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Page 2 of 14 Ciardullo et al. Metab Target Organ Damage 2024;4:30 https://dx.doi.org/10.20517/mtod.2024.39

Keywords: Nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease
(MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-
related liver disease(MetALD), insulin resistance, nomenclature

AND EPIDEMIOLOGIC ASPECTS
HISTORICAL
[1,2]
Descriptions of liver steatosis by pathologists date back to the first half of the nineteenth century . Several

Authors identified associations between liver fat and alcohol consumption, visceral adiposity and conditions
[3,4]
such as tuberculosis . Decades later, in the mid-twentieth century, sporadic observations started to suggest

a possible link between liver fat and the development of more advanced forms of liver disease, including
[5]
cirrhosis . Nonetheless, this association remained controversial for many years, with many authors
skeptical of this theory .
[6,7]

The first description of liver steatosis with inflammation and a thorough description of the associated
[8]
histologic changes were made in 1980 by Ludwig et al. . The Authors studied a sample of middle-aged

patients with overweight obesity and a high prevalence of type 2 diabetes who consumed little or no alcohol.

They showed that the histologic changes within their livers were undistinguishable from those typically

associated with elevated alcohol consumption (including lobular inflammation, Mallory bodies, and various

degrees of liver fibrosis). Therefore, they named this condition “nonalcoholic steatohepatitis (NASH)”. In

the following years, the term nonalcoholic fatty liver disease (NAFLD) was introduced as an umbrella term

including patients with liver steatosis not related to alcohol and all stages of histologic changes in terms of
[9]
inflammation and fibrosis . It became clear that this was not always a benign condition and that it could
lead to liver cirrhosis and related complications .
[10]

In the last few decades, the interest in this condition increased dramatically and several pieces of the puzzle

were put into place. On the one hand, many studies showed that insulin resistance was a major contributor

[11]
to the development and progression of NAFLD , which was strictly associated with features of the

metabolic syndrome including diabetes , visceral adiposity , hypertension , and dyslipidemia . Indeed,
[15]
[13]
[14]
[12]

paralleling the increasing rates of obesity and type 2 diabetes, NAFLD became by far the most common

chronic liver condition worldwide, affecting 30% of adults [16-19] and 10%-15% of children/adolescents [20,21] ,

with significant differences across continents. On the other, specific histologic scoring systems were

introduced to evaluate the grade and stage of the disease and assist in the standardization of histology-based

[22]
studies . It became evident that the degree of liver fibrosis was the major predictor of the future

development of liver-related events and hepatocellular carcinoma, as it occurs in several chronic liver

conditions [23-25] . Nonetheless, it should be mentioned that approximately 30% of cases of hepatocellular
carcinoma diagnosed in patients with NAFLD/metabolic dysfunction-associated steatotic liver disease
(MASLD) develop on a non-cirrhotic liver, making it extremely challenging to detect in the early stages [26,27] .

Today, NAFLD is viewed as a heterogeneous condition with a complex pathophysiology [Figure 1].

Noxious stimuli are from different origins. Apart from lifestyle factors related to excessive caloric intake,

[28]

reduced energy expenditure and the relative increase in visceral and ectopic fat deposition , ethnicity and
[29]

genetic factors can influence its development and progression . The most robust associations have been
[31]
[30]
made with variants in the PNPLA3 , TM6SF2 , and MBOAT7 genes [32,33] . It is believed that genetic factors,

alongside differences in lifestyle, diet, metabolic comorbidity profile and socioeconomic status, account for
[34]

a large proportion of the differences in prevalence across different ethnic groups . Indeed, several studies
have shown a higher prevalence of NAFLD/MASLD among Hispanic individuals and a lower prevalence
[35]
among African individuals, compared with non-Hispanic whites . Moreover, environmental factors such
as pollutants and endocrine disruptors are believed to play a significant role as well [36-38] .