S100A8/A9 and Innate Immunity in Liver Disease

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infections; Cirrhosis, Liver; Ascites Hepatic; Immune Suppression; Liver Failure, Acute on Chronic

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Arjuna Singanayagam, MBBS; PhD; Phone Number: 30125 02086729944; Email: asingana@sgul.ac.uk

Study Locations

• United Kingdom
  • London
    • London Borough Of Wandsworth, London, United Kingdom, SW17 0RE
      • Recruiting
      • Arjuna Singanayagam
      • Contact: Arjuna Singanayagam, MBBS; PhD; Phone Number: 30125 02086729944; Email: asingana@sgul.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Primary population is patients with acute or chronic liver disease admitted to hospital (including intensive care unit) or out-patient setting. Control subjects includes patients with sepsis, patients without liver disease but on continuous ambulatory peritoneal dialysis for renal replacement therapy (ascites control) and healthy subjects.

Description

Inclusion Criteria:

A) Patients with acute or chronic liver disease:

1. Presence of chronic liver disease, or cirrhosis due to any aetiology (latter based upon a histopathological diagnosis or compatible laboratory data and radiological findings)
2. Acute alcoholic hepatitis (definition as per Crabb et al, 2016)35
3. Acute liver failure due to any aetiology
4. 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

1. Intubated patients with liver disease in intensive care
2. 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:

1. 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)
2. Presence of clinically significant ascites
3. 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)

Study Plan

How is the study designed?

Number of groups / cohorts

11

Cohorts and Interventions

Group / Cohort
Healthy subjects
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; Acute liver failure due to any aetiology; Acute-on-chronic liver failure
Patients undergoing diagnostic or therapeutic abdominal paracentesis; Patients with acute or chronic liver disease of any aetiology undergoing clinically-indicated paracentesis for ascites
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
Patients with acute or chronic liver disease undergoing liver biopsy
Patients with undergoing transjugular intrahepatic shunt (TIPSS) placement
Patients with acute or chronic liver disease undergoing orthoptic liver transplantation
Patients undergoing surgical liver resection or hepatectomy for liver-related diseases
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
Patients with sepsis without acute or chronic liver disease
Patients with haemochromatosis who undergo regular venesection

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St George's, University of London
• Collaborators: King's College Hospital NHS Trust
• Investigators: Principal Investigator: Arjuna Singanayagam, MBBS; PhD, St George's, University of London

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2021
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 1, 2024

Study Registration Dates

• First Submitted: October 8, 2021
• First Submitted That Met QC Criteria: March 30, 2023
• First Posted (Actual): March 31, 2023

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 30, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: cirrhosis; acute-on-chronic liver failure; immune paralysis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure; Liver Cirrhosis; Ascites; Liver Failure, Acute
• Other Study ID Numbers: 2021.0073; 285573 (Other Identifier: Integrated Research Application System)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No