Plasma cathepsin D as an early indicator of alcohol-related liver disease

Mengying Li; Tom Houben; Albert V Bitorina; Dennis M Meesters; Mads Israelsen; Maria Kjærgaard; Ger H Koek; Tim Hendrikx; Jef Verbeek; Aleksander Krag; Maja Thiele; Ronit Shiri-Sverdlov

doi:10.1016/j.jhepr.2024.101117

Plasma cathepsin D as an early indicator of alcohol-related liver disease

JHEP Rep. 2024 May 9;6(9):101117. doi: 10.1016/j.jhepr.2024.101117. eCollection 2024 Sep.

Authors

Affiliations

¹ Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands.
² Center for Liver Research, Odense University Hospital and University of Southern Denmark, Kloevervaenget 10, entrance 112, DK-5000 Odense, Denmark.
³ Department of Internal Medicine Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁴ Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
⁵ Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Belgium; Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium.

Abstract

Background & aims: People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD.

Methods: We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers.

Results: Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers.

Conclusion: Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD.

Impact and implications: Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD.

Keywords: alcohol use disorder; alcohol-related liver disease; cathepsin D; persistent heavy drinking.