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Background and objectives: SARS-C0V-2 infections have varied manifestations among individuals ranging from asymptomatic or mild symptoms to severe disease and death. This study is done to look into various histopathological changes in lung, liver, and kidney tissues among Covid19 positive autopsies with cellular tropism and viral load among various organs by immunohistochemistry (IHC) for the SARS-C0V-2 viral marker. Method(s): A prospective descriptive study of core biopsies from covid19 positive autopsies from the lung, liver, and kidneys were taken from 20 cases. A routine histopathological examination of the tissues with IHC staining for SARS-CoV-2 cocktail antibodies was performed and assessed. Result(s): Histopathological changes in the lung, liver, and kidney tissues showed changes of varying severity. On IHC, in the lung, the tropism for SARS-CoV-2 was seen in pneumocytes, bronchial epithelial cells, endothelial cells, and macrophages. In the kidney, tropism was seen towards tubular epithelial cells and endothelial cells. In the liver, hepatocytes and bile duct epithelial cells were positive. Variable viral density was seen in different organs which varied from case to case. The density of the viral load was highest in the lung and lower in the kidney and least in the liver. Conclusion(s): In this study the various histopathological changes and cellular tropism of the SARS-CoV-2 among Lung, liver, and kidney tissues have been described and compared with various similar studies across the globe.Copyright © 2023 International Journal of Life Sciences Biotechnology and Pharma Research. All rights reserved.
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In patients with coronavirus disease 2019 (COVID-19), hepatic involvement occurs in up to 53% of all cases. Via the primary target for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the angiotensin-converting enzyme 2 (ACE2) receptor, expressed on cholangiocytes, sinusoidal endothelial cells, and hepatocytes, direct damage to the liver may occur. Furthermore, indirect (= not receptor-mediated) damage to the liver plays a crucial role in the context of COVID-19 due to severe systemic inflammation with cytokine storm, hepatic thrombosis, and systemic hypoxia. In COVID-19, liver enzymes are considered significant predictors of outcome. Thus, it is essential to rule out other causes of liver enzyme elevation, such as other viral infections, drug-induced liver injury, and metabolic, autoimmune and other liver diseases. Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is highly relevant in treating critically ill patients in the intensive care unit (ICU). Risk factors for SSC-CIP include high doses of catecholamines, high positive end-expiratory pressure (PEEP), and extracorporeal membrane oxygenation (ECMO) therapy. Early recognition of this disease and treatment by endoscopic retrograde cholangiography (ERC) is crucial. Furthermore, liver transplantation should be evaluated. Some patients with COVID-19 are diagnosed with SSC, which is termed COVID-19-associated SSC. COVID-19-associated SSC and SSC-CIP are comparable with regard to clinical phenotype, risk factors, prognosis, and graft-free survival. Patients with pre-existing liver disease are not at increased risk for infection with SARS-CoV-2 but show more severe clinical courses of COVID-19 than patients without pre-existing liver disease. Patients with pre-existing liver cirrhosis may develop acute-on-chronic liver failure (ACLF) upon infection with SARS-CoV-2. ACLF has a high mortality rate, which must be treated in the ICU.Copyright © 2023, The Author(s).
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Background: The remarkable ability of the liver to regenerate by proliferation of mature hepatocytes constitutes the first mechanism of repair commonly named the hepatocyte-driven regeneration. Yet, during chronic liver injury or acute severe hepatocyte death, proliferation of hepatocytes becomes exhausted. In these cases, alternative cholangiocyte-driven regeneration occurs during which cholangiocytes differentiate into healthy hepatocytes. Despite these two mechanisms of repair, end stage liver disease remains the 12th most common cause of death in the US, begging for therapeutic strategies to harness intrinsic mechanisms of regeneration. My lab investigates various strategies using nucleoside-modified mRNA complexed in lipid nanoparticles (mRNA-LNP) to harness hepatocyte-and cholangiocyte-driven liver repair to treat acute and chronic liver disease mouse models. Method(s): We recently pioneered mRNA-LNP as a technology to deliver regenerative factors to the liver for liver regeneration application, departing from the original protein replacement or immunization applications whose safety is widely validated with the current mRNA-based COVID-19 vaccines. Acute and chronic liver diseases were recapitulated in mice with the single dose of acetaminophen (APAP) overdose model and the choline-deficient ethioninesupplemented (CDE) diet, respectively. Mice were also injected with AAV8-Tbg-p21 prior to liver injury to mimic hepatocyte senescence. Result(s): We demonstrate that delivery via mRNA-LNP to the liver of the known key hepatocyte mitogen hepatocyte growth factor (HGF) and epidermal growth factor (EGF) enhances hepatocyte-driven repair by sharply reversing steatosis and accelerating restoration of liver function in the CDE chronic model, while accelerating liver regeneration in APAP acute model with rapid return to baseline serum ALT levels. Interestingly, the overlooked factor, growth hormone, delivered with mRNA-LNP significantly accelerates liver repair after APAP overdose. To harness cholangiocyte-driven repair, we delivered VEGFA in acute and chronic injured mouse livers. We found that VEGFA mRNA-LNP induces robust cholangiocyte conversion to hepatocytes, and importantly, reverts steatosis and fibrosis. Conclusion(s): Our study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness both hepatocyte-and cholangiocyte-driven liver regeneration to ultimately treat human acute and chronic liver diseases.
