to pulmonary complications, liver injury is not uncommon in patients with novel COVID-19. Although the prevalence of liver injury varies widely among COVID-19 patients, its incidence is significantly increased in severe cases. Hence, there is an urgent need to understand liver injury caused by COVID-19. Clinical features of liver injury include detectable liver function abnormalities and liver imaging changes. Liver function tests, computed tomography scans, and ultrasound can help evaluate liver injury. Risk factors for liver injury in patients with COVID-19 include male sex, preexisting liver disease including liver transplantation and chronic liver disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-19-related liver injury is not fully understood. Its pathophysiological basis can generally be explained by systemic inflammatory response, hypoxic damage, ischemia-reperfusion injury, and drug side effects. In this review, we systematically summarize the existing literature on liver injury caused by COVID-19, including clinical features, underlying mechanisms, and potential risk factors. Finally, we discuss clinical management and provide recommendations for the care of patients with liver injury.     

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.     

The impact of coronavirus disease 2019 (COVID-19) on liver injury in China: A systematic review and meta-analysis

Introduction:The evidence for the incidence and severity of liver injury in Chinese patients with coronavirus disease 2019 (COVID-19) is still controversial. The purpose of this study was to summarize the incidence of liver injury and the differences between liver injury markers among different patients with COVID-19 in China.Methods:Computer searches of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and medRxiv were used to obtain reports on the incidence and markers of liver injury in Chinese patients with COVID-19, from January 1, 2020 to April 10, 2020. (No. CRD42020181350)Results:A total of 57 reports from China were included, including 9889 confirmed cases of COVID-19 infection. The results of the meta-analysis showed that among the patients with early COVID-19 infection in China, the incidence of liver injury events was 24.7% (95% CI, 23.4%–26.4%). Liver injury in severe patients was more common than that in non-severe patients, with a risk ratio of 2.07 (95% CI, 1.77–2.43). Quantitative analysis showed that the severe the coronavirus infection, the higher the level of alanine aminotransferase (ALT), aspertate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and the lower the level of albumin (ALB).Conclusion:There is a certain risk of liver injury in Chinese patients with COVID-19, and the risk and degree of liver injury are related to the severity of COVID-19.     

COVID-19-induced transaminitis and hyperbilirubinemia: Presentation and outcomes

The risk of liver injury in patients with coronavirus disease 2019(COVID-19) infection is quite evident. Furthermore, liver function test abnormalities are still detected in COVID-19 patients despite the development of antivirals and the availability of several types of vaccines. This editorial describes liver involvement during COVID-19 infection in patients with or without preexisting liver injury, such as chronic liver disease, to elucidate COVID-19-induced liver function abnormalities and th...     

Potential role of the microbiome in liver injury during COVID-19: Further research is needed

Although different studies have associated coronavirus disease 2019 (COVID-19) with the occurrence of liver injury, the hepatic injury route during the COVID-19 course is not yet fully understood. In order to better understand the mechanisms of the disease, the human gut microbiota has been the subject of extensive discussion in the context of COVID-19 pathophysiology. However, many questions remain, including the risks of liver injury due to COVID-19 specific populations. Further research in this field could allow the discovery of new personalized treatment strategies aimed at improving the microbiota composition, thereby reducing COVID-19 severity and its complications in different populations. In this article, we discussed basic mechanisms of severe acute respiratory syndrome coronavirus 2 infection and recent evidence on the relationship between COVID-19, the gut microbiome and liver injury as well as proposed recommendations for further research.     

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.     

COVID-19 related biliary injury:A review of recent literature

Since its emergence in 2019, it has become apparent that coronavirus 2019(COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests(LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However,...     

