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 the liver: A brief and core review

Coronavirus disease 2019 has a wide range of clinical spectrum from asymptomatic infection to severe infection resulting in death within a short time. Currently, it is known that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not only cause a respiratory tract infection but a more complicated disease that can lead to multiple system involvement including the liver. Herein, we evaluate the epidemiology, the impact of liver injury/ dysfunction on disease prognosis, the pathophysiological mechanisms and management of liver injury. More than one-fourth of the patients have abnormal liver function tests, mostly a mild-to-moderate liver dysfunction. Liver injury is significantly associated with a poor clinical outcome. Direct cytotoxic effect of SARS-CoV-2, the immune response (“cytokine storm”), the complications related to the disease, and drugs used in the treatments are the pathophysiological mechanisms responsible for liver injury. However, the exact mechanism is not yet clearly explained. The binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 receptors and entering the hepatocyte and cholangiocytes can cause cytotoxic effects on the liver. Excessive immune response has an important role in disease progression and causes acute respiratory distress syndrome and multi-organ failures accompanied by liver injury. Treatment drugs, particularly lopinavir/ritonavir, remdesivir and antibiotics are a frequent reason for liver injury. The possible reasons should be meticulously investigated and resolved.     

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.     

Acute liver injury in COVID-19 patients hospitalized in the intensive care unit: Narrative review

In recent years, humanity has been confronted with a global pandemic due to coronavirus disease 2019 (COVID-19), which has caused an unprecedented health and economic crisis worldwide. Apart from the respiratory symptoms, which are considered the principal manifestations of COVID-19, it has been recognized that COVID-19 constitutes a systemic inflammatory process affecting multiple organ systems. Across the spectrum of organ involvement in COVID-19, acute liver injury (ALI) has been gradually gaining increasing attention by the international scientific community. COVID-19 associated liver impairment can affect a considerable proportion of COVID-19 patients and seems to correlate with the severity of the disease course. Indeed, COVID-19 patients hospitalized in the intensive care unit (ICU) run a greater risk of developing ALI due to the severity of their clinical condition and in the context of multi-organ failure. The putative pathophysiological mechanisms of COVID-19 induced ALI in ICU patients remain poorly understood and appear to be multifactorial in nature. Several theories have been proposed to explain the occurrence of ALI in the ICU setting, such as hypoperfusion and ischemia due to hemodynamic instability, passive liver congestion as a result of congestive heart failure, ischemia-reperfusion injury, hypoxia due to respiratory failure, mechanical ventilation itself, sepsis and septic shock, cytokine storm, endotheliitis with concomitant coagulopathy, drug-induced liver injury, parenteral nutrition and direct cytopathic viral effect. It should be noted that no specific therapy for COVID-19 induced ALI exists. Therefore, the therapeutic approach lies in preventive measures and is exclusively supportive once ALI ensues. The aim of the current review is to scrutinize the existing evidence on COVID-19 associated ALI in ICU patients, explore its clinical implications, shed light on the underlying pathophysiological mechanisms and propose potential therapeutic approaches. Ongoing research on the particular scientific field will further elucidate the pathophysiology behind ALI and address unresolved issues, in the hope of mitigating the tremendous health consequences imposed by COVID-19 on ICU patients.     

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 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...     

Current and New Drugs for COVID-19 Treatment and Its Effects on the Liver

Corona virus disease (COVID)-19 is caused by the novel severe acute respiratory syndrome coronavirus-2 (commonly referred to as SARS-CoV-2). In March 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. Though the target organ for the virus is primarily the lungs, with the recent understanding of the pathobiology of this disease and the immune dysregulation associated with it, it is now clear that COVID-19 affects multiple organ systems. Several drugs and therapies have been tried or repurposed to combat the wrath posed by this disease. On October 22, 2020, the USA Food and Drug Administration approved remdesivir for use in adults and pediatric patients (12 years of age and older). Several of the drugs being tried against COVID-19 have hepatotoxicity as their potential side effect. This review aims to provide the latest insights on various drugs being used in the treatment of COVID-19 and their effects on the liver.     