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Introduction: Vaccines revolutionised the management of COVID19. Nevertheless, they lack efficacy in high-risk or vulnerable groups (e.g., immunosuppressed patients), who may not mount an appropriate immune response. Monoclonal antibodies represent the gold-standard agents for such cases;but they are limited by availability, need for parenteral administration and the risk for viral escape because of spike protein mutations. Therefore, there is a pressing need for new prophylactic agents less prone to resistance.The viral receptor ACE2 represents an ideal target as it is essential for viral entry and transmission and because being a host protein it is not affected by viral mutations. However, the regulation of ACE2 remains elusive, due to the lack of appropriatein vitromodels. Cholangiocytes show one of the highest ACE2 expression levels in the body, representing an ideal platform for these studies. Here, we use cholangiocyte organoids as proof-of-principleto identify that the bile acid receptor FXR regulates ACE2 expression and SARS-CoV-2 infectionin vitro. We validate these findings in lung and gut organoids, animal models, human organs perfusedex situand patient cohorts. Aims & Methods: 1. Identify pathways controlling the transcriptional regulation of ACE2 2. Identify drugs modulating these pathways as novel prophylactic and therapeutic agents for COVID19. Organoids were propagated using established protocols. Marker expression was assessed using single-cell RNA sequencing, QPCR, and immunofluorescence. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Syrian golden hamsters were infected via direct inoculation and QPCR on oral swab, nasal turbinate and lung samples was used to measure SARS-CoV-2 infection. Human livers and lungs not used for transplantation were perfusedex-situusing normothermic perfusion. Nasopharyngeal swabs were used to measure ACE2 expression in nasal epithelial cells of healthy individuals taking UDCA at the standard therapeutic dose of 15 mg/kg/day. Patient registry data were compared using propensity score matching for sex, age, diabetes, NAFLD and Child- Turcotte-Pugh score. Result(s): We identified that FXR directly regulates ACE2 transcription in cholangiocyte organoids, while FXR inhibition with the approved drug ursodeoxycholic acid (UDCA), reduced ACE2 expression and SARS-CoV-2 infectionin vitro. We confirmed this mechanism in organoids from other COVID19-affected tissues, including the respiratory and intestinal systems. We validated our findingsin vivoin Syrian golden hamsters, showing that treatment with UDCA downregulates ACE2 and prevents SARS-CoV-2 infection. We confirmed that UDCA reduces ACE2 and SARS-CoV-2 infection in human lungs and livers perfusedex-situ. We performed a clinical study demonstrating that UDCA lowers ACE2 levels in the nasal epithelium of 6 healthy volunteers. Finally, we identified a correlation between UDCA and better clinical outcomes (hospitalisation, ICU admission and death) in COVID19 patients receiving UDCA for cholestatic diseases using the COVID-Hep and SECURELiver registry data. Conclusion(s): We identified FXR as a novel regulator of ACE2 expression. Using a bench-to-bedside approach combining in vitroand in vivomodels, exsituperfused human organs and clinical data we showed that FXR inhibition prevents or reduces SARS-CoV-2 infection and identified UDCA as an approved, cost-effective drug which could be repurposed for COVID19, paving the road for future clinical trials.
