Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis

Guido Viel, Rafael Boscolo-Berto, Giovanni Cecchetto, Paolo Fais, Alessandro Nalesso, Santo Davide Ferrara, Guido Viel, Rafael Boscolo-Berto, Giovanni Cecchetto, Paolo Fais, Alessandro Nalesso, Santo Davide Ferrara

Abstract

The present paper aims at a systematic review of the current knowledge on phosphatidylethanol (PEth) in blood as a direct marker of chronic alcohol use and abuse. In March 2012, the search through "MeSH" and "free-text" protocols in the databases Medline/PubMed, SCOPUS, Web of Science, and Ovid/Embase, combining the terms phosphatidylethanol and alcohol, provided 444 records, 58 of which fulfilled the inclusion criteria and were used to summarize the current evidence on the formation, distribution and degradation of PEth in human blood: (1), the presence and distribution of different PEth molecular species (2), the most diffused analytical methods devoted to PEth identification and quantization (3), the clinical efficiency of total PEth quantification as a marker of chronic excessive drinking (4), and the potential utility of this marker for identifying binge drinking behaviors (5). Twelve papers were included in the meta-analysis and the mean (M) and 95% confidence interval (CI) of total PEth concentrations in social drinkers (DAI ≤ 60 g/die; M = 0.288 μM; CI 0.208-0.367 μM) and heavy drinkers (DAI > 60 g/die; M = 3.897 μM; CI 2.404-5.391 μM) were calculated. The present analysis demonstrates a good clinical efficiency of PEth for detecting chronic heavy drinking.

Figures

Figure 1
Figure 1
Search strategy and paper selection for inclusion in the systematic review and/or in the meta-analysis.
Figure 2
Figure 2
Schematic representation of the results of the meta-analysis performed on the 12 papers described in Tables 1 and 2. The investigated populations were classified based on daily alcohol intake (DAI): social drinkers (DAI ≤ 60 g/die), and heavy drinkers (DAI > 60 g/die). The black diamond represents the calculated mean and 95% CI for each subgroup. Lower case letters in brackets refer to multiple groups of subjects included in the selected studies (see Table 1).

