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Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20 Page 5 of 17

included MASLD patients showed signs of moderate to excessive alcohol consumption.

There is an ongoing debate on the impact of alcohol consumption and its effect on the prognosis of
MASLD, with studies proposing both positive [51-56] and negative effects [57-60] , and with some of the studies
suggesting a J-shaped curve where modest levels of alcohol consumption might be beneficial. This is in
concordance with earlier studies reporting that modest alcohol consumption is associated with decreased
[61]
risk of cardiovascular disease and mortality . However, in a recent study including 28 million individuals,
it was suggested that any level of alcohol use is linked to negative outcomes . Moreover, in two recent
[62]
studies, it was shown that alcohol consumption (mostly moderate use) was associated with fibrosis
progression in patients with MASLD [63,64] . Additionally, in a study by Younossi et al., they found that more
than 3 or 1.5 (for men and women, respectively) drinks per day was associated with increased mortality - an
[65]
association that was more evident amongst individuals with metabolic syndrome .
In summary, alcohol does not seem to attenuate the presence of SLD but rather aggravates the accumulation
of steatosis and the progression to fibrosis. Although alcohol seems to be associated with decreased
cardiovascular disease, real-world data on alcohol consumption indicate an increased all-cause mortality.
Even though these two entities are histopathologically similar, treatment and management vastly differ.
Therefore, separating MASLD from MetALD and ALD is of outermost importance, and using the
recommended questionnaire (i.e., AUDIT) to estimate a patient´s alcohol consumption can be lined with
non-differential misclassification bias . Nevertheless, differentiating ALD from MASLD, or MetALD, is
[66]
probably more complicated than previously perceived, and the use of direct alcohol markers (e.g., PEth)
should be considered.

Methotrexate
Methotrexate (MTX) is an effective and widely used drug in the management of autoimmune and
dermatological disorders. The notion of liver damage has been attributed to MTX on the basis of
accumulation of MTX-polyglutamate - a metabolite that triggers oxidative stress, inflammation, steatosis,
fibrosis, and apoptosis . Albeit high-dose MTX treatment (used for its cytotoxic-antiproliferative action in
[67]
[68]
adult and childhood malignancies) has been reported to cause liver damage in up to 80% , the evidence of
low-dose MTX treatment and hepatotoxicity is debatable, with fluctuations of liver enzyme levels often
[69]
returning to normal despite continuation of MTX .
In a Swedish study, the most prominent predictor of elevated aminotransferases was signs of elevated
[70]
aminotransferases pre-treatment, use of statins, and increased body mass index (BMI) . Similarly, a
German study of patients with inflammatory bowel disease noted that the presence of hepatic steatosis
verified by ultrasound, and not MTX treatment, predicted elevated aminotransferases . Both these studies
[71]
indicate that pre-existing risk factors for elevated liver enzymes are often the cause of elevated
aminotransferases, which was also shown by Mori et al., who reported that chronically elevated
aminotransferases were not associated with the cumulative dose of MTX but rather with BMI, dyslipidemia
and type 2 diabetes mellitus (T2DM) . Similarly, in follow-up studies with repeat liver biopsy, the effect of
[72]
MTX on current and future histopathological changes is mild, and in patients with concomitant SLD,
secondary causes such as alcohol overconsumption or obesity are often present [73-76] .

In a Danish population-based cohort study, approximately 40,000 individuals (70% rheumatoid arthritis
[RA], 16% psoriatic arthritis [PsA], and 14% psoriasis [PsO]) with MTX treatment were followed for a mean
of 6.5-8.4 years . Although cumulative MTX dose was higher in the RA population, liver disease outcomes
[77]
were more common in the PsO and PsA groups, with alcohol abuse and the presence of T2DM acting as the