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Using biomarkers to quantify problematic alcohol use
Author(s)
Rahul Chaudhari, MD
Dilip Moonka, MD
Frederick Nunes, MD

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

  1. Routine lab tests (liver panel and complete blood count).
  2. Blood or urine alcohol level.
  3. Phosphatidylethanol (PEth) level in the blood.
  4. Ethyl glucuronide (EtG) in the urine.
  5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,1 and 1 in 10 children live in a home with a parent who has a drinking problem.2 While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,1 the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.3 A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.7

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.8 Systematic screening for AUD can identify many of these people.8 Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.9 Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.10 Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 111-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.11 Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.19 The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.20 Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.2

Table of screening tools for alcohol use disorder

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).21 Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

 

 

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.22 The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.23-31)

Table of Indirect and direct alcohol biomarkers

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.32

MCV is the average volume of erythrocytes,33 and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.34 Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.35

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.36 It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,36 can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.37

Continue to: CDT is approved...

 

 

CDT is approved by the FDA as an assay for alcohol consumption.37 While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.38 This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.41 Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 223-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.42

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.33,43 But the short half-life of ethanol in blood limits its use as a biomarker,33 and it is not a good indicator of chronic drinking.44

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.45 They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.46 Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.47

Continue to: EtG has been detectable...

 

 

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.48 Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.49 Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.50

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.51 In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.29 These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.29 It is elevated for up to 99 hours in heavy alcohol drinkers.30 It can be detected in hair for a longer period than in blood.52 Detection of FAEEs in meconium can help establish fetal alcohol exposure.53

Continue to: PEth

 

 

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.54 PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.59 There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.61 PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.62 With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.63 A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.21 It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.61 PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.55 The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,66 and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.67TABLE 322,68 explains the currently accepted ranges for various PEth results.

Table of PEth values and their significance

Continue to: CASE ANSWER

 

 

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

References

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2. Fleming MF, Smith MJ, Oslakovic E, et al. Phosphatidylethanol detects moderate-to-heavy alcohol use in liver transplant recipients. Alcohol Clin Exp Res. 2017;41:857-862.

3. National Institute on Alcohol Abuse and Alcoholism. Drinking levels defined. Accessed November 12, 2021. www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking

4. Herreros-Villanueva M, Hijona E, Bañales JM, et al. Alcohol consumption on pancreatic diseases. World J Gastroenterol. 2013;19:638-647.

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10. Miller PM, Thomas SE, Mallin R. Patient attitudes towards self-report and biomarker alcohol screening by primary care physicians. Alcohol Alcohol. 2006;41:306-310. doi: 10.1093/alcalc/agl022

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20. Kitchens JM. Does this patient have an alcohol problem? JAMA. 1994;272:1782-1787.

21. Kummer N, Lambert WE, Samyn N, et al. Alternative sampling strategies for the assessment of alcohol intake of living persons. Clin Biochem. 2016;49:1078-1091.

22. Ulwelling W, Smith K. The PEth blood test in the security environment: what it is; why it is important; and interpretative guidelines. J Forensic Sci. 2018;63:1634-1640.

23. Mundle G, Ackermann K, Munkes J, et al. Influence of age, alcohol consumption and abstinence on the sensitivity of carbohydrate‐deficient transferrin, gamma‐glutamyltransferase and mean corpuscular volume. Alcohol Alcohol. 1999;34:760-766.

24. Neumann T, Spies C. Use of biomarkers for alcohol use disorders in clinical practice. Addiction. 2003;98(suppl 2):81-91.

25. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20:11684-11699.

26. Helander A. Biological markers of alcohol use and abuse in theory and practice. In: Agarwal DP, Seitz HK, eds. Alcohol in Health and Disease. Marcel Dekker. 2001:177-205.

27. Stewart SH, Koch DG, Burgess DM, et al. Sensitivity and specificity of urinary ethyl glucuronide and ethyl sulfate in liver disease patients. Alcohol Clin Exp Res. 2013;37:150-155.

28. Helander A, Dahl H. Urinary tract infection: a risk factor for false-negative urinary ethyl glucuronide but not ethyl sulfate in the detection of recent alcohol consumption. Clin Chem. 2005;51:1728-1730.

29. Ghosh S, Jain R, Jhanjee S, et al. Alcohol biomarkers and their relevance in detection of alcohol consumption in clinical settings. Accessed November 12, 2021. https://www.clinmedjournals.org/articles/iasar/international-archives-of-substance-abuse-and-rehabilitation-iasar-1-002.php?jid=iasar

30. Borucki K, Dierkes J, Wartberg J, et al. In heavy drinkers, fatty acid ethyl esters remain elevated for up to 99 hours. Alcohol Clin Exp Res. 2007;31:423-427.

