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

Background & Aims People who excessively drink alcohol 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 to detect MetALD/ALD. Methods We included 303 persistent heavy drinkers classified as MetALD or ALD (n=152) and abstinent patients with a history of excessive drinking (n=151). Plasma CTSD levels of MetALD/ALD patients without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. ROC-AUC 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 MetALD/ALD patients compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, transient elastography (TE)) were higher at advanced histopathological stages as assessed by liver biopsy, plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with TE and AST/ALT ratio yielded enhanced diagnostic precision (ROC-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 for MetALD/ALD.