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self index.cfm
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Alan Trachtenberg, Md  
     
     

Evidence-Based Reviews

PDF version of this article

Vol. 7, No. 9 / September 2008

?I?m sober, Doctor, really?: Best biomarkers for underreported alcohol use

?CASE 1: Depression and substance abuse
?Markers of alcohol abuse
?Combinations improve detection
?Consider patients? comorbidities
?CASE 2: Altered mental status
?CASE 3: Suicide attempt?

When and how to use highly specific combinations to assess withdrawal risk.

David R. Spiegel, MD

Associate professor of clinical psychiatry and behavioral sciences, Director of consultation-liaison services

Department of psychiatry and behavior sciences, Eastern Virginia Medical School, Norfolk

Neetu Dhadwal, MD

Resident

Department of psychiatry and behavior sciences, Eastern Virginia Medical School, Norfolk

Frances Gill, MD

Resident

Department of psychiatry and behavior sciences, Eastern Virginia Medical School Norfolk

Hospitalized patients who are not truthful about their alcohol consumption may be at risk for an unplanned withdrawal. Self-reports of alcohol use?such as CAGE and the Alcohol Use Disorders Identification Test (AUDIT)?are valid, inexpensive, and noninvasive, but patients easily can feign results.1 Biochemical measures are more objective, and combinations of markers are an effective tool to detect recent heavy drinking in the 10% to 25% of patients who underreport alcohol use.2

Biochemical measures can detect acute alcohol intoxication and recent prolonged drinking. Because marker levels return to normal after long-term abstinence, ongoing monitoring can help detect a relapse before a patient admits to it.3

This article presents 3 cases in which biochemical markers helped prevent alcohol withdrawal in patients who denied alcohol abuse. We discuss why we ordered biochemical tests and which combinations provided highly sensitive results.

CASE 1: Depression and substance abuse

Ms. C, age 39, presents with bleeding gums due to excessive warfarin, which she takes prophylactically for a history of deep vein thrombosis. She is seen by the psychiatric consultation service for depression?which she says she has experienced since ?the day I was born??and substance abuse that includes a history binge drinking. Ms. C says she has stopped drinking and remained abstinent for the past year because she is fearful of further damaging her kidneys. She also denies psychosis. She does not have a history or symptoms of hepatobiliary or hematologic disease.

Clinical Point

Because biomarker levels return to normal after abstinence, ongoing monitoring can help detect relapse

Challenge. Despite Ms. C?s self-reported 1 year of sobriety, her history of binge drinking and depression calls for evaluating her alcohol withdrawal risk. Laboratory markers of alcohol abuse are the only means to assess her recent drinking behavior.

Discussion. Lab results include serum albumin of 3.4 g/dL, total bilirubin of 0.3 mg/dL, total protein of 6.3 g/dL, aspartate aminotransferase (AST) of 13 U/L, alanine aminotransferase (ALT) of 19 U/L, alkaline phosphatase of 136 U/L, and blood ammonia level of 37 ?g/dL. Gamma-glutamyl transferase (GGT) is elevated at 104 U/L (normal range for women: 0 to 45 U/L). Mean corpuscular volume (MCV) is elevated at 101 fL (normal range 80 to 100 fL).

The combination of elevated MCV and GGT has a 95% sensitivity for alcohol abuse.4 GGT levels become elevated after 24 hours to 2 weeks of heavy alcohol consumption and return to normal within 2 to 6 weeks of abstinence, which allows them to detect binge drinking. MCV takes 6 to 8 weeks of heavy drinking?we which we define as consuming ?40 grams of alcohol/day5?to become elevated and returns to normal within 3 months of abstinence.

These data provide evidence that Ms. C recently consumed substantial amounts of alcohol. As a result, we start her on alcohol withdrawal precautions (AWP).

Markers of alcohol abuse

Biochemical markers commonly used to detect alcohol abuse (Table 1) include:

  • blood alcohol level (BAL)

  • MCV

  • liver function tests (LFTs) such as ALT, AST, and GGT

  • carbohydrate deficient transferrin (CDT).

