COVID-19 and non-alcoholic fatty liver disease: Biological insights from multi-omics data.

We explored the shared pathophysiological mechanisms between COVID-19 and non-alcoholic fatty liver disease (NAFLD) by integrating multi-omics data. We studied common genetic risk factors and underlying biological processes using functional enrichment analysis. To understand the sex-specific pathways involved in the clinical course of SARS-CoV-2 infection, we processed sex-stratified data from COVID-19 genome-wide association datasets. We further explored the transcriptional signature of the liver cells in healthy and COVID-19 tissue specimens. We also integrated genetic and metabolomic information. We found that COVID-19 and NAFLD share biological disease mechanisms, including pathways that regulate the inflammatory and lipopolysaccharide response. Single-cell transcriptomics revealed enrichment of complement-related pathways in Kupffer cells, syndecan-mediated signalling in plasma cells, and epithelial-to-mesenchymal transition in hepatic stellate cells. The strategy of pathway-level analysis of genomic and metabolomic data uncovered l-lactic acid, Krebs cycle intermediate compounds, arachidonic acid and cortisol among the most prominent shared metabolites.

Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency.

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS: In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).

The Artificial-Liver Blood-Purification System Can Effectively Improve Hypercytokinemia for COVID-19.

Since the December 2019 outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, the infection has spread locally and globally resulting in a pandemic. As the numbers of confirmed diagnoses and deaths continue to rise, COVID-19 has become the focus of international public health. COVID-19 is highly contagious, and there is no effective treatment yet. New treatment strategies are urgently needed to improve the treatment success rate of severe and critically ill patients. Increasing evidence has shown that a cytokine storm plays an important role in the progression of COVID-19. The artificial-liver blood-purification system (ALS) is expected to improve the outcome of the cytokine storm. In the present study, the levels of cytokines were detected in 12 COVID-19 patients pre- and post-ALS with promising results. The present study shows promising evidence that ALS can block the cytokine storm, rapidly remove the inflammatory mediators, and hopefully, suppress the progression of the disease, thereby providing a new strategy for the clinical treatment of 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.

Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection.

The ongoing COVID-19 pandemic has already caused over a million deaths worldwide, and this death toll will be much higher before effective treatments and vaccines are available. The causative agent of the disease, the coronavirus SARS-CoV-2, shows important similarities with the previously emerged SARS-CoV-1, but also striking differences. First, SARS-CoV-2 possesses a significantly higher transmission rate and infectivity than SARS-CoV-1 and has infected in a few months over 60 million people. Moreover, COVID-19 has a systemic character, as in addition to the lungs, it also affects the heart, liver, and kidneys among other organs of the patients and causes frequent thrombotic and neurological complications. In fact, the term "viral sepsis" has been recently coined to describe the clinical observations. Here I review current structure-function information on the viral spike proteins and the membrane fusion process to provide plausible explanations for these observations. I hypothesize that several membrane-associated serine proteinases (MASPs), in synergy with or in place of TMPRSS2, contribute to activate the SARS-CoV-2 spike protein. Relative concentrations of the attachment receptor, ACE2, MASPs, their endogenous inhibitors (the Kunitz-type transmembrane inhibitors, HAI-1/SPINT1 and HAI-2/SPINT2, as well as major circulating serpins) would determine the infection rate of host cells. The exclusive or predominant expression of major MASPs in specific human organs suggests a direct role of these proteinases in e.g., heart infection and myocardial injury, liver dysfunction, kidney damage, as well as neurological complications. Thorough consideration of these factors could have a positive impact on the control of the current COVID-19 pandemic.

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.

Pharmacokinetics and tissue distribution of remdesivir and its metabolites nucleotide monophosphate, nucleotide triphosphate, and nucleoside in mice.

Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.

COVID 19 and liver: An A-Z literature review.

