S100A8/A9 and Innate Immunity in Liver Disease

Study Overview
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Brief Summary
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This observational study evaluates the concentration of immune protein S100A8/A9 in different liver failure syndromes, its interaction with the immune system and validity as an immunotherapeutic target to improve survival in patients with advanced cirrhosis and/or acute on chronic liver failure.

Detailed Description
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A paradox exists in chronic liver disease whereby there is a general recognition that chronic inflammation is part of the pathophysiology, heightened when there is an acute deterioration and organ failure (acute-on-chronic liver failure), yet there is an increased susceptibility to infection due to a dysfunctional immune system, which is often the trigger for organ failure and the reason for death in these patients. A danger signal reported in other inflammatory conditions called S100A8/A9 (calprotectin) is known to activate the immune system by production of pro-inflammatory cytokines but has also been observed to promote the development immunosuppressive signals (e.g. IL-10 and MDSCs). In an attempt to explain this paradox in liver disease, this study proposes to identify at the cellular and molecular level, the triggers for S100A8/A9 production, how it varies with time in stable patients and those that have acute deteriorations including the development of organ failure, and its interaction with innate immune cells in the circulation and at tissue level. By studying this, the Investigators hope to be able to identify immunotherapeutic targets and understand whether potential immunotherapy could be applied locally or systemically. The Investigators' observations in this study could provide the basis for the future development of clinical immunomodulating agents, which may ameliorate immunopathology, reduce susceptibility to infection and could reduce mortality in critically ill patients with liver disease. Findings in this study may also have more generalizable impact especially with the recent recognition in the COVID-19 pandemic that immunomodulatory therapies may improve the clinical outcomes of inflammatory phenotypes in virus-induced severe sepsis.

Official Title
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The Interaction of the S100A8/A9 Protein With the Innate Immune System in the Immunopathology of Acute and Chronic Liver Disease

Conditions
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Infections, Cirrhosis, Liver, Immune Suppression, Liver Failure, Acute on Chronic, Ascites Hepatic

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A) Patients with acute or chronic liver disease: Presence of chronic liver disease, or cirrhosis due to any aetiology (latter based upon a histopathological diagnosis or compatible laboratory data and radiological findings) Acute alcoholic hepatitis (definition as per Crabb et al, 2016)35 Acute liver failure due to any aetiology Acute-on-chronic liver failure (defined as per EASL-CLIF definition)17 B) Patients undergoing diagnostic or therapeutic abdominal paracentesis Patients with acute or chronic liver disease of any aetiology undergoing clinically-indicated paracentesis for ascites C) Patients undergoing broncho-alveolar lavage Intubated patients with liver disease in intensive care Undergoing a bronchoscopy or a non-directed broncho-alveolar lavage as part of their routine clinical care D) Patients with acute or chronic liver disease undergoing liver biopsy (percutaneous or transjugular) as routine part of their clinical care E) Patients with portal hypertension (cirrhotic or non-cirrhotic) undergoing transjugular intrahepatic shunt (TIPSS) placement as part of their routine care F) Patients with acute or chronic liver disease undergoing orthoptic liver transplantation G) Patients undergoing surgical liver resection or hepatectomy for liver-related diseases Control groups: A) Patients with ascites without chronic liver disease: Absence of cirrhosis based on clinical, radiological or histopathological features, including patients with non-cirrhotic portal hypertension, cardiac ascites (ascites due to heart failure) or patients with chronic kidney disease undergoing continuous ambulatory peritoneal dialysis (CAPD) Presence of clinically significant ascites Undergoing diagnostic or therapeutic paracentesis B) Patients with sepsis without acute or chronic liver disease C) Patients with haemochromatosis without liver disease or end-organ damage who undergo regular venesection D) Healthy subjects Exclusion Criteria: Age under 18 or over 80 Evidence of disseminated malignancy (isolated cancers including hepatocellular carcinoma are not an exclusion criteria) Patients with known immunodeficiency syndromes (e.g. HIV infection)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with acute or chronic liver disease<br>Presence of chronic liver disease, or cirrhosis due to any aetiology (latter based upon a histopathological diagnosis or compatible laboratory data and radiological findings) Acute alcoholic hepatitis Acute liver failure due to any aetiology Acute-on-chronic liver failure | |
| Patients undergoing diagnostic or therapeutic abdominal paracentesis<br>Patients with acute or chronic liver disease of any aetiology undergoing clinically-indicated paracentesis for ascites | |
| Patients undergoing broncho-alveolar lavage<br>Intubated patients with liver disease in intensive care Undergoing a bronchoscopy or a non-directed broncho-alveolar lavage as part of their routine clinical care | |
| Patients with acute or chronic liver disease undergoing liver biopsy<br> | |
| Patients with undergoing transjugular intrahepatic shunt (TIPSS) placement<br> | |
| Patients with acute or chronic liver disease undergoing orthoptic liver transplantation<br> | |
| Patients undergoing surgical liver resection or hepatectomy for liver-related diseases<br> | |
| Patients with ascites without chronic liver disease<br>Absence of cirrhosis based on clinical, radiological or histopathological features, including patients with non-cirrhotic portal hypertension, cardiac ascites (ascites due to heart failure) or patients with chronic kidney disease undergoing continuous ambulatory peritoneal dialysis (CAPD) Presence of clinically significant ascites Undergoing diagnostic or therapeutic paracentesis | |
| Patients with sepsis without acute or chronic liver disease<br> | |
| Patients with haemochromatosis who undergo regular venesection<br> | |
| Healthy subjects<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of plasma S100A8/A9 | The study will evaluate whether S100A8/A9 concentration can be used to predict clinical outcomes, such as mortality, the development of infection and/or organ failure. In the laboratory, it will evaluate the effect S100A8/A9 has on immune functional readouts including phagocytosis, oxidative burst and cytokine production, all of which are required for an effect immune response. Similarly, by blocking its action, the study will identify whether this is a potential immunotherapeutic strategy to improve the outcome of patients with high concentrations of the protein. | 1 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | 28-, 90-day and 1 year mortality and its relationship to baseline and serial S100A8/A9 concentration | 1 years | 
| Development of infection | Incidence of infection in patients with liver disease and its relationship to baseline or dynamic S100A8/A9 concentration | 1 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, acute-on-chronic liver failure, immune paralysis