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Background: The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China and spread around the world. Genomic analysis revealed that SARS-CoV-2 is phylogenetically related to severe acute respiratory syndrome-like (SARS-like) bat viruses, therefore bats could be the possible primary reservoir.The intermediate source of origin and transfer to humans is not known, however, the rapid human to human transfer has been confirmed widely. There is no clinically approved antiviral drug or vaccine available to be used against COVID-19. However, few broad-spectrum antiviral drugs have been evaluated against COVID-19 in clinical trials, resulted in clinical recovery.The liver, the largest internal organ in the body, is essential in keeping the body functioning properly. It removes or neutralizes poisons from the blood, produces immune agents to control infection, and removes germs and bacteria from the blood. It makes proteins that regulate blood clotting and produces bile to help absorb fats and fat-soluble vitamins. Several studies have shown a significant risk of mortality in patients with cirrhosis and in liver transplantation recipients.2, 3, 4 The severity of presentation and risk of mortality is more in patients with decompensated cirrhosis.5,6 COVID-19 had lead to a significant decrease in number of liver transplant surgeries being performed, which would lead to an increased wait list mortality in these patients.
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The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV2) initially was perceived as a lower respiratory tract infection. However, with time coronavirus disease (COVID-19) presented with a wide variability of symptoms, including gastrointestinal and hepatic. This because the viral tropism to the angiotensin-converting enzyme 2 (ACE2) receptor found in liver and bile-duct epithelial cells. The ACE2 expression is mainly in cholangiocytes (60% of cells), minimally expressed in hepatocytes (3% of cells) and absent in Kupffer cells. Hepatic involvement can be evidenced with elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), these alterations have been evidenced in up to 43% of patients. The aim of this study is to evaluate liver damage in pediatric patients with COVID-19. Material(s) and Method(s): A retrospective cohort was carried out between March 2020 to October 2021 at the Instituto Nacional de Pediatria in Mexico City. We include all patients between 0 to 18 years with positive COVID-19 PCR test or antigen rapid test. Result(s): We had a total population of 161 subjects of which 83 had liver function tests (inflammation, excretion, or synthesis) during SARS-CoV2 infection;82 had ALT value. Mean age was 5.3 years and 56% were men (n: 47). Fifty-four patients (65%) had previous comorbidity, with oncological diseases being the most frequent (33%). Of the 54 patients with previous comorbidity, 3 had liver disease (Graft-versus-host disease, nonalcoholic fatty liver disease and autoimmune hepatitis). Regarding treatment, 32 patients did not require oxygen support, 32 patients had non-invasive devices and 19 patients required mechanical ventilation. Fifty-four percent (n = 45) were using steroid management. In relation to the outcome of the patients, 11 die and the rest were discharged. Liver function tests were submitted 2 days after admission, 51 patients (62%) presented elevation of ALT (according to age and sex). Second liver function tests were taken around day 23 53 patients. Table 1 shows the average of each of the parameters. It has been documented that severe COVID-19 is associated with higher levels of inflammatory mediators like C-reactive protein (CRP) and ferritin. Therefore, levels of this inflammatory mediators were evaluated, the average of this parameters was 1601 ng/mL and 8.19 mg/L respectively in the first test. Analysis: We evaluated the difference that existed in liver function tests by comparing the first and second determination. Regarding AST, INR and PT, a significant difference was found (p = <0.05) with improvement compared to baseline. While the ALT did not show a significant difference, there was an improvement compared to baseline. Secondary to the association described between elevation of inflammatory mediators and severity of the disease, a Pearson Correlation test was performed between liver inflammatory tests and ferritin/prealbumin. A significant correlation was obtained when comparing ALT with ferritin (r = 0.301, p = 0.033) and AST with ferritin (r = 0.311, p= 0.028), which demonstrate a weak correlation probably associated with the amount of population. The correlation between ALT/AST and prealbumin was carried out without being significant. In search of associated factors, it was found that the alteration of liver function tests is a risk factor for needing support with supplemental oxygen with an Odds Ratio of 2.007 (CI: 0.77-5.31). From 19 patients who required mechanical ventilation, 73.7% had altered liver function tests. Conclusion(s): SARS-CoV2 is a virus that has been shown to have liver involvement which can be demonstrated with elevation of liver function test. In our series, 62% had elevated ALT, being the most sensitive parameter of liver inflammation. With respect to factors associated with liver impairment, we found that higher ferritin levels are associated with greater liver involvement, as well as that having hepatic impairment is a risk factor for the use of supplemental oxygen. Therefore, it is important to consider in patients with COVID-19 liver function tests and thus make a timely detection of alterations at this level. Studies with more population are required to have external validity.