The coronavirus pandemic has changed the priorities of the whole medical society. During the clinical course of COVID-19, it has been observed that hepatic injury occurs in a significant proportion of patients, particularly in those with severe or critical illness. In this literature review, we summarize the most recent studies, which covered the pathophysiology of COVID-19 induced liver injury including; hepatic pathological findings, therapy related liver damage, and the effects of the viral infection on pre-existing liver diseasesin context of the most recent recommendations. Conclusions: This review sheds light on the impact of COVID-19 infection on the liver, as well as the prognostic effect of liver laboratory markers on disease outcome. Temporal variations in liver parameters during disease course as well as different patterns of derangement are depicted. More intensive surveillance and individualized therapeutic approaches should be tailored for immunocompromised patients with advanced liver disease, hepatocellular carcinoma, and liver transplant patients. Despite the limited studies on COVID-19 infected patients with preexisting liver disease, this comprehensive overview provides a perspective on the management of liver disease during COVID-19.

COVID-19: Endogenous Retinoic Acid Theory and Retinoic Acid Depletion Syndrome.

This study presents two new concepts and definitions to the medical literature. One of those is "endogenous retinoic acid theory" and the other "retinoic acid depletion syndrome". A new classification will be provided for the immune system: "retinoic acid-dependent component" and "retinoic acid non-dependent component". If this theory is verified, all the diseases where the retinoic acid metabolism is defective and retinoic acid levels are low will be identified and new approaches will be developed fortreating such diseases. When the need for retinoic acids increases, such as acute infection, high fever, severe catabolic process, or chronic antigenic stimulation, cytochrome oxidase enzymes are inhibited by drugs or internal mechanisms. Metabolism and excretion of retinoic acids stored in the liver are prevented. In this way, retinoic acid levels in the blood are raised to therapeutic levels. This is called "Endogenous Retinoic Acid Theory". Retinoic acids also manage their metabolism through feedback mechanisms. Despite compensatory mechanisms, causes such as high fever, serious catabolic process and excessively large viral genome (SARS-CoV-2), excessive use of RIG-I and Type I interferon synthesis pathway using retinoic acid causes emptying of retinoic acid stores. As a result, the RIG-I pathway becomes ineffective, Type I IFN synthesis stops, and the congenital immune system collapses. Then the immune mechanism passes to TLR3, TLR7, TLR8, TLR9, MDA5 and UPS pathways in the monocyte, macrophage, neutrophil and dendritic cells of the adaptive immune defense system that do not require retinoic acid. This leads to excessive TNFα and cytokine discharge from the pathway. With the depletion of retinoic acid stores as a result of this overuse, the immune defense mechanism switches from the congenital immune system to the adaptive immune system, where retinoic acids cannot be used. As a result of this depletion of retinoic acids, the shift of the immune system to the NFκB arm, which causes excessive cytokine release, is called "retinoic acid depletion syndrome". COVID-19 and previously defined sepsis, SIRS and ARDS are each retinoic acid depletion syndrome. We claim that retinoic acid metabolism is defective in most inflammatory diseases, particularly COVID-19 (cytokine storm) sepsis, SIRS and ARDS. Finding a solution to this mechanism will bring a new perspective and treatment approach to such diseases.

Liver injury in patients with COVID-19: clinical profiles, CT findings, the correlation of the severity with liver injury.

BACKGROUND AND AIMS: Liver injury is found in some of patients with COVID-19. Liver injury of COVID-19 patients based on severity grading and abdominal radiological signs have not been reported until now. The aim of our study is to determine clinical profiles of the patients based on severity grading, describe abdominal radiological signs, and investigate the correlations of the severity with clinical profiles and radiological signs. METHODS: This retrospective cohort study included 115 patients with COVID-19 from Jan 2020 to Feb 2020. Medical records of the patients were collected and CT images were reviewed. RESULTS: Common clinical manifestations of patients with COVID-19 were fever (68.70%), cough (56.52%), fatigue (31.30%); some of them had gastrointestinal symptoms (diarrhea, 12.17%; nausea or vomiting 7.83%; inappetence, 7.83%). Abnormal liver function was observed in some of patients with COVID-19. Significant differences in the levels of AST, albumin,CRP were observed among different groups classified by the severity. Common findings of upper abdominal CT scan were liver hypodensity (26.09%) and pericholecystic fat stranding (21.27%); liver hypodensity was more frequently found in critical cases (58.82%). The severity of COVID-19 correlated with semi-quantitative CT score of pulmonary lesions, CT-quantified liver/spleen attenuation ratio in patients with COVID-19. CONCLUSIONS: Some of the patients with COVID-19 displayed liver damage revealed by liver functional tests and upper abdominal CT imaging, and the severity of COVID-19 patients correlated with some of liver functional tests and CT signs; thus, it will allow an earlier identification of high-risk patients for early effective intervention.

