Biochemical markers of alcohol consumption
Alan S. Rosman
A biochemical marker of alcohol consumption is a laboratory test that provides information about a person’s alcohol use independent of the patient’s self-report. Current biochemical markers of alcohol consumption have limited diagnostic utility. Thus, research is underway to indentify more accurate markers for different applications.
THEORETICAL MARKERS–PRACTICAL
Among the types of biochemical markers of alcohol use that are needed by clinicians and researchers are a reliable screening marker of alcohol abuse and alcoholism, a marker ,of relapse ,to drinking, and a marker of long-term alcohol consumption.
Screening for Alcohol Abuse and
Alcoholism
Physicians need a reliable screening marker of alcoholism to identify patients who are chronic heavy consumers of alcohol. This marker would assist with diagnosis of alcoholism, especially in patients who fail to provide an accurate history of their alcohol consumption. Coupled with treatment, early detection of alcoholism could help to prevent some of the most devastating medical and social consequences of excessive alcohol consumption.
In addition, this marker would have forensic applications. Persons arrested for drinking and driving could be screened for chronic, heavy alcohol consumption and referred to an appropriate treatment program (Luchi et al. 1978; Gjerde and Morland 1987), and public safety workers could be monitored effectively for alcohol abuse.
Monitoring Abstinence
A biochemical marker of relapse that is sensitive even to low levels of drinking is needed to monitor abstinence, the goal of most alcoholism treatment programs (Peele 1984). This marker not only would improve efforts to monitor sobriety in alcoholics undergoing treatment, but also could be used to identify relapse in formerly treated patients. Thus, some previously treated alcoholics who relapse to drinking might be referred to treatment settings less intensive than hospital impatient programs.
Further, a marker of low level alcohol consumption would aid investigators conducting clinial research. Currently, clinical trials (see the article by Fuller in this issue, pp. 239-244) to evaluate the effectiveness of various treatments for alcoholism usually rely on the patients’ self-reports of alcohol consumption as a therapeutic end point. Because patients’ self-reports are not always reliable (Fuller et al. 1988), a biochemical marker of alcohol consumption should assist researchers by providing an objective assessment of abstinence.
Further, this marker would assist the selection of candidates for liver transplantation from among patients with alcohol-induced liver disease (Maddrey and Van Thiel 1988). By providing objective verification of abstinence, a reliable biochemical marker would improve the selection process.
Assessing Long-Term Consumption
A biochemical marker of long-term alcohol consumption also would assist physicians in the diagnosis of diseases other than alcoholism. For example, a common complication of excessive alcohol consumption is chronic pancreatitis. However, because many alcoholic patients with chronic pancreatitis fail to give a reliable history of their alcohol consumption, these patients usually are subjected to exhaustive diagnostic workups to search for causes of pancreatitis that are not alcohol related. To rule out congenital anatomic abnormalities that can predispose to pancreatitis, physicians may require an invasive x-ray of the pancreas, performed by injecting a special dye into a small tube that is inserted from the mouth into the pancreatic duct. This and other invasive procedures would be unnecessary if a blood test could corroborate history of excessive alcohol consumption.
LIMITATIONS OF CURRENT
DIAGNOSTIC TOOLS
At present, physicians base a diagnosis of alcoholism primarily on a patient’s history. However, several studies have reported that patients fail to give an accurate history of alcohol consumption. In a recent Swedish study (Persson and Magnusson 1988), only 16 percent of alcoholics attending a general medical clinic admitted to their physicians that they consumed alcohol heavily. Even when a physician identifies a patient as alcohol dependent and refers the patient for treatment, the patient’s self-report often is the only means available to the physician for long-term monitoring of sobriety.
Various studies (Orrego et al. 1979; Peachey and Kapur 1986; Fuller et al. 1988) have demonstrated the unreliability of patient self-reports of relapse. In Fuller and colleagues’ Veterans Administration Cooperative Study evaluating the effectiveness of disulfiram (Antabuse), the researchers determined through collateral reports and blood alcohol analysis that 35 percent of the patients who claimed to be abstinent in fact were drinking (Fuller et al. 1988). Furthermore, patients reported 28-percent fewer drinking days than were reported by the collaterals.