31. Hartmann S, Aradottir S, Graf M, et al. Phosphatidylethanol as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin. Addict Biol. 2007;12:81-84.

32. Choe YM, Lee BC, Choi IG, et al. Combination of the CAGE and serum gamma-glutamyl transferase: an effective screening tool for alcohol use disorder and alcohol dependence. Neuropsychiatr Dis Treat. 2019 31;15:1507-1515.

33. Niemelä O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377:39-49.

34. Kauffmann T, Evans DS. Macrocytosis. Accessed November 12, 2021. https://www.ncbi.nlm.nih.gov/books/NBK560908/

35. Maenhout TM, De Buyzere ML, Delanghe JR. Non-oxidative ethanol metabolites as a measure of alcohol intake. Clin Chim Acta. 2013;415:322-329.

36. Solomons HD. Carbohydrate deficient transferrin and alcoholism. Germs. 2012;2:75-78.

37. Allen JP, Wurst FM, Thon N, et al. Assessing the drinking status of liver transplant patients with alcoholic liver disease. Liver Transpl. 2013;19:369-376.

38. Bortolotti F, De Paoli G, Tagliaro F. Carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse: a critical review of the literature 2001-2005. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;841:96-109.

39. Hannuksela ML, Liisanantti MK, Nissinen AE, et al. Biochemical markers of alcoholism. Clin Chem Lab Med. 2007;45:953-961.

40. Arndt T. Carbohydrate-deficient transferrin as a marker of chronic alcohol abuse: a critical review of preanalysis, analysis, and interpretation. Clin Chem. 2001;47:13-27.

41. Cabarcos P, Hassan HM, Tabernero MJ, et al. Analysis of ethyl glucuronide in hair samples by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). J Appl Toxicol. 2013;33:638-643.

42. Piano MR, Mazzuco A, Kang M, et al. Binge drinking episodes in young adults: how should we measure them in a research setting? J Stud Alcohol Drugs. 2017;78:502-511.

43. Adinoff B, Bone GH, Linnoila M. Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol Adverse Drug Exp. 1988;3:172-196.

44. Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis (Hoboken). 2016;8:59-63.

45. Wurst FM, Alling C, Aradottir S, et al. Emerging biomarkers: new directions and clinical applications. Alcohol Clin Exp Res. 2005;29:465-473.

46. Helander A, Péter O, Zheng Y. Monitoring of the alcohol biomarkers PEth, CDT and EtG/EtS in an outpatient treatment setting. Alcohol Alcohol. 2012;47:552-557.

47. Helander A, Böttcher M, Fehr C, et al. Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification. Alcohol Alcohol. 2009;44:55-61.

48. Jatlow P, O’Malley SS. Clinical (nonforensic) application of ethyl glucuronide measurement: are we ready? Alcohol Clin Exp Res. 2010;34:968-975.

49. Jatlow PI, Agro A, Wu R, et al. Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials. Alcohol Clin Exp Res. 2014;38:2056-2065.

50. Gonzalo P, Radenne S, Gonzalo S. Biomarkers of chronic alcohol misuse. Curr Biomark Find. 2014;4:9-22.

51. Bornhorst JA, Mbughuni MM. Alcohol biomarkers: clinical issues and analytical methods. In: Critical Issues in Alcohol and Drugs of Abuse Testing. 2nd ed. Academic Press. 2019:25-42.

52. Soderberg BL, Salem RO, Best CA, et al. Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake. Am J Clin Pathol. 2003;119(suppl):S94-S99.

53. Cheng CT, Ostrea EM Jr, Alviedo JN, et al. Fatty acid ethyl esters in meconium: a biomarker of fetal alcohol exposure and effect. Exp Biol Med (Maywood). 2021;246:380-386.

54. Andresen-Streichert H, Beres Y, Weinmann W, et al. Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study. Transpl Int. 2017;30:611-620.

55. Viel G, Boscolo-Berto R, Cecchetto G, et al. Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis. Int J Mol Sci. 2012;13:14788-14812.

56. Gnann H, Weinmann W, Thierauf A. Formation of phosphatidylethanol and its subsequent elimination during an extensive drinking experiment over 5 days. Alcohol Clin Exp Res. 2012;36:1507-1511.

57. Aradóttir S, Moller K, Alling C. Phosphatidylethanol formation and degradation in human and rat blood. Alcohol Alcohol. 2004;39:8-13.

58. Varga A, Alling C. Formation of phosphatidylethanol in vitro in red blood cells from healthy volunteers and chronic alcoholics. J Lab Clin Med. 2002;140:79-83.