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Background: On March 11, 2020, the World Health Organization (WHO) proclaimed Corona-virus Infection 2019 (COVID-19) to be a pandemic. Older subjects and those with underlying medical disorders such hypertension, asthma, diabetes mellitus, chronic lung infection, cardiovascular infections, obesity, and chronic kidney infection have been shown to have a more serious infection course and a greater fatality risk. Aims and Objectives: A study on biochemical parameters of HBV positive individuals suffering from Covid 19 & its effect on their final outcome Material and Methods: The research was conducted in the Department of Biochemistry L.N. Medical College, Bhopal. 200 subjects who are Covid positive will be included in the research. Category-1-60 corona positive subjects who are Hepatitis B virus positive. Category-2-140 corona positive subjects. Results: Out of total 200 covid positive cases, 60 individuals were also HBV positive & rest were only having Covid positive status. When we compared for the pathological/ laboratory diagnostic parameters of all the covid cases, Mean White blood cell Count was more in HBV positive individuals. Lymphocyte count was grossly decreased in HBV positive individuals. Neutrophil count, Platelet count, Alanine aminotransferase, Aspartate aminotransferase, Total bilirubin, Gamma-glutamyltransferase, Alkaline phosphatase, Albumin all these were comparatively on higher side in HBV positive individuals. Conclusion: Cholangiocytes have a role in various immune response-related activities of the hepatic, and when their function is disturbed, it can cause hepatobiliary damage due to a cytopathic effect. The hypothesis that cholangiocytes express more ACE2 receptors than other cell types could help to explain why hepatic function is dysregulated.
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Introduction Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), can commonly lead to abnormal liver tests, mostly transaminase elevation. Recently, a novel entity of cholangiopathy was discovered in patients who recovered from critical COVID-19 infection. However, understanding of this disease is limited due to its rarity. Methods We reviewed Pubmed, Embase, and Web of Science Core Collection databases from inception to Nov 30th, 2021, to identify studies reporting cholangiopathy after severe COVID-19 infection. “SARS-CoV-2” or “COVID-19” with “cholangiopathy” were used as keywords to search. Our study is to summarize the clinical features and characteristics of cholangiopathy after severe COVID-19 illness. Results Literature review identified 15 articles including 33 patients for reviews. Most studies were performed in the United States. The mean age of participants from all studies is 52.17 ± 13.98 years old. Among the 33 included patients, the majority are male (29, 88%) and the common medical histories include hypertension (n=11), obesity (n=8), and diabetes mellitus (n=8). The length of stay (LOS) during hospitalization was prolonged with a mean of 80.23 ± 33.14 days. All patients were intubated and put on mechanical ventilation during medical intensive care stay with 12 patients having a history of endotracheal cardiac output monitoring. The mean peak of serum alkaline phosphatase, aspartate aminotransferase, alanine transaminase and total bilirubin were 2106.96 (U/l) ± 784.04, 1456.09 (U/l) ± 2325.10, 983.57 (U/l) ± 1244.44 and 14.04 (mg/dl) ± 8.41, respectively. Cholangiopathy after severe COVID illness mimics secondary sclerosing cholangitis on magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography studies with ductal beading but the presence of unique severe cholangiocyte injury and intrahepatic microangiopathy is suggestive of direct hepatic injury due to COVID-19. In terms of outcome, 7 patients were documented as deceased. Eight patients underwent liver transplantation (Table 1). Discussion Cholangiopathy is a late complication of severe COVID-19 after prolonged ICU stay with potential for long-term liver morbidity and liver failure needing liver transplantation. Further studies are warranted to understand pathogenesis, natural history, therapeutic interventions, and prognostic indicators. (Table Presented)
