Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) infection caused by the severe acute respiratory syndrome coronavirus 2 virus, its symptoms, treatment, and post-COVID-19 effects have been a major focus of research since 2020. In addition to respiratory symptoms, different clinical variants of the virus have been associated with dynamic symptoms and multiorgan diseases, including liver abnormalities. The release of cytokines by the activation of innate immune cells during viral infection and the high doses of drugs used for COVID-19 treatment are considered major drivers of liver injury in COVID-19 patients. The degree of hepatic inflammation in patients suffering from chronic liver disease and having COVID-19 could be severe and can be estimated through different liver chemistry abnormality markers. Gut microbiota influences liver chemistry through its metabolites. Gut dysbiosis during COVID-19 treatment can promote liver inflammation. Here, we highlighted the bidirectional association of liver physiology and gut microbiota (gut-liver axis) and its potential to manipulate drug-induced chemical abnormalities in the livers of COVID-19 patients.

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target.

Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.

Age-adjusted mortality and predictive value of liver chemistries in a Viennese cohort of COVID-19 patients.

BACKGROUND AND AIMS: The coronavirus disease of 2019 (COVID-19) causes considerable mortality worldwide. We aimed to investigate the frequency and predictive role of abnormal liver chemistries in different age groups. METHODS: Patients with positive severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test between 03/2020-07/2021 at the Vienna General Hospital were included. Patients were stratified for age: 18-39 vs. 40-69 vs. ≥70 years (y). Aspartate aminotransferase (AST), alanine-aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) were recorded. RESULTS: 900 patients (18-39 years: 32.2%, 40-69 years: 39.7%, ≥70 years: 28.1%) were included. Number of comorbidities, median D-dimer and C-reactive protein increased with age. During COVID-19, AST/ALT and ALP/GGT levels significantly increased. Elevated hepatocellular transaminases (AST/ALT) and cholestasis parameters (ALP/GGT/BIL) were observed in 40.3% (n  = 262/650) and 45.0% (n  = 287/638) of patients respectively. Liver-related mortality was highest among patients with pre-existing decompensated liver disease (28.6%, p < .001). 1.7% of patients without pre-existing liver disease died of liver-related causes, that is consequences of hepatic dysfunction or acute liver failure. Importantly, COVID-19-associated liver injury (16.0%, p < .001), abnormal liver chemistries and liver-related mortality (6.5%, p < .001) were most frequent among 40-69 years old patients. Elevated AST and BIL after the first positive SARS-CoV-2 PCR independently predicted mortality in the overall cohort and in 40-69 years old patients. CONCLUSIONS: Almost half of the COVID-19 patients exhibit abnormal hepatocellular and cholestasis-related liver chemistries with 40-69 years old patients being at particularly high risk for COVID-19-related liver injury and liver-related mortality. Elevated AST and BIL after SARS-CoV-2 infection are independent predictors of mortality, especially in patients aged 40-69 years.

Variation in Expression of Cytochrome P450 3A Isoforms and Toxicological Effects: Endo- and Exogenous Substances as Regulatory Factors and Substrates.

The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.

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.

COVID-19 and the liver: an adverse outcome pathway perspective.

Liver damage is observed in up to half of hospitalized COVID-19 patients and can result either from actions of SARS-CoV-2 as such or from pharmacological treatment. The present paper introduces an adverse outcome pathway construct that mechanistically describes the pathways induced by SARS-CoV-2 leading to liver injury. This can be caused by direct binding of the virus and local actions in cholangiocytes, but may also indirectly result from the general state of hypoxia and systemic inflammation in COVID-19 patients. Further research is urgently needed to fill remaining knowledge gaps. This will be anticipated to create a solid basis for future and more targeted development of vaccines and, in particular, therapies.

The clinical course of COVID in pregnancy.

The 2019 novel coronavirus disease (COVID-19) pandemic poses unique challenges to the medical community as the optimal treatment has not been determined and is often at the discretion of institutional guidelines. Pregnancy has previously been described as a high-risk state in the context of infectious diseases, given a particular susceptibility to pathogens and adverse outcomes. Although ongoing studies have provided insight on the course of this disease in the adult population, the implications of COVID-19 on pregnancy remains an understudied area. The objective of this study is to review the literature and describe clinical presentations among pregnant women afflicted with COVID-19.

Molecular and cellular mechanisms of liver dysfunction in COVID-19.

Liver injury has been reported as a common complication in Coronavirus disease 2019 (COVID-19). Recently, more and more studies reported that the degree of liver damages was associated with the severity of COVID-19. Although the exact mechanism of liver injury in COVID-19 patients is unknown, recent studies have made some explorations and investigations. In this review, we summarized the potential mechanisms of liver dysfunction in COVID-19 patients gleaned from recently published research reports, which suggested that the progression of pre-existing liver diseases, direct damage of liver by SARS-CoV-2, systemic inflammation caused by SARS-CoV-2 infection, anti-viral drug toxicity, and hypoxia-reperfusion may be associated with liver injury in patients with COVID-19. Hypoxic liver injury due to ischemia and shock, cholestasis-related liver injury due to altered bile metabolism, and hepatocellular injury due to drug toxicity or overwhelming inflammation might occur in severe COVID-19 patients with sepsis. To understand the pathogenesis of liver dysfunction in COVID-19 patients, further research is needed to focus on liver-related comorbidities, the evidence of viral replication in hepatocytes and bile duct cells, histological features of liver injury, and the influence of hepatotoxic antiviral drugs. We also suggested that special attention should be paid to monitoring inflammatory cytokines and hypoxia for the prevention and treatment of liver injury in severe COVID-19 patients. A deep understanding of the mechanism of liver injury is helpful for the management and treatment of COVID-19 patients.