59. Javors MA, Hill-Kapturczak N, Roache JD, et al. Characterization of the pharmacokinetics of phosphatidylethanol 16:0/18:1 and 16:0/18:2 in human whole blood after alcohol consumption in a clinical laboratory study. Alcohol Clin Exp Res. 2016;40:1228-1234.

60. Schröck A, Pfäffli M, König S, et al. Application of phosphatidylethanol (PEth) in whole blood in comparison to ethyl glucuronide in hair (hEtG) in driving aptitude assessment (DAA). Int J Legal Med. 2016;130:1527-1533.

61. Stewart SH, Koch DG, Willner IR, et al. Validation of blood phosphatidylethanol as an alcohol consumption biomarker in patients with chronic liver disease. Alcohol Clin Exp Res. 2014;38:1706-1711.

62. Nanau RM, Neuman MG. Biomolecules and biomarkers used in diagnosis of alcohol drinking and in monitoring therapeutic interventions. Biomolecules. 2015 29;5:1339-1385.

63. Hill-Kapturczak N, Dougherty DM, Roache JD, et al. Phosphatidylethanol homologs in blood as biomarkers for the time frame and amount of recent alcohol consumption. In: Preedy VR (ed) Neuroscience of Alcohol. Academic Press; 2019:567-576.

64. Jain J, Evans JL, Briceño A, et al. Comparison of phosphatidylethanol results to self-reported alcohol consumption among young injection drug users. Alcohol Alcohol. 2014;49:520-524.

65. Schröck A, Wurst FM, Thon N, et al. Assessing phosphatidylethanol (PEth) levels reflecting different drinking habits in comparison to the alcohol use disorders identification test - C (AUDIT-C). Drug Alcohol Depend. 2017;178:80-86.

66. McDonnell MG, Skalisky J, Leickly E, et al. Pilot investigation of a phosphatidylethanol-based contingency management intervention targeting alcohol use. Psychol Addict Behav. 2017;31:608-613.

67. Asrani SK, Trotter J, Lake J, et al. Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis. Liver Transpl. 2020;26:127-140.

68. WHO. International Guide for Monitoring Alcohol Consumption and Harm. 2000. Accessed November 12, 2021. http://apps.who.int/iris/bitstream/handle/10665/66529/WHO_MSD_MSB_00.4.pdf?sequence=1

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Rahul Chaudhari, MD
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Dilip Moonka, MD
Frederick Nunes, MD
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CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

  1. Routine lab tests (liver panel and complete blood count).
  2. Blood or urine alcohol level.
  3. Phosphatidylethanol (PEth) level in the blood.
  4. Ethyl glucuronide (EtG) in the urine.
  5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,1 and 1 in 10 children live in a home with a parent who has a drinking problem.2 While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,1 the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.3 A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.7

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.8 Systematic screening for AUD can identify many of these people.8 Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.9 Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.10 Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 111-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.11 Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.19 The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.20 Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.2

Table of screening tools for alcohol use disorder

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).21 Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

 

 

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.22 The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.23-31)

Table of Indirect and direct alcohol biomarkers

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.32

MCV is the average volume of erythrocytes,33 and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.34 Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.35

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.36 It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,36 can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.37

Continue to: CDT is approved...

 

 

CDT is approved by the FDA as an assay for alcohol consumption.37 While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.38 This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.41 Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 223-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.42

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.33,43 But the short half-life of ethanol in blood limits its use as a biomarker,33 and it is not a good indicator of chronic drinking.44

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.45 They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.46 Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.47

Continue to: EtG has been detectable...

 

 

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.48 Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.49 Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.50

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.51 In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.29 These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.29 It is elevated for up to 99 hours in heavy alcohol drinkers.30 It can be detected in hair for a longer period than in blood.52 Detection of FAEEs in meconium can help establish fetal alcohol exposure.53

Continue to: PEth

 

 

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.54 PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.59 There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.61 PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.62 With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.63 A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.21 It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.61 PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.55 The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,66 and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.67TABLE 322,68 explains the currently accepted ranges for various PEth results.

Table of PEth values and their significance

Continue to: CASE ANSWER

 

 

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

  1. Routine lab tests (liver panel and complete blood count).
  2. Blood or urine alcohol level.
  3. Phosphatidylethanol (PEth) level in the blood.
  4. Ethyl glucuronide (EtG) in the urine.
  5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,1 and 1 in 10 children live in a home with a parent who has a drinking problem.2 While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,1 the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.3 A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.7

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.8 Systematic screening for AUD can identify many of these people.8 Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.9 Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.10 Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 111-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.11 Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.19 The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.20 Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.2

Table of screening tools for alcohol use disorder

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).21 Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

 

 

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.22 The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.23-31)

Table of Indirect and direct alcohol biomarkers

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.32

MCV is the average volume of erythrocytes,33 and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.34 Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.35

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.36 It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,36 can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.37

Continue to: CDT is approved...

