Alcohol Use Biomarkers

Medical Experts

Contributor

Johnson-Davis

Kamisha L. Johnson-Davis, PhD, DABCC (CC, TC)

Professor of Pathology (Clinical), Adjunct Assistant Professor, Pharmacology and Toxicology; Director, Clinical Chemistry Fellowship Program, University of Utah

Medical Director, Clinical Toxicology, ARUP Laboratories

Approximately 20% of primary care patients in the United States drink alcohol (ethanol) at levels harmful to health. A blood-alcohol concentration over 250 mg/dL is considered toxic and may result in loss of motor function, impaired consciousness, respiratory depression, and death. Other effects of alcohol exposure include cardiomyopathy, stroke, fatty liver disease, fibrosis, pancreatitis, increased risk of developing cancer, psychological disorders, and vitamin deficiency, as well as fetal alcohol syndrome for those exposed in utero. Ethanol ingestion by children may cause hypoglycemia.

Diagnostic criteria for alcohol use disorder (AUD) vary, but the most widely used criteria are found in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Laboratory tests for acute alcohol ingestion include ethanol, ethyl glucuronide (EtG), and ethyl sulfate (EtS) tests. Carbohydrate-deficient transferrin (CDT) and phosphatidylethanol (PEth) are useful markers for monitoring abstinence after long-term use.

Quick Answers for Clinicians

Which markers have the greatest specificity for detecting alcohol exposure, and which markers are nonspecific?

The most specific markers for detecting acute alcohol exposure are ethanol, ethyl glucuronide (EtG), and ethyl sulfate (EtS). Specific markers for chronic alcohol use are carbohydrate-deficient transferrin (CDT) and phosphatidylethanol (PEth). Nonspecific markers include gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV), aspartate aminotransferase (AST), and alanine aminotransferase (ALT).

What is the detection window for each analyte?

The window of detection depends on the sample type and quantity of alcohol consumed. See Attributes of Ethanol Biomarkers table for general ranges.

Which specimen types are best to detect alcohol exposure?

Oral fluid is easy to collect and shows a strong correlation with blood-alcohol levels.

Urine is the most widely used specimen type for drugs-of-abuse testing because of ease of collection and analysis; many tests can be performed on site. However, urine is susceptible to contamination and dilution and is not optimal for determining level of consumption.

Blood provides the best evidence of use and corresponding drug levels; it lends itself more to clinical and emergency toxicology settings than to routine screening.

Hair can provide a history of drug use because drugs can remain in the hair for a long period of time, but testing cannot distinguish drinking levels.

Sweat has been shown to be sensitive and accurate, but testing is less practical than for other specimen types.

What are the pharmacokinetics of ethanol (absorption, distribution, metabolism, and elimination) in adults and children?

In adults, some ethanol is absorbed by the stomach, although the majority is quickly absorbed into the intestines. Ingestion of food delays absorption. The distribution of ethanol into body tissues and fluids is proportionate to the body’s water content, which varies by age, weight, and sex. More than 90% of ethanol is metabolized by either alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), or catalase, and the rest is eliminated unchanged in breath, sweat, and urine. Of that metabolized, a small amount is not oxidized, which results in substrates that can be used as biomarkers of consumption.

In neonates and children, absorption may be reduced because of slower and more irregular stomach emptying, and the volume of distribution in children is greater because of greater body water content, less fat, and variable blood flow. Metabolism is affected by decreased ADH and CYP2E1 levels, and decreased renal function may slow elimination.

How is alcohol use classified?

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) uses the following definitions:

Moderate drinking is considered one drink per day for women and up to two drinks per day for men.
Binge drinking refers to consumption that causes the blood alcohol concentration to reach 0.08 g/dL.
Women are considered to be at low risk of developing alcohol use disorder (AUD) if they consume fewer than four drinks in 1 day and fewer than eight drinks per week; men are considered at low risk for AUD if they consume fewer than five drinks in 1 day and fewer than 15 drinks per week. For symptoms of AUD, see Criteria for Diagnosis.

When is it appropriate to perform laboratory testing for the ingestion of toxic alcohols (acetone, isopropanol, and methanol)?

Laboratory testing for acetone, isopropanol, and methanol concentrations is confirmatory and is not used in the initial evaluation of potential toxicity. The typical test methodology used to measure these toxic alcohols is gas chromatography. Because this method is not available in all healthcare settings, this testing may need to be sent to another laboratory, increasing the turnaround time to receive a result. Due to the time-sensitive nature of acute toxic alcohol consumption, clinical observation and other tests are preferred for immediate diagnosis and treatment.

Indications for Testing

Laboratory testing is appropriate in the context of suspicion of alcohol use or exposure, trauma-related injury, substance abuse treatment monitoring, or follow-up testing to investigate other biomarker abnormalities that suggest alcohol use or exposure, including abnormalities in mean corpuscular volume (MCV) or in gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), or alanine aminotransferase (ALT) concentrations.

Laboratory Testing

Acute Alcohol Use Biomarkers

Ethanol

Serum ethanol testing provides the most accurate determination of a patient’s alcohol level. Acute ethanol intoxication is not reliably detected by serum ethanol testing beyond the first 6-8 hours.

Ethyl Glucuronide and Ethyl Sulfate

EtG and EtS are direct minor metabolites of ethanol and are considered good markers of acute, short-term (up to 36 hours in the blood, up to 5 days in urine) alcohol ingestion. The sensitivity of these tests is highest in heavy drinkers but wanes after 24 hours and with lower doses. Results do not accurately correlate with the amount or frequency of ethanol use.

