LiverTREM-1: Hepatic TREM-1 Expression and Prognosis in Severe Alcoholic Hepatitis

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Total Enrollment

300 participants

Study Classification

OBSERVATIONAL

Study Start Date

2025-10-01

Study Completion Date

2026-12-31

Brief Summary

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Background \& Rationale Severe alcohol-related hepatitis (SAH) is a serious condition with a 3-month mortality rate of \~30%. Diagnosis and prognosis are complex due to non-specific and insensitive clinical, biological, and histological indicators. Corticosteroids-the only validated treatment-are only effective in 50% of cases and can worsen outcomes in non-responders by promoting infections. Liver transplantation remains a limited option due to organ scarcity and patient eligibility.

TREM-1, a pro-inflammatory receptor, has shown promise in inflammatory liver diseases. Its expression in hepatocytes may serve as a biomarker to better classify patients, guide treatment, and improve outcomes.

Objectives

Primary Objective:

Compare TREM-1 expression (via immunohistochemistry) between SAH patients and controls with other liver diseases (e.g., HCC, metastatic colon cancer, cholangiocarcinoma).

Secondary Objectives:

Determine optimal antibody dilution for TREM-1 staining.

Assess diagnostic performance (sensitivity, specificity, PPV, NPV).

Identify homogeneous SAH subgroups using clinical, histological, and biological data.

Evaluate prognostic value of TREM-1 expression for:

2-month mortality

Corticosteroid response (bilirubin regression at Day 7)

Lille score \<0.45 at Day 7

Compare TREM-1's predictive power to standard scores (MELD, Maddrey, Lille, etc.).

Methodology

Population:

Cases: Adults treated at CHRU de Nancy (2013-2023) for SAH, with archived liver biopsies.

Controls: Adults with liver malignancies and archived biopsies.

Sample Size:

Phase I: 12 cases, 6 controls

Phase II: 150 cases, 150 controls

Data Sources: Medical records, archived pathology slides

Statistical Tools: Logistic regression, survival analysis, ROC curves, clustering, SAS/R software

Expected Outcomes \& Impact Improved prognostic stratification and therapeutic guidance for SAH patients

Better targeting of corticosteroid therapy to reduce unnecessary risk

Early referral for liver transplantation when appropriate

Validation of TREM-1 as a diagnostic/prognostic biomarker

Foundation for future TREM-1-targeted clinical trials

Potential paradigm shift linking liver histology with real-time clinical decision-making

Enhanced resource allocation and patient management

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Detailed Description

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Study Title

Official Title:

Liver TREM-1: Hepatic Expression of TREM-1 in Severe Alcoholic Hepatitis

Brief Summary (250 words max) Severe alcohol-associated hepatitis (sAH) is a life-threatening liver disease with a 3-month mortality rate of up to 30%. The only validated treatment-corticosteroids-fails in approximately 40% of patients, increases infection risk, and offers no survival benefit beyond 28 days. Therefore, there is an urgent need to identify prognostic biomarkers to guide therapy.

TREM-1 (Triggering Receptor Expressed on Myeloid cells 1) is a pro-inflammatory receptor expressed on hepatic immune and endothelial cells. Preclinical murine studies suggest it plays a pivotal role in alcohol-induced liver injury. This observational study aims to assess the diagnostic and prognostic value of hepatic TREM-1 expression in patients with severe alcohol-associated hepatitis using archived liver biopsy samples.

A total of 300 archived liver specimens (150 sAH cases, 150 controls with hepatic malignancies) will be analyzed via immunohistochemistry using a validated TREM-1 scoring system. Outcomes include TREM-1 expression levels, correlation with clinical parameters, mortality at 2 months, and response to corticosteroid therapy.

Detailed Description The study will determine whether hepatic TREM-1 expression can serve as a biomarker to stratify sAH patients into prognostic subgroups. TREM-1 expression will be measured via immunostaining and categorized as high vs. low using a score developed by Duan et al. Secondary analyses include diagnostic accuracy, treatment response (based on jaundice regression and Lille score at Day 7), and survival at 2 months. Statistical models (logistic regression, survival analysis, ROC curves, clustering) will be used.

This study complies with the Declaration of Helsinki, EU Regulation 536/2014, MR004 guidelines (CNIL), and French Public Health laws 2004-806, 2004-800, and 2016-41.

Study Type Observational

Observational Model: Cross-sectional

Time Perspective: Retrospective

Biospecimen Retention: Samples retained (Slides; No DNA)

Primary Outcome Measure Hepatic TREM-1 Expression

Type: Binary categorical variable (high vs. low)

Time Frame: At the day of liver biopsy

Method: Immunohistochemistry (Duan et al. score)

Secondary Outcome Measures Diagnostic Accuracy of TREM-1

Sensitivity, specificity, PPV, NPV for sAH diagnosis

Gold standard: multidisciplinary diagnosis

Time Frame: at the day of liver biopsy

Jaundice Resolution

Binary variable: resolved/persistent at Day 7

Time Frame: 7 days after corticosteroid start

Lille Score \< 0.45

Prognostic response to corticosteroids

Time Frame: Day 7

Mortality at 2 Months

Time Frame: 60 days post-diagnosis

Analysis: Cox regression

Cluster Analysis of sAH Subgroups

Based on TREM-1 expression and clinico-biological profiles

Comparison to Established Prognostic Scores

MELD, AHHS, Glasgow, Maddrey, SALVE, Lille, Lille-MELD

TREM-1 expression in RNAseq3' in SAH patients

categorical variable (detected vs undetected) and quantitative variable (TREM expression as fragments per millions)

