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)