Drug-induced liver injury and COVID-19: A review for clinical practice

Coronavirus disease 2019 (COVID-19) consists of a systemic disease that can present many complications. The infection presents broad clinical symptoms and a high rate of transmissibility. In addition to severe acute respiratory syndrome, the patients manifest complications beyond the respiratory system. The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients. One should pay attention to drug-induced liver injury (DILI) in patients with COVID-19, especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales. This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity. We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases. Four studies were selected, involving the medicines remdesivir, tocilizumab and a pharmacovigilance analysis study. The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment. However, drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry. The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals. It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions, and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity. Liver disorders in COVID-19 patients and the use of several concomitant off-label medications — with a potential risk of further damaging the liver - should at least be a warning sign for rapid identification and early intervention, thus preventing liver damage from contributing to severe impairment in patients.     

SARS-CoV-2 induced liver injury: Incidence,risk factors,impact on COVID-19 severity and prognosis in different population groups

Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with “bystander hepatitis”, cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.     

Alcohol use disorder and liver injury related to the COVID-19 pandemic

Alcohol use disorder is a complex and heterogeneous phenomenon that can be studied from several points of view by focusing on its different components. Alcohol is a hepatotoxin whose metabolism creates profound alterations within the hepatocyte. The liver is the central organ in the metabolism of alcohol, a process that also involves other organs and tissues such as the brain, heart and muscles, but the most relevant organ is the liver. The anatomopathological alterations in the liver associated with the prolonged use of alcohol range from the simple accumulation of neutral fats in the hepatocytes, to cirrhosis and hepatocellular carcinoma. Alcohol abuse frequently leads to liver disease such as steatosis, steatohepatitis, fibrosis, cirrhosis, and tumors. Following the spread of coronavirus disease 2019 (COVID-19), there was an increase in alcohol consumption, probably linked to the months of lockdown and smart working. It is known that social isolation leads to a considerable increase in stress, and it is also recognized that high levels of stress can result in an increase in alcohol intake. Cirrhotic patients or subjects with liver cancer are immunocompromised, so they may be more exposed to COVID-19 infection with a worse prognosis. This review focuses on the fact that the COVID-19 pandemic has made the emergence of alcohol-induced liver damage a major medical and social problem.     

Insight into the liver dysfunction in COVID-19 patients: Molecular mechanisms and possible therapeutic strategies

As of June 2022, more than 530 million people worldwide have become ill with coronavirus disease 2019(COVID-19). Although COVID-19 is most commonly associated with respiratory distress(severe acute respiratory syndrome), metaanalysis have indicated that liver dysfunction also occurs in patients with severe symptoms. Current studies revealed distinctive patterning in the receptors on the hepatic cells that helps in viral invasion through the expression of angiotensinconverting enzyme receptors. I...     

COVID-19 and liver injury in individuals with obesity

Coronavirus disease 2019 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 that manifests as a variety of clinical manifestations, including liver damage commonly detected by a hepatocellular pattern from liver function tests. Liver injury is associated with a worse prognosis overall. Conditions associated with the severity of the disease include obesity and cardiometabolic comorbidities, which are also associated with nonalcoholic fatty liver disease (NAFLD). The presence of NAFLD, similarly to obesity, is associated with an unfavourable impact on the coronavirus disease 2019 outcome. Individuals with these conditions could present with liver damage and elevated liver function tests due to direct viral cytotoxicity, systemic inflammation, ischemic or hypoxic liver damage or drug side effects. However, liver damage in the setting of NAFLD could also be attributed to a pre-existing chronic low-grade inflammation associated with surplus and dysfunctional adipose tissue in these individuals. Here we investigate the hypothesis that a pre-existing inflammatory status is exacerbated after severe acute respiratory syndrome coronavirus 2 infection, which embodies a second hit to the underestimated liver damage.     

