Editorial: Revolutionising Steatotic Liver Disease Diagnosis With Phosphatidylethanol—Authors' Reply

We thank Ho and Mak for their positive comments on our recently published work, in which we demonstrate that phosphatidylethanol (PEth) is an accurate, quantitative, objective, blood-based alcohol biomarker for diagnosing the newly defined metabolic dysfunction and alcohol-related liver disease (MetALD) [1]. Leveraging a well-characterised United States (U.S.) cohort of 374 community-dwelling individuals with overweight or obesity and steatotic liver disease (SLD) assessed through advanced magnetic resonance imaging (MRI) techniques [2], we showed that PEth exhibited a robust diagnostic accuracy in differentiating MetALD from metabolic dysfunction-associated steatotic liver disease (MASLD) (AUROC 0.81, 95% CI 0.73–0.89) with an optimal cut-off of 25 ng/mL, and outperformed indirect alcohol biomarkers, including aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, gamma glutamyltransferase (GGT), mean corpuscular volume (MCV) and the ALD/non-alcoholic fatty liver disease index (ANI).

PEth is an abnormal cellular membrane phospholipid formed in human erythrocytes exclusively during alcohol ingestion. Specifically, PEth is synthesised from phosphatidylcholine through a transphosphatidylation reaction catalysed by the enzyme phospholipase D only in the presence of ethanol (Figure 1) [3].

Given the physiopathology underlying PEth formation and degradation, Ho and Mak astutely highlighted that factors such as anaemia, cirrhosis and drinking patterns may significantly influence PEth levels [4]. However, a handful of studies have specifically investigated the impact of these conditions on PEth levels. Limited evidence suggests that the elimination of PEth, rather than its formation, may be affected by conditions that alter red blood cell turnover and the presence of cirrhosis [3, 5, 6]. Additional research is required to fully address these questions.

Regarding drinking patterns, PEth has shown potential as a biomarker for identifying excessive drinking episodes and binge drinking behaviours, but this area of research warrants further investigation in the SLD population [3, 7]. Notably, another important question that needs to be addressed clearly is the exact quantity of ethanol that must be consumed over a specific time period to yield a positive PEth test [3].

In conclusion, a body of evidence from studies conducted in medical settings outside of SLD, such as screening in emergency departments, alcohol detoxification programs, pre-employment medical examinations, liver transplant evaluation and forensic context, demonstrated that PEth is a reliable biomarker for detecting heavy alcohol consumption [7-9]. Our study represents an initial effort within the setting of the newly defined SLD to support PEth as a quantitative, objective biomarker for identifying SLD subcategories and enhancing SLD subclassification alongside self-reported alcohol use. Despite these promising findings, many critical questions remain to be addressed in larger and more diverse studies. These include the establishment of specific PEth thresholds corresponding to levels of alcohol consumption and the investigation of variability in PEth formation and degradation across different diseases and drinking patterns.

Federica Tavaglione: writing – review and editing, writing – original draft. Rohit Loomba: writing – original draft, writing – review and editing.

This article is linked to Tavaglione et al papers. To view these articles, visit https://doi.org/10.1111/apt.18506 and https://doi.org/10.1111/apt.18529.