Association of ACEI/ARB, inflammatory cytokines, and antiviral drugs with liver dysfunction in patients with hypertension and COVID-19.

Background: Currently, SARS-CoV-2 liver invasion, inflammatory cytokines, and antiviral drugs are widely thought to be associated with liver dysfunction in COVID-19 patients. Besides, previous studies indicated that ACEI/ARB drugs can increase the expression of hepatic ACE2, a cell entry receptor for SARS-CoV-2. This study aims to investigate whether ACEI/ARB aggravates liver injury and the association of inflammatory cytokines and antiviral drugs with liver dysfunction in patients with hypertension and COVID-19.Method: This retrospective study included 127 hypertensive patients with long-term use or nonuse of ACEI/ARBs hospitalized for COVID-19 from January 30 to April 7, 2020, in Tongji hospital of Wuhan, China. Demographic, clinical, laboratory, treatment, and outcome data were collected.Results: Of the 127 patients with COVID-19 and hypertension, 43 taking long-term of ACEI/ARBs and 84 without using ACEI/ARBs. Abnormal liver function was observed in part of ACEI/ARB and non-ACEI/ARB users but without significant differences between these two groups. Serum inflammatory cytokines, IL-6, IL-8, and TNFα, as well as inflammation-related markers, ferritin, procalcitonin, and C-reactive protein, were significantly elevated in patients with liver dysfunction. IL-6 level was positively correlated with liver function tests on admission and highly consistent with the changes of abnormal ALT, AST, and GGT during hospitalization, but the correlations of other inflammatory cytokines were low. There was no significant association between the use of antiviral drugs and liver dysfunction in these patients.Conclusion: The elevation of inflammatory cytokine, IL-6, but not ACEI/ARB and antiviral drugs, is closely associated with liver dysfunction in patients with hypertension and COVID-19.

Liver injury with COVID-19 based on gastrointestinal symptoms and pneumonia severity.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.

Characteristics and Outcomes of Patients 80 Years and Older Hospitalized With Coronavirus Disease 2019 (COVID-19).

Patients older than 65 years hospitalized with COVID-19 have higher rates of intensive care unit admission and death when compared with younger patients. Cardiovascular conditions associated with COVID-19 include myocardial injury, acute myocarditis, cardiac arrhythmias, cardiomyopathies, cardiogenic shock, thromboembolic disease, and cardiac arrest. Few studies have described the clinical course of those at the upper extreme of age. We characterize the clinical course and outcomes of 73 patients with 80 years of age or older hospitalized at an academic center between March 15 and May 13, 2020. These patients had multiple comorbidities and often presented with atypical clinical findings such as altered sensorium, generalized weakness and falls. Cardiovascular manifestations observed at the time of presentation included new arrhythmia in 7/73 (10%), stroke/intracranial hemorrhage in 5/73 (7%), and elevated troponin in 27/58 (47%). During hospitalization, 38% of all patients required intensive care, 13% developed a need for renal replacement therapy, and 32% required vasopressor support. All-cause mortality was 47% and was highest in patients who were ever in intensive care (71%), required mechanical ventilation (83%), or vasopressors (91%), or developed a need for renal replacement therapy (100%). Patients older than 80 years old with COVID-19 have multiple unique risk factors which can be associated with increased cardiovascular involvement and death.

COVID-19 and the liver.

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a major public health crisis over the past few months. Overall case fatality rates range between 2-6%; however, the rates are higher in the elderly and those with underlying comorbidities like diabetes, hypertension and heart disease. Recent reports showed that about 2-11% of patients with COVID-19 had underlying chronic liver disease. During the previous SARS epidemic, around 60% of patients were reported to develop various degrees of liver damage. In the current pandemic, hepatic dysfunction has been seen in 14-53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been reported and are associated with higher mortality. Hepatic involvement in COVID-19 could be related to the direct cytopathic effect of the virus, an uncontrolled immune reaction, sepsis or drug-induced liver injury. The postulated mechanism of viral entry is through the host angiotensin-converting enzyme 2 (ACE2) receptors that are abundantly present in type 2 alveolar cells. Interestingly, ACE2 receptors are expressed in the gastrointestinal tract, vascular endothelium and cholangiocytes of the liver. The effects of COVID-19 on underlying chronic liver disease require detailed evaluation and, with data currently lacking, further research is warranted in this area.

A brief review of liver injury in patients with Corona Virus Disease-19 during the pandemic.

The novel coronavirus Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) infection has been mostly leading to respiratory distress syndrome, but liver injury has also been documented. The mechanism of liver injury is limited and poorly understood. However, the hepatic injury could be due to a consequence of systemic inflammatory response, viral infection of hepatocytes, or as a result of intensive care treatment or drug toxicity. Based on the current studies, this review article emphasizes on the demographic and potential mechanisms of Corona Virus Disease (COVID)-19-related liver dysfunction.

Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19).

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory disease, which can evolve into multi-organ failure (MOF), leading to death. Several biochemical alterations have been described in COVID-19 patients. To date, many biomarkers reflecting the main pathophysiological characteristics of the disease have been identified and associated with the risk of developing severe disease. Lymphopenia represents the hallmark of the disease, and it can be detected since the early stage of infection. Increased levels of several inflammatory biomarkers, including c-reactive protein, have been found in COVID-19 patients and associated with an increased risk of severe disease, which is characterised by the so-called "cytokine storm". Also, the increase of cardiac and liver dysfunction biomarkers has been associated with poor outcome. In this review, we provide an overview of the main biochemical characteristics of COVID-19 and the associated biomarkers alterations.