The usefulness of S-PEth as an indicator of alcohol consumption

Transcription

1 Page 1 of 14 The usefulness of S-PEth as an indicator of alcohol consumption By Eirik Engel- Vågsholm Supervisor: Anne Björk

2 Page 2 of 14 Abstract: Background: Alcohol consumption is something that has been a challenge to monitor and treat in Swedish primary care settings. Recommendations for screening and intervention have existed for 30 years but are hard to implement. Phosphatidylethanol (PEth) is a biomarker that has been proposed as a helpful screening method for alcohol consumption. Aim: To assess how well do PEth values in blood correlate with the consumption of alcohol in the outpatient setting with regard to the national recommendations and under different clinical scenarios. Method: Systematic review of 5 experimental drinking studies made specifically on PEth to assess its sensitivity and specificity. Studies were acquired from PubMed and quality assessed using Swedish guidelines. Results: The PEth level depends on amount consumed, time duration, and individuals metabolism affecting half-life. PEth is specific and appears better than other bio-markers for detecting alcohol consumption. It is hard to correlate PEth values with alcohol consumption above national guidelines for risk consumption. Conclusion: In light of this, possible uses in primary care include: to verify abstinence and to detect chronic high alcohol consumption. The difficult part is the intermediate range where the PEth score should be complemented by patient history other screening methods. Sammanfattning: Bakgrund: Alkoholöverkonsumtion har sedan länge varit en utmaning att övervaka och behandla för slutenvården och primärvården. Rekommendationer för screening och intervention har funnits i ca 30 år men är svåra att implementera. Fosfatidyletanol (PEth) är en biomarkör för alkoholkonsumtion och är en av många screeningmetoder i Sverige. Målsättning: Att utforska hur bra PEth värden i blodet kan korrelera till alkoholkonsumtion med hänsyn till nationella rekommendationer för alkoholkonsumtion samt i olika kliniska scenarion. Metod: Litteraturgranskning av 5 experimentella studier där fokus låg på att bedöma sensitiviteten och specificiteten av PEth. Studier togs från PubMed och kvalitetsgranskades med SBUs mallar. Resultat: PEth värden i blod beror på mängd alkoholkonsumtion, tid och individuell metabolism. PEth är väldigt specifik och ter sig bättre än andra biomarkörer på att upptäcka alkoholkonsumtion. Det finns svårigheter att korrelera PEth värden med nationella riktlinjer för riskbruk. Konklusion: Optimala användningsområden för PEth är: Verifiering av nykterhet samt kunna hitta kroniskt förhöjd alkoholkonsumtion. Svårigheterna kommer när PEth i blod visar måttlig konsumtion, varpå blodprovet bör kompletteras av alkoholanamnes och andra screeningmetoder.

3 Page 3 of 14 Introduction: Identifying alcohol abuse is a major challenge for preventive medicine in general practice. As alcohol abuse is related to several health problems, (1) identifying those having an alcohol consumption representing a health risk, is critical. Another important area is to assure abstention over time, when absolutely necessary, for certain jobs such as offshore oil rig workers. In the Swedish medical journal Läkartidningen, a special issue discussing the relevance of alcohol monitoring and intervention in primary care, appeared October Recommendations for screening and intervention have existed for 30 years but are not practical (2). One challenge was that few seek a doctor for their alcohol related problems, and one recommendation was increased screening for alcohol problems. The overall aim is a more patient oriented approach to alcohol related problems (2). Thus, an evaluation of available screening methods such as Phosphatidylethanol (PEth) is needed. PEth has been used to monitor alcohol consumption and possible alcohol related risks in Sweden (3) during the last 10 years. PEth s usefulness appears to be better than other alcohol biological indicators due to its 100% diagnostic specificity (4) (5) (6), as PEth is only produced in the body during as long as the blood contains alcohol. This means that individuals not exposed to alcohol will test negative. Consequently, there should be no false positives in terms of alcohol exposure, while the interpretation of PEth results regarding moderate or high consumption is more difficult. According to the WHO guidelines low, moderate and high consumption of alcohol is defined as < 40g/day, 40-60g/day, and > 60g/day for males (1). Moreover, following reference values are for PETh 16:0/18:1 used in Sweden (Table 1). Table 1: Categories for alcohol consumption and their reference values for PETh 16:0/18:1 as used in Sweden Category Cutoff values values Comment or criteria Negligible alcohol consumption < 0,05 µmol/l Persons with no or very limited alcohol consumption last month Intermediate 0,05-0,30 µmol/l This group is heterogeneous including both those with moderate consumption and binge drinkers High alcohol consumption > 0,30 µmol/l Indicate excessive drinking recent month above recommended levels and risk for alcohol related