COVID-19 and Indirect Liver Injury: A Narrative Synthesis of the Evidence

The liver is frequently affected by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. The most common manifestations are mildly elevated alanine aminotransferase and aspartate aminotransferase, with a prevalence of 16-53% among patients. Cases with severe coronavirus disease 2019 (COVID-19) seem to have higher rates of acute liver dysfunction, and the presence of abnormal liver tests at admission signifies a higher risk of severe disease during hospitalization. Patients with chronic liver diseases also have a higher risk of severe disease and mortality (mainly seen in patients with metabolic-associated fatty liver disease). Several pathways of damage have been proposed in the liver involvement of COVID-19 patients; although, the end-cause is most likely multifactorial. Abnormal liver tests have been attributed to the expression of angiotensin-converting enzyme 2 receptors in SARS-CoV-2 infection. This enzyme is expressed widely in cholangiocytes and less in hepatocytes. Other factors attributed to liver damage include drug-induced liver injury, uncontrolled release of proinflammatory molecules (“cytokine storm”), pneumonia-associated hypoxia, and direct damage by the infection. Hepatic steatosis, vascular thrombosis, fibrosis, and inflammatory features (including Kupffer cell hyperplasia) are the most common liver histopathological findings in deceased COVID-19 patients, suggesting important indirect mechanisms of liver damage. In this translational medicine-based narrative review, we summarize the current data on the possible indirect mechanisms involved in liver damage due to COVID-19, the histopathological findings, and the impact of these mechanisms in patients with chronic liver disease.     

Liver injury in COVID-19: Detection,pathogenesis, and treatment

In the early December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 was first reported in Wuhan, China, followed by an outbreak that spread around the world. Numerous studies have shown that liver injury is common in patients with coronavirus disease 2019 (COVID-19), and may aggravate the severity of the disease. However, the exact cause and specific mechanism of COVID-associated liver injury needs to be elucidated further. In this review, we present an analysis of the clinical features, potential mechanisms, and treatment strategies for liver injury associated with COVID-19. We hope that this review would benefit clinicians in devising better strategies for management of such patients.     

COVID-19 and liver dysfunction in children: Current views and new hypotheses

Coronavirus disease 2019(COVID-19) poses an extremely serious global impact on public healthcare for individuals of all ages,including children.Increasing evidence has shown that liver abnormalities are commonly found in children with COVID-19,and age-related features in innate and adaptive response have been demonstrated.However,there are few reports and studies on COVID-19 related liver injury in children,and the data are scattered.So that many contradictions have arose.This situation is not o...     

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...     

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.     

Interaction between hepatitis B virus and SARS-CoV-2 infections

Coronavirus disease 2019(COVID-19)has become a global pandemic and garnered international attention.The causative pathogen of COVID-19 is severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),a novel,highly contagious coronavirus.Numerous studies have reported that liver injury is quite common in patients with COVID-19.Hepatitis B has a worldwide distribution as well as in China.At present,hepatitis B virus(HBV)remains a leading cause of cirrhosis,liver failure,and hepatocellular carcinoma.Because both viruses challenge liver physiology,it raises questions as to how coinfection with HBV and SARS-CoV-2 affect disease progression and mortality.Is there an increased risk of COVID-19 in patients with HBV infection?In this review,we summarize the current reports of SARS-CoV-2 and HBV coinfection and elaborate the interaction of the two diseases.The emphasis was placed on evaluating the impact of HBV infection on disease severity and clinical outcomes in patients with COVID-19 and discussing the potential mechanism behind this effect.     

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.     

Progressive liver injury and increased mortality risk in COVID-19 patients: A retrospective cohort study in China

BACKGROUND Liver injury is common and also can be fatal,particularly in severe or critical patients with coronavirus disease 2019(COVID-19).AIM To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk.METHODS A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9,2020 at Tongji Hospital,Wuhan,China.Data on clinical features,laboratory parameters,medications,and prognosis were collected.RESULTS COVID-19-associated liver injury more frequently occurred in patients aged≥65 years,female patients,or those with other comorbidities,decreased lymphocyte count,or elevated D-dimer or serum ferritin(P<0.05).The disease severity of COVID-19 was an independent risk factor for liver injury(severe patients:Odds ratio[OR]=2.86,95%confidence interval[CI]:1.78-4.59;critical patients:OR=13.44,95%CI:7.21-25.97).The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk(P<0.001).Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury.Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury.CONCLUSION More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients,especially patients aged≥65 years,female patients,or those with other comorbidities.Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.