The FGL-1/LAG-3 Axis is Associated With Disease Course in Alcohol-associated Hepatitis: A Preliminary Report

Sep 28, 2026

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Alcohol-associated hepatitis (AH) has high short-term mortality, driven by impaired hepatocyte regeneration and uncontrolled liver inflammation involving innate and adaptive immune cells. Hepatocyte-derived fibrinogen-like protein 1 (FGL-1) stimulates hepatocyte proliferation and also serves as a ligand for the inhibitory receptor LAG-3. This study characterizes FGL-1 and LAG-3 in AH patients and links them to disease state and 3-year clinical course. Patients showed increased hepatic FGL-1 mRNA, reduced hepatic LAG-3 mRNA, unchanged circulating sLAG-3, and diagnostic immune profiles associated with severity and mortality.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages9

Reading Time23 min

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Background

Aims

Methods

Results

Conclusions

Original Article JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY The FGL-1/LAG-3 Axis is Associated With Disease Course in Alcohol-associated Hepatitis: A Preliminary Report Lasse Pedersen * , Lotte L. Eriksen * , y , Frederik H. Brix * , Hendrik Vilstrup * , y , Bent Deleuran z , x , Thomas D. Sandahl * , Sidsel Støy * *Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark, y Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, z Department of Rheumatology, Biomedicine, Aarhus University Hospital, Aarhus, Denmark and x Department of Biomedicine, Aarhus University, Aarhus, Denmark Background: Alcohol-associated hepatitis (AH) has a short-term mortality rate of up to 40% primarily related to impaired hepatocyte regeneration and uncontrolled liver inﬂammation. The acute phase protein ﬁbrinogen-like protein 1 (FGL-1) produced by hepatocytes stimulates hepatocyte proliferation by autocrine signaling. FGL-1 also is a ligand for the inhibitory T cell receptor lymphocyte activation gene 3 (LAG-3). In these ways, FGL-1 and LAG-3 have beneﬁcial interactions that could be interrupted in AH. Aims: We aimed to characterize FGL-1 and LAG-3 in patients with AH and describe their relationship with the disease state and course. Methods: Thirty-two patients with AH were included at diagnosis and followed up for 3 years. We measured the hepatic gene expression ofFGL-1 and LAG-3 using RNA sequencing, plasma FGL-1 and soluble (s)LAG-3 using ELISA, and LAG-3+CD8+ T cells using ﬂow cytometry. Healthy persons (HC) and patients with stable alcohol-associated cirrhosis served as controls. Results: At diagnosis ofAH, liver FGL-1 mRNA was increased when compared to HC, whereas plasma FGL-1 was unchanged. In contrast, liver LAG-3 mRNA was reduced in AH. Plasma sLAG- 3 levels and the frequency of LAG-3+CD8+ T cells were as in HC. However, those patients who had the lowest plasma FGL-1 and the lowest frequency of LAG-3+CD8+ T cells at diagnosis had the highest disease severity and mortality. Conclusions: Our data suggest that an impaired FGL-1/LAG-3 axis may be involved in the pathogenesis and course ofAH. (J CLIN EXP HEPATOL 2025;15:102424) Alcohol-associated hepatitis threatening disease with a rate of up to 40% .1 The (AH) is a lifesix-month mortality incidence of AH is increasing; however, no pharmacological treatment has shown convincing effects on clinical outcomes. Therefore, the key treatment remains careful supportive care and moderate hyperalimentation.2,3 The disease mechanisms are only partially understood. Acute alcohol-induced liver Keywords: ﬁbrinogen-like protein 1, lymphocyte activation gene 3, alcoholassociated liver disease, acute phase protein, checkpoint inhibitor Received: 27.11.2023; Accepted: 5.10.2024; Available online 10 October 2024 Address for correspondence: Sidsel Hyldgaard Støy, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. Tel.: +45 7845 3813. E-mail: [sidsel.stoy@clin.au.dk](sidsel.stoy@clin.au.dk) Abbreviations: AH: Alcoholic hepatitis; ALT: Alanine aminotransferase; ELISA: Enzyme-linked immunosorbent assay; FGL-1: Fibrinogen-like protein 1; GAHS: Glasgow Alcoholic Hepatitis Score; HC: Healthy Controls; HE: Hepatic encephalopathy; INR: international normalized ratio; LAG-3: Lymphocyte activation gene 3; MELD: Model of end-stage liver disease; MHCII: Major histocompatibility complex class II; NK cells: natural killer cells; PBMC: Peripheral Blood Mononuclear Cells; PD1: Programmed death receptor-1; SD: standard deviation; sFGL-1: soluble FGL-1; sLAG- 3: soluble LAG-3; TIM-3: T cell Immunoglobulin Mucin-3; Treg: Regulatory T cells [https://doi.org/10.1016/j.jceh.2024.102424](https://doi.org/10.1016/j.jceh.2024.102424) damage results in uncontrolled inﬂammation of the liver, which involves both innate and adaptive immune cells, and this further exacerbates

FAQs

What is the main focus of this preliminary report on alcohol-associated hepatitis?

The report investigates how the FGL-1/LAG-3 axis relates to disease state and the clinical course in patients with alcohol-associated hepatitis.

How were FGL-1 and LAG-3 measured in alcohol-associated hepatitis patients?

Hepatic gene expression was assessed by RNA sequencing, plasma FGL-1 and soluble LAG-3 were measured by ELISA, and LAG-3+CD8+ T cells were quantified using flow cytometry.

What diagnostic associations were found with disease severity and mortality?

Patients with the lowest plasma FGL-1 and the lowest frequency of LAG-3+CD8+ T cells at diagnosis had the highest disease severity and mortality.

Sep 28, 2026

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