In other clinical studies where alcohol consumption was monitored by both patient’s self-reports and daily urine specimens for alcohol (Orrego et al. 1979; Peachey and Kapur 1986), more than half of the alcoholic patients who drank while undergoing therapy denied any alcohol use. Thus, self-reports appear to underestimate alcohol consumption in a sizable proportion of patients.
A number of questionnaires (Selzer 1971; Mayfield et al. 1974; Skinner et al. 1984) have been developed in order to improve the detection of alcoholism. Most of the questions inquire about the social consequences of drinking behavior rather than the quantity and frequency of alcohol consumption. Screening questionnaires include the 25-item Michigan Alcoholism Screening Test (MAST) (Selzer 1971), the CAGE questionnaire (Mayfield et al. 1974), and the Skinner trauma questionnaire (Skinner et al. 1984). These tests are relatively easy to administer and may have a high degree of accuracy (Lumeng 1986). Nevertheless, the test results depend on patient cooperation and veracity and can be affected by socioeconomic and cultural factors. In addition, the utility of the questionnares in monitoring alcoholic patients for relapse has not been validated.
CLINICAL UTILITY OF
LABORATORY TESTS
When a clinical evaluation results in uncertainty, a physician may turn to laboratory tests to assist with diagnosis. Gottfried and Wagar (1983) reviewed the principles for evaluating diagnostic tests (including laboratory tests), which are summarized here. The utility of a diagnostic test is determined by its ability to accurately discriminate patients with a disease from patients without a disease. The characteristics used to assess the discriminating ability of a test include sensitivity (the proportion of patients with the disease who have a positive, or abnormal, test) and specificity (the proportion of patients without the disease who have a negative, or normal, test). Both sensitivity and specificity are affected by the cutoff point used to define a positive test and by the types of populations being studied.
When laboratory tests are used for diagnostic purposes, the prevalence of a disease will affect the predictive value of a test. For example, a positive test is more likely to identify a patient with alcoholism in populations in which alcoholism is prevalent than in populations is which it is not prevalent.
To evaluate the accuracy of a laboratory test, a “gold standard” that ascertains the true disease state is needed. At present, however, the various components of the alcohol field have not agreed on a “gold standard” definition of alcoholism. Although the revised third edition of the Diagnostic and Statistical Manual of Mental Disroders (SDM-III-R) (American Psychiatric Association 1987) lists specific guidelines for diagnosing alcohol abuse and alcohol dependence, the utility of these guidelines is dependent on physician awareness, patient cooperation, and social factors.
An alternative approach to defining alcoholism relates to the quantity of alcohol consumed. The findings of several studies suggest that the risk of alcohol-related organ damage is related to cumulative level of alcohol consumption (Lelbach 1975; Pequignot et al. 1978; Tuyns and Pequignot 1984). According to some of these researchers, the risk of organ damage is increased when chronic alcohol consumption exceeds three drinks each day for males and one-and-one-half drinks each day for females (Pequignot et al. 1978; Tuyns and Pequignot 1984). The average alcoholic beverage contains about 14 grams of alcohol. Whereas this approach may allow greater objectivity than the DSM-III-R guidelines, diagnosis nevertheless remains handicapped by the failure of many patients to give an accurate history of alcohol consumption (Fuller et al. 1988; Persson and Magnusson 1988).
CHARACTERISTICS OF THE
IDEAL MARKER
For optimal clinical application, a marker of alcohol use should be noninvasive (e.g., blood, urine, or breath tests). (Figure 1 describes how blood specimens are processed for many laboratory tests.) In addition, the marker should have both high sensitivity and high specificity. Because of the stigma associated with a diagnosis of alcoholism, the possible causes of false-positive tests (i.e., abnormal test results that suggest the possibility of alcoholism in nonalcoholic patients) should be identified readily and excluded easily. Thus, an ideal marker should not be elevated significantly in patients with nonalcoholic liver disease or malnutrition. Finally, the ideal marker should persist for several days after a drinker resumes abstinence, but then would revert to a normal state after a reasonable period of abstinence (approximately 2-4 weeks). A marker that meets all these criteria has not been identified (Salaspuro 1989). For example, blood alcohol content (BAC) identifies recent but not chronic consumption. Because alcohol is metabolized by the liver at a rate of approximately 10 grams each hour (approximately one drink every 90 minutes) (Rowland and Tozer 1988), an alcoholic patient who drinks only in the evenings may evidence a negative BAC the following mornings.