References

    1. Domino K.B., Hornbein T.F., Polissar N.L., Renner G., Johnson J., Alberti S., Hankes L. Risk factors for relapse in health care professionals with substance use disorders. JAMA. 2005;293:1453–1460.
    1. Li T.K. Quantifying the risk for alcohol-use and alcohol-attributable health disorders: Present findings and future research needs. J. Gastroenterol. Hepatol. 2008;23:S2–S8.
    1. Ferrara S.D., Bajanowski T., Cecchi R., Boscolo-Berto R., Viel G. Bio-medicolegal scientific research in Europe: A comprehensive bibliometric overview. Int. J. Legal. Med. 2011;125:393–402.
    1. Ferrara S.D., Bajanowski T., Cecchi R., Snenghi R., Case C., Viel G. Bio-medicolegal guidelines and protocols: Survey and future perspectives in Europe. Int. J. Legal. Med. 2010;124:345–350.
    1. Bradley K.A., DeBenedetti A.F., Volk R.J., Williams E.C., Frank D., Kivlahan D.R. AUDIT-C as a brief screen for alcohol misuse in primary care. Alcohol. Clin. Exp. Res. 2007;31:1208–1217.
    1. Ewing J.A. Detecting alcoholism. The CAGE questionnaire. JAMA. 1984;252:1905–1907.
    1. Ferrara S.D. Alcohol, drugs and traffic safety. Br. J. Addict. 1987;82:871–883.
    1. Favretto D., Nalesso A., Frison G., Viel G., Traldi P., Ferrara S.D. A novel and an effective analytical approach for the LC-MS determination of ethyl glucuronide and ethyl sulfate in urine. Int. J. Legal Med. 2010;124:161–164.
    1. Conigrave K.M., Degenhardt L.J., Whitfield J.B., Saunders J.B., Helander A., Tabakoff B. CDT, GGT, and AST as markers of alcohol use: The WHO/ISBRA collaborative project. Alcohol. Clin. Exp. Res. 2002;26:332–339.
    1. Musshoff F. Chromatographic methods for the determination of markers of chronic and acute alcohol consumption. J. Chromatogr. B. 2002;781:457–480.
    1. 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. 2006;841:96–109.
    1. Golka K., Wiese A. Carbohydrate-deficient transferrin (CDT)—A biomarker for long-term alcohol consumption. J. Toxicol. Environ. Health B. 2004;7:319–337.
    1. Favretto D., Nalesso A., Frison G., Viel G., Traldi P., Ferrara S.D. No-discharge atmospheric pressure chemical ionization mass spectrometry of ethyl glucuronide and ethyl sulfate. J. Mass Spectrom. 2010;45:121–124.
    1. Hoiseth G., Morini L., Polettini A., Christophersen A., Morland J. Ethyl glucuronide in hair compared with traditional alcohol biomarkers—A pilot study of heavy drinkers referred to an alcohol detoxification unit. Alcohol. Clin. Exp. Res. 2009;33:812–816.
    1. Litten R.Z., Bradley A.M., Moss H.B. Alcohol biomarkers in applied settings: Recent advances and future research opportunities. Alcohol. Clin. Exp. Res. 2010;34:955–967.
    1. Bordignon M., Viel G., Peserico A., Alaibac M. Non-alcoholic fatty liver disease, alcohol intake and psoriasis. J. Hepatol. 2010;53:587.
    1. Alling C., Gustavsson L., Anggard E. An abnormal phospholipid in rat organs after ethanol. FEBS Lett. 1983;152:24–28.
    1. Alling C., Gustavsson L., Mansson J.E., Benthin G., Anggard E. Phosphatidylethanol formation in rat organs after ethanol treatment. Biochim. Biophys. Acta. 1984;793:119–122.
    1. Benthin G., Anggard E., Gustavsson L., Alling C. Formation of phosphatidylethanol in frozen kidneys from ethanol-treated rats. Biochim. Biophys. Acta. 1985;835:385–389.
    1. Gustavsson L., Alling C. Formation of phosphatidylethanol in rat brain by phospholipase D. Biochem. Biophys. Res. Commun. 1987;142:958–963.
    1. Lundqvist C., Aradottir S., Alling C., Boyano-Adanez M.C., Gustavsson L. Phosphatidylethanol formation and degradation in brains of acutely and repeatedly ethanol-treated rats. Neurosci. Lett. 1994;179:127–131.
    1. Gustavsson L., Moehren G., Hoek J.B. Phosphatidylethanol formation in rat hepatocytes. Ann. N. Y. Acad. Sci. 1991;625:438–440.
    1. Kobayashi M., Kanfer J.N. Phosphatidylethanol formation via transphosphatidylation by rat brain synaptosomal phospholipase D. J. Neurochem. 1987;48:1597–1603.
    1. Mueller G.C., Fleming M.F., LeMahieu M.A., Lybrand G.S., Barry K.J. Synthesis of phosphatidylethanol—A potential marker for adult males at risk for alcoholism. Proc. Natl. Acad. Sci. USA. 1988;85:9778–9782.