Table 1By the numbers: Biomarkers of excessive alcohol consumption


Biomarker


CDT

GGT

AST

ALT

MCV


Blood test normal range

<60>

Women: 0 to 45 U/L Men: 0 to 53 U/L

10 to 34 U/L

8 to 37 U/L

80 to 100 fL


Blood test abnormal range

>1.3% of total transferrin concentration

Women: >45 U/L Men: >53 U/L

Levels rarely exceed 500 U/L

Levels rarely exceed 300 U/L

>100 fL


Time to elevation

2 to 3 weeks

24 hours to 2 weeks

3 to 7 days

3 to 7 days

After 6 weeks


Time to descent to normal levels

2 to 4 weeks of abstinence

2 to 6 weeks of abstinence

Half-life 12 to 24 hours

Half-life 37 to 57 hours

3 months


Dose-response of alcohol

60 g/d

80 to 200 g/d

?40 g/d

?40 g/d

?40 g/d


Sensitivity

55% to 90%a-e

37% to 85%b, f, g

AST:ALT ratio >2:1 has a 70% sensitivity and 92% to 100% specificity for alcoholic-induced liver diseaseh-j

20% to 70%b,k


Relapse sensitivity

55% to 76%a,l,m

50%a,e

20%a,n


Specificity

92% to 97%a,b

18% to 93%a,b,e

64% to 66%b,k,n


Positive predictive value

46% to 75%c,g

41%g

36%g


Negative predictive value

72% to 98%a,c,g

69% to 92%a,e,g

67%g


AST: aspartate aminotransferase; ALT: alanine aminotransferase; CDT: carbohydrate deficient transferrin; GGT: gamma-glutamyl transferase; MCV: mean corpuscular volume


Source: Reference Citations: click here

BAL can document acute alcohol intoxication, but its use is limited because alcohol has a 4-hour half-life and an elimination rate of 7 grams/hour?equivalent to 1 drink/hour.6 (A ?drink? typically is defined as a 12-ounce bottle of beer or wine cooler, a 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits.) Therefore, BAL will identify as false negatives alcohol-dependent patients who abstain from alcohol within 24 hours of testing.

MCV is an index of the average volume of erythrocytes. Macrocytosis occurs when the volume exceeds 100 fL. Elevated MCV is the most typical morphologic abnormality associated with excessive alcohol consumption7,8 and macrocytosis?sometimes without associated anemia?is often evident in persons with alcoholism. MCV elevates after 6 weeks of alcohol misuse and may remain elevated for up to 3 months after a person has stopped drinking.9

Clinical Point

Gamma-glutamyl transferase levels >30 U/L reflect alcohol consumption of >4 drinks per day

Because patients with disorders unrelated to alcohol use can have elevated MCV, alone it is not a useful screening marker for alcohol abuse.10 Additionally, because macrocytosis can persist under strictly controlled alcohol abstinence, MCV is not a reliable clinical indicator of relapse.11

LFTs measure enzymes and proteins. ALT, AST, and GGT are the most relevant for detecting heavy drinking. An AST:ALT ratio >2:1 supports a suspicion of alcohol abuse.12 More than 90% of patients with an AST:ALT ratio of 2:1 have alcoholic liver disease. This increases to more than 96% if the ratio is 3:1.13

GGT is an enzyme concentrated in the liver, bile ducts, and kidneys; normal range is 0 to 45 U/L (for females) or 53 U/L (for males).14 GGT levels >30 U/L correlate with alcohol consumption of >4 drinks per day.15 GGT has a half-life of 14 to 26 days and remains elevated for 4 to 6 weeks after drinking cessation, which make it useful for monitoring abstinence in treatment programs.16 Sensitivity ranges from 37% to 85% and specificity is as high as 93% in nonmedical populations.17 Although nonalcoholic liver disease can elevate GGT in persons who do not abuse alcohol, 50% to 72% of GGT elevations can be explained by excessive alcohol consumption.18

CDT is a newer biomarker used to monitor alcohol consumption. The most accurate way to express CDT level is as a percentage of total transferrin concentration. This method accounts for individual variations in transferrin levels, thus minimizing false positives.18 In persons who consume >4 or 5 drinks per day for 2 weeks or more, CDT is >1.3% of total transferrin.19 Unfortunately, because it is expensive and requires sophisticated test methodology, CDT testing is not available at most hospitals.20

Combinations improve detection

Each biochemical measure has strengths and weaknesses as a marker for determining patients? alcohol consumption (Table 2). CDT and GGT show the highest sensitivity for heavy drinking, and CDT has a higher specificity than GGT (Table 3).21,22 Relapse to alcohol use after abstinence may be best identified by a simultaneous 30% increase in CDT and GGT.5