Although an ideal marker has yet to be identified, some recent research findings have advanced our understanding of the biochemical and physiological consequences of chronic alcohol use (Lieber 1988). For example, it is now known that excessive drinking can be associated with lasting effects to the liver, blood proteins, and red blood cells (Lieber 1988). Further characterization of these effects could result in an improved marker of long-term alcohol consumption.
CURRENTLY AVAILABLE
MARKERS
Physicians use a variety of blood tests–some of which can be affected by heavy alcohol consumption–to evaluate a patient’s blood count and liver function. However, abnormalities in these tests are neither highly sensitive nor specific for alcoholism. Despite their limitations, clinicians use these tests for corroborating their clinical suspicion of alcoholism. Commonly used markers include the gamma glutamyl transpeptidase (GGT); mean corpuscular volume (MCV); liver enzymes, especially the transaminases; and high density lipoprotein (HDL) cholesterol.
Gamma Glutamyl Transpeptidase
Gamma glutamyl transpeptidase (GGT) is an enzyme involved in the metabolism of glutathione, an important component of liver and biliary tract cells (Tate and Meister 1981). In the liver cell, GGT is localized to cell membranes (Ishii et al. 1986). The cell membranes prevent GGT and other liver enzymes from leaking from the liver cells to the bloodstream. However, liver enzymes can leak to the bloodstream if the cell membrane is damaged or if cell death occurs as mediated by alcohol and other toxins.
Alcohol consumption can affect GGT level in three ways:
* Chronic consumption can stimulate the liver cells to synthesize GGT (Shaw and Lieber 1980).
* Alcohol exposure can cause the liver cell membranes to leak, resulting in the release of GGT and other liver enzymes into the bloodstream (Yamada et al. 1985).
* Chronic consumption occasionally causes liver cell death, also resulting in the release of GGT and other liver enzymes into the bloodstream.
In a study of nonalcoholic volunteers (Belfrage et al. 1973), high does of alcohol administered over a 5-week period caused a significant increase in GGT. However, the degree of GGT elevation varied considerably among the study participants. Numerous clinical studies (as reviewed by Rosman and Lieber in press) also have demonstrated that serum GGT levels vary among alcoholic patients. After pooling the results of several studies, the authors estimated the sensitivity of serum GGT for alcoholism at approximately 62 percent in hospitalized alcoholics and approximately 43 percent in ambulatory alcoholics (Rosman and Lieber in press). The disparity in rates for the two populations may reflect the greater severity of alcoholism in the hospitalized patients.
Serum GGT has been shown to be a more sensitive marker of alcoholism in patients with suspected liver disease than in patients without apparent liver disease (Moussavian et al. 1985). In addition, GGT level may be a useful means of monitoring patients being treated for alcoholism: A serum GGT level greater than a patient’s serum GGT level during abstinence may be a marker of relapse (Shaw et al. 1979).
However, elevated serum GGT is not specific for excessive alcohol consumption. A variety of medications, such as anticonvulsants, anticoagulants, and oral contraceptives, can increase the serum GGT level (Salaspuro 1989), as can a variety of medical conditions, such as nonalcoholic liver disease, gall bladder inflammation, biliary tract disease, lipid disorders, and obesity (Salaspuro 1989). In ambulatory patients, the specificity of serum GGT for alcoholism is approximately 85 percent (Baxter et al 1980; Chick et al. 1981; Skinner et al. 1984).
Because of its moderate sensitivity, serum GGT is not an ideal screening test of alcoholism. Even so, serum GGT level may be useful for confirming a clinical suspicion of alcoholism and for monitoring patients in alcoholism treatment.
Mean Corpuscular Volume
A laboratory test that measures the size of red blood cells, the mean corpuscular volume (MCV) usually is performed as part of a routine blood count. Alcohol consumption can elevate the MCV in several ways:
* Heavy consumption can increase the size of the red blood cells by a mechanism that, although poorly understood, is believed to be related to a direct toxic effect of alcohol on the red cells.
