A novel, accurate, easy-to-use biomarker test might help flag excessive alcohol use in steatotic liver disease (SLD), distinguishing metabolic and alcohol-associated liver disease (MetALD) and ALD from metabolic dysfunction-associated SLD (MASLD).

The new tool, called the MetALD-ALD prediction Index (MAPI), is a formula that integrates sex together with four routine laboratory tests to derive a score that identifies when SLD is driven by excessive alcohol use vs metabolic factors only.

“This new score gives clinicians a simple and accessible way to uncover hidden alcohol-related injury,” senior author Rohit Loomba, MD, MHSc, professor of medicine, director of the MASLD Research Center, and chief of the Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, California, said in a press release. “By improving how we classify liver disease, we can help patients achieve better long-term health outcomes.”

The study was published online in Gastroenterology.

Synergistic Interaction

MASLD, MetALD, and ALD were previously regarded as “completely distinct entities” but are now seen as “part of a continuum defined by alcohol use and metabolic risk factors,” the authors wrote.

The “newly adopted umbrella term SLD captures a dynamic spectrum of conditions characterized by abnormal lipid accumulation in the liver (hepatic steatosis) and includes MASLD, MetALD, and ALD,” recognizing that metabolic and alcoholic steatosis “often coexist and interact synergistically to exacerbate the development and profession of liver disease.” Accurately quantifying alcohol use is “essential for correctly classifying individuals within the newly defined subcategories of SLD.”

The “current classification of steatotic liver disease relies primarily on self-reported alcohol consumption, via standardized self-reporting questionnaires and medical interviews,” Loomba told Medscape Medical News. But self-reporting is often unreliable, so the extent of alcohol consumption is “often underreported.”

Phosphatidylethanol (PEth) testing is often used as a biomarker for detecting excessive alcohol use in SLD. PEth has high sensitivity and specificity, is observable for up to 4 weeks after ethanol consumption, and has outperformed other indirect alcohol biomarkers in revealing excessive alcohol consumption. But despite its advantages, PEth testing has distinct limitations.

“PEth is an objective, quantitative biomarker of alcohol use; however, it’s not widely available, particularly in low-resource settings, and requires additional cost and expense,” Loomba noted. He and his colleagues therefore “aimed to develop an accurate and scalable biomarker panel that could be implemented in routine clinical practice alongside self-reported alcohol use.”

MAPI, the biomarker panel, included four routine laboratory tests — mean corpuscular volume (MCV), gamma-glutamyltransferase (GGT), high-density lipoprotein cholesterol, and A1c — and sex to create a single score.

To test the accuracy of MAPI, the researchers studied 503 community-dwelling adults (mean age, 51 years [SD, 13 years]) with overweight or obesity (mean BMI, 32.9 [SD, 5.8]; 53% female), who were called the “derivation cohort.” Participants underwent MRI or magnetic resonance elastography assessment as well as PEth testing, which was used to categorize alcohol consumption and to “define the study outcome,” Loomba explained.

PEth-based categories of alcohol consumption were < 35 ng/mL (no or light drinking), ≥ 35-200 ng/mL (moderate drinking), and ≥ 200 ng/mL (heavy drinking).

Additional external validation was conducted in an independent population-based Swedish cohort drawn from the HERALD study, including 1777 people with PEth measurements.

The researchers defined SLD subcategories in accordance with the “new nomenclature,” with all subcategories requiring at least one cardiometabolic risk factor plus varying amounts of average alcohol consumption: < 20 g/d for women and < 30 g/d for men (MASLD), 20-50 g/d for women and 30-60 g/d for men (MetALD), and > 50 g/d for women and > 60 g/d for men (ALD).

Enhanced Precision

The prevalence of MASLD, MetALD, and ALD, as defined by integrating PEth results with self-reported alcohol use, was 81%, 12%, and 7%, respectively.

MAPI emerged as the “top-performing” predictive model among all commonly used indirect alcohol biomarkers (eg, ANI, MCV, GGT, and the aspartate aminotransferase/alanine aminotransferase ratio), with an area under the receiver operating characteristic curve of 0.76 for the derivation cohort and 0.75 for the validation cohort.

“Notably, integrating PEth alongside self-reported alcohol use enhanced precision and enabled us to derive a biomarker that is both practical and robust while minimizing the risk of misclassification due to alcohol underreporting,” Loomba commented.

Loomba regards the findings and potential role of MAPI as “relevant for both clinical and research settings.” In clinical practice, “it can help identify patients with MetALD or ALD who may be underreporting alcohol consumption, while in settings where PEth testing is available, these patients represent good candidates for confirmatory PEth testing.”

The authors note several limitations. The study cohorts didn’t include structured interviews quantifying alcohol intake during the week immediately preceding blood sampling, making it “challenging” to interpret elevated PEth levels in participants who may engage in heavy episodic drinking but otherwise have low-to-moderate intake. And although PEth is a reliable biomarker of alcohol exposure over the prior 2- to 4-week period, it may not fully reflect longer-term patterns.

Nevertheless, they conclude, it is a “highly practical” and “valuable” tool in “improving diagnostic accuracy and guiding appropriate clinical management.”

‘Simple Tool’

Commenting for Medscape Medical News, K. Rajender Reddy, MD, Founder’s Professor in Hepatology and Professor of Medicine in Surgery, Liver Transplant Office, University of Pennsylvania, Philadelphia, called MAPI a “simple tool” to help community physicians distinguish metabolic syndrome from metabolic syndrome-associated and alcohol liver disease.” He hopes there will be “uptake of this tool in the community, especially since it does not require an outrageous data element.”

Reddy, who was not involved with the study, also hopes MAPI will be validated in further clinical trials. And it can be useful in clinical practice as a “screen to see if the patient falls into alcohol-associated liver disease, since PEth testing is expensive, and this might be a cheap, earlier test to identify patients.” After identifying patients with an alcoholic component to their SLD, clinicians can help these patients understand the impact of their alcohol use.

Funding support was provided to individual authors by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; the John C. Martin Foundation; and the National Institute on Alcohol Abuse and Alcoholism. Loomba reported being a consultant or advisory board member for Arrowhead Pharmaceuticals; AstraZeneca; Bird Rock Bio, Inc.; Boehringer Ingelheim; Bristol Myer Squibb; Celgene Corporation; Cirius Therapeutics; CohBar, Inc.; Conatus Pharmaceuticals; Eli Lilly and Company; Galmed Pharmaceuticals; Gemphire Therapeutics; Gilead Sciences; Glympse Bio; GNI; GRI Bio, Inc.; Intercept Pharmaceuticals; Ionis Pharmaceuticals, Inc.; Janssen Inc.; Merck Sharp & Dohme; Metacrine, Inc.; NGM Biopharmaceuticals; Novartis; Novo Nordisk; Pfizer; Prometheus; Sanofi; Siemens; and Viking Therapeutics. In addition, his institution received grant support from Allergan; Boehringer Ingelheim; Bristol Myers Squibb; Cirius Therapeutics; Eli Lilly and Company; Galectin Therapeutics; Galmed Pharmaceuticals; GE; GENFIT; Gilead Sciences; Intercept Pharmaceuticals; Grail; Janssen Pharmaceuticals; Madrigal Pharmaceuticals; Merck Sharp & Dohme; NGM Biopharmaceuticals, Inc.; NuSirt Biopharma; Pfizer; pH Pharma; Prometheus; and Siemens. Loomba also reported being a co-founder of LipoNexus, Inc. The other authors’ disclosures are listed on the original paper. Reddy reported having no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).