 

 

CDT is approved by the FDA as an assay for alcohol consumption.37 While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.38 This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.41 Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 223-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.42

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.33,43 But the short half-life of ethanol in blood limits its use as a biomarker,33 and it is not a good indicator of chronic drinking.44

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.45 They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.46 Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.47

Continue to: EtG has been detectable...

 

 

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.48 Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.49 Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.50

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.51 In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.29 These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.29 It is elevated for up to 99 hours in heavy alcohol drinkers.30 It can be detected in hair for a longer period than in blood.52 Detection of FAEEs in meconium can help establish fetal alcohol exposure.53

Continue to: PEth

 

 

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.54 PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.59 There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.61 PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.62 With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.63 A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.21 It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.61 PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.55 The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,66 and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.67TABLE 322,68 explains the currently accepted ranges for various PEth results.

Table of PEth values and their significance

Continue to: CASE ANSWER

 

 

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; [email protected]

References

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2. Fleming MF, Smith MJ, Oslakovic E, et al. Phosphatidylethanol detects moderate-to-heavy alcohol use in liver transplant recipients. Alcohol Clin Exp Res. 2017;41:857-862.

3. National Institute on Alcohol Abuse and Alcoholism. Drinking levels defined. Accessed November 12, 2021. www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking

4. Herreros-Villanueva M, Hijona E, Bañales JM, et al. Alcohol consumption on pancreatic diseases. World J Gastroenterol. 2013;19:638-647.

5. Rocco A, Compare D, Angrisani D, et al. Alcoholic disease: liver and beyond. World J Gastroenterol. 2014;20:14652-14659.

6. Gardner JD, Mouton AJ. Alcohol effects on cardiac function. Compr Physiol. 2015;5:791-802.

7. Sebastiani G, Borrás-Novell C, Casanova MA, et al. The effects of alcohol and drugs of abuse on maternal nutritional profile during pregnancy. Nutrients. 2018;10:1008.

8. Rehm J, Anderson P, Manthey J, et al. Alcohol use disorders in primary health care: what do we know and where do we go? Alcohol Alcohol. 2016;51:422-427. doi: 10.1093/alcalc/agv127

9. ASAM. Caring for patients during the COVID-19 pandemic. Accessed November 12, 2021. www.asam.org/docs/default-source/covid-19/acute-care_062620.pdf?sfvrsn=e66d54c2_10

10. Miller PM, Thomas SE, Mallin R. Patient attitudes towards self-report and biomarker alcohol screening by primary care physicians. Alcohol Alcohol. 2006;41:306-310. doi: 10.1093/alcalc/agl022

11. Zoorob R, Snell H, Kihlberg C, et al. Screening and brief intervention for risky alcohol use. Curr Probl Pediatr Adolesc Health Care. 2014;44:82-87.

12. Smith PC, Schmidt SM, Allensworth-Davies D, et al. Primary care validation of a single-question alcohol screening test. J Gen Intern Med. 2009;24:783-788.

13. Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA. 1984;252:1905-1907.

14. Sokol RJ, Martier SS, Ager JW. The T-ACE questions: practical prenatal detection of risk-drinking. Am J Obstet Gynecol. 1989;160:863-868.

15. Cherpitel CJ. A brief screening instrument for problem drinking in the emergency room: the RAPS4. Rapid Alcohol Problems Screen. J Stud Alcohol. 2000;61:447-449.

16. WHO. AUDIT: The alcohol use identification test. Accessed November 14, 2021. http://apps.who.int/iris/bitstream/handle/10665/67205/WHO_MSD_MSB_01.6a.pdf?sequence=1

17. Westermeyer J, Yargic I, Thuras P. Michigan assessment-screening test for alcohol and drugs (MAST/AD): evaluation in a clinical sample. Am J Addict. 2004;13:151-162.

18. Powers JS, Spickard A. Michigan Alcoholism Screening Test to diagnose early alcoholism in a general practice. South Med J. 1984;77:852-856.

19. NIH. Treatment for alcohol problems: finding and getting help. Accessed November 12, 2021. www.niaaa.nih.gov/publications/brochures-and-fact-sheets/treatment-alcohol-problems-finding-and-getting-help

20. Kitchens JM. Does this patient have an alcohol problem? JAMA. 1994;272:1782-1787.

21. Kummer N, Lambert WE, Samyn N, et al. Alternative sampling strategies for the assessment of alcohol intake of living persons. Clin Biochem. 2016;49:1078-1091.