* Chronic alcohol consumption occasionally results in folic acid deficiency, which also can increase the MCV.
* Advanced liver disease may produce an elevated MCV.
However, only 35 to 40 percent of alcoholic patients experience an elevated MCV. Thus, an MCV test is less sensitive for detecting alcoholism than the GGT test. In addition, alcoholic patients may have an elevated MCV for several months, despite abstinence and despite folic acid replacement; for this reason, the MCV is not useful for monitoring abstinence (Shaw et al. 1979). Finally, a variety of other conditions (folic acid deficiency independent of alcoholism, [B.sup.12] deficiency, hypothyroidism, nonalcoholic liver disease, and leukemias, for example) can increase red cell size (Davidson and Hamilton 1978).
Because these other causes of an elevated MCV are not common in outpatient settings, the MCV test is 90- to 95-percent specific for alcoholism (Baxter et al. 1980; Chick et al. 1981; Skinner et al. 1984). Because this specificity is greater than that of most markers for alcoholism, the MCV occasionally is useful for detecting alcoholism.
Transaminases
The liver enzymes most commonly used as markers include the transaminases, a group of enzymes involved in amino acid metabolism. The levels of two transaminases–aspartate aminotransferase (AST), also known as glutamic oxaloacetic transaminase (GOT), and alanine aminotransferase (ALT), also known as glutamic pyruvic transaminase (GPT)–often are tested in routine screening for liver damage.
Because AST also is present in muscle and heart cells, this enzyme may be elevated in muscular disorders and in myocardial infarctions (Zimmerman and West 1963), as well as in alcoholism. In contrast, ALT is abundant in the liver but is present in other tissues only in trace amounts. Thus, elevations in serum ALT are highly suggestive of liver disease (Zimmerman and West 1963). Heavy alcohol intake can cause increased leaking of the transaminases from the liver cells into the bloodstream either by causing the cell membranes to become leaky or by severely injuring liver cells, thus causing cell death (Clermont and Chalmers 1967).
Researchers have demonstrated that chronic ethanol administration can elevate serum transaminase levels both in experimental animals (Lieber et al. 1975) and in human subjects (Belfrage et al. 1973). In the human study, Belfrage and colleagues (1973) found that the elevations in serum transaminases were modest, only infrequently exceeding the upper limits of normal. After pooling the results of several studies, the authors estimated the sensitivity of the serum transaminases for detecting alcoholism at only 35 percent (Rosman and Lieber in press).
Despite this low sensitivity, significant elevations in serum transaminases may suggest severe liver injury in alcoholic patients (Salaspuro 1989), although considerable individual variability has been observed (Worner and Lieber 1980). In addition, when tested in conjunction with other possible markers of alcoholism, the transaminases may be useful in corroborating a clinical suspicion of alcoholism.
High Density Lipoprotein
Cholesterol
High density lipoprotein (HDL) functions in the transport of excess cholesterol from various tissues to the liver and may have a protective role against atherosclerosis, or hardening of the arteries. A major component of HDL is cholesterol, which can be measured easily by most commercial laboratories.
The effects of alcohol consumption on HDL cholesterol are complex. Even moderate alcohol consumption (2-3 drinks each day) can elevate serum HDL cholesterol (Haskell et al. 1984). This elevation may be due in part to increased HDL production by the liver in response to alcohol consumption.
However, serum HDL decreases with liver cirrhosis, the scarring that can result from years of heavy drinking. The development of cirrhosis causes a decrease in the liver’s production of HDL (Devenyi et al. 1981; Tateossian et al. 1985).
Alcohol’s complex effects on HDL metabolism limit the application of HDL cholesterol as a marker of alcohol consumption. The estimated sensitivity of HDL cholesterol is just 30 percent (Rosman and Lieber in press). Further, because even moderate drinking can increase HDL cholesterol levels, HDL cholesterol is not specific for heavy alcohol consumption. In contrast to other markers, HDL cholesterol also is affected strongly by gender: Females tend to have higher levels than males. In addition, such other factors as diet, exercise, and medications can affect HDL cholesterol levels.
