Mechanisms of severe acute respiratory syndrome coronavirus-2 induced liver damage and alteration of some liver biomarkers: A review.

The most serious problem for people suffering from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is liver damage. The liver is a frequently affected organ due to the metabolizing and detoxifying functions of several endogenous and exogenous molecules. In COVID-19-affected individuals, even moderate loss of hepatic function could dramatically affect the therapeutic efficacy of antiviral drugs metabolized in the liver. The clear mechanism of hepatocellular damage from SARS-CoV-2 infection is not fully understood. The main objective of this review is to identify potential mechanisms of SARS-2 induced liver damage, treatment outcomes in SARS-CoV-2-infected patients, and future direction. Electronic databases including Web of Science, Google Scholar, MEDLINE, Scopus, and Cochrane library were used to systematically search without limitation of publication date and status. Observational, retrospective cohort, prospective case-control, cohort studies, cross-sectional studies, or clinical trials were included. Liver damage in coronavirus patients is characterized by histopathological changes and abnormal elevation of some liver function tests. These abnormalities include elevation of Alanine aminotransferase, Aspartate aminotransferase, Gamma-glutamyl transferase, Alkaline phosphatase, and Serum bilirubin levels. Histopathological changes of the liver might consist of complete or partial thrombosis of the portal and sinusoidal vessels, portal tract fibrosis, and focally markedly enlarged and fibrotic hepatocytes. Understanding the fundamental molecular and immunological processes of COVID-19-related liver injury is essential for the selection of appropriate drugs and the logical development of successful treatment.

Alcohol-Associated Liver Disease Mortality Rates by Race Before and During the COVID-19 Pandemic in the US.

This cross-sectional study examines the national- and state-level age-adjusted mortality rates for alcohol-associated liver disease in 4 racial groups, with a focus on the American Indian or Alaska Native population.

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 their severity, pathophysiology, clinical manifestations, and clinical and laboratory outcomes. We also discuss the effect of vaccination against COVID-19 to better understand host factors, such as age, gender, and race, on the incidence and severity of liver dysfunction at initial presentation and during the illness. Finally, we summarize the results of relevant meta-analyses published to date and highlight the importance of adequate liver function monitoring in the current climate of the overwhelming COVID-19 pandemic.

Histology and cytokine levels in hepatic injury accompanying a case of non-severe COVID-19.

The pathogenesis of liver dysfunction that complicates coronavirus disease 2019 (COVID-19) remains unclear, especially in mild to moderate severity cases. In this case, a novel coronavirus infection was detected by polymerase chain reaction (PCR) in a 76-year-old woman hospitalized after presenting with fever. No other abnormal physical findings were observed, and oxygen administration was not required. Chest computed tomography (CT) showed a ground-glass-like and an infiltrative shadow in the right lung, and moderate COVID-19 was diagnosed. Initially, the fever resolved, and PCR turned negative; however, the fever reappeared on hospitalization day 14, and CT showed pneumonia exacerbation accompanied by new onset of fatty liver. Biochemical testing revealed marked liver dysfunction, accompanied by elevated serum interleukin (IL)-6, IL-10, and tumor necrosis factor-α levels. Physical findings and all laboratory parameters improved after conservative treatment, and she was discharged on day 22. A liver biopsy performed 44 days post-discharge showed T-cell-dominant inflammatory cell infiltration, mainly in the portal region. Some hepatocytes showed fatty degeneration.We report a case of moderate COVID-19 in which histological hepatitis persisted after a substantial period had passed since the initial infection had cleared and associated transaminase elevations had resolved, with a comparison of serum cytokine dynamics.

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.

Increased Prevalence of Alcohol-Related Gastrointestinal and Liver Diseases During the COVID-19 Pandemic.

BACKGROUND: Higher prevalence of alcohol-related gastrointestinal (GI) and liver diseases (ARGLDs) were anecdotally reported during the COVID-19 pandemic, but little published evidence exists. METHODS: A healthcare system audit of inpatient GI consults was performed during the pandemic's lockdown phase (3/23/2020-5/10/2020, n=558) and reopening phase (6/1/2020-7/19/2020, n=711) with comparison to those timeframes in 2019. RESULTS: Consult volume decreased by 27.7% during the lockdown, but the proportion of ARGLDs increased by 59.6% (p=0.03). This trend continued during reopening, with potentially more severe disease as more patients required endoscopic intervention. Patients with alcoholic hepatitis during reopening were younger compared to the lockdown. CONCLUSIONS: Our study demonstrates increased prevalence and severity of ARGLDs amongst younger individuals during the COVID-19 pandemic. This increase started during the lockdown but worsened despite relaxation of restrictions. Systems to increase screening for and treatment of alcohol use disorder as society recovers from the pandemic remain imperative.

Involvement of the digestive system in covid-19. A review. / Afectación del aparato digestivo en la covid-19. Una revisión sobre el tema.

The SARS-CoV-2 pandemic is leading to high mortality and a global health crisis. The primary involvement is respiratory; however, the virus can also affect other organs, such as the gastrointestinal tract and liver. The most common symptoms are anorexia and diarrhea. In about half of the cases, viral RNA could be detected in the stool, which is another line of transmission and diagnosis. covid19 has a worse prognosis in patients with comorbidities, although there is not enough evidence in case of previous digestive diseases. Digestive endoscopies may give rise to aerosols, which make them techniques with a high risk of infection. Experts and scientific organizations worldwide have developed guidelines for preventive measures. The available evidence on gastrointestinal and hepatic involvement, the impact on patients with previous digestive diseases and operating guidelines for Endoscopy Units during the pandemic are reviewed.

