The usefulness of S-PEth as an indicator of alcohol consumption¤t/Vårdgivare/ST_lakare/2018... ·...
Transcript of The usefulness of S-PEth as an indicator of alcohol consumption¤t/Vårdgivare/ST_lakare/2018... ·...
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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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