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Case report-IntroductionCOVID-19, the infectious disease caused by the novel coronavirus SARS-CoV-2, and first described in Wuhan, China in December 2019, has affected more than 19 million patients worldwide and resulted in more than 700,000 deaths at the time of writing1. Patients with rheumatic diseases and those receiving immunosuppressive treatment are felt to be at greater risk of complications from this illness, though registry and trial data should help refine our understanding of these risks. We hereby describe a case of COVID-19 complicating an unusual rheumatic illness, resulting in severe multi-system disease and premature death.Case report-Case descriptionA 69 year-old male presented to rheumatology and haematology with symmetrical polyarthritis, thrombocytopenia (18 x 109/L), eosinophilia (25.4 x 109/L), raised C-reactive protein (CRP, 43 mg/L), positive rheumatoid factor (>200), antinuclear antibody (ANA) and anti-Ro. Bone marrow biopsy did not demonstrate evidence of haematological malignancy.Seropositive rheumatoid arthritis and connective tissue disease overlap were diagnosed, and treatment with Prednisolone 60mg daily was initiated. Despite rituximab and intravenous immunoglobulins, thrombocytopenia deteriorated on reducing corticosteroids, however the addition of mycophenolate mofetil (MMF) allowed gradual prednisolone tapering to 3mg daily. Hydroxychloroquine was briefly added but discontinued due to headaches. MMF was discontinued after he developed fungal pneumonia followed by jaundice. Liver biopsy was consistent with drug-induced cholestasis, attributed to co-amoxiclav, and his liver function tests (LFTs) improved on ursodeoxycholic acid. Following a further deterioration in thrombocytopenia, hyperferritinaemia and new onset erythema nodosum, he had a repeat bone marrow examination. This demonstrated large areas of fibrosis and granulomatous inflammation with a dense, pleomorphic T-cell infiltrate, but no haemophagocytosis. Haematologists felt this was reactive and prednisolone dose was increased to 10mg daily.Six months later he developed cholangitis. Magnetic resonance cholangiopancreatography (MRCP) demonstrated a tight 4cm stricture of the distal common bile duct (CBD) within the head of pancreas, which was diffusely swollen without any clear focal mass. Serum amylase was mildly elevated (316 units/L). Concurrent CT thorax, abdomen and pelvis demonstrated bilateral ground-glass changes within the lungs, and a SARS-CoV-2 nasopharyngeal PCR test was positive, though he had no respiratory symptoms or oxygen requirement at that stage.Sadly, four days after the CT scan and before a planned endoscopic retrograde cholangiopancreatography (ERCP) could be performed, he became markedly hypoxic with plain chest X-ray features suggestive of COVID-19 pneumonia. Despite medical management, including doubling of his prednisolone dose, he rapidly deteriorated and died.Case report-DiscussionThis case highlights an unusual presentation of COVID-19 in a patient with a complex background of inflammatory arthritis with immune-mediated thrombocytopenia. At the time of his final illness, these conditions were managed with steroid monotherapy. Based on the COVID-19 risk matrix recommended by the British Society for Rheumatology, he was not identified as a patient requiring shielding.Cholangitis was the major problem precipitating his final admission to hospital, and at the time of admission he had no respiratory symptoms. One week prior to this admission, his father-in-law had died of COVID-19 pneumonia, though they had not been in recent direct contact. Interstitial lung changes were incidentally noted on a CT performed to identify the cause of cholangitis, which prompted the nasopharyngeal PCR that detected SARS-CoV-2. This occurred prior to widespread routine testing of hospital inpatients for SARS-CoV-2 by PCR. Unfortunately he then rapidly developed COVID-19 pneumonia and died before the underlying cause of cholangitis could be definitively identified, though an MRCP demonstrated an obstructed CBD within a diffusely swollen pancreas, where a differential diagnosis of pancreatic malignancy or autoimmune pancreatitis was suggested by the reporting radiologist.There are emerging case reports of COVID-19 resulting in significant pancreatic injuryand a further recent laboratory analysis has suggested that ACE2 receptors, which are utilised by SARS-CoV-2 to gain entry to host cells, are highly expressed on cholangiocytes at a comparable level to type II alveolar cells. Whilst the ultimate cause of cholangitis will remain unknown in this patient, this case highlights the potential for atypical presentations and extra-pulmonary manifestations of COVID-19.Case report-Key learning points COVID-19 is a multi-system illness which can cause significant extra-pulmonary as well as pulmonary pathology, with emerging reports that the biliary tract and pancreas are frequently affected.Evidence to inform accurate prediction of which patients with rheumatic diseases are at highest risk of acquiring severe COVID-19 disease remains insufficient, with current shielding guidelines based on expert consensus.This case highlights the importance of widespread testing for COVID-19 in hospital patients, as not all patients carrying the SARS-CoV-2 virus will demonstrate classical respiratory features of the disease at the point of admission.