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Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75 Page 7 of 22

Regarding the observational studies using magnetic resonance imaging (MRI) for the diagnosis of NAFLD,
it is possible to observe that the prevalence of NAFLD ranges from 50% to 70%. For instance, in a study
[12]
enrolling 103 patients with T2DM and normal plasma aminotransferase levels, Portillo-Sanchez et al.
reported that the prevalence of NAFLD was approximately 50%. Moreover, in that study, the authors
[12]
reported a high prevalence of NASH in a subgroup of patients who underwent liver biopsy . Indeed,
[12]
approximately 55% of patients with NAFLD on MRI had histological features suggestive of NASH .
These data strongly support the assertion that patients with T2DM have a high risk of developing severe
forms of NAFLD, such as NASH and advanced fibrosis, which are the histological features more closely
[1-4]
[82]
associated with hepatic and extrahepatic complications . Also in this regard, Bazick et al. found in an
observational study involving approximately 350 patients with T2DM who underwent liver biopsy, that
the prevalence of NASH and advanced fibrosis was 69 and 41%, respectively. In another study including
108 patients with biopsy-proven NAFLD, McPherson et al. reported that approximately 80% of patients
[83]
who had had progression in fibrosis were diabetics, whereas among non-progressor patients only 25%
had diabetes mellitus. The association between T2DM and the more severe forms of NAFLD was also
[84]
reported by Loomba et al. in an observational study enrolling 1,069 T2DM patients with biopsy-proven
NAFLD, documenting a significant association between history of diabetes mellitus, NASH and advanced
fibrosis, even after adjusting for age, sex, body mass index, ethnicity, and presence of metabolic syndrome.
Moreover, in a retrospective analysis of 235 patients with biopsy-proven NAFLD with and without T2DM,
[85]
Puchakayala et al. documented that among T2DM patients with NAFLD, the prevalence of advanced
fibrosis and ballooning were significantly greater as compared to patients with NAFLD but without T2DM.
Interestingly and importantly, in the multivariate regression analysis, T2DM was associated with NASH
and fibrosis in all patients with NAFLD .
[85]
These data were additionally replicated in a recent meta-analysis by Younossi et al. including 80
[86]
observational studies for a total of nearly 49,500 individuals with T2DM (mean age: 58 years; mean body
2
mass index: 28 kg/m ; percentage of men: 53%). In this meta-analysis, the authors found that the overall
prevalence of NAFLD was approximately 55%, the global prevalence of NASH was 37%, and the prevalence
of advanced fibrosis was 17% .
[86]

Importantly, the coexistence of NAFLD and T2DM is also associated with a poorer cardiometabolic profile
in terms of glycemic control, atherogenic dyslipidemia and hypertension [4,87] . Coexisting NAFLD and
T2DM may also increase insulin requirement in T2DM patients treated with basal bolus insulin regimen .
[87]
NAFLD and risk of incident T2DM
Several epidemiological studies have documented that NAFLD, as detected by ultrasound, is associated
with an increased risk of incident T2DM, even after adjustment for many metabolic confounders, such
as age, sex, body mass index, smoking status, alcohol intake, physical activity, family history of diabetes,
lipids and insulin resistance [88-106] . This finding was also replicated by a 2018 meta-analysis including 19
cohort studies for a total of approximately 300,000 individuals (30% with NAFLD) and nearly 16,000
cases of incident diabetes over a median of 5 years [107] . In fact, in this study, Mantovani et al. [107] reported
that patients with NAFLD had a higher risk of incident diabetes mellitus when compared to those with
2
no liver involvement [random-effects hazard ratio (HR) 2.22, 95% confidence interval 1.84-2.60; I =79%].
In addition, in that study, patients with more “severe” NAFLD were also more likely to develop incident
diabetes mellitus [107] . More recently, a 2020 meta-analysis of nearly 500,000 individuals reported similar
results [108] .

Few studies have assessed the risk of incident T2DM in relation to the modification of NAFLD status over
time [7,97,109,110] . For instance, in a retrospective longitudinal study including approximately 13,000 Korean
individuals followed for 5 years, Sung et al. [109] documented that alterations in fatty liver content (on