Using biomarkers to quantify problematic alcohol use

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doi:doi: 10.12788/jfp.0317

Applied Evidence

Using biomarkers to quantify problematic alcohol use

J Fam Pract. 2021 December;70(10):474-481 | doi: 10.12788/jfp.0317

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References

1. APA. Diagnostic and Statistical Manual of Mental Disorders. 5th edition. American Psychiatric Publishing. 2013:490-497.

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

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)

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...