Biomarkers for alcohol use and misuseBiomarkers for alcohol use and misuse

The use of alcohol is widely accepted especially in western countries. This social acceptance with ease of access may lead to over-use. Alcoholism is not only a major socio-economic problem, but it is a leading cause of severe health disorders and contributes to mortality.

There are several alcohol biomarkers available to detect alcohol consumption. However, they vary in sensitivity and specificity. This can result in the physician missing patients with alcohol abuse depending on the marker used in the screening. The first step in the correct management of alcohol abuse is the initial assessment of the case, which relies upon dependable biomarkers. This article represents an update on alcohol biomarkers and their optimum clinical uses.

Metabolism of Alcohol (Ethanol)

The liver is the primary organ responsible for the detoxification of alcohol. Liver cells produce alcohol dehydrogenase (ADH), the enzyme primarily responsible for metabolising alcohol and breaking it down into ketones. Alcohol is also metabolised in extrahepatic tissues that do not contain ADH, such as the brain, by enzymes cytochrome P450 and catalase.

In addition to the oxidative pathways mentioned, alcohol can also be metabolised by at least two nonoxidative pathways. Although the nonoxidative metabolism of alcohol is minimal, its products have a significant diagnostic relevance. The first pathway leads to the formation of molecules called fatty acid ethyl esters (FAEEs) from the reaction of alcohol with fatty acids. The second requires the enzyme phospholipase D (PLD) results in the formation of a phospholipid known as phosphatidyl ethanol.

The products of both the oxidative and non-oxidative pathways are quickly released into circulation, through which ethanol metabolites affect the peripheral organs (see figure 1).

Women have lower levels of gastric alcohol dehydrogenase, the enzyme primarily responsible for metabolising alcohol than men, and as a result, they experience higher blood alcohol concentrations upon consuming similar amounts of ethanol per kilogram of body weight.

What is the ideal marker to detect alcohol use or misuse?

To decide which marker should be used, it is helpful to understand the utility of both direct and indirect biomarkers and the suitable clinical application.

Indirect alcohol biomarkers

Indirect biomarkers are enzymes or cells which undergo typical changes in response to chronic alcohol consumption. The main indirect biomarkers are liver enzymes aspartate and alanine aminotransferases (AST and ALT), gamma glutamyl transferase (GGT), mean corpuscular volume (MCV) and carbohydrate-deficient transferrin (CDT).

ALT and AST: Both non-specific markers signify liver damage or disease at high concentrations in the blood. This could be caused by long-term alcohol abuse. They are found predominantly in the liver, but AST can also be present in the heart, muscles, and kidneys, etc. ALT levels can also increase in extra-hepatic conditions such as type 2 diabetes, metabolic syndrome, and insulin resistance.

GGT: An enzyme found in the hepatocytes. Elevation of GGT level is usually considered an early indicator of liver diseases and chronic drinking. However, data has shown that GGT levels only increased in 30 to 50 per cent of excessive drinkers, so it is not a very sensitive marker.

MCV: The MCV of red blood cells increases with excessive alcohol intake after four to eight weeks and returns to normal about four months after consumption stops. it has been reported to lack sensitivity and produces false positives in cases of smoking, liver diseases, thyroid diseases, and vitamin B12 or folic acid deficiency.

CDT: This is a biomarker for moderate to heavy alcohol consumption. Drinking 50 to 80 grammes of alcohol/day for several days decreases the carbohydrate content of transferrin, thus giving rise to free sialic acid and sialic-acid deficient transferrin. CDT levels return to normal within approximately two weeks of drinking cessation. Testing for CDT is the only FDA-approved lab test available to help doctors monitor progress toward reducing alcohol consumption.

Direct alcohol biomarkers

Direct biomarkers of alcohol use are ethanol metabolites created through the metabolism of ethanol. They reflect alcohol consumption over a period of several days, making them useful to detect acute alcohol intake. Direct alcohol biomarkers include EtG, EtS, FAEEs and PEth.

EtG: This is considered a stable marker to detect recent ethanol ingestion. The metabolite appears one hour after ethanol ingestion, with a detection window of up to 36 hours in blood and five days in urine. Due to this big-time window, many studies demonstrated the importance of measuring urine EtG in those who do not admit to consuming alcohol and provide negative breathalyser test. In addition to blood and urine, EtG is detectable in hair and other body fluids. False positive results may be reported after the use of ethanol-based mouthwash and after the consumption of non-alcoholic beers.

Peth: This can be detected in blood from one to two hours, and up to 12 days after one-time alcohol consumption, meaning this biomarker can be used to determine both current consumption and abstinence. It is also considered as the most sensitive and highly specific alcohol biomarker, as it is not affected by liver or kidney diseases. This also means it can identify recent heavy drinking earlier than indirect markers. The one drawback is that the cut-off levels tend to arbitrary and vary with different guidelines.

FAEEs: These are sensitive and specific markers for distinguishing social drinkers from heavy or alcohol-dependent drinkers. FAEE levels have been detected in blood up to 24 hours after the last drink or 99 hours for chronic drinkers, combined with blood ethanol levels which increase for only eight hours. It also detects serum concentrations of ethyl oleate, which is observed to be higher in chronic alcohol users than in binge drinkers.

In summary, which marker should be used to detect alcoholism?

Testing for alcohol biomarkers should be aligned with clinical needs/expectations e.g. acute or chronic alcohol use, ruling out recent alcohol use, or monitoring alcohol abstinence. A combination of different biomarkers is often advisable, as they differ in their underlying pathomechanism.

In case of acute ethanol intoxication after the first six to eight hours is not reliably predicted by serum testing, so other biomarkers are often used to detect alcohol use as EtG and EtS. They also are useful in short-term monitoring for abstinence. On the other hand, Carbohydrate deficient transferrin (CDT) is markedly increased by moderate to heavy alcohol use and is the most useful for long-term abstinence monitoring (up to two weeks). Finally, alcohol biomarker results should be always interpreted in the context of all relative values such as history, physical and mental examination, and clinical picture.

Dr. Shereen Atef, MD is the Acting Head of Clinical Chemistry at the National Reference Laboratory, and Adjunct Clinical Faculty at the College of Medicine and Health Sciences at Khalifa University. 

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This article appears in the latest issue of Omnia Health Magazine. Read the full issue online today.

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