Because GGT has a longer half-life than CDT, its diagnostic efficiency in detecting alcohol relapse may not develop until 4 weeks after alcohol detoxification, whereas CDT may become clinically useful for detecting relapse as early as 1 week after detoxification.23

Table 2Biomarkers of alcohol use: Strengths and weaknesses

Biomarker

Strengths

Weaknesses


CDT

High specificity for alcohol use; few factors cause false positivesHigh sensitivity in distinguishing alcoholics from social drinkersMarker of relapse and abstinence from drinkingConfirmatory test for patients suspected of alcohol abuse

Low sensitivity; more valuable to confirm than exclude heavy drinkingCost (average $30/assay) and low availability of testingLikely less sensitive for women and younger patients compared with menPoor screening tool for alcohol use in general population


GGT

Elevations precede alcohol-induced liver damageHigh specificity in patients with suspected alcohol abuseEffective marker for patients suspected of binge drinkingInexpensive (<$10)

Can be falsely elevated by liver and biliary disease, smoking, obesity, and medications that induce microsomal enzymesLow sensitivity makes it a poor screening tool in general populationPoor marker of relapse


AST:ALT >2:1

Highly sensitive and specific for alcohol-induced liver damage

Enzyme elevations can be detected only after periods of heavy drinkingElevations secondary to liver damage at the hepatocellular level (after fatty changes)


MCV

Accuracy similar in male and female patientsElevations in suspected cases of alcohol use indicate chronicity of drinkingRoutine laboratory test

Poor biomarker for relapseFalse positives caused by liver disease, hemolysis, bleeding disorders, anemia, folate deficiency, and medications that reduce folateLow sensitivity and specificity for alcohol use make it a poor screening tool for alcohol abuse


AST: aspartate aminotransferase; ALT: alanine aminotransferase; CDT: carbohydrate deficient transferrin; GGT: gamma-glutamyl transferase; MCV: mean corpuscular volume

Table 3Interpreting diagnostic test performance

Term

Definition

Applicability


Sensitivity

Percent of persons with disease who test positive

High value is desirable for ruling out disease (low false-negative rate)


Specificity

Percent of persons without disease who test negative

High value is desirable for ruling in disease (low false-positive rate)


Positive predictive value

Percent of positive test results that are true positives

Probability that a person with a positive test result has the disease


Negative predictive value

Percent of negative test results that are true negatives

Probability that a person with a negative test result is disease-free


Source: References 21,22

There is evidence that combining tests can improve alcohol use detection.24 For example, Dolman et al25 found that the ability of the AUDIT questionnaire to correctly predict which patients would experience alcohol withdrawal increases when it is used in combination with biochemical markers. Specifically, the positive predictive value of an AUDIT score ?8 increased from 17% to 47% when found in combination with ?2 abnormal biochemical marker levels; the study looked at GGT, ALT, AST, and MCV. Sensitivity was 94% and specificity was 98%.

Similarly, combinations of biochemical markers?especially CDT and GGT?have improved detection of alcohol use and subsequent risk of withdrawal.26Table 4 provides a summary of studies that evaluated using combinations of biochemical markers.4,5,27-31

Table 4Combining biomarker tests: An effective approach

Combination

Study

Sensitivity*


GGT + MCV

Morgan et al4

95%


GGT + CDT

Hietala et al5

90%


Mundle et al29

90%


Bell et al30

90%


Sillanaukee et al31

95%


GGT + AST:ALT >2:1

Gluud et al27

92%


Morgan et al4

100%


MCV + AST:ALT >2:1

Kawachi et al28

97%


Morgan et al4

95%


GGT + MCV + AST:ALT >2:1

Morgan et al4

100%


GGT + MCV + CDT

Sillanaukee et al31

70%


* Sensitivity for detecting excessive alcohol consumption


AST: aspartate aminotransferase; ALT: alanine aminotransferase; CDT: carbohydrate deficient transferrin; GGT: gamma-glutamyl transferase; MCV: mean corpuscular volume

Consider patients? comorbidities

Patients at risk for underreporting alcohol use include those with unemployment histories, previous alcohol treatment, and higher scores on the Alcohol Dependence Scale (18.5, SD=8.1).2 Interpret biochemical testing results in the context of a patient?s overall clinical picture.

