Phosphatidylethanol levels distinguish steatotic liver disease subgroups and are associated with risk of major liver outcomes

Abstract

Background & aims: Phosphatidylethanol (PEth) is an ethanol metabolite used as a specific biomarker for recent alcohol consumption. We aimed to determine the proportion of patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) who had PEth levels indicative of harmful alcohol consumption, and to assess associations between PEth levels and the risk of major adverse liver outcomes (MALOs).

Methods: We conducted a cohort study involving persons tested for PEth in Stockholm, Sweden between 2012 and 2020 (N = 46,406), including patients with various steatotic liver disease (SLD) subtypes and individuals without SLD. Cumulative incidences of MALOs were calculated for the different groups while accounting for competing risk. Cox regression was used to evaluate the association between baseline PEth levels and the incidence of MALOs.

Results: Among 6,377 patients with presumed MASLD, 1,294 (20%) had baseline PEth levels between 0.05 and 0.30 μmol/L (35-210 ng/ml), indicating excessive alcohol intake (MetALD), while 854 patients (13%) had values >0.30 μmol/L, indicating alcohol-related liver disease (ALD). Patients with MASLD and PEth levels between 0.05-0.30 μmol/L had similar median FIB-4 and cirrhosis prevalence as those with MASLD and PEth levels <0.05 μmol/L. However, patients with PEth levels between 0.05-0.30 μmol/L had higher cumulative incidences of MALOs compared to those with PEth levels <0.05 μmol/L. Elevated PEth levels were linked to significantly higher rates of MALOs in patients without cirrhosis, even after adjustments for age, sex, SLD subtype, and FIB-4. Patients with ALD had the highest PEth levels and worst prognosis.

Conclusions: PEth is a valuable alcohol biomarker for distinguishing between SLD subtypes, especially ALD, and predicts adverse outcomes in people with and without SLD.

Impact and implications: There is controversy regarding the various proposed steatotic liver disease (SLD) subtypes, with the most recent definition suggesting that patients with elevated alcohol consumption and MASLD should be classified as having MetALD. Here, we address this challenge by classifying patients with SLD using phosphatidylethanol (PEth), a direct and reliable biomarker for recent alcohol consumption. Our analysis of 46,406 patients revealed that PEth may be a valuable tool for distinguishing between MASLD and MetALD, and that PEth is strongly associated with the risk of liver outcomes in individuals with and without known SLD. Integrating PEth testing into routine diagnostic evaluations could enhance knowledge on the underlying pathophysiology in SLD, reduce the potential for misclassification, and ultimately improve patient outcomes by enabling clinicians to offer appropriate therapies. Further research is needed to validate these findings in other populations and to explore the potential integration of PEth into broader clinical guidelines for managing SLD.

Keywords: Phosphatidylethanol; alcohol consumption; alcohol use disorder; alcohol-related liver disease; direct alcohol biomarker; metabolic dysfuntion-associated steatotic liver disease; prognosis.