Refer to the ARUP Consult Emergency Toxicology topic for more information about acute alcohol use testing.

Chronic Alcohol Use Biomarkers

Carbohydrate-Deficient Transferrin

CDT, an indirect metabolite of ethanol, is a serum marker of long-term, heavy alcohol use (≥40 g/day for up to 2 weeks) or relapse. CDT concentrations generally correlate well with an individual’s drinking pattern, especially during the preceding 30 days, and is most useful for long-term abstinence monitoring. Factors that affect CDT levels include body mass index (BMI), female sex, and smoking. CDT testing cannot be used in individuals suspected of having congenital glycosylation disorders.

Phosphatidylethanol

PEth is a direct ethanol metabolite and can be tested to detect longer term exposure (within 1-2 weeks or longer). Because blood PEth levels are closely correlated with alcohol consumption, PEth testing can be used to monitor alcohol consumption, identify early signs of harmful alcohol consumption, and track cases of AUD or dependence.

Nonspecific Biomarkers

Gamma-Glutamyl Transferase

GGT is an inexpensive and sensitive indirect marker of alcohol consumption. Even moderate drinkers (<60 g/week), especially men, show higher levels of GGT than abstainers do.

The limitations of GGT include lack of specificity; levels may be elevated with nonalcoholic fatty liver disease, drug intoxication, obesity, diabetes, and hepatobiliary disorders. GGT is also age dependent; concentrations increase with age, even in abstinent individuals. Normalization of GGT requires 2-3 weeks of abstinence.

Mean Corpuscular Volume

MCV, the average size of a person’s red blood cells, increases with high quantities of alcohol ingestion. Compared with other biomarkers, MCV has low sensitivity but higher specificity for alcohol use. Because this test can detect previous alcohol exposure, even after a long period without alcohol consumption, it is not useful for monitoring abstinence in those recovering from AUD.

Aspartate Aminotransferase and Alanine Aminotransferase

AST and ALT enzymes have low sensitivity and specificity to screen for excessive alcohol consumption, but they are highly sensitive and specific for detecting alcohol-induced liver damage. The AST/ALT ratio increases with alcohol consumption; an AST/ALT ratio >1 is considered suggestive of alcohol as the cause of liver dysfunction. ALT is less sensitive than AST, but both can be effective tools in combination with other biomarkers to identify heavy drinking.

Attributes of Ethanol Biomarkers

Biomarker	Window of Detection	Positive Cutoff Value	Associated ARUP Tests
Ethanol	1-12 hrs in blood or urine	Varies based on instrumentation	Ethanol, Serum or Plasma – Medical 0090120
EtG/EtS	1-5 days in urine 36 hrs in blood Months in hair, nails Last trimester of full-term pregnancy in umbilical tissue	≥100 ng/mL	Ethyl Glucuronide and Ethyl Sulfate, Urine, Quantitative 2007909
		≥500 ng/mL	Ethyl Glucuronide Screen with Reflex to Confirmation, Urine 2007912
		5 ng/g	Ethyl Glucuronide, Umbilical Cord Tissue, Qualitative 3000443
CDT	2-3 wks in serum/plasma	≥1.7%	Carbohydrate Deficient Transferrin for Alcohol Use 0070412
PEth	1-2 wks or longer (blood)	≥20 (moderate alcohol consumption) ≥200 ng/mL (heavy alcohol consumption or chronic alcohol use)	Phosphatidylethanol (PEth) 3002598
GGT	2-3 wks in serum/plasma	Varies based on instrumentation	Gamma Glutamyl Transferase, Serum or Plasma 0020009
AST	1-4 wks in serum/plasma	Varies based on instrumentation	Aspartate Aminotransferase, Serum or Plasma 0020007
ALT	Unknown	Varies based on instrumentation	Alanine Aminotransferase, Serum or Plasma 0020008
Blood cell counts (MCV)	2-4 mos (blood)	>100 fL	n/a
FAEE	Up to 24 hrs in serum Months in hair	>0.5 ng/mg of hair	n/a
AA-Ab	1-3 wks in blood	Not established	n/a
Beta-hexosaminidase	1-2 wks in serum 2-4 wks in urine	Varies based on instrumentation	n/a
Sialic acid	Variable in serum	>60 mg/dL	n/a
AA-Ab, acetaldehyde adduct and associated antibodies; FAEE, fatty acid ethyl esters; n/a, not available Sources: Nanau, 2015; Allen, 2020; Jastrzębska, 2016; Niemelä, 2016; Dasgupta, 2014

Criteria for Diagnosis

The DSM-5 includes a list of 11 criteria for defining AUD with mild, moderate, and severe subclassifications. Mild AUD is classified as the presence of two or three symptoms over the past year; moderate, four or five symptoms; and severe, six or more symptoms. A brief description of the 11 criteria follows:

Alcohol is often used in larger amounts or over a longer period than intended.
The individual has had a persistent desire or unsuccessful attempts to cut down or control alcohol use.
A significant amount of time is spent in activities necessary to obtain, use, or recover from alcohol.
The individual has a craving or urge to use alcohol.
Recurrent alcohol use has resulted in failure to fulfill obligations at work, school, or home.
Alcohol use has continued despite alcohol-related social or interpersonal problems.
Alcohol use has continued despite persistent or recurrent alcohol-related physical or psychological problems.
Important activities have been given up or reduced because of alcohol use.
The individual has engaged in recurrent alcohol use in physically hazardous situations.
The individual demonstrates evidence of tolerance.
The individual has demonstrated withdrawal symptoms or syndrome.