A 36-year-old man presented for evaluation of elevated liver enzymes 2 months after undergoing a liver transplant for acute-on-chronic liver failure due to alcohol-associated hepatitis. He had metabolic comorbidities including obesity (body mass index of 30.6) and dyslipidemia. After the liver transplant, there was no evidence of organ rejection or biliary complications. He was asymptomatic and reported last alcohol use was prior to liver transplant. Vital signs were normal and physical examination revealed a well-healed abdominal surgical scar. Serum alcohol level was undetectable and urine drug screening results were positive for cannabinoids. Liver ultrasonography findings were normal. Liver biopsy showed 50% to 60% macrovesicular steatosis (normal <5%), mild portal inflammation, scattered apoptotic bodies, and hepatocyte ballooning (Table 1).

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B. Alcohol-associated liver disease.

Phosphatidylethanol (PEth) is a whole blood marker of alcohol that can be detectable for up to 4 weeks after alcohol consumption. PEth is not a single molecule. It is a group of phospholipid homologues with a phosphoethanol head and 2 carboxylic acid side chains that attach to the erythrocyte surface in the presence of blood ethanol, catalyzed by the enzyme phospholipase D.¹ PEth species are categorized by the number of carbon atoms (typically 14-22) and double bonds; the 16:0/18:1 and 16:0/18:2 homologues are the most common forms.¹ Testing for PEth can be performed using dried blood spots or whole blood collected in ethylenediamine tetra-acetic acid tubes.

PEth is a direct biomarker of alcohol that forms after ethanol consumption. A study of 16 recently abstinent volunteers who consumed alcohol to achieve a blood alcohol concentration of 1 g/kg (single ingestion of 110-230 mL of 40% vodka) demonstrated that PEth was detectable within 1 hour of alcohol consumption, peaked at 8 hours, and was detectable for 3 to 12 days after consumption, with a mean half-life of 3 days.² A PEth concentration less than 20 ng/mL indicates minimal or no recent alcohol consumption and a PEth concentration greater than 200 ng/mL correlates with heavy alcohol consumption (≥4 standard drinks daily). A standard drink is defined as equivalent to 12 fl oz of beer, 5 fl oz of wine, or 1.5 fl oz of distilled spirits.³

PEth formation and degradation are not affected by age, sex, or organ dysfunction such as chronic kidney disease or hepatic dysfunction.¹ The rate of PEth formation depends on the level and activity of phospholipase D, which varies among individuals. The degradation rate of PEth also varies, with an estimated mean half-life of 4 to 10 days. PEth may be detectable up to 5 weeks after heavy alcohol consumption.¹ Blood PEth level increases with higher quantity and frequency of alcohol consumption and decreases with time elapsed since last ingestion of alcohol.

A false-positive PEth test result may occur if an individual receives a blood transfusion from a person who recently consumed alcohol, due to PEth on donated erythrocytes.⁴ Falsely low PEth concentrations may occur in patients with low haptoglobin levels, consistent with intravascular hemolysis.⁵ PEth has a sensitivity of 94.5% to 99% and a specificity of 100% for high levels of alcohol consumption (≥4 standard drinks daily) and a sensitivity of 81.8% for lower levels of alcohol ingestion.⁶ In 2024, Medicare reimbursement was $114.43 for PEth testing.⁷

The patient’s PEth concentration of 137 ng/dL was consistent with recent alcohol ingestion despite his undetectable serum alcohol level and initial report of no recent alcohol consumption.

Blood, breath, and urine alcohol levels detect alcohol consumed in the preceding 12 to 24 hours. Ethyl glucuronide and ethyl sulfate are formed by enzymatic conjugation of ethanol with glucuronic acid and sulfate, respectively, and may be detected in urine within 2 to 3 hours of alcohol consumption and remain detectable for 4 to 5 days after consumption.⁸ False-positive urinary ethyl glucuronide and ethyl sulfate test results may occur due to kidney dysfunction or bacterial fermentation in the urine (eg, cystitis); false-negative results may occur with use of diuretics or intentional dilution of urine specimens.¹ Ethyl glucuronide can be detected in hair and nails for approximately 2 months after alcohol cessation in frequent drinkers⁹ (Table 2).^7,10 Direct alcohol biomarkers (PEth and ethyl glucuronide) have been studied and validated in patients with and without liver disease.

Additional testing revealed a urine ethyl sulfate level of 45 475 ng/mL (reference, <100 ng/mL) and urine ethyl glucuronide level of >10 000 ng/mL (reference, <500 ng/mL). The patient disclosed consuming 5 shots of vodka daily for 7 days prior to presentation. He was prescribed naltrexone and referred to an intensive outpatient program for alcohol use disorder. Liver chemistries were normal 2 weeks after presentation and PEth was undetectable 3 weeks later. In the clinic 2 months later, he reported alcohol abstinence; was meeting with his psychotherapy, psychiatry, and social work teams; and had undetectable blood PEth levels and normal liver graft function.

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Corresponding Author: Amanda Cheung, MD, 676 N St Clair St, Ste 1900, Chicago, IL 60611 (amanda.cheung@nm.org).

Published Online: May 15, 2024. doi:10.1001/jama.2024.3607

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient for granting permission to publish this information.