22. Ulwelling W, Smith K. The PEth blood test in the security environment: what it is; why it is important; and interpretative guidelines. J Forensic Sci. 2018;63:1634-1640.

23. Mundle G, Ackermann K, Munkes J, et al. Influence of age, alcohol consumption and abstinence on the sensitivity of carbohydrate‐deficient transferrin, gamma‐glutamyltransferase and mean corpuscular volume. Alcohol Alcohol. 1999;34:760-766.

24. Neumann T, Spies C. Use of biomarkers for alcohol use disorders in clinical practice. Addiction. 2003;98(suppl 2):81-91.

25. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20:11684-11699.

26. Helander A. Biological markers of alcohol use and abuse in theory and practice. In: Agarwal DP, Seitz HK, eds. Alcohol in Health and Disease. Marcel Dekker. 2001:177-205.

27. Stewart SH, Koch DG, Burgess DM, et al. Sensitivity and specificity of urinary ethyl glucuronide and ethyl sulfate in liver disease patients. Alcohol Clin Exp Res. 2013;37:150-155.

28. Helander A, Dahl H. Urinary tract infection: a risk factor for false-negative urinary ethyl glucuronide but not ethyl sulfate in the detection of recent alcohol consumption. Clin Chem. 2005;51:1728-1730.

29. Ghosh S, Jain R, Jhanjee S, et al. Alcohol biomarkers and their relevance in detection of alcohol consumption in clinical settings. Accessed November 12, 2021. https://www.clinmedjournals.org/articles/iasar/international-archives-of-substance-abuse-and-rehabilitation-iasar-1-002.php?jid=iasar

30. Borucki K, Dierkes J, Wartberg J, et al. In heavy drinkers, fatty acid ethyl esters remain elevated for up to 99 hours. Alcohol Clin Exp Res. 2007;31:423-427.

31. Hartmann S, Aradottir S, Graf M, et al. Phosphatidylethanol as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin. Addict Biol. 2007;12:81-84.

32. Choe YM, Lee BC, Choi IG, et al. Combination of the CAGE and serum gamma-glutamyl transferase: an effective screening tool for alcohol use disorder and alcohol dependence. Neuropsychiatr Dis Treat. 2019 31;15:1507-1515.

33. Niemelä O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377:39-49.

34. Kauffmann T, Evans DS. Macrocytosis. Accessed November 12, 2021. https://www.ncbi.nlm.nih.gov/books/NBK560908/

35. Maenhout TM, De Buyzere ML, Delanghe JR. Non-oxidative ethanol metabolites as a measure of alcohol intake. Clin Chim Acta. 2013;415:322-329.

36. Solomons HD. Carbohydrate deficient transferrin and alcoholism. Germs. 2012;2:75-78.

37. Allen JP, Wurst FM, Thon N, et al. Assessing the drinking status of liver transplant patients with alcoholic liver disease. Liver Transpl. 2013;19:369-376.

38. Bortolotti F, De Paoli G, Tagliaro F. Carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse: a critical review of the literature 2001-2005. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;841:96-109.

39. Hannuksela ML, Liisanantti MK, Nissinen AE, et al. Biochemical markers of alcoholism. Clin Chem Lab Med. 2007;45:953-961.

40. Arndt T. Carbohydrate-deficient transferrin as a marker of chronic alcohol abuse: a critical review of preanalysis, analysis, and interpretation. Clin Chem. 2001;47:13-27.

41. Cabarcos P, Hassan HM, Tabernero MJ, et al. Analysis of ethyl glucuronide in hair samples by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). J Appl Toxicol. 2013;33:638-643.

42. Piano MR, Mazzuco A, Kang M, et al. Binge drinking episodes in young adults: how should we measure them in a research setting? J Stud Alcohol Drugs. 2017;78:502-511.

43. Adinoff B, Bone GH, Linnoila M. Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol Adverse Drug Exp. 1988;3:172-196.

44. Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis (Hoboken). 2016;8:59-63.

45. Wurst FM, Alling C, Aradottir S, et al. Emerging biomarkers: new directions and clinical applications. Alcohol Clin Exp Res. 2005;29:465-473.

46. Helander A, Péter O, Zheng Y. Monitoring of the alcohol biomarkers PEth, CDT and EtG/EtS in an outpatient treatment setting. Alcohol Alcohol. 2012;47:552-557.

47. Helander A, Böttcher M, Fehr C, et al. Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification. Alcohol Alcohol. 2009;44:55-61.

