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Three Part Question

In [Adult patients with chronic alcohol abuse presenting to the ED] are [CDT, Gamma GT and MCV reliable biological markers] at [predicting patients likely to suffer alcohol withdrawal syndrome?]

Clinical Scenario

A 47 year old female patient is brought to your ED. She admits to regular alcohol consumption, is tachycardic with extremities tremor and ataxia. She asks you for something to help her with her symptoms. She has not drunk any alcohol for two days. You wonder if any biological marker would allow you to predict if she is really at risk of developing an alcohol withdrawal syndrome.

Search Strategy

Medline using the OVID interface (1946 to March 2013)
[(CDT.mp) OR (gamma GT.mp) OR (exp Erythrocyte Indices/) OR (MCV.mp) OR (exp gamma-glutamyl transferase/) OR (mean corpuscular volume.mp)] AND [(exp alcohol withdrawal seizures/) OR (withdrawal.mp) OR (exp alcohol withdrawal delirium/) OR (exp substance withdrawal syndrome/)]. Limit search to humans and English language.

Search Outcome

Eighty-seven papers were found using the above search strategy, of which five were relevant to the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Brathen et al 2000 Norway	January 1995 to October 1996, 158 patients admitted with seizures were included The AUDIT questionnaire was used as the gold standard Blood samples obtained on admission	Prospective Study	Comparison to AUDIT questionnaire	CDT was found to have a sensitivity of 41% and a specificity of 84%	Lack of blinding and Randomisation
Reynaud et al 1998 France	Study conducted on 31 volunteers (22 men and 9 women) over a 4-week detoxification period Alcohol dependence was diagnosed based on DSM-IV criteria and normal GGT levels GGT, ALT, AST, MCV and CDT were measured on days 0 and 15 Compared to a control group of 39 people (students and hospital staff)	Controlled Trial	CDT levels	Sensitivity and Specificity of CDT of 83.9% and 92.2%	Lack of randomisation. No gold standard to compare to
Wetterling et al 1998 Germany	161 Subjects recruited on a detoxification ward, 40 women and 121 men, all alcohol dependent according to DSM-III-R criteria Each had CDT, GGT, ALT, AST and MCV measured and alcohol withdrawal score assessed during withdrawal	Comparative Study	Correlation between AWS and alcohol markers; Sensitivity	CDT: 26.5%, Gamma-GT 20%, ALT 22.9%, AST 23.9%, MCV 29.2 %	Small sample size
			Correlation between AWS and alcohol markers; Specificity	CDT 81%, Gamma-GT 65.2%, ALT 73.1%, AST 76.7%, MCV 83.1%
Findley et al, 2010 USA	423 Consecutive trauma patients with positive toxicology had MCV and AST levels measured Compared against outcome of delirium tremens diagnosis	Retrospective cohort study	Sensitivity, specificity, PPV, NPV and LR for predicting the outcome of delirium tremens	Of the 80 patients with normal MCV/AST three (3.8%) required treatment for delirium tremens (+LR=0.08% (95% CI 0.026 to 0.248)) Of the 112 patients with abnormally elevated MCV/AST 72 (64.3%) required treatment for delirium tremens (+LR 3.698 (95% CI 2.706 to 5.053))	Trauma patients Young male predominance Retrospective nature Diagnosis was made by a single psychiatrist Positive toxicology not limited to alcohol
Karagülle et al, 2012	189 Patients (153 men, 36 women) with ICD-10 classification of alcohol dependency recruited on a single detoxification unit All patients were treated with clomethiazole and carbamazepine so none had a withdrawal seizure during the study History of previous withdrawal seizure was used to assess risk of seizure All patients had HCT, CDT and PRL measured on admission before administration of any drugs Group comparisons between patients with versus without a history of withdrawal seizure were made	Retrospective cohort study	Sensitivity, specificity, AUC, ROC for predicting risk of alcohol withdrawal study	51 (44 Men, 7 women) had previously had an alcohol withdrawal seizure. CDT best cut-off 3.75% (sensitivity 76.5%, specificity 44.2%). ROC curve showed combined assessment of HCT and CDT was better than CDT alone (AUC 0.69 vs 0.63, p=0.03)	Small study size Male predominance. Retrospective review of larger prospective study: Previous history of withdrawal fit taken as a proxy Large exclusion criteria means results cannot be generalised

Comment(s)

All the retrieved papers have severe methodological flaws, but one point is common to all in that all demonstrate that there is no evidence that any one biomarker is a reliable predictor of alcohol withdrawal and its sequelae. The largest paper (Findley et al) showed that the absence of elevated MCV/AST at admission was associated with a lower risk of withdrawal phenomenon. This unsurprisingly suggests that chronic alcohol abusers presenting to hospital with a normal biochemical profile are unlikely to have an alcohol withdrawal syndrome.

Editor Comment

AUC, area under the curve; CDT, carbohydrate-deficient transferrin; DSM, Diagnostic and Statistical Manual of Mental Disorders; GGT, gamma-glutamyl transferase; HCT, homocysteine; ICD, International Classification of Disease; LR, likelihood ratio; MCV, mean corpuscular volume; NPV, negative predictive value; PPV, positive predictive value; PRL, prolactin; ROC, receiver operating characteristic.

Clinical Bottom Line

Biological markers are not reliable enough to be used as stand-alone predictors of alcohol withdrawal syndrome. An entirely normal biochemical profile including MCV/AST/CDT may be associated with a low risk.

References

1. Bråthen G, Bjerve KS, Brodtkorb E et al. Validity of carbohydrate deficient transferrin and other markers as diagnostic aids in the detection of alcohol related seizures. J Neurol Neurosurg Psychiatry 2000;68;342-348.
2. Reynaud M, Hourcade F, Planche F, et al. Usefulness of Carbohydrate Deficient Transferrin in Alcoholic patients with Normal gammaglutamyltransferase. Alcoholism: Clin Exp Res 1998;22;615–18.
3. Wetterling T, Kanitz RD, Renner F et al. Does Carbohydrate Deficient Tranferrin Predict The Severity of Alcohol Withdrawal Syndrome. Alcoholism: Clin Exp Res. 1998:22;1053–6.
4. Findley JK, Park LT, Siefert CJ et al. Two routine blood tests—mean corpuscular volume and aspartate aminotransferase—as predictors of delirium tremens in trauma patients. J Trauma 2010;69:199–201.
5. Karagülle D, Heberlein A, Wilhelm J et al. Biological markers for alcohol withdrawal seizures: a retrospective analysis. Eur Addict Res 2012;18:97–102.