4 Page 4 of 14 Source: (3) [ These Swedish cut-off values are slightly higher than the US values, and US cut-off value is 40% lower for negligible alcohol consumption. Furthermore, one technical issue when interpreting results of studies is the difference of a standard unit of alcohol which in Europe is 12 grams of alcohol while in United States it is 14 grams. Another (7) is that the PEth values are given in PEth (µmol/l) that must be multiplied with 703 to get the US PEth values in ng/ml. The Public Health Agency of Sweden has published guidelines for risk consumption of alcohol. These are above 3 and 4 standard units per day for women and men, and above 9 and 14 standard units of alcohol per week for women and men respectively (8). However, some regions have lower thresholds; e.g. Stockholm defined low risk consumption as less than 10 standard units a week for men and women (2). There seems to be a consensus internationally for the number of drinks considered to be moderate and high on a weekly basis and the US and Swedish guidelines are closely aligned (9). In this review therefore, the guidelines used for moderate and high consumption will be the ones issued by Public Health Agency of Sweden. A European alcohol unit is illustrated for common beverages in Figure 1 while Figure 2 illustrates common serving sizes. The practical consequence is that a glass of wine or beer includes more than one unit of alcohol. Figure 1: Alcohol units for which males should not drink more than 14 per week and females more than 9 per week, and less than 4 for males and 2-3 for females on each occasion. Source: LE/Alkohol/

5 Page 5 of 14 Figure 2: transforming common alcohol consumption into units that is used in the recommendations Source: Biomechanisms of PEth: PEth was first described as an abnormal phospholipid found in the tissues of rats exposed to alcohol (10). Phosphatidylethanol is a phospholipid that can only be created on the erythrocyte membrane when there is alcohol present (11). The creation of PEth is catalyzed by phospholipase-d (PLD), a cell-membrane associated enzyme that in the presence of water catalyzes phosphatidylcholine to phosphatidylic acid and choline. In the presence of ethanol however PLD will instead synthesize Phosphatidylethanol from phosphatidylcholine [Figure 3] (11). Figure 3: Formation of phosphatidylethanol in blood

6 Page 6 of 14 Source: ClinicalKey Image: Phosphatidylethanol PEth is measured in whole blood with mass spectrometry (11). PEth has around 50 homolouges and is in Sweden generally recommended to be monitored in the 16:0/18:1 variant, as this homologue (in addition to 16:0/18:2) is found both in moderate drinkers and heavy drinkers (12). The concentration of PEth 16:0/18:1 in whole blood is high compared to other variants, approximately 36% in moderate drinkers and up to 46% of total PEth in heavy drinkers. The variant 16:0/18:2 appear to be slightly lower approximately 30% of total PEth (12). Phosphatidylethanol can be used for analysis of sobriety due to its half-life of ~4 days. In general practice, psychiatry and occupational medicine it is seen as the better test for sobriety due to its high specificity (3) (11). Aim: The aim of the study was to assess how well serum PEth (S-PEth) values correlate with the consumption of alcohol in the outpatient setting with regard to the national recommendations and under different clinical scenarios where examples include driver s license issues, liver transplant patients and pregnancy. The focus of this review was to find the experimental drinking studies with predetermined amounts of alcohol consumption where S-PEth was measured over time. Methods: PubMed was used 04 november 2018 for finding articles. The first PubMed keywords being Phosphatidylethanol, with experimental. The second keywords used were Phosphatidylethanol with drinking study. No limitations were applied in the search engine. MESH terms drinking study :

7 Page 7 of 14 ("phosphatidylethanol"[supplementary Concept] OR "phosphatidylethanol"[all Fields]) AND ("drinking"[mesh Terms] OR "drinking"[all Fields] OR "alcohol drinking"[mesh Terms] OR ("alcohol"[all Fields] AND "drinking"[all Fields]) OR "alcohol drinking"[all Fields]) AND study[all Fields] MESH terms experimental : ("phosphatidylethanol"[supplementary Concept] OR "phosphatidylethanol"[all Fields]) AND experimental[all Fields] In addition, the references therein were also scrutinized. All articles selected for this review were assessed for quality using the criteria from the Swedish agency for health technology assessment and assessment of social services (SBU). PICO P: PEth as a biomarker for alcohol consumption in clinical practice I: Prognostic factor for alcohol exposure C: Experimental studies O: Identify knowledge gained from PEth screening under different scenarios. Results: Results of this review appear in Figure 4 and Table 2. Figure 4: Search strategy and paper selection for inclusion in the review.

