MERTK Signalling in Monocytes/Macrophages in Patients With Liver Disease

This study is to investigate MER receptor tyrosine kinase (MERTK) signalling cascade on monocytes and tissue macrophages in respect to innate immune function of the cells in patients with cirrhosis at different stages of disease (Child A, B, C, acute decompensation, acute-on-chronic liver failure (ACLF)) and in comparison to patients with acute liver failure and to healthy controls.

Study Overview

• Status: Recruiting
• Conditions: Liver Failure; Acute-On-Chronic Liver Failure; Liver Disease; Cirrhosis of the Liver
• Intervention / Treatment: Other: blood sampling for research purpose; Other: clinical data collection; Other: Health-related Questionnaires; Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)

Detailed Description

MER receptor tyrosine kinase (MERTK) signalling cascade becomes activated on monocytes/macrophages during disease progression of liver cirrhosis from Child Pugh A to B/C, corresponding to early stages of decompensation, and before the receptor expression is increased. Factors involved in activation of the MERTK signalling cascade might be microbial products such as bacterial deoxyribonucleic acid (DNA) and other toll-like receptor (TLR)-ligands, MERTK ligands and cytokines, as shown elevated in cirrhotic patients.

Given the observation that MERTK levels peak on the day of admission with organ failure and decrease in patients surviving the episode of acute-on-chronic liver failure (ACLF), MERTK Inhibition at a time during progression of cirrhosis but before manifestation of acute decompensation with no cirrhosis (AD) or ACLF might prevent infectious complications, decompensation and improve survival in patients with cirrhosis.

This study is to investigate MER receptor tyrosine kinase (MERTK) signalling cascade on monocytes and tissue macrophages in respect to innate immune function of the cells in patients with cirrhosis at different stages of disease (Child A, B, C, acute decompensation, acute-on-chronic liver failure (ACLF)) and in comparison to patients with acute liver failure and to healthy controls.

• Study Type: Observational
• Enrollment (Anticipated): 240

Contacts and Locations

• Study Contact: Name: Christine Bernsmeier, PD Dr. Dr.; Phone Number: +41 61 77 77575; Email: C.Bernsmeier@unibas.ch
• Study Contact Backup: Name: Markus Heim, Prof. Dr. MD; Phone Number: +41 61 77 77490; Email: markus.heim@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel, Hepatology Department and Laboratory
    • Contact: Markus Heim, Prof. Dr. MD; Phone Number: +41 61 265 55 19; Email: markus.heim@usb.ch
  • St. Gallen, Switzerland, 9007
    • Recruiting
    • Cantonal Hospital St. Gallen
    • Contact: Christine Bernsmeier, PD Dr. Dr.; Phone Number: +41 71 494 11 11; Email: Christine.Bernsmeier@kssg.ch
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital, Institute of Liver studies
    • Contact: Julia A Wendon, Prof.; Phone Number: +44 20 3299 3367; Email: Julia.wendon@kcl.ac.uk
  • London, United Kingdom, W2 1PG
    • Recruiting
    • St. Mary's Hospital, Imperial College London, Section of Hepatology
    • Contact: Charalambos G Antoniades, Dr. med; Phone Number: +44 20 331 21903; Email: c.antoniades@imperial.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Prospective recruitment of patients with cirrhosis, acute decompensation, acute liver failure as pathological controls and healthy controls or controls with no liver disease at the Cantonal Hospital St. Gallen (KSSG), University Hospital Basel, St. Mary's Hospital, Imperial College London and King's College Hospital, London, UK.

Description

Inclusion Criteria:

• Patients with compensated or decompensated chronic liver disease
• Patients with acute- or acute-on-chronic chronic liver failure
• Controls with no liver disease

Exclusion Criteria:

• Evidence of disseminated malignancy

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
cirrhosis of the liver, stadium Child A; sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L); Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies); Other biological material (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies) will only be investigated if sampled for clinical reasons and if excessive material is available that is not needed for clinical purpose.
cirrhosis of the liver, stadium Child B; sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L); Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies); Other biological material (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies) will only be investigated if sampled for clinical reasons and if excessive material is available that is not needed for clinical purpose.
cirrhosis of the liver, stadium Child C; sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L); Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies); Other biological material (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies) will only be investigated if sampled for clinical reasons and if excessive material is available that is not needed for clinical purpose.
cirrhosis of the liver, acutely decompensated; sampling of biological material and health related data collection on days 1 (Baseline), 3, 7, and 14. If acutely decompensated patients re-compensate they will be followed 6-monthly for up to 36 months	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L); Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies); Other biological material (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies) will only be investigated if sampled for clinical reasons and if excessive material is available that is not needed for clinical purpose.
acute liver failure; sampling of biological material and health related data collection on days 1 (Baseline), 3, 7, and 14. If acutely decompensated patients re-compensate they will be followed 6-monthly for up to 36 months	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L); Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies); Other biological material (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies) will only be investigated if sampled for clinical reasons and if excessive material is available that is not needed for clinical purpose.
healthy controls; sampling of biological material and health related data collection on day 1 (Baseline)	Other: blood sampling for research purpose; blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place; Other: clinical data collection; clinical data collection in order to document the stage of disease, the presence of infection and existing complications of cirrhosis (ascites, hepatic encephalopathy, renal dysfunction, pulmonary dysfunction) and concomitant disease. These data will be collected for clinical reasons as highly important in the context of patients with cirrhosis and possible decompensation or liver failure and will therefore not require additional time; Other: Health-related Questionnaires; Health-related Questionnaires (Questionnaire_CLD) regarding sleep characteristics (Pittsburgh sleep Quality index, PSQI), daytime sleepiness (Epworth sleepiness scale, ESS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (EQ-5D-5L)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MERTK signalling cascade on monocytes	Change in MERTK signalling cascade on monocytes in respect to innate immune function of the cells in patients with cirrhosis at different stages of disease (Child A, B, C, acute decompensation, ACLF) and in comparison to patients with acute liver failure and to healthy controls	days 1 (Baseline), 3, 7, and 14; then followed 6-monthly for up to 36 months
Change in MERTK signalling cascade on tissue macrophages	Change in MERTK signalling cascade on tissue macrophages in respect to innate immune function of the cells in patients with cirrhosis at different stages of disease (Child A, B, C, acute decompensation, ACLF) and in comparison to patients with acute liver failure and to healthy controls	days 1 (Baseline), 3, 7, and 14; then followed 6-monthly for up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mechanism of MERTK activation in cell culture models using monocytes	Change in mechanism of MERTK activation in cell culture models using healthy and diseased monocytes in vitro and ex vivo	days 1 (Baseline), 3, 7, and 14; then followed 6-monthly for up to 36 months

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Christine Bernsmeier, PD Dr. Dr., Universitätsspital Basel, Departement Biomedizin, Gastroenterologie und Hepatologie

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 27, 2015
• Primary Completion (ANTICIPATED): August 1, 2022
• Study Completion (ANTICIPATED): December 1, 2022

Study Registration Dates

• First Submitted: October 3, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (ACTUAL): October 4, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 18, 2021
• Last Update Submitted That Met QC Criteria: November 17, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: immunoparesis; monocyte dysfunction; MER receptor tyrosine kinase (MERTK); innate immune dysfunction; circulating monocytes/macrophages; MERTK signalling
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Failure, Acute; Fibrosis; Liver Diseases; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure; Liver Cirrhosis
• Other Study ID Numbers: EKSG 15/074; me19Bernsmeier2

Drug and device information, study documents

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