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Page 2 of 17 Nasr et al. Metab Target Organ Damage 2023;3:19 https://dx.doi.org/10.20517/mtod.2023.20

during histopathological evaluation of liver biopsies and imaging examinations (e.g., ultrasonography,
computed tomography, and magnetic resonance imaging). The most common cause of elevated liver
[1]
enzyme levels is SLD, which is present in approximately a third of the population . The most common
[2,3]
cause of hepatic lipid accumulation is non-alcoholic fatty liver disease (NAFLD) , recently renamed to
metabolic-dysfunction associated steatotic liver disease (MASLD) , with an estimated global prevalence of
[4,5]
[7]
30% . The difference between NAFLD and MASLD is small, with a high overlap , but with the common
[6]
denominator being the presence of hepatic steatosis with the absence of other steatogenic causes. In
addition, in MASLD, the presence of at least one cardiometabolic risk factor (i.e., overweight/obesity,
hyperglycemia/insulin resistance, hypertension, and dyslipidemia) is a prerequisite for the diagnosis .
[8]
Additionally, a new entity of increased alcohol intake in combination with MASLD was also introduced,
labeled MetALD - which includes a continuum of alcohol consumption where the contribution of MASLD
and alcohol-related liver disease (ALD) will vary .
[8]
Steatotic liver disease can be defined as an accumulation of fat, mainly triglycerides, exceeding 5% of the
liver weight . Even though this definition is appealing, it is not feasible in a common clinical setting. After
[9]
liver biopsy is performed, the histopathological diagnosis of SLD is set if more than 5% of the hepatocytes
contain lipid vacuoles [10,11] . Because liver biopsy is associated with adverse events (both minor and serious),
several non-invasive techniques for defining hepatic triglyceride content have emerged, such as magnetic
[14]
resonance imaging [12,13] and controlled attenuation parameter .
Nonetheless, in the wake of a growing body of research in the field of MASLD, focus on other causes of SLD
has been set aside [Table 1]. Therefore, in this review, we will focus on other common (and uncommon but
clinically important) causes of hepatic lipid accumulation that are important to exclude, or take into
consideration, when diagnosing MASLD.

Alcohol
Consumption of alcohol is common in the Western world, with nearly two-thirds of all adults in the United
States consuming alcohol (approximately 4 drinks per week) . The corresponding numbers in Sweden
[15]
show that nine out of ten adults in Sweden consume approximately 9 drinks per week [16,17] . Alcohol
consumption can lead to hepatic lipid accumulation. However, it is uncertain how much, how long, and at
what rate alcohol consumption induces SLD. Although acute alcohol consumption induces SLD in mouse
models [18,19] , it does not, over a period of 5-12 weeks, seem to induce similar traits in humans [20,21] . Therefore,
it is probable that chronic consumption of alcohol, rather than acute, induces significant SLD. Nevertheless,
in studies of patients with confirmed alcohol overconsumption who have undergone liver biopsy,
approximately one in three have no histological signs of SLD [22,23] .

Initially, alcohol-induced SLD was thought to be a result of oxidative stress and diminished lipid oxidation
secondary to enzymatic metabolism of ethanol. However, new discoveries have shed light on the complex
[24]
multifactorial process that leads to ethanol-induced lipid accumulation in hepatocytes . Many mechanisms
are similar to that of MASLD, which, to some extent, explains the hurdle of separating the entities.

It is important to exclude excessive alcohol consumption in diagnosing MASLD. However, it is difficult to
define excessive alcohol consumption in order to separate MASLD, or MetALD, from alcohol-related liver
disease (ALD). The threshold for defining excessive alcohol consumption has ranged from abstinence [25-27] to
252 g/week in different studies . However, the European Association for the Study of the Liver (EASL)
[28]
reached a consensus in 2016 suggesting a cut-off of 210 and 140 grams per week for men and women,
respectively, for the diagnosis of NAFLD . These cut-offs are also suggested for the diagnosis of MASLD,
[29]