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The usefulness of S-PEth as an indicator of alcohol

consumption

By Eirik Engel- Vågsholm

Supervisor: Anne Björk

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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.

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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 2018. 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

or criteria

Comment

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

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Source: (3) [http://www.lakartidningen.se/Opinion/Debatt/2013/09/Nationell-harmonisering-av-

alkoholmarkoren-fosfatidyletanol-PEth/].

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: http://www.lul.se/sv/Extranat/For_vardgivare/MOT-PATIENTEN/Sjukvard1/Halsokedjan-

LE/Alkohol/

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Figure 2: transforming common alcohol consumption into units that is used in the recommendations

Source: http://alkohollinjen.se/om-alkohol-och-halsa/

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

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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”:

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("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.

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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

interest

Results and

conclusions

Duration of

follow-up

Numbe

r of

subject

s

Quality

of study

accordin

g to

SBU

outline

Risk for

bias

according

too SBU

outline

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Kechagias et

al.

2015 Compare PEth

16:0/18:1 with

other alcohol

markers to

distinguish

abstinence and

moderate

consumption

PEth was

detected in all

participants

randomized to

alcohol

consumption

3 months

drinking

44 High Low

Gnann

et al.

2012 Observe

formation and

elimination of

PEth 16:0/18:1

by simulating

extensive

drinking

PEth

concentrations

was measurable

but rather low

compared to

alcohol abusers in

previous studies.

5 days

drinking + 16

days

abstinence

11 High Low

Schrök

et al.

2017 Asses detection

window of PEth

16:0/18:1 and

PEth 16:0/18:2

after ingesting

single high dose

of alcohol

PEth can be

detected for up to

12 days Further

studies are

needed to

establish cut-off

levels for PEth as

a diagnostic

marker

1 day

drinking + 13

days

abstinence

16 High Medium

Varga

et al.

1998 Elucidate how

different levels

and patterns of

alcohol intake

affect S-PEth

Compare PEth

with other

markers

Substantial

alcohol intake is

needed to elevate

S-PEth. PEth

appears more

sensitive than

CDT.

Exp: 1 day

drinking, ~20

days

abstinence.

Observationa

l: 3 weeks

drinking.

5

experi

mental

and 12

observa

tional.

Low

due to it

being

very old

Low

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Javros

et al.

2016 Characterization

of of

pharmacokinetics

of 2 homolouges

of PEth (PEth

16:0/18:1 and

PEth 16:0/18:2)

and their

combined total in

uncoagulated

blood after

consumption of

low doses of

EtOH

Combined PEth

is a sensitive

biomarker for

indentification of

low levels of

EtOH

consumption.

Measurement of

these 2

homolouges may

provide

additional

sensitivity to

identify low

levels of drinking

1 day

drinking + 13

days

abstinence

27 High Low

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).

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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

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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 bio-

marker 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

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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.

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