Clinical Point

A simultaneous 30% increase in CDT and GGT suggests relapse to alcohol use after abstinence

The following 2 case patients denied or underreported recent alcohol use but we determined they were at high risk for an alcohol disorder because of their medical and/or psychiatric histories. Analysis of biochemical markers helped assess the risk of alcohol withdrawal.

CASE 2: Altered mental status

Family members bring Mr. N, age 44, to the hospital because of his odd behavior. He presents with paranoid delusions and an inappropriate elated mood. His medical history includes acquired immune deficiency syndrome (AIDS). After cerebrospinal fluid analysis, computed tomography of the head, electroencephalogram, and metabolic workup are within normal limits, the patient is diagnosed with human immunodeficiency virus (HIV) mania and is admitted.

On admission, Mr. N denies alcohol use. A blood alcohol/urine toxicity screen is negative. One day after admission, Mr. M develops elevated blood pressure and tachycardia and reports headache and nausea.

Challenge. Gathering a valid history of Mr. N?s alcohol use is difficult because of his acutely altered mental status and manic-like state. We use laboratory data to assess his risk of alcohol withdrawal. His liver function tests include an AST of 33 U/L, ALT of 30 U/L, and an alkaline phosphatase of 94 U/L. MCV is normal at 90 fL. Interestingly, the GGT level is elevated almost 4 times normal at 164 U/L.

Clinical Point

Risk factors for underreporting alcohol use include a history of unemployment and previous alcohol treatment

Discussion. Although Mr. N denied alcohol use and presented with a negative BAL, laboratory data support alcohol dependence. His GGT was elevated well beyond normal limits, without evidence of hepatobiliary disease. GGT has a sensitivity as high as 85%32 and limited specificity for alcohol abuse. Because of his high probability of recent alcohol consumption, we place Mr. N on AWP.

We postulate that our patient?s autonomic instability, headache, and nausea are related to alcohol withdrawal. We are aware that delirium occurs frequently in patients with HIV infection, and although Mr. N?s medical workup is negative, HIV infection can produce an acute encephalopathy that could resemble our patient?s clinical picture.33

Mr. N?s autonomic instability, headache, and nausea abated after treatment for alcohol withdrawal.

CASE 3: Suicide attempt?

Mr. S, age 28, presents to the trauma service with a self-inflicted gunshot wound to the face. He reports feeling depressed for the last year but denies a history of psychotic symptoms or heroin withdrawal symptoms. He also denies recent or past alcohol abuse and does not have a history of biliary tract disease or megaloblastic anemia. His mother tells us Mr. S has had a history of depression since childhood.

Challenge. Based on Mr. S? apparent suicide attempt and history, we feel he is at high risk for alcohol abuse. We use laboratory markers to assess the likelihood of alcohol consumption and possibly decrease his risk of alcohol withdrawal.

Clinical Point

Interpret biomarker results in the context of the patient?s overall clinical picture

Discussion. Mr. S? lab data show an MCV of 91 fL, AST of 95 U/L, alanine ALT of 156 U/L, and alkaline phosphatase of 160 U/L. GGT was elevated at 122 U/L.

Although Mr. S? MCV is within the normal range, his GGT is elevated, and the combination of an elevated GGT and MCV has a 95% sensitivity for the diagnosis of alcohol abuse. We place Mr. S on alcohol withdrawal precautions and discuss with him the potential life-threatening complications of alcohol withdrawal. Confronted with this information and the possible implication of his elevated LFTs, the patient admits his alcohol history?which consists of drinking 12 beers/day for at least the past 2 years. He admits this despite exhibiting no signs or symptoms of alcohol withdrawal.

Related Resources

  • National Institute on Alcohol Abuse and Alcoholism Data/Statistical Tables.www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts.

  • Maisto SA, Connors GJ, Allen JP. Contrasting self-report screens for alcohol problems: a review. Alcohol Clin Exp Res 1995;19(6):1510-6.

  • Coulton S, Drummond C, James D, et al. Opportunistic screening for alcohol use disorders in primary care: comparative study. BMJ 2006;332:511-7.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors acknowledge Daiana Radac, BA, a third-year medical student at Eastern Virginia Medical School, for her contributions to this article.

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