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

Official title

Measurement of Hepatocyte TREM-1 Expression Level to Evaluate Its Intrinsic Performance and Prognostic Value in Severe Symptomatic Alcohol-related Hepatitis

Overview

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

Detailed description

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

Interventions

• Diagnostic test 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

Primary outcome measures

• Baseline Hepatocyte TREM-1 expression in SAH patients vs. controls on the day of biopsy [Time frame: Day 0 index liver biopsy]

Secondary outcome measures (1)

• Baseline TREM-1 expression (via RNAseq3') in patients with severe alcohol-associated hepatitis (SAH) [Time frame: Day 0 (index liver biopsy)]

Eligibility criteria

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.

Exclusion criteria

• None

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Duan M, Wang ZC, Wang XY, Shi JY, Yang LX, Ding ZB, Gao Q, Zhou J, Fan J. TREM-1, an inflammatory modulator, is expressed in hepatocellular carcinoma cells and significantly promotes tumor progression. Ann Surg Oncol. 2015 Sep;22(9):3121-9. doi: 10.1245/s10434-014-4191-7. Epub 2014 Dec 3. PMID 25465376
• Ichou L, Carbonell N, Rautou PE, Laurans L, Bourcier S, Pichereau C, Baudel JL, Nousbaum JB, Renou C, Anty R, Tankovic J, Maury E, Guidet B, Landraud L, Ait-Oufella H. Ascitic fluid TREM-1 for the diagnosis of spontaneous bacterial peritonitis. Gut. 2016 Mar;65(3):536-8. doi: 10.1136/gutjnl-2015-310160. Epub 2015 Jul 3. No abstract available. PMID 26141143
• Francois B, Lambden S, Garaud JJ, Derive M, Grouin JM, Asfar P, Darreau C, Mira JP, Quenot JP, Lemarie J, Mercier E, Lacherade JC, Vinsonneau C, Fivez T, Helms J, Badie J, Levy M, Cuvier V, Salcedo-Magguilli M, Laszlo-Pouvreau AL, Laterre PF, Gibot S; ESSENTIAL investigators. Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory PMID 37350989
• Francois B, Lambden S, Fivez T, Gibot S, Derive M, Grouin JM, Salcedo-Magguilli M, Lemarie J, De Schryver N, Jalkanen V, Hicheur T, Garaud JJ, Cuvier V, Ferrer R, Bestle M, Pettila V, Mira JP, Bouisse C, Mercier E, Vermassen J, Huberlant V, Vinatier I, Anguel N, Levy M, Laterre PF; ASTONISH investigators. Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for PMID 37269870
• Francois B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sanchez M, Salcedo-Magguilli M, Laterre PF. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med. 2020 Jul;46(7):1425-1437. doi: 10.1007/s00134-020-06109-z. Epub 2020 May 28. PMID 32468087
• Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, Chaput JC, Rueff B, Poynard T. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology. 1996 Jun;110(6):1847-53. doi: 10.1053/gast.1996.v110.pm8964410. PMID 8964410

Identifiers

NCT: NCT07176741 · 2023PI101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