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Page 6 of 17 Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20

strongest predictors. These findings could be related to the findings of psoriasis being strongly associated
with MASLD, socioeconomic status, steatogenic treatment, metabolic syndrome, and alcohol consumption
[78]
pattern . Furthermore, metabolic components, such as central adiposity or insulin resistance, and not
MTX, seem to be of great importance in predicting elevated elastographic values [79,80] . Although several
studies on MTX and liver damage often focus on fibrosis or elastographic values, few focus on steatosis.
However, in a study by Choi et al., 368 patients with RA were evaluated with ultrasound, of whom 92 had
SLD. There was no difference in cumulative dose between patients with and without SLD
[81]
(1.9 ± 1.8 vs. 1.9 ± 2.1 g) . However, BMI and hypercholesterolemia were significantly associated with the
presence of SLD. Furthermore, in two studies investigating the association of steatosis and MTX treatment,
there was a significant difference in cumulative dose, but no adjustment for metabolic features or alcohol
consumption was undertaken - making these data difficult to interpret [82,83] .

The assumption that MTX is a steatogenic drug in the absence of overweight/obesity, T2DM, dyslipidemia
and alcohol overconsumption is disputable. Further studies determining the association of low-dose MTX
and steatosis while adjusting for known steatogenic co-morbid diseases are needed.

Tamoxifen
Tamoxifen (TMX) is an effective selective estrogen receptor modulator used to treat estrogen receptor-
positive breast cancer. It has been linked to liver toxicity mainly through the induction of SLD [84,85] . The
effect of TMX on hepatic lipid metabolism and accumulation remains unclear. However, animal studies
have proposed both inhibition of fatty acid oxidation and increased triglyceride synthesis [86,87] . This was,
however, questioned in a study by Cole et al., where mice injected with TMX had higher hepatic
triacylglycerol compared to controls but unchanged fatty acid uptake, triacylglycerol secretion, and fatty
[88]
acid oxidation . These data would suggest that TMX increases de novo fatty acid synthesis, causing hepatic
lipid accumulation. Furthermore, in human subjects, TMX is highly associated with SLD. In a meta-analysis
by Lee et al., data on 6,962 patients and 975 controls were analyzed . The incidence rate for SLD in TMX-
[85]
treated patients and controls was 40.25 and 12.37 per 100 patients, respectively, with an incidence rate ratio
of 3.12. However, the main risk factors for concomitant SLD were body mass index (BMI) and
hypercholesterolemia. Similar results were observed in a multicenter trial of more than 5,000 women, where
TMX treatment was associated with a two-fold risk of developing MASLD . This risk, however, seemed
[89]
synergistic, since patients with a normal BMI had no increased risk of TMX-induced SLD, compared to
patients with overweight or obesity, where TMX treatment was associated with an increased risk of MASLD
development compared to controls. Similarly, hypercholesterolemia, dyslipidemia, and glucose intolerance
seem to predict TMX-induced SLD and/or elevated enzyme levels [89,90] . Albeit SLD is often benign and the
risk of severe liver damage in TMX-treated patients is absent (or at best anecdotal), the co-morbidly
associated metabolic syndrome entails an increased risk of T2DM and cardiovascular disease . Although
[91]
risk mitigation with lipid-lowering drugs may have a theoretical place in the management of these patients,
further studies are required before such treatment can be proposed.

Corticosteroids
Corticosteroids are used in a variety of medical conditions for their anti-inflammatory effects and are
commonly prescribed. At present, approximately 1% of the general population receives corticosteroids, with
a more than two-fold increase in senior citizens [92,93] .

The use of corticosteroids is associated with an adverse metabolic profile, including insulin resistance and
T2DM, conditions also associated with hepatic lipid accumulation . The means by which corticosteroids
[94]
induce fatty liver is not fully understood, although corticosteroids are often referred to as steatogenic .
[84]
Rodent studies have shown that corticosteroids increase appetite and caloric intake as well as