MERTK Signalling in Monocytes/Macrophages in Patients With Liver Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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MERTK Signalling in Monocytes/Macrophages in Patients With Liver Disease

Conditions
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Liver Disease, Cirrhosis of the Liver, Acute-On-Chronic Liver Failure, Liver Failure

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| cirrhosis of the liver, stadium Child A<br>sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months | Other: blood sampling for research purpose<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)<br>* 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.<br>|
| cirrhosis of the liver, stadium Child B<br>sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months | Other: blood sampling for research purpose<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)<br>* 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.<br>|
| cirrhosis of the liver, stadium Child C<br>sampling of biological material and health related data collection longitudinally in 6-monthly intervals up to 36 months | Other: blood sampling for research purpose<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)<br>* 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.<br>|
| cirrhosis of the liver, acutely decompensated<br>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<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)<br>* 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.<br>|
| acute liver failure<br>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<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>Other: Sampling other biological materials (e.g. liver biopsies, liver resections, ascites, urine, gut biopsies)<br>* 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.<br>|
| healthy controls<br>sampling of biological material and health related data collection on day 1 (Baseline) | Other: blood sampling for research purpose<br>* blood sampling for research purpose (about 30ml) taken by venepuncture or from intravenous catheters if already in place<br>Other: clinical data collection<br>* 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<br>Other: Health-related Questionnaires<br>* 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)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MER receptor tyrosine kinase (MERTK), innate immune dysfunction, circulating monocytes/macrophages, MERTK signalling, immunoparesis, monocyte dysfunction