Body Composition Findings by Computed Tomography in SARS-CoV-2 Patients: Increased Risk of Muscle Wasting in Obesity.

Obesity is a characteristic of COVID-19 patients and the risk of malnutrition can be underestimated due to excess of fat: a paradoxical danger. Long ICU hospitalization exposes patients to a high risk of wasting and loss of lean body mass. The complex management precludes the detection of anthropometric parameters for the definition and monitoring of the nutritional status. The use of imaging diagnostics for body composition could help to recognize and treat patients at increased risk of wasting with targeted pathways. COVID-19 patients admitted to the ICU underwent computed tomography within 24 hours and about 20 days later, to evaluate the parameters of the body and liver composition. The main results were the loss of the lean mass index and a greater increase in liver attenuation in obese subjects. These could be co-caused by COVID-19, prolonged bed rest, the complex medical nutritional therapy, and the starting condition of low-grade inflammation of the obese. The assessment of nutritional status, with body composition applied to imaging diagnostics and metabolic profiles in COVID-19, will assist in prescribing appropriate medical nutritional therapy. This will reduce recovery times and complications caused by frailty.

Coronavirus disease (COVID-19) and the liver: a comprehensive systematic review and meta-analysis.

BACKGROUND: Liver function derangements have been reported in coronavirus disease (COVID-19), but reported rates are variable. METHODS: We searched PubMed and Embase with terms COVID and SARS-COV-2 from December 1, 2019 till April 5, 2020. We estimated overall prevalence, stratified prevalence based on severity, estimated risk ratio (RR), and estimated standardized mean difference (SMD) of liver function parameters in severe as compared to non-severe COVID. Random effect method utilizing inverse variance approach was used for pooling the data. RESULTS: In all, 128 studies were included. The most frequent abnormalities were hypoalbuminemia [61.27% (48.24-72.87)], elevations of gamma-glutamyl transferase (GGT) [27.94% (18.22-40.27)], alanine aminotransferase (ALT) [23.28% (19.92-27.01)], and aspartate aminotransferase (AST) [23.41% (18.84-28.70)]. Furthermore, the relative risk of these abnormalities was higher in the patients with severe COVID-19 when compared to non-severe disease [Hypoalbuminemia-2.65 (1.38-5.07); GGT-2.31 (1.6-3.33); ALT-1.76 (1.44-2.15); AST-2.30 (1.82-2.90)]. The SMD of hypoalbuminemia, GGT, ALT, and AST elevation in severe as compared to non-severe were - 1.05 (- 1.27 to - 0.83), 0.76 (0.40-1.12), 0.42 (0.27-0.56), and 0.69 (0.52-0.86), respectively. The pooled prevalence and RR of chronic liver disease as a comorbidity was 2.64% (1.73-4) and 1.69 (1.05-2.73) respectively. CONCLUSION: The most frequent abnormality in liver functions was hypoalbuminemia followed by derangements in gamma-glutamyl transferase and aminotransferases, and these abnormalities were more frequent in severe disease. The systematic review was, however, limited by heterogeneity in definitions of severity and liver function derangements. Graphical depiction of the summary of meta-analytic findings a) pooled prevalence of abnormalities b) Risk ratio of abnormality in severe versus non-severe COVID-19 c) standardized mean difference (SMD) between severe and non-severe group and d) pooled prevalence for parameters based on severity stratification for bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), albumin, globulin and acute hepatic injury (AHI) . Also estimates for overall/total liver disease (TLD) and chronic liver disease (CLD) amongst COVID-19 patients are depicted in a, b, d. For d) In addition to severity stratification, Overall (all studies for a particular estimate) and combined (only those studies which reported severity) estimates are provided.

