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Page 4 of 17 Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20

Furthermore, in addition to both AUDIT or the abbreviated AUDIT-C, indirect alcohol markers, such as
mean corpuscular volume, gamma-glutamyl transferase, and aspartate and alanine aminotransferase, are
occasionally used. However, indirect alcohol markers all depend on chronic excessive drinking over an
extended period, and they are usually associated with multiple confounders resulting in an inadequate
accuracy, specificity, and sensitivity [34-38] . Additionally, carbohydrate-deficient transferrin (CDT) is
[39]
occasionally used to diagnose or screen for (chronic) excessive alcohol consumption . However, CDT
mainly indicates heavy alcohol consumption (50-80 g/day or 350-560 g/week) over a period of more than 1-
2 weeks, reflecting a threshold above the limit for MASLD (i.e., 210 g/week for men and 140 g/week for
women). Moreover, CDT is susceptible to inaccurate levels secondary to confounding factors [40-42] .

Direct alcohol markers portray a much higher sensitivity and specificity in comparison to questionnaires
(e.g., AUDIT) and indirect alcohol markers (e.g., CDT), since they are direct products of the non-oxidative
metabolism of ethanol. In addition, compared to direct determination of ethanol in exhaled air or blood/
serum, direct alcohol markers have a much wider window of detection [4-12 h vs. 3-90 days (and up to 6
months)]. There are several direct biomarkers for ethanol, one of which is phosphatidylethanol (PEth), a
[43]
direct biomarker showing both high specificity and sensitivity . In a study by Schröck et al., 16 volunteers
received one dose of vodka (ranging from 34 to 72 g of alcohol) in order to attain a blood ethanol
[44]
concentration of circa 1 g/kg of weight . Phosphatidylethanol was measured every other hour from intake
and up to eight hours after intake. The highest value of PEth was reported and ranged from 0.06 to 0.31 μ
mol/L (reference value in Sweden for moderate alcohol consumption ranges from 0.05 to 0.30 μmol/L).
Moreover, in a study by Kechagias et al., 44 subjects were randomized to abstaining from alcohol or
consuming 32 g or 16 g (if male or female, respectively) of wine per day for three months . Most of the
[45]
participants in the consumption group had values of PEth below 0.04 μmol/L (< 0.05 μmol/L is according to
Swedish reference values defined as low or no alcohol consumption), while three subjects had elevated
[45]
(signs of moderate) PEth values of 0.07, 0.12, and 0.17 μmol/L .
Both the studies by Schröck et al. and Kechagias et al. suggest that long-standing or occasional intake of up
to 30 g of alcohol per day results in classifying alcohol consumption as low to moderate according to current
clinical decision thresholds for PEth, while consumption exceeding 70 g/day will almost certainly result in
values of PEth above 0.30 µmol/L, which is considered heavy alcohol consumption in clinical practice [44,45] .
This is corroborated in a study by Walther et al. that showed an almost linear association between alcohol
consumption and PEth .
[46]
The more commonly used direct alcohol marker is ethyl glucuronide (EtG), where, to date, the
determination of conjugated EtG in urine (uEtG) is applied in several European countries . Depending on
[30]
the consumption of alcohol, uEtG is detectable for up to 80 hours. However, in contrast, measurement of
EtG in hair (hEtG) provides a more reliable means of estimating chronic consumption over a period of 3 to
6 months, where 1 cm of hair represents 1 month (however, hair length below 3 cm or more than 6 cm
should be interpreted with caution) . In recent years, the interest in hEtG has increased, however, mostly
[30]
in forensic settings.

Consumption of alcohol is not uncommon in individuals with MASLD, and it also seems to increase the
risk of incident steatosis in individuals with presumed MASLD [47,48] , with an almost direct dose-response
[49]
relationship between alcohol consumption and hepatic steatosis . As mentioned, the gold standard for
excluding patients with excessive alcohol consumption (i.e., disqualifying them from a MASLD diagnosis) is
self-reported alcohol consumption. However, in a recent study by Staufer et al., subjects with presumed
MASLD were evaluated with direct alcohol markers . Interestingly, approximately one-third (29%) of the
[50]