    1. Gustavsson L. ESBRA 1994 Award Lecture. Phosphatidylethanol formation: specific effects of ethanol mediated via phospholipase D. Alcohol Alcohol. 1995;30:391–406.
    1. Colley W.C., Sung T.C., Roll R., Jenco J., Hammond S.M., Altshuller Y., Bar-Sagi D., Morris A.J., Frohman M.A. Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr. Biol. 1997;7:191–201.
    1. Steed P.M., Clark K.L., Boyar W.C., Lasala D.J. Characterization of human PLD2 and the analysis of PLD isoform splice variants. FASEB J. 1998;12:1309–1317.
    1. Vinggaard A.M., Hansen H.S. Bradykinin and vasopressin activate phospholipase D in rat Leydig cells by a protein kinase C-dependent mechanism. J. Endocrinol. 1993;136:119–126.
    1. Shukla S.D., Sun G.Y., Wood W.G., Savolainen M.J., Alling C., Hoek J.B. Ethanol and lipid metabolic signaling. Alcohol. Clin. Exp. Res. 2001;25:33S–39S.
    1. Lundqvist C., Alling C., Aradottir S., Gustavsson L. Agonist-stimulated and basal phosphatidylethanol formation in neutrophils from alcoholics. Alcohol. Clin. Exp. Res. 1994;18:580–586.
    1. Magai R.M., Shukla S.D. Metabolic fate of [14C]-ethanol into endothelial cell phospholipids including platelet-activating factor, sphingomyelin and phosphatidylethanol. J. Biomed. Sci. 2001;8:143–150.
    1. Aradottir S., Moller K., Alling C. Phosphatidylethanol formation and degradation in human and rat blood. Alcohol Alcohol. 2004;39:8–13.
    1. Aradottir S., Lundqvist C., Alling C. Phosphatidylethanol in rat organs after ethanol exposure. Alcohol. Clin. Exp. Res. 2002;26:514–518.
    1. Isaksson A., Walther L., Hansson T., Andersson A., Alling C. Phosphatidylethanol in blood (B-PEth): A marker for alcohol use and abuse. Drug Test Anal. 2011;3:195–200.
    1. Selle H., Chapman B.E., Kuchel P.W. Release of choline by phospholipase D and a related phosphoric diester hydrolase in human erythrocytes. 1H spin-echo n.m.r. studies. Biochem. J. 1992;284:61–65.
    1. Metz S.A., Dunlop M. Production of phosphatidylethanol by phospholipase D phosphatidyl transferase in intact or dispersed pancreatic islets: Evidence for the in situ metabolism of phosphatidylethanol. Arch. Biochem. Biophys. 1990;283:417–428.
    1. Bruhl A., Faldum A., Loffelholz K. Degradation of phosphatidylethanol counteracts the apparent phospholipase D-mediated formation in heart and other organs. Biochim. Biophys. Acta. 2003;1633:84–89.
    1. Moehren G., Gustavsson L., Hoek J.B. Activation and desensitization of phospholipase D in intact rat hepatocytes. J. Biol. Chem. 1994;269:838–848.
    1. Pai J.K., Liebl E.C., Tettenborn C.S., Ikegwuonu F.I., Mueller G.C. 12-O-tetradecanoylphorbol-13-acetate activates the synthesis of phosphatidylethanol in animal cells exposed to ethanol. Carcinogenesis. 1987;8:173–178.
    1. Aradottir S., Asanovska G., Gjerss S., Hansson P., Alling C. PHosphatidylethanol (PEth) concentrations in blood are correlated to reported alcohol intake in alcohol-dependent patients. Alcohol Alcohol. 2006;41:431–437.
    1. Hansson P., Caron M., Johnson G., Gustavsson L., Alling C. Blood phosphatidylethanol as a marker of alcohol abuse: Levels in alcoholic males during withdrawal. Alcohol Clin. Exp. Res. 1997;21:108–110.
    1. Hartmann S., Aradottir S., Graf M., Wiesbeck G., Leech O., Ramskogler K., Wolfersdorf M., Alling C., Wurst F.M. 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.
    1. Varga A., Hansson P., Lundqvist C., Alling C. Phosphatidylethanol in blood as a marker of ethanol consumption in healthy volunteers: comparison with other markers. Alcohol. Clin. Exp. Res. 1998;22:1832–1837.
    1. Wurst F.M., Alexson S., Wolfersdorf M., Bechtel G., Forster S., Alling C., Aradottir S., Jachau K., Huber P., Allen J.P., et al. Concentration of fatty acid ethyl esters in hair of alcoholics: Comparison to other biological state markers and self reported-ethanol intake. Alcohol Alcohol. 2004;39:33–38.