48. Jatlow P, O’Malley SS. Clinical (nonforensic) application of ethyl glucuronide measurement: are we ready? Alcohol Clin Exp Res. 2010;34:968-975.

49. Jatlow PI, Agro A, Wu R, et al. Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials. Alcohol Clin Exp Res. 2014;38:2056-2065.

50. Gonzalo P, Radenne S, Gonzalo S. Biomarkers of chronic alcohol misuse. Curr Biomark Find. 2014;4:9-22.

51. Bornhorst JA, Mbughuni MM. Alcohol biomarkers: clinical issues and analytical methods. In: Critical Issues in Alcohol and Drugs of Abuse Testing. 2nd ed. Academic Press. 2019:25-42.

52. Soderberg BL, Salem RO, Best CA, et al. Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake. Am J Clin Pathol. 2003;119(suppl):S94-S99.

53. Cheng CT, Ostrea EM Jr, Alviedo JN, et al. Fatty acid ethyl esters in meconium: a biomarker of fetal alcohol exposure and effect. Exp Biol Med (Maywood). 2021;246:380-386.

54. Andresen-Streichert H, Beres Y, Weinmann W, et al. Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study. Transpl Int. 2017;30:611-620.

55. Viel G, Boscolo-Berto R, Cecchetto G, et al. Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis. Int J Mol Sci. 2012;13:14788-14812.

56. Gnann H, Weinmann W, Thierauf A. Formation of phosphatidylethanol and its subsequent elimination during an extensive drinking experiment over 5 days. Alcohol Clin Exp Res. 2012;36:1507-1511.

57. Aradóttir S, Moller K, Alling C. Phosphatidylethanol formation and degradation in human and rat blood. Alcohol Alcohol. 2004;39:8-13.

58. Varga A, Alling C. Formation of phosphatidylethanol in vitro in red blood cells from healthy volunteers and chronic alcoholics. J Lab Clin Med. 2002;140:79-83.

59. Javors MA, Hill-Kapturczak N, Roache JD, et al. Characterization of the pharmacokinetics of phosphatidylethanol 16:0/18:1 and 16:0/18:2 in human whole blood after alcohol consumption in a clinical laboratory study. Alcohol Clin Exp Res. 2016;40:1228-1234.

60. Schröck A, Pfäffli M, König S, et al. Application of phosphatidylethanol (PEth) in whole blood in comparison to ethyl glucuronide in hair (hEtG) in driving aptitude assessment (DAA). Int J Legal Med. 2016;130:1527-1533.

61. Stewart SH, Koch DG, Willner IR, et al. Validation of blood phosphatidylethanol as an alcohol consumption biomarker in patients with chronic liver disease. Alcohol Clin Exp Res. 2014;38:1706-1711.

62. Nanau RM, Neuman MG. Biomolecules and biomarkers used in diagnosis of alcohol drinking and in monitoring therapeutic interventions. Biomolecules. 2015 29;5:1339-1385.

63. Hill-Kapturczak N, Dougherty DM, Roache JD, et al. Phosphatidylethanol homologs in blood as biomarkers for the time frame and amount of recent alcohol consumption. In: Preedy VR (ed) Neuroscience of Alcohol. Academic Press; 2019:567-576.

64. Jain J, Evans JL, Briceño A, et al. Comparison of phosphatidylethanol results to self-reported alcohol consumption among young injection drug users. Alcohol Alcohol. 2014;49:520-524.

65. Schröck A, Wurst FM, Thon N, et al. Assessing phosphatidylethanol (PEth) levels reflecting different drinking habits in comparison to the alcohol use disorders identification test - C (AUDIT-C). Drug Alcohol Depend. 2017;178:80-86.

66. McDonnell MG, Skalisky J, Leickly E, et al. Pilot investigation of a phosphatidylethanol-based contingency management intervention targeting alcohol use. Psychol Addict Behav. 2017;31:608-613.

67. Asrani SK, Trotter J, Lake J, et al. Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis. Liver Transpl. 2020;26:127-140.

68. WHO. International Guide for Monitoring Alcohol Consumption and Harm. 2000. Accessed November 12, 2021. http://apps.who.int/iris/bitstream/handle/10665/66529/WHO_MSD_MSB_00.4.pdf?sequence=1

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21. Kummer N, Lambert WE, Samyn N, et al. Alternative sampling strategies for the assessment of alcohol intake of living persons. Clin Biochem. 2016;49:1078-1091.

22. Ulwelling W, Smith K. The PEth blood test in the security environment: what it is; why it is important; and interpretative guidelines. J Forensic Sci. 2018;63:1634-1640.