Comparison of TREM-1 expression in RNAseq3' in SAH patients to prognostic scores and outcomes

MELD, AHHS, Glasgow, Maddrey, SALVE, Lille, Lille-MELD Infection from day 3 to day 180 Mortality at M2, M3 and M6 Overall Mortality Response to steroids

Enrollment Estimated Enrollment: 300

Sampling Method: Non-probability sample

Eligibility Criteria

Inclusion Criteria (Cases):

Adults (≥18) with biopsy-proven severe alcohol-associated hepatitis (2013-2024)

Available liver biopsy slides at CHRU Nancy

Non-opposition documented

Inclusion Criteria (Controls):

Adults (≥18) with hepatic resection for colorectal metastases, cholangiocarcinoma, or HCC

Archived liver samples available

Non-opposition documented

Exclusion Criteria:

No histologic diagnosis of sAH

Depleted paraffin blocks unsuitable for staining

Study Dates Start Date: Upon ethics approval

Primary Completion Date: \~9 months after start

Study Completion Date: \~15 months after start

Locations CHRU Nancy, France Lead Pathology and Hepatology Units Collaborating Site: Hôpital Henri Mondor (AP-HP)

Sponsor and Contacts Sponsor: CHRU Nancy Scientific PI: Dr. Vincent Haghnejad Email: [email protected] Phone: +33 625150180

Regulatory Compliance

This study adheres to the following regulations and ethical standards:

Declaration of Helsinki

EU Regulation (EU) 536/2014

French Public Health Law: 2004-806, 2004-800, 2016-41

Bioethics Law and GDPR (EU 2016/679)

CNIL MR004 framework for retrospective, non-interventional data use

Statistical Methods

Primary Objective:

Logistic regression (univariate p\<0.2 threshold, stepwise multivariate model) to compare TREM-1 expression between cases and controls.

Secondary Objectives:

ROC curve analysis to determine optimal antibody dilution (AUC, Youden index).

Diagnostic accuracy metrics (sensitivity, specificity, PPV, NPV).

Clustering (Multiple Correspondence Analysis + Ward's Hierarchical Clustering) for subgroup discovery.

Cox model for 2-month mortality.

Logistic regression for treatment response (Day 7 jaundice, Lille score \<0.45).

Comparative model performance vs. MELD, Maddrey, etc.

Software: SAS 9.4 or R

Significance Level: 5% (two-sided)

Conditions

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Severe Alcoholic Hepatitis

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

RETROSPECTIVE

Study Groups

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Biopsy-proven severe alcoholic hepatitis and control liver specimens

Cases: Adults treated at CHRU de Nancy (2013-2023) for Severe Alcoholic Hepatitis, with archived liver biopsies.

Controls: Adults with liver malignancies and archived biopsies.

TREM-1 expression (via immunohistochemistry) between SAH patients and controls

Intervention Type DIAGNOSTIC_TEST

this is the first study to focus on hepatocyte-specific TREM-1 expression in human liver tissue

What Distinguishes This Study Tissue-Level Focus: Unlike most studies that assess blood biomarkers or systemic inflammation, this research directly measures TREM-1 expression in liver tissue (hepatocytes), offering localized insights into disease severity and immune response.

Retrospective Biobank Utilization: Leverages a rich biobank of archival biopsies spanning 10 years, ensuring real-world data and long-term clinical follow-up-rarely combined at this scale in similar research.

Dual Purpose (Diagnostic \& Prognostic): Most biomarkers are evaluated for either diagnostic or prognostic value-this study uniquely addresses both in a single, comprehensive framework.

Therapeutic Translation Potential: TREM-1 is already a target for pharmacological inhibition (e.g., with peptide inhibitors tested safely in humans for other conditions). This positions the study for rapid clinical translation,

Interventions

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TREM-1 expression (via immunohistochemistry) between SAH patients and controls

this is the first study to focus on hepatocyte-specific TREM-1 expression in human liver tissue

What Distinguishes This Study Tissue-Level Focus: Unlike most studies that assess blood biomarkers or systemic inflammation, this research directly measures TREM-1 expression in liver tissue (hepatocytes), offering localized insights into disease severity and immune response.

Retrospective Biobank Utilization: Leverages a rich biobank of archival biopsies spanning 10 years, ensuring real-world data and long-term clinical follow-up-rarely combined at this scale in similar research.

Dual Purpose (Diagnostic \& Prognostic): Most biomarkers are evaluated for either diagnostic or prognostic value-this study uniquely addresses both in a single, comprehensive framework.

Therapeutic Translation Potential: TREM-1 is already a target for pharmacological inhibition (e.g., with peptide inhibitors tested safely in humans for other conditions). This positions the study for rapid clinical translation,

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

Cases:

* Individuals who received full information about the study and did not object to the use of their data within this research.
* Patients managed in one of the intensive care or hepatogastroenterology departments at CHRU de Nancy for severe alcohol-related hepatitis between January 1, 2013, and December 31, 2023.
* Archived liver biopsy slides available at CHRU de Nancy.
* Adult patients at the time of diagnosis.

Controls:

* Individuals who received full information about the study and did not object to the use of their data within this research.
* Patients treated and operated on at CHRU de Nancy for hepatocellular carcinoma, colorectal cancer liver metastasis, or cholangiocarcinoma between January 1, 2013, and December 31, 2023.
* Archived liver biopsy slides available at CHRU de Nancy.
* Adult patients at the time of diagnosis.