    1. Wurst F.M., Thon N., Aradottir S., Hartmann S., Wiesbeck G.A., Leech O., Skala K., Wolfersdorf M., Weinmann W., Alling C. Phosphatidylethanol: Normalization during detoxification, gender aspects and correlation with other biomarkers and self-reports. Addict. Biol. 2010;15:88–95.
    1. Wurst F.M., Thon N., Weinmann W., Tippetts S., Marques P., Hahn J.A., Alling C., Aradottir S., Hartmann S., Lakshman R. Characterization of sialic acid index of plasma apolipoprotein J and phosphatidylethanol during alcohol detoxification—A pilot study. Alcohol. Clin. Exp. Res. 2012;36:251–257.
    1. Varga A., Hansson P., Johnson G., Alling C. Normalization rate and cellular localization of phosphatidylethanol in whole blood from chronic alcoholics. Clin. Chim. Acta. 2000;299:141–150.
    1. 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 doi: 10.1111/j.1530-0277.2012.01768.x.
    1. Bocckino S.B., Wilson P.B., Exton J.H. Ca2+-mobilizing hormones elicit phosphatidylethanol accumulation via phospholipase D activation. FEBS Lett. 1987;225:201–204.
    1. Helander A., Zheng Y. Molecular species of the alcohol biomarker phosphatidylethanol in human blood measured by LC-MS. Clin. Chem. 2009;55:1395–1405.
    1. Holbrook P.G., Pannell L.K., Murata Y., Daly J.W. Molecular species analysis of a product of phospholipase D activation. Phosphatidylethanol is formed from phosphatidylcholine in phorbol ester- and bradykinin-stimulated PC12 cells. J. Biol. Chem. 1992;267:16834–16840.
    1. Morrill G.A., Ma G., Kostellow A. Molecular species analysis of 1,2-diacylglycerol released in response to progesterone binding to the amphibian oocyte plasma membrane. Cell. Signal. 2000;12:787–796.
    1. Huusko T.J., Liisanantti M.K., Nissinen A.E., Kakko S., Savolainen E.R., Vuoristo J.T., Savolainen M.J. Effects of phosphatidylethanol on mouse adipocyte differentiation and expression of stearoyl-CoA desaturase 1. Alcohol. Clin. Exp. Res. 2007;31:376–382.
    1. Ikegwuonu F.I., Pai J.K., Mueller G.C. Effects of steroids on the synthesis and metabolism of phosphatidylethanol in phorbol ester-activated lymphocytes. Carcinogenesis. 1990;11:1927–1935.
    1. Gnann H., Engelmann C., Skopp G., Winkler M., Auwarter V., Dresen S., Ferreiros N., Wurst F.M., Weinmann W. Identification of 48 homologues of phosphatidylethanol in blood by LC-ESI-MS/MS. Anal. Bioanal. Chem. 2010;396:2415–2423.
    1. Gnann H., Weinmann W., Engelmann C., Wurst F.M., Skopp G., Winkler M., Thierauf A., Auwarter V., Dresen S., Bouzas N.F. Selective detection of phosphatidylethanol homologues in blood as biomarkers for alcohol consumption by LC-ESI-MS/MS. J. Mass Spectrom. 2009;44:1293–1299.
    1. Nalesso A., Viel G., Cecchetto G., Mioni D., Pessa G., Favretto D., Ferrara S.D. Quantitative profiling of phosphatidylethanol molecular species in human blood by liquid chromatography high resolution mass spectrometry. J. Chromatogr. A. 2011;1218:8423–8431.
    1. Zheng Y., Beck O., Helander A. Method development for routine liquid chromatography-mass spectrometry measurement of the alcohol biomarker phosphatidylethanol (PEth) in blood. Clin. Chim. Acta. 2011;412:1428–1435.
    1. Sarri E., Servitja J.M., Picatoste F., Claro E. Two phosphatidylethanol classes separated by thin layer chromatography are produced by phospholipase D in rat brain hippocampal slices. FEBS Lett. 1996;393:303–306.
    1. Gunnarsson T., Ekblad L., Karlsson A., Michelsen P., Odham G., Jergil B. Separation of polyphosphoinositides using normal-phase high-performance liquid chromatography and evaporative light scattering detection or electrospray mass spectrometry. Anal. Biochem. 1997;254:293–296.
    1. Gunnarsson T., Karlsson A., Hansson P., Johnson G., Alling C., Odham G. Determination of phosphatidylethanol in blood from alcoholic males using high-performance liquid chromatography and evaporative light scattering or electrospray mass spectrometric detection. J. Chromatogr. B. 1998;705:243–249.
    1. 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.
    1. Yon C., Han J.S. Analysis of trimethylsilyl derivatization products of phosphatidylethanol by gas chromatography-mass spectrometry. Exp. Mol. Med. 2000;32:243–245.