23. Mundle G, Ackermann K, Munkes J, et al. Influence of age, alcohol consumption and abstinence on the sensitivity of carbohydrate‐deficient transferrin, gamma‐glutamyltransferase and mean corpuscular volume. Alcohol Alcohol. 1999;34:760-766.

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25. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20:11684-11699.

26. Helander A. Biological markers of alcohol use and abuse in theory and practice. In: Agarwal DP, Seitz HK, eds. Alcohol in Health and Disease. Marcel Dekker. 2001:177-205.

27. Stewart SH, Koch DG, Burgess DM, et al. Sensitivity and specificity of urinary ethyl glucuronide and ethyl sulfate in liver disease patients. Alcohol Clin Exp Res. 2013;37:150-155.

28. Helander A, Dahl H. Urinary tract infection: a risk factor for false-negative urinary ethyl glucuronide but not ethyl sulfate in the detection of recent alcohol consumption. Clin Chem. 2005;51:1728-1730.

29. Ghosh S, Jain R, Jhanjee S, et al. Alcohol biomarkers and their relevance in detection of alcohol consumption in clinical settings. Accessed November 12, 2021. https://www.clinmedjournals.org/articles/iasar/international-archives-of-substance-abuse-and-rehabilitation-iasar-1-002.php?jid=iasar

30. Borucki K, Dierkes J, Wartberg J, et al. In heavy drinkers, fatty acid ethyl esters remain elevated for up to 99 hours. Alcohol Clin Exp Res. 2007;31:423-427.

31. Hartmann S, Aradottir S, Graf M, et al. Phosphatidylethanol as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin. Addict Biol. 2007;12:81-84.

32. Choe YM, Lee BC, Choi IG, et al. Combination of the CAGE and serum gamma-glutamyl transferase: an effective screening tool for alcohol use disorder and alcohol dependence. Neuropsychiatr Dis Treat. 2019 31;15:1507-1515.

33. Niemelä O. Biomarkers in alcoholism. Clin Chim Acta. 2007;377:39-49.

34. Kauffmann T, Evans DS. Macrocytosis. Accessed November 12, 2021. https://www.ncbi.nlm.nih.gov/books/NBK560908/

35. Maenhout TM, De Buyzere ML, Delanghe JR. Non-oxidative ethanol metabolites as a measure of alcohol intake. Clin Chim Acta. 2013;415:322-329.

36. Solomons HD. Carbohydrate deficient transferrin and alcoholism. Germs. 2012;2:75-78.

37. Allen JP, Wurst FM, Thon N, et al. Assessing the drinking status of liver transplant patients with alcoholic liver disease. Liver Transpl. 2013;19:369-376.

38. Bortolotti F, De Paoli G, Tagliaro F. Carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse: a critical review of the literature 2001-2005. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;841:96-109.

39. Hannuksela ML, Liisanantti MK, Nissinen AE, et al. Biochemical markers of alcoholism. Clin Chem Lab Med. 2007;45:953-961.

40. Arndt T. Carbohydrate-deficient transferrin as a marker of chronic alcohol abuse: a critical review of preanalysis, analysis, and interpretation. Clin Chem. 2001;47:13-27.

41. Cabarcos P, Hassan HM, Tabernero MJ, et al. Analysis of ethyl glucuronide in hair samples by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). J Appl Toxicol. 2013;33:638-643.

42. Piano MR, Mazzuco A, Kang M, et al. Binge drinking episodes in young adults: how should we measure them in a research setting? J Stud Alcohol Drugs. 2017;78:502-511.

43. Adinoff B, Bone GH, Linnoila M. Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol Adverse Drug Exp. 1988;3:172-196.

44. Cabezas J, Lucey MR, Bataller R. Biomarkers for monitoring alcohol use. Clin Liver Dis (Hoboken). 2016;8:59-63.

45. Wurst FM, Alling C, Aradottir S, et al. Emerging biomarkers: new directions and clinical applications. Alcohol Clin Exp Res. 2005;29:465-473.

46. Helander A, Péter O, Zheng Y. Monitoring of the alcohol biomarkers PEth, CDT and EtG/EtS in an outpatient treatment setting. Alcohol Alcohol. 2012;47:552-557.

47. Helander A, Böttcher M, Fehr C, et al. Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification. Alcohol Alcohol. 2009;44:55-61.

48. Jatlow P, O’Malley SS. Clinical (nonforensic) application of ethyl glucuronide measurement: are we ready? Alcohol Clin Exp Res. 2010;34:968-975.

49. Jatlow PI, Agro A, Wu R, et al. Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials. Alcohol Clin Exp Res. 2014;38:2056-2065.