SPECIAL LABORATORY MARKERS
Some special laboratory markers of alcoholism have been developed during the last 10 years. Some of these markers show considerable promise for clinical application in the near future.
Alpha Amino-N-Butyric Acid
Alpha amino-n-butyric acid (AANB) is an amino acid that is derived from other amino acids such as methionine, serine, and threonine (Lieber and Shaw 1983). The findings of studies both in experimental animals and in humans have demonstrated that chronic alcohol consumption can increase plasma AANB levels (Lieber and Shaw 1983).
However, because a variety of nutritional and metabolic factors also can affect AANB metabolism, plasma AANB is not an accurate screening marker of alcoholism (Lieber and Shaw 1983). Nevertheless, sequential AANB measurements may be helpful in identifying relapses in patients in treatment for alcoholism (Shaw et al. 1979).
Carbohydrate-Deficient Transferrin
Transferrin is a plasma protein, synthesized and secreted by the liver, that is involved primarily in the transport of iron. The results of recent studies (Stibler and Borg 1986; Stibler et al. 1986; Behrens et al. 1988) suggest that alcohol may have important effects on transferrin metabolism.
The transferrin molecule usually is attached to various carbohydrate components. Stibler and Borg (1986) reported that some of the transferrin molecules found in the blood of alcoholic patients were lacking some of these carbohydrate components. The mechanism of this alteration is not clear.
Having developed and applied laboratory tests to measure the amount of carbohydrate-deficient transferrin (CDT) in serum, several investigators (Stibler et al. 1986; Kapur et al. 1989) have reported that most alcoholic patients have elevated levels of CDT. A recent study at the Bronx Veterans Administration Medical Center (Behrens et al. 1988) reported that the sensitivity of CDT for detecting alcoholism is at least 80 percent (Figure 2)–a sensitivity that is superior to that of other available markers.
Further, elevated CDT levels appear to be specific for heavy alcohol consumption (Stibler et al. 1986). CDT was elevated neither by moderate alcohol consumption (fewer than four drinks each day) nor by various medications (anticonvulsants, for example) that are known to elevate serum GGT and transminases (Stibler et al. 1986). In addition, studies (Stibler and Hultcrantz 1987; Behrens et al. 1988) have reported that most types of nonalcoholic liver disease do not affect CDT levels. However, CDT on occasion can be elevated in nonalcoholic patients with primary biliary cirrhosis, a rare type of autoimmune liver disease (Figure 3) (Behrens et al. 1988).
The findings of these initial studies suggest that serum CDT, with both
higher sensitivity and higher specificity than other available markers, may be a useful marker of alcoholism. Additional research is required to determine whether monitoring serum CDT levels in alcoholics is useful in identifying relapses. Currently, the CDT test is not commercially available, but practical tests are being developed (Xin et al. in press).
Red Blood Cell Acetaldehyde
Typically, alcohol is converted by the liver to acetaldehyde. Because plasma acetaldehyde is metabolized to carbon dioxide within a few hours after drinking (Korsten et al. 1975; DiPadova et al. 1987), plasma acetaldehyde is not a reliable marker of alcohol consumption. However, most blood acetaldehyde is found not in the plasma but in the red blood cells (Baraona et al. 1987). In contrast to elevations in plasma acetaldehyde, elevations in red blood cell acetaldehyde may persist for days or weeks even in alcoholic patients who resume abstinence (Figure 4) (Hernandez-Munoz et al. 1989). In addition, researchers (Hernandez-Munoz et al. 1989) found elevations in red blood cell acetaldehyde in most of the alcoholic patients hospitalized for detoxification at the Bronx Veterans Administration Medical Center. However, it should be noted that, although findings of this study suggest that red blood cell acetaldehyde may be a sensitive test of alcoholism, at least one preliminary observation (Upeal et al. 1990) has reported that the marker may be elevated in nonalcoholic patients with liver disease such as viral hepatitis and drug-induced liver injury.
Red Blood Cell Cysteine
A recent study (Hernandez-Munoz et al. 1989) in alcoholic patients revealed that their red blood cells haad elevated levels of cysteine (a nonessential amino acid) compared with the red blood cells of healthy laboratory volunteers. Further, the elevations in red blood cell cysteine associated with alcoholism may persist for several weeks after abstinence (Figure 5).