Cytochrome P450-mediated drug interactions in COVID-19 patients: Current findings and possible mechanisms.

At the end of 2019, the entire world has witnessed the birth of a new member of coronavirus family in Wuhan, China. Ever since, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has swiftly invaded every corner on the planet. By the end of April 2020, almost 3.5 million cases have been reported worldwide, with a death toll of about 250,000 deaths. It is currently well-recognized that patient's immune response plays a pivotal role in the pathogenesis of Coronavirus Disease 2019 (COVID-19). This inflammatory element was evidenced by its elevated mediators that, in severe cases, reach their peak in a cytokine storm. Together with the reported markers of liver injury, such hyperinflammatory state may trigger significant derangements in hepatic cytochrome P450 metabolic machinery, and subsequent modulation of drug clearance that may result in unexpected therapeutic/toxic response. We hypothesize that COVID-19 patients are potentially vulnerable to a significant disease-drug interaction, and therefore, suitable dosing guidelines with therapeutic drug monitoring should be implemented to assure optimal clinical outcomes.

Characteristics of laboratory indexes in COVID-19 patients with non-severe symptoms in Hefei City, China: diagnostic value in organ injuries.

This study compared the laboratory indexes in 40 non-severe COVID-19 patients with those in 57 healthy controls. In the peripheral blood system of non-severe symptom COVID-19 patients, lymphocytes, eosinophils, basophils, total procollagen type 1 amino-terminal propeptide, osteocalcin N-terminal, thyroid-stimulating hormone, growth hormone, and insulin-like growth factor-binding protein 3 significantly decreased, and total protein, albumin, alanine transaminase, alkaline phosphatase, γ-glutamyl transferase, activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimer, fibrinogen degradation products, human epididymal protein 4, serum ferritin, and C-reactive protein were elevated. SARS-CoV-2 infection can affect hematopoiesis, hemostasis, coagulation, fibrinolysis, bone metabolism, thyroid, parathyroid glands, the liver, and the reproductive system.

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19.

Background & Aims: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). Whether or not severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to liver damage per se remains unknown. Herein, we reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with liver enzyme abnormalities. Methods: We analyzed 156 patients diagnosed with COVID-19 from 2 designated centers in China and compared clinical features between patients with or without elevated aminotransferases. Postmortem liver biopsies were obtained from 2 cases who had elevated aminotransferases. We investigated the patterns of liver impairment by electron microscopy, immunohistochemistry, TUNEL assay and pathological studies. Results: Sixty-four out of 156 (41.0%) patients with COVID-19 had elevated aminotransferases. The median levels of alanine aminotransferase were 50 U/L vs. 19 U/L, respectively, aspartate aminotransferase were 45.5 U/L vs. 24 U/L, respectively in abnormal and normal aminotransferase groups. Liver enzyme abnormalities were associated with disease severity, as well as a series of laboratory tests including higher alveolar-arterial oxygen partial pressure difference, higher gamma-glutamyltransferase, lower albumin, decreased CD4+ T cells and B lymphocytes. Ultrastructural examination identified typical coronavirus particles, characterized by spike structures, in the cytoplasm of hepatocytes in 2 COVID-19 cases. SARS-CoV-2-infected hepatocytes displayed conspicuous mitochondrial swelling, endoplasmic reticulum dilatation and glycogen granule decrease. Histologically, massive hepatic apoptosis and some binuclear hepatocytes were observed. Taken together, both ultrastructural and histological evidence indicated a typical lesion of viral infection. Immunohistochemical results showed scarce CD4+ and CD8+ lymphocytes. No obvious eosinophil infiltration, cholestasis, fibrin deposition, granuloma, massive central necrosis, or interface hepatitis were observed. Conclusions: SARS-CoV-2 infection in the liver directly contributes to hepatic impairment in patients with COVID-19. Hence, a surveillance of viral clearance in liver and long-term outcome of COVID-19 is required. Lay summary: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). We reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with elevated liver enzymes. Our findings suggested that SARS-CoV-2 infection of the liver is a crucial factor contributing to hepatic impairment in patients with COVID-19.