8 Page 8 of 14 Reasons for exclusion (Figure 4) were: 1. After reading abstract: Obvious after reading abstract that there was no relevance to this study (meaning no human studies, in vitro studies, PEth not part of the study, not relevant to the aim of this literature review) 2. Not experimental drinking studies with a controlled group and amount of alcohol determined on beforehand. Table 2: summarizing the experimental drinking studies: Study Year Main aim of Results and Duration of Numbe Quality Risk for interest conclusions follow-up r of of study bias subject accordin according s g to too SBU SBU outline outline

9 Page 9 of 14 Kechagias et 2015 Compare PEth PEth was 3 months 44 High Low al. 16:0/18:1 with detected in all drinking other alcohol participants markers to randomized to distinguish alcohol abstinence and consumption moderate consumption Gnann 2012 Observe PEth 5 days 11 High Low et al. formation and concentrations drinking + 16 elimination of was measurable days PEth 16:0/18:1 but rather low abstinence by simulating compared to extensive alcohol abusers in drinking previous studies. Schrök 2017 Asses detection PEth can be 1 day 16 High Medium et al. window of PEth detected for up to drinking :0/18:1 and 12 days Further days PEth 16:0/18:2 studies are abstinence after ingesting needed to single high dose establish cut-off of alcohol levels for PEth as a diagnostic marker Varga 1998 Elucidate how Substantial Exp: 1 day 5 Low Low et al. different levels alcohol intake is drinking, ~20 experi due to it and patterns of needed to elevate days mental being alcohol intake S-PEth. PEth abstinence. and 12 very old affect S-PEth appears more Observationa observa Compare PEth sensitive than l: 3 weeks tional. with other CDT. drinking. markers

10 Page 10 of 14 Javros 2016 Characterization Combined PEth 1 day 27 High Low et al. of of is a sensitive drinking + 13 pharmacokinetics biomarker for days of 2 homolouges indentification of abstinence of PEth (PEth low levels of 16:0/18:1 and EtOH PEth 16:0/18:2) consumption. and their Measurement of combined total in these 2 uncoagulated homolouges may blood after provide consumption of additional low doses of sensitivity to EtOH identify low levels of drinking PEth appears to detect chronic alcohol abuse well. Nevertheless S-PEth is not as accurate at detecting other risk behaviors in relation to alcohol. However for a binge drinking episode there is evidence of good sensitivity ~2 weeks thereafter (13) [Schrök et al.], and for example a drinking event of 1-3 US alcohol units could even be detected after 2 weeks of confirmed abstinence (14) [Javros et al.]. Discussion: There is a need for reliable screening tests for risk consumption of alcohol. PEth appears to be the best screening test available. However, test results should be interpreted with some care with regard to the scenarios foreseen on alcohol consumption. In Sweden the S-PEth results are interpreted into 3 categories of alcohol consumption: 1 sobriety or negligible consumption (<0,05µmol/L). Here the test is seen as very useful due to its 100% specificity (4). It can be applied in many outpatient and occupational situations as a validation of abstinence, for example airline pilots, power-plant and oil-rig workers and for insurance companies monitoring abstinence (15).

11 Page 11 of 14 2 moderate drinking (>0,05 - <0,3µmol/L). Here the S-PEth results needs to be interpreted with regard to results from other screening tests, patient history and clinical experience (7) (5) (6). False positives and false negatives are a much greater concern here and care is needed when concluding. 3 consumption considered to be a health risk (>0,3µmol/L). At these blood values one should assume a risk consumption of alcohol and the patient should be informed of dangers of consumption. Viel et al. found significant differences in total S-PEth concentrations between heavy and social drinkers (5). There are difficulties with identifying binge drinkers if the test was taken too many weeks after consumption. Examples include periodical drinkers and summer vacation drinkers, that not always will be flagged by S-PEth (4) (16). PEth would be useful for detecting periodic drinking if the person was tested during the appropriate time window. PEth appears to be more sensitive and specific than markers such as CDT, GGT and MCV used to detect and quantify alcohol intake (4) (17). The clinical scenarios would include follow-up on those individuals who should abstain from alcohol due to pregnancy, occupational obligations, airline pilots or persons working offshore on oil rigs. Another aim could be identifying persons with chronic alcohol problems, and a third could be a part of the Swedish public health screening. PEth can also be useful in forensic or legal situations if the tests are timed appropriately, e.g., insurance screening (15). Methodological questions: Nalesso et al. examined blood samples collected from heavy drinkers (n=11), social drinkers (n=8), and teetotalers (n=10) (12). This study could be considered to have low statistical power and the participants were reporting their consumption. An issue with several of the experimental studies that were used in this review is that they have small study populations and most of them are over short time-spans, which is surprising since PEth is used clinically to target long term consumption. A larger experimental study over a longer period is needed, such as more than 3 months. There can be raised ethical questions if such a study would be performed however, having a group randomized to be heavy drinkers over a longer period. One advantage of the experimental approach is the better control of exposure, when the alcohol was drunk, and the amounts consumed. On the other hand, few studies are published and in which there are limited duration of exposures less than two weeks. The use of self-selected participants in experiments is another source of bias. Moreover, not all bad alcohol habits were accounted for in