Although a test for red blood cell cysteine holds promise as a screening marker of alcoholism, further investigation is needed to confirm the preliminary findings.
Other Acetaldehyde Adducts
Several chemical studies reviewed by Sorrell and Tuma (1987) suggest that acetaldehyde may bind to a variety of amino acids and proteins. These amino acids and proteins that are coupled to acetaldehyde are known also as alcohol adducts. Just as the amount of glucose coupled to hemoglobin can serve as a measure of long-term blood glucose in diabetics (Jovanovic and Peterson 1981), the amount of acetaldehyde adducts formed in the blood may reflect the quantity of acetaldehyde generated in the body. Because the most common source of acetaldehyde is from ethanol, acetaldehyde adducts may serve as a marker of long-term alcohol consumption.
At present, acetaldehyde adducts have
[TABULAR DATA OMITTED]
not been consistently identified in the blood of alcoholic patients. Thus, acetaldehyde adducts remain a theoretical marker of alcoholism.
Other Liver Enzymes
Heavy alcohol intake may cause the release of other liver enzymes into the blood. Two of these enzymes, betahexosaminidase (Karkhainen et al. 1990) and the form of aspartate aminotransferase (AST) found in the mitochondria (the cell’s principal energy source) (Nalpas et al. 1984), were reported to be increased in the serum of most alcoholic patients. However, these enzymes also may be elevated in nondrinking patients with nonalcoholic liver disease.
COMBINING MARKERS
Because no available marker has been shown to have sufficient diagnostic accuracy to be used for screening ambulatory patients for alcoholism (Salaspuro 1989), investigators have attempted to combine markers in order to improve diagnostic accuracy.
Markers may be combined qualitatively to improve sensitivity or specificity. To improve sensitivity, physicians may use a battery of laboratory tests and require that at least one of the tests is positive for a diagnosis of alcoholism. However, this type of combination will decrease specificity.
Alternatively, physicians may improve specificity by using a battery of laboratory markers and diagnosing alcoholism only if all the tests are positive. However, this type of combination will decrease sensitivity.
Finally, various statistical techniques, such as discriminant analysis, [1] may be used to combine the laboratory markers mathematically, generating a formula for diagnostic classification. Whereas discriminant analysis techniques can improve diagnostic accuracy, these techniques have some limitations in alcohol research, as described by Dolinsky and Schnitt (1988).
First, because the accuracy of these techniques may decrease in some populations, the formulas require extensive statistical validation. Second, the computations may be quite complex and not easily amenable to clinical practice. Despite these limitations, however, discriminant analysis can be a valuable research tool in studies evaluating a large number of laboratory markers.
CONCLUSIONS
Used alone, available markers of alcohol consumption (Table 1 ) may be helpful in corroborating a clinical suspicion of alcoholism. Combined in a qualitative or quantiative fashion, available markers can improve diagnostic accuracy stll further. Nevertheless, no conventional marker or combination of markers has sufficient diagnostic accuracy to be used with complete confidence.
Research is underway to identify more-accurate markers and to improve the utility of the markers discussed in this review. The success of those investigations will portend substantial improvements in the diagnosis and treatment of alcoholism.
ALAN S. ROSMAN, M.D., is assistant chief of the Alcohol Treatment Program, Veterans Affairs Medical Center, Bronx, New York, and clinical instructor at Mount Sinai School of Medicine (City University of New York).
CHARLES S. LIEBER, M.D., is director of the Alcohol Research and Treatment Center and the GI-Liver-Nutrition Program, Veterans Affairs Medical Center, Bronx, New York, and professor of medicine and pathology at Mount Sinai School of Medicine (City University of New York).
The original studies reviewed in this article were supported by DHHS Grants AA07802 and AA03508 and the Veterans Administration.
(1) A common example of the use of discriminant analysis can be demonstrated by college admissions committees that generate a composite score of a high school applicant by weighing the high school grade point average, verbal SAT score, and mathematical SAT score. Discriminant analysis is a statistical device that generates and validates the composite scoring system.
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