Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease

Thit Mynster Kronborg; Qian Gao; Kajetan Trošt; Henriette Ytting; Malene Barfod O'Connell; Mikkel Parsberg Werge; Mira Thing; Lise Lotte Gluud; Ole Hamberg; Søren Møller; Thomas Moritz; Flemming Bendtsen; Nina Kimer

doi:10.1016/j.jhepr.2023.100953

Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease

JHEP Rep. 2023 Nov 1;6(2):100953. doi: 10.1016/j.jhepr.2023.100953. eCollection 2024 Feb.

Authors

Affiliations

¹ Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark.
² Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴ Medical Department, University Hospital of Zealand, Koege, Denmark.
⁵ Centre for Functional and Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Hvidovre, Denmark.

Abstract

Background & aims: Alcohol-related hepatitis (AH) and alcohol-related cirrhosis are grave conditions with poor prognoses. Altered hepatic lipid metabolism can impact disease development and varies between different alcohol-related liver diseases. Therefore, we aimed to investigate lipidomics and metabolomics at various stages of alcohol-related liver diseases and their correlation with survival.

Methods: Patients with newly diagnosed alcohol-related cirrhosis, who currently used alcohol (ALC-A), stable outpatients with decompensated alcohol-related cirrhosis with at least 8 weeks of alcohol abstinence (ALC), and patients with AH, were compared with each other and with healthy controls (HC). Circulating lipids and metabolites were analysed using HPLC and mass spectrometry.

Results: Forty patients with ALC, 95 with ALC-A, 30 with AH, and 42 HC provided plasma. Lipid levels changed according to disease severity, with generally lower levels in AH and cirrhosis than in the HC group; this was most pronounced for AH, followed by ALC-A. Nine out of 10 free fatty acids differed between cirrhosis groups by relative increases of 0.12-0.66 in ALC compared with the ALC-A group (p <0.0005). For metabolomics, total bile acids increased by 19.7, 31.3, and 80.4 in the ALC, ALC-A, and AH groups, respectively, compared with HC (all p <0.0001). Low sphingolipid ([d42:1] and [d41:1]) levels could not predict 180-day mortality (AUC = 0.73, p = 0.95 and AUC = 0.73, p = 0.95) more accurately than the model for end-stage liver disease score (AUC = 0.71), but did predict 90-day mortality (AUC _d42:1 = 0.922, AUC _d41:1 = 0.893; p_d42:1 = 0.005, p_d41:1 = 0.007) more accurately than the MELD score AUC_MELD = 0.70, p_MELD = 0.19).

Conclusions: Alcohol-related severe liver disease is characterised by low lipid levels progressing with severity of liver disease, especially low sphingomyelins, which also associate to poor prognoses.

Impact and implications: Lipidomics has the potential to diagnose and risk stratify patients with liver diseases. Lipidomics differed between patients with alcohol-related hepatitis and alcohol-related cirrhosis with and without recent alcohol use. Furthermore, lipidomics could predict short-term mortality and might be suitable as a prognostic tool in the future.

Clinical trials registration: Scientific Ethics Committee of the Capital Region of Denmark, journal no. H-21013476.

Keywords: Alcohol-related cirrhosis; Alcohol-related hepatitis; Free fatty acids; Lipidomics; Triglycerides.