Clinical predictors of recovery of COVID-19 associated-abnormal liver function test 2 months after hospital discharge.

This study investigated whether acute liver injury (ALI) persisted and identified predictors of ALI recovery [as indicated by alanine aminotransferase (ALT) level] at hospital discharge and 2 months post-discharge for 7595 hospitalized COVID-19 patients from the Montefiore Health System (03/11/2020-06/03/2021). Mild liver injury (mLI) was defined as ALT = 1.5-5 ULN, and severe livery injury (sLI) was ALT ≥ 5 ULN. Logistic regression was used to identify predictors of ALI onset and recovery. There were 4571 (60.2%), 2306 (30.4%), 718 (9.5%) patients with no liver injury (nLI), mLI and sLI, respectively. Males showed higher incidence of sLI and mLI (p < 0.05). Mortality odds ratio was 4.15 [95% CI 3.41, 5.05, p < 0.001] for sLI and 1.69 [95% CI 1.47, 1.96, p < 0.001] for mLI compared to nLI. The top predictors (ALT, lactate dehydrogenase, ferritin, lymphocytes) accurately predicted sLI onset up to three days prior. Only 33.5% of mLI and 17.1% of sLI patients (survivors) recovered completely at hospital discharge. Most ALI patients (76.7-82.4%) recovered completely ~ 2 months post-discharge. The top predictors accurately predicted recovery post discharge with 83.2 ± 2.2% accuracy. In conclusion, most COVID-19 patients with ALI recovered completely ~ 2 months post discharge. Early identification of patients at-risk of persistent ALI could help to prevent long-term liver complications.

COVID-19-associated liver injury: Clinical characteristics, pathophysiological mechanisms and treatment management.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global epidemic and poses a major threat to public health. In addition to COVID-19 manifesting as a respiratory disease, patients with severe disease also have complications in extrapulmonary organs, including liver damage. Abnormal liver function is relatively common in COVID-19 patients; its clinical manifestations can range from an asymptomatic elevation of liver enzymes to decompensated hepatic function, and liver injury is more prevalent in severe and critical patients. Liver injury in COVID-19 patients is a comprehensive effect mediated by multiple factors, including liver damage directly caused by SARS-CoV-2, drug-induced liver damage, hypoxia reperfusion dysfunction, immune stress and inflammatory factor storms. Patients with chronic liver disease (especially alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma) are at increased risk of severe disease and death after infection with SARS-CoV-2, and COVID-19 aggravates liver damage in patients with chronic liver disease. This article reviews the latest SARS-CoV-2 reports, focusing on the liver damage caused by COVID-19 and the underlying mechanism, and expounds on the risk, treatment and vaccine safety of SARS-CoV-2 in patients with chronic liver disease and liver transplantation.

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.

Longitudinal relationship of liver injury with inflammation biomarkers in COVID-19 hospitalized patients using a joint modeling approach.

The mechanisms underlying liver disease in patients with COVID-19 are not entirely known. The aim is to investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19. The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy. The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19.

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.

Elevated liver enzymes in hospitalized patients with COVID-19 in Singapore.

ABSTRACT: Liver dysfunction in patients with COVID-19 (coronavirus disease 2019) has been described. However, it is not clear if the presence of abnormal liver function tests at presentation was related to underlying undiagnosed liver disease, or a result of the viral infection.We retrospectively examined the first 554 consecutive polymerase chain reaction positive SARS-CoV-2 patients admitted from February 2020 to April 2020 to our academic medical centre. We reviewed their clinical data, chest radiography and laboratory studies obtained within 24 hour of admission.Despite similar hemodynamic parameters, we found significant aspartate transaminase elevation (64 ±â€Š141 vs 35 ±â€Š23 U/L, P < .001) in those with pneumonia compared to those without. Elevated liver enzymes were seen in 102 patients (18.4%). They presented with higher temperatures (38.5 ±â€Š0.9 vs 37.5 ±â€Š0.8 degC, P = .011), higher total white cell counts (6.95 ±â€Š2.29 vs 6.39 ±â€Š2.19 x109/L, P = .021), serum ferritin (240 ±â€Š274 vs 165 ±â€Š198 ng/ml, P = .002) and lactate dehydrogenase (632 ±â€Š912 vs 389 ±â€Š107 U/L, P < .001). These patients were more likely to require intensive care (6.9% vs 2.7% P = .036) and mechanical ventilation (5.9% vs 2.2%, P = .046). Migrant workers from dormitories had a higher rate of baseline liver function test abnormalities (88/425 vs 14/129, P = .01), which were more likely to persist at the time of discharge.Despite relatively mild COVID-19 disease, there was a significant prevalence of liver dysfunction, particularly amongst migrant workers. Elevated liver enzymes were associated with more severe disease, despite similar haemodynamic characteristics. Future studies should explore whether pre-existing liver disease may predispose to more severe COVID-19 disease.

Liver Disease: Induction, Progression, Immunological Mechanisms, and Therapeutic Interventions.

The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver's ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.

Liver injury in COVID-19: clinical features and treatment management.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread to many countries around the world. In addition to lung disease, severe cases also displayed varying degrees of liver injury. This article will describe the latest developments regarding coronavirus and the pathogenesis of liver injury, the prone population and clinical characteristics of these patients, as well as providing some suggestions for clinical treatment.