50. Gonzalo P, Radenne S, Gonzalo S. Biomarkers of chronic alcohol misuse. Curr Biomark Find. 2014;4:9-22.

51. Bornhorst JA, Mbughuni MM. Alcohol biomarkers: clinical issues and analytical methods. In: Critical Issues in Alcohol and Drugs of Abuse Testing. 2nd ed. Academic Press. 2019:25-42.

52. Soderberg BL, Salem RO, Best CA, et al. Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake. Am J Clin Pathol. 2003;119(suppl):S94-S99.

53. Cheng CT, Ostrea EM Jr, Alviedo JN, et al. Fatty acid ethyl esters in meconium: a biomarker of fetal alcohol exposure and effect. Exp Biol Med (Maywood). 2021;246:380-386.

54. Andresen-Streichert H, Beres Y, Weinmann W, et al. Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study. Transpl Int. 2017;30:611-620.

55. Viel G, Boscolo-Berto R, Cecchetto G, et al. Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis. Int J Mol Sci. 2012;13:14788-14812.

56. Gnann H, Weinmann W, Thierauf A. Formation of phosphatidylethanol and its subsequent elimination during an extensive drinking experiment over 5 days. Alcohol Clin Exp Res. 2012;36:1507-1511.

57. Aradóttir S, Moller K, Alling C. Phosphatidylethanol formation and degradation in human and rat blood. Alcohol Alcohol. 2004;39:8-13.

58. Varga A, Alling C. Formation of phosphatidylethanol in vitro in red blood cells from healthy volunteers and chronic alcoholics. J Lab Clin Med. 2002;140:79-83.

59. Javors MA, Hill-Kapturczak N, Roache JD, et al. Characterization of the pharmacokinetics of phosphatidylethanol 16:0/18:1 and 16:0/18:2 in human whole blood after alcohol consumption in a clinical laboratory study. Alcohol Clin Exp Res. 2016;40:1228-1234.

60. Schröck A, Pfäffli M, König S, et al. Application of phosphatidylethanol (PEth) in whole blood in comparison to ethyl glucuronide in hair (hEtG) in driving aptitude assessment (DAA). Int J Legal Med. 2016;130:1527-1533.

61. Stewart SH, Koch DG, Willner IR, et al. Validation of blood phosphatidylethanol as an alcohol consumption biomarker in patients with chronic liver disease. Alcohol Clin Exp Res. 2014;38:1706-1711.

62. Nanau RM, Neuman MG. Biomolecules and biomarkers used in diagnosis of alcohol drinking and in monitoring therapeutic interventions. Biomolecules. 2015 29;5:1339-1385.

63. Hill-Kapturczak N, Dougherty DM, Roache JD, et al. Phosphatidylethanol homologs in blood as biomarkers for the time frame and amount of recent alcohol consumption. In: Preedy VR (ed) Neuroscience of Alcohol. Academic Press; 2019:567-576.

64. Jain J, Evans JL, Briceño A, et al. Comparison of phosphatidylethanol results to self-reported alcohol consumption among young injection drug users. Alcohol Alcohol. 2014;49:520-524.

65. Schröck A, Wurst FM, Thon N, et al. Assessing phosphatidylethanol (PEth) levels reflecting different drinking habits in comparison to the alcohol use disorders identification test - C (AUDIT-C). Drug Alcohol Depend. 2017;178:80-86.

66. McDonnell MG, Skalisky J, Leickly E, et al. Pilot investigation of a phosphatidylethanol-based contingency management intervention targeting alcohol use. Psychol Addict Behav. 2017;31:608-613.

67. Asrani SK, Trotter J, Lake J, et al. Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis. Liver Transpl. 2020;26:127-140.

68. WHO. International Guide for Monitoring Alcohol Consumption and Harm. 2000. Accessed November 12, 2021. http://apps.who.int/iris/bitstream/handle/10665/66529/WHO_MSD_MSB_00.4.pdf?sequence=1

Issue
The Journal of Family Practice - 70(10)
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The Journal of Family Practice - 70(10)
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MDedge Family Medicine
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Using biomarkers to quantify problematic alcohol use
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Using biomarkers to quantify problematic alcohol use
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PRACTICE RECOMMENDATIONS

› Use a quick screening instrument such as the single-question tool or the AUDIT 1-3 to objectively determine whether patients’ drinking is risky for themselves or for others. C

› Suspect alcoholic liver disease if the ratio of aspartate aminotransferase to alanine aminotransferase is > 3. C

› Consider using the PEth assay in high-risk patients to differentiate between heavy alcohol use and social drinking. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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