COVID-19 emergency: Changes in quality of life perception in patients with chronic liver disease-An Italian single-centre study

BACKGROUNDIn December 2019, the coronavirus disease-2019 (COVID-19) emerged and rapidly spread worldwide, becoming a global health threat and having a tremendous impact on the quality of life (QOL) of individuals.AIMTo evaluate the awareness of patients with chronic liver disease (CLD) regarding the COVID-19 emergency and how it impacted on their QOL. METHODSPatients with an established diagnosis of CLD (cirrhosis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) who had been evaluated at our Outpatient Liver Disease Clinic during the 6-mo period preceding the start of Italian lockdown (March 8, 2020) were enrolled. Participants were asked to complete a two-part questionnaire, administered by telephone according to governmental restrictions: The first section assessed patients’ basic knowledge regarding COVID-19, and the second evaluated the impact of the COVID-19 emergency on their QOL. We used the Italian version of the CLD questionnaire (CLDQ-I). With the aim of evaluating possible changes in the QOL items addressed, the questionnaire was administered to patients at the time of telephone contact with the specific request to recall their QOL perceptions during two different time points. In detail, patients were asked to recall these perceptions first during time 0 (t0), a period comprising the 2 wk preceding the date of ministerial lockdown decree (from February 23 to March 7, 2020); then, in the course of the same phone call, they were asked to recall the same items as experienced throughout time 1 (t1), the second predetermined time frame encompassing the 2 wk (from April 6 to April 19) preceding our telephone contact and questionnaire administration. All data are expressed as number (%), and continuous variables are reported as the median (interquartile range). The data were compared using the Wilcoxon paired non-parametric test. RESULTSA total of 111 patients were enrolled, of whom 81 completed the questionnaire. Forty-nine had liver cirrhosis, and all of them had compensated disease; 32 patients had autoimmune liver disease. The majority (93.8%) of patients were aware of COVID-19 transmission modalities and on how to recognize the most common alarm symptoms (93.8%). Five of 32 (15.6%) patients with autoimmune liver disease reported having had the need to receive more information about the way to manage their liver disease therapy during lockdown and nine (28.2%) thought about modifying their therapy without consulting their liver disease specialist. About the impact on QOL, all CLDQ-I total scores were significantly worsened during time t1 as compared to time t0. CONCLUSIONThe COVID-19 epidemic has had a significant impact on the QOL of our population of patients, despite a good knowledge of preventive measure and means of virus transmission.     

Cytokine profiling in Iranian patients with COVID-19; association with clinical severity

Background: SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is recognized for the first time in Wuhan, China. The cytokine storm is a known factor causing major clinical symptoms leading to death in COVID-19 patients. Objective: To investigate and compare the serum levels of different cytokines in COVID-19 patients with different clinical severity. Methods: Concentrations of serum cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and GM-CSF, were measured in 61 COVID-19 patients and 31 normal controls with ELISA. We investigated the correlation between the levels of these cytokines and clinical severity, CRP level, neutrophil and lymphocyte count in patients with COVID-19. Results: Our data indicated that the levels of IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, but not IL-10 were significantly increased in COVID-19 patients compared to normal controls. Statistical analysis showed that the level of IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF were higher in severe COVID-19 than those of mild cases. The concentrations of all mentioned cytokines were negatively associated with the absolute count of lymphocytes, and positively correlated with the CRP level and the absolute count of neutrophils. Conclusion: The current study suggests that high levels of various cytokines correlate with the disease severity and immunopathogenesis of COVID-19.     

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 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,...     

Clinical characteristics and risk factors for liver injury in COVID-19 patients in Wuhan