    1. Varga A., Nilsson S. Nonaqueous capillary electrophoresis for analysis of the ethanol consumption biomarker phosphatidylethanol. Electrophoresis. 2008;29:1667–1671.
    1. Nalesso A., Viel G., Cecchetto G., Frison G., Ferrara S.D. Analysis of the alcohol biomarker phosphatidylethanol by NACE with on-line ESI-MS. Electrophoresis. 2010;31:1227–1233.
    1. Nissinen A.E., Makela S.M., Vuoristo J.T., Liisanantti M.K., Hannuksela M.L., Horkko S., Savolainen M.J. Immunological detection of in vitro formed phosphatidylethanol—An alcohol biomarker—With monoclonal antibodies. Alcohol. Clin. Exp. Res. 2008;32:921–928.
    1. Nissinen A.E., Laitinen L.M., Kakko S., Helander A., Savolainen M.J., Horkko S. Low plasma antibodies specific for phosphatidylethanol in alcohol abusers and patients with alcoholic pancreatitis. Addict. Biol. 2011 doi: 10.1111/j.1369-1600.2010.00279.x.
    1. Tolonen A., Lehto T.M., Hannuksela M.L., Savolainen M.J. A method for determination of phosphatidylethanol from high density lipoproteins by reversed-phase HPLC with TOF-MS detection. Anal. Biochem. 2005;341:83–88.
    1. Faller A., Richter B., Kluge M., Koenig P., Seitz H.K., Thierauf A., Gnann H., Winkler M., Mattern R., Skopp G. LC-MS/MS analysis of phosphatidylethanol in dried blood spots versus conventional blood specimens. Anal. Bioanal. Chem. 2011;401:1163–1166.
    1. Marques P., Tippetts S., Allen J., Javors M., Alling C., Yegles M., Pragst F., Wurst F. Estimating driver risk using alcohol biomarkers, interlock blood alcohol concentration tests and psychometric assessments: Initial descriptives. Addiction. 2010;105:226–239.
    1. Marques P., Hansson T., Isaksson A., Walther L., Jones J., Lewis D., Jones M. Detection of phosphatidylethanol (PEth) in the blood of drivers in an alcohol ignition interlock program. Traffic Inj. Prev. 2011;12:136–141.
    1. Stewart S.H., Reuben A., Brzezinski W.A., Koch D.G., Basile J., Randall P.K., Miller P.M. Preliminary evaluation of phosphatidylethanol and alcohol consumption in patients with liver disease and hypertension. Alcohol Alcohol. 2009;44:464–467.
    1. Stewart S.H., Law T.L., Randall P.K., Newman R. Phosphatidylethanol and alcohol consumption in reproductive age women. Alcohol. Clin. Exp. Res. 2010;34:488–492.
    1. Wurst F.M., Vogel R., Jachau K., Varga A., Alling C., Alt A., Skipper G.E. Ethyl glucuronide discloses recent covert alcohol use not detected by standard testing in forensic psychiatric inpatients. Alcohol. Clin. Exp. Res. 2003;27:471–476.
    1. Comasco E., Nordquist N., Leppert J., Oreland L., Kronstrand R., Alling C., Nilsson K.W. Adolescent alcohol consumption: biomarkers PEth and FAEE in relation to interview and questionnaire data. J. Stud. Alcohol. Drugs. 2009;70:797–804.
    1. Hahn J.A., Dobkin L.M., Mayanja B., Emenyonu N.I., Kigozi I.M., Shiboski S., Bangsberg D.R., Gnann H., Weinmann W., Wurst F.M. Phosphatidylethanol (PEth) as a Biomarker of Alcohol Consumption in HIV-Positive Patients in Sub-Saharan Africa. Alcohol. Clin. Exp. Res. 2012;36:854–862.
    1. Kip M.J., Spies C.D., Neumann T., Nachbar Y., Alling C., Aradottir S., Weinmann W., Wurst F.M. The usefulness of direct ethanol metabolites in assessing alcohol intake in nonintoxicated male patients in an emergency room setting. Alcohol. Clin. Exp. Res. 2008;32:1284–1291.
    1. Viel G., Boscolo-Berto R., Cecchi R., Bajanowski T., Vieira N.D., Ferrara S.D. Bio-medicolegal scientific research in Europe. A country-based analysis. Int. J. Legal. Med. 2011;125:717–725.
    1. Boscolo-Berto R., Viel G., Montagnese S., Raduazzo D.I., Ferrara S.D., Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of randomized controlled trials. Sleep Med. Rev. 2012;16:431–443.
    1. Boscolo-Berto R. Clinical testing and evidence-based medicine: when the absence of evidence doesn’t mean evidence of absence. G. Ital. Nefrol. 2009;26:417.
    1. DerSimonian R., Laird N. Meta-analysis in clinical trials. Control Clin. Trials. 1986;7:177–188.

Source: PubMed

Подписаться