Phosphatidylethanol and ethyl glucuronide to categorize alcohol consumption in alcohol-related cirrhosis

Abstract

Background & aims: Phosphatidylethanol (PEth) is an alcohol-use biomarker that could bridge the detection windows of urinary ethyl glucuronide (uEtG) and scalp hair ethyl glucuronide (hEtG), but has been rarely validated in patients with liver disease. Reported detection windows of these biomarkers also vary significantly, and available studies have focused solely on any alcohol use. Yet, categorizing patients with liver disease based on their level of alcohol use would be highly informative. Here, we assessed the diagnostic accuracy and optimal detection windows of whole-blood PEth, uEtG, hEtG, and the novel biomarker fingernail ethyl glucuronide (nEtG), for different levels of alcohol use in patients with alcohol-related cirrhosis.

Methods: Patients with alcohol-related cirrhosis were questioned on their alcohol use over the previous 3 months using the Alcohol Timeline Followback (n = 116). In addition, 1-7-day (uEtG), 1-5-week (PEth), and 3-month (hEtG and nEtG) detection windows were assessed for any, increased (women ≥2 units/day or men ≥3 units/day), or excessive alcohol use (women ≥5 units/day or men ≥6 units/day).

Results: uEtG, PEth, and hEtG had high diagnostic accuracies for any alcohol use at optimal detection windows of 3 days [area under the receiver operating characteristic curve (AUROC): 0.990 (95% confidence interval (CI): 0.975-1.000)], 3 weeks [AUROC: 0.986 (95% CI: 0.958-1.000)], and 3 months [AUROC: 0.925 (95% CI: 0.862-0.987)], respectively. They had high negative predictive values (>92%) for increased and excessive use. nEtG showed promising results for assessing any alcohol use over the previous 3 months [AUROC: 0.962 (95% CI: 0.924-1.000)].

Conclusions: PEth and EtG have excellent and complementary diagnostic accuracies to detect any alcohol use and rule out increased alcohol use in patients with alcohol-related cirrhosis. nEtG provides an alternative for hEtG, but requires further validation.

Impact and implications: The correct identification and categorization of alcohol use is a major challenge in the treatment of patients with liver disease. Furthermore, given the new nomenclature toward steatotic liver disease, it has become essential to be able to categorize alcohol use into any, increased, or excessive use. The validation of PEth and urine, scalp hair, and nail EtG in patients with alcohol-related liver disease provides us with reliable options to overcome these issues in both clinical care and pharmacological trials on steatotic liver disease.

Clinical trials registration: The study is registered at ClinicalTrials.gov (NCT04363424).

Keywords: Alcohol drinking; Alcoholic cirrhosis; Alcoholic liver diseases; Ethyl glucuronide; Metabolic dysfunction-associated steatotic liver disease; Phosphatidylethanol.

Graphical abstract

Fig. 1

Direct alcohol-use biomarkers to detect any alcohol use. ROCs of (A) uEtG and uEtS for any alcohol use at a 3-day detection window, (B) PEth, CDT_(Nef), and CDT_(CZE) for any alcohol use at a 3-week detection window, and (C) of hEtG and nEtG for any alcohol use at a 3-month detection window. CDT_(Nef), carbohydrate-deficient transferrin by nephelometric analysis; hEtG, hair ethyl glucuronide; nEtG, nail ethyl glucuronide; ROC, receiver operating characteristic curve; uEtG, urinary ethyl glucuronide.

Fig. 2

Absolute levels of direct alcohol-use biomarkers per alcohol use category. Box plots representing absolute levels of (A) uEtG, (B) uEtS, (C) PEth, (D) CDT_(Nef), (E) hEtG, and (F) nEtG per alcohol use category. Bars represent IQR, bold lines inside the box plot indicate median levels, and whiskers represent minimum and maximum values. CDT_(Nef): carbohydrate-deficient transferrin by nephelometric analysis; hEtG, hair ethyl glucuronide; nEtG, nail ethyl glucuronide; PEth, phosphatidylethanol; uEtG, urinary ethyl glucuronide; uEtS, urinary ethyl sulfate.

Fig. 3

Direct alcohol-use biomarkers to detect increased and excessive alcohol use. ROCs of uEtG for (A) increased alcohol use and (B) excessive alcohol use at a 3-day detection window. ROCs of PEth, CDT_(Nef) and CDT_(CZE) for (C) increased alcohol use and (D) excessive alcohol use at a 3-week detection window. ROCs of hEtG and nEtG for (E) increased alcohol use and (F) excessive alcohol use at a 3-month detection window. CDT_(CZE): carbohydrate-deficient by capillary zone electrophoresis; CDT_(Nef), carbohydrate-deficient transferrin by nephelometric analysis; hEtG, hair ethyl glucuronide; nEtG, nail ethyl glucuronide; PEth, phosphatidylethanol; ROC, receiver operating characteristic curve; uEtG, urinary ethyl glucuronide;