12 Page 12 of 14 the experimental studies for example binge drinking. Five experimental studies were included of which one (Varga et al.) was older than 20 years. During which the methodology of measuring PEth has evolved. A source of uncertainty is when people are reporting their own consumption via AUDIT, and consequent risk for underestimation of consumption. On the other hand, there are published many more observational studies. The conclusions from these two approaches should be aligned for valid inferences. Another interesting aspect is that one size fits all in the Swedish PEth recommended cut-off values, while the Swedish definitions for alcohol over-consumption are different between men and women >14 standard units/ week and >9 standard units /week, respectively (8). There is evidence suggesting that chronic alcoholics metabolize PEth faster than social drinkers. The variations in phosphatidylethanol formation and half-life amongst in persons with different lifestyles (6, 13) should be further investigated. The patterns of consumption may vary where binge drinking can include 10 standard units at once in the weekend and may still not register high PEth values as suggested by studies (4) (13) (16). This can present uncertainties in interpreting PEth results in for example northern Europe (Finland) where binge-drinking problems are more frequent (18). Conclusion: S-PEth is helpful in several clinical settings such as public health screening, further research into alcohol related issues, occupational and insurance questions. In particular, S-PEth is a good biomarker for verifying consumption or abstinence for the previous 2 weeks and for detecting chronic alcohol consumption. Moderate S-PEth values may represent a risk consumption according to the Swedish guidelines. Keywords: phosphatidylethanol, ethanol, drinking study, monitoring Abbreviations: AUDIT = Alcohol Use Disorder Identification Test

13 Page 13 of 14 PEth = Phosphatidylethanol S-PEth = Serum PEth (detected blood level of PEth) CDT = Carbohydrate-deficient transferrin GGT = Gammaglutaminyltransferase EtOH = Ethanol (alcohol) Conversion of values: PEth in µmol/l 703 = PEth in ng/ml. BIBLIOGRAPHY: eng.pdf [Internet]. [cited 04 november 2018]. Available at: 2. Läkartidningen - Nya metoder behövs för alkoholarbetet i primärvården [Internet]. [cited 04 november 2018]. Available at: 3. Hel ers, er, Professor A, sjukhuskemist, universitetslaboratoriet K, laboratoriemedicin H institutionen för, m.fl. Nationell harmonisering av alkoholmarkören PEth [Internet]. [cited 04 november 2018]. Available at: 4. 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. november 1998;22(8): Viel G, Boscolo-Berto R, Cecchetto G, Fais P, Nalesso A, Ferrara SD. Phosphatidylethanol in blood as a marker of chronic alcohol use: a systematic review and meta-analysis. Int J Mol Sci. 13 november 2012;13(11): Kechagias S, Dernroth DN, Blomgren A, Hansson T, Isaksson A, Walther L, m.fl. Phosphatidylethanol Compared with Other Blood Tests as a Biomarker of Moderate Alcohol Consumption in Healthy Volunteers: A Prospective Randomized Study. Alcohol Alcohol Oxf Oxfs. juli 2015;50(4): 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. 01 november 2018;63(6): Ansvarsfull alkoholservering.pdf [Internet]. [cited 03 october 2018]. Available at: ull-alkoholservering-studentpubarnas-utbildningsmaterial.pdf 9. CDC - Fact Sheets- Moderate Drinking - Alcohol [Internet] [cited 04 november 2018]. Available at: Alling C, Gustavsson L, Månsson JE, Benthin G, Anggård E. Phosphatidylethanol formation

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