Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets. 

/pdf/molecular-consequences-of-sars-cov-2-liver-tropism-14812m4q.pdf

Molecular consequences of SARS-CoV-2 liver tropism

A new perspective on NAFLD: focusing on lipid droplets.

The pathogenesis of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not fully unraveled. Though preventive vaccines and treatment methods are out on the market, a specific cure for the disease has not been discovered. Recent investigations and research studies primarily focus on the immunopathology of the disease. A healthy immune system responds immediately after viral entry, causing immediate viral annihilation and recovery. However, an impaired immune system causes extensive systemic damage due to an unregulated immune response characterized by the hypersecretion of chemokines and cytokines. The elevated levels of cytokine or hypercytokinemia leads to acute respiratory distress syndrome (ARDS) along with multiple organ damage. Moreover, the immune response against SARS-CoV-2 has been linked with race, gender, and age; hence, this viral infection’s outcome differs among the patients. Many therapeutic strategies focusing on immunomodulation have been tested out to assuage the cytokine storm in patients with severe COVID-19. A thorough understanding of the diverse signaling pathways triggered by the SARS-CoV-2 virus is essential before contemplating relief measures. This present review explains the interrelationships of hyperinflammatory response or cytokine storm with organ damage and the disease severity. Furthermore, we have thrown light on the diverse mechanisms and risk factors that influence pathogenesis and the molecular pathways that lead to severe SARS-CoV-2 infection and multiple organ damage. Recognition of altered pathways of a dysregulated immune system can be a loophole to identify potential target markers. Identifying biomarkers in the dysregulated pathway can aid in better clinical management for patients with severe COVID-19 disease. A special focus has also been given to potent inhibitors of proinflammatory cytokines, immunomodulatory and immunotherapeutic options to ameliorate cytokine storm and inflammatory responses in patients affected with COVID-19.

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

BACKGROUND & AIMS: Little is known about cholestasis, including its most severe variant secondary sclerosing cholangitis (SSC), in critically ill patients with coronavirus disease 19 (COVID-19). In this study, we analysed the occurrence of cholestatic liver injury and SSC, including clinical, serological, radiological and histopathological findings. METHODS: We conducted a retrospective single-centre analysis of all consecutive patients admitted to the intensive care unit (ICU) as a result of severe COVID-19 at the University Hospital Zurich to describe cholestatic injury in these patients. The findings were compared to a retrospective cohort of patients with severe influenza A. RESULTS: A total of 34 patients with severe COVID-19 admitted to the ICU were included. Of these, 14 patients (41%) had no cholestasis (group 0), 11 patients (32%, group 1) developed mild and 9 patients (27%, group 2) severe cholestasis. Patients in group 2 had a more complicated disease course indicated by significantly longer ICU stay (median 51 days, IQR 25-86.5) than the other groups (group 0: median 9.5 days, IQR 3.8-18.3, P = .001; and group 1: median 16 days, IQR 8-30, P < .05 respectively). Four patients in group 2 developed SSC compared to none in the influenza A cohort. The available histopathological findings suggest an ischaemic damage to the perihilar bile ducts. CONCLUSIONS: The development of SSC represents an important complication of critically ill COVID-19 patients and needs to be considered in the diagnostic work up in prolonged cholestasis. The occurrence of SSC is of interest in the ongoing pandemic since it is associated with considerable morbidity and mortality.

Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.

The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a world-wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID-19. Although liver failure does not seem to occur in the absence of pre-existing liver disease, hepatic involvement in COVID-19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID-19 may range from direct infection by SARS-CoV-2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS-CoV-2 hepatic tropism as well as acute and possibly long-term liver injury in COVID-19.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/liv.14730

Pathophysiological mechanisms of liver injury in COVID-19.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.

https://www.mdpi.com/2073-4425/12/5/645/pdf

The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD.

Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL/PNPLA2) ameliorates dietary induced steatohepatitis in mice

Bile salt export pump (Bsep) (Abcb11)−/− mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2) (Abcb4)−/− mouse. Cholestatic liver injury in Mdr2−/−Bsep−/− double knockout (DKO), Mdr2−/−, Bsep−/−, and wild‐type mice was studied for comparison. Mdr2−/− mice were treated with a THBA (3α,6α,7α,12α‐Tetrahydroxycholanoic acid). RNA/protein expression of inflammatory/fibrotic markers were investigated. Serum BA‐profiling was assessed by ultra‐performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro, the THBA effect on chenodeoxycholic acid (CDCA)–induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)/interferon‐γ (IFN‐γ)–induced macrophage activation was analyzed. In contrast to Mdr2−/−, DKO mice showed no features of sclerosing cholangitis. Sixty‐seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2−/− mice did not have these BAs. Compared with Mdr2−/−, DKO animals were protected from hepatic inflammation/fibrosis. THBA feeding in Mdr2−/− mice improved liver injury. FACS analysis in DKO and Mdr2−/− THBA‐fed mice showed changes of the hepatic immune cell profile towards an anti‐inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2−/− THBA‐fed mice compared with Mdr2−/− control mice. In vitro, THBA‐reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS/IFN‐γ–induced macrophage activation was ameliorated by THBA. THBAs repress EGR1‐related key pro‐inflammatory pathways. Conclusion: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases.

Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2−/− mouse model of sclerosing cholangitis via immunomodulatory effects

Peroxisome proliferator activated receptor gamma regulates patatin-like phospholipase domain-containing protein 3 in adipocytes in vitro and in vivo in a mouse model of non-alcoholic steatohepatitis

Emmanuel D Dixon

Papers

Pathophysiological mechanisms of liver injury in COVID-19.

The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD.

Hepatocyte-specific deletion of adipose triglyceride lipase (ATGL/PNPLA2) ameliorates dietary induced steatohepatitis in mice

Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2−/− mouse model of sclerosing cholangitis via immunomodulatory effects

Peroxisome proliferator activated receptor gamma regulates patatin-like phospholipase domain-containing protein 3 in adipocytes in vitro and in vivo in a mouse model of non-alcoholic steatohepatitis