BACKGROUND Coronavirus disease 2019(COVID-19) has become a worldwide pandemic. We investigated the clinical characteristics and risk factors for liver injury in COVID-19 patients in Wuhan by retrospectively analyzing the epidemiological, clinical, and laboratory data for 218 COVID-19 patients and identifying the risk factors for liver injury by multivariate analysis.AIM To investigate the clinical characteristics and risk factors for liver injury in COVID-19 patients in Wuhan.METHODS The 218 patients included 94 males(43.1%), aged 22 to 94(50.1 ± 18.4) years. Elevated aspartate aminotransferase(AST) and alanine aminotransferase(ALT) were present in 42(53.2%) and 36(45.6%) cases, respectively, and 79(36.2%) patients had abnormally elevated transaminase levels at admission. Patients with liver injury were older than those with normal liver function by a median of 12 years, with a significantly higher frequency of males(68.4% vs 28.8%, P 0.001) and more coexisting illnesses(48.1% vs 27.3%, P = 0.002). Significantly more patients had fever and shortness of breath(87.3% vs 69.8% and 29.1% vs 14.4%, respectively) in the liver injury group. Only 12(15.2%) patients had elevated total bilirubin. ALT and AST levels were mildly elevated [1-3 × upper limit of normal(ULN)] in 86.1% and 92.9% of cases, respectively. Only two(2.5%) patients had an ALT or AST level 5 × ULN. Elevated γ-glutamyl transpeptidase was present in 45(57.0%) patients, and 86.7% of these had a γ-glutamyl-transpeptidase level 135 U/L(3 × ULN). Serum alkaline phosphatase levels were almost normal in all patients. Patients with severe liver injury had a significantly higher frequency of abnormal transaminases than non-severe patients, but only one case had very high levels of aminotransferases.RESULTS Multivariate analysis revealed that male sex, high D-dimer level, and high neutrophil percentage were linked to a higher risk of liver injury. The early stage of COVID-19 may be associated with mildly elevated aminotransferase levels in patients in Wuhan. Male sex and high D-dimer level and neutrophil percentage may be important predictors of liver injury in patients with COVID-19.CONCLUSION Male sex and high D-dimer level and neutrophil percentage may be important predictors of liver injury in patients with COVID-19.     

Correlation between COVID-19 and hepatitis B: A systematic review

BACKGROUNDThere is growing evidence that patients with coronavirus disease 2019 (COVID-19) frequently present with liver impairment. Hepatitis B virus (HBV) remains a major public health threat in current society. Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HBV can cause liver damage, and current findings on whether HBV infection increases disease severity in COVID-19 patients are inconsistent, and whether SARS-CoV-2 infection accelerates hepatitis B progression or leads to a worse prognosis in hepatitis B patients has not been adequately elucidated.AIMTo explore the complex relationship between COVID-19 and hepatitis B in order to inform the research and management of patients co-infected with SARS-CoV-2 and HBV.METHODSAn experienced information specialist searched the literature in the following online databases: PubMed, China National Knowledge Infrastructure, Google Scholar, Scopus, Wiley, Web of Science, Cochrane, and ScienceDirect. The literature published from December 2019 to September 1, 2022 was included in the search. We also searched medRxiv and bioRxiv for gray literature and manually scanned references of included articles. Articles reporting studies conducted in humans discussing hepatitis B and COVID-19 were included. We excluded duplicate publications. News reports, reports, and other gray literature were included if they contained quantifiable evidence (case reports, findings, and qualitative analysis). Some topics that included HBV or COVID-19 samples but did not have quantitative evidence were excluded from the review.RESULTSA total of 57 studies were eligible and included in this review. They were from 11 countries, of which 33 (57.9%) were from China. Forty-two of the 57 studies reported abnormalities in liver enzymes, three mainly reported abnormalities in blood parameters, four indicated no significant liver function alterations, and another eight studies did not provide data on changes in liver function. Fifty-seven studies were retrospective and the total number of co-infections was 1932, the largest sample size was 7723, and the largest number of co-infections was 353. Most of the studies suggested an interaction between hepatitis B and COVID-19, while 12 studies clearly indicated no interaction between hepatitis B and COVID-19. Six of the 57 studies clearly reported HBV activation. Six studies were related to liver transplant patients.CONCLUSIONThere is some association between COVID-19 and hepatitis B. Future high-quality randomized trials are needed to further elucidate the interaction between COVID-19 and hepatitis B.     

Strategy for the control of drug-induced liver injury due to investigational treatments/drugs for COVID-19

Investigational treatments/drugs for coronavirus disease 2019 (COVID-19) have been applied, with repurposed or newly developed drugs, and their effectiveness has been evaluated. Some of these drugs may be hepatotoxic, and each monotherapy or combination therapy may increase the risk of drug-induced liver injury (DILI). We should aim to control dysregulation of liver function, as well as the progression of COVID-19, as much as possible. We discussed the potential risks of investigational treatments/drugs and promising drugs for both COVID-19 and DILI due to investigational treatments/drugs.