Page 911 - Read Online

Page 8 of 22 Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75

ultrasound) over time was associated with changeable risks of incident T2DM. Recently, in an observational
study including 2,726 patients in which NAFLD status change was assessed by serial abdominal
ultrasonography and fatty liver index (FLI) during a follow-up of 10 years, Cho et al. [110] documented that
the progression and regression of NAFLD were respectively associated with positive and negative risk
of incident diabetes mellitus. These findings additionally corroborate the assumption that NAFLD is a
modifiable trigger factor associated with the progression to the advanced stages of diabetes mellitus [111] .

Sex as key modulator of NAFLD in patients with T2DM
Experimental data and computer modeling now indicate that female and male livers may be metabolically
distinct with specific and different regulators [112,113] . In particular, accumulating data suggest that
the prevalence and severity of NAFLD tend to be greater in men as compared to women during the
reproductive age. Conversely, after menopause, the prevalence of NAFLD tends to be higher in women,
thereby indicating a potential protective role of the estrogens [113] . However, most observational studies
available so far, including those conducted in patients with T2DM, did not have specific statistical analyses
considering sex differences or sex hormones/menopausal status as potential modifiers. In a 2020 meta-
analysis of 33 cohort studies, Mantovani et al. [108] did not observe an effect of sex on the relationship
between NAFLD and risk of incident T2DM, but this may partly reflect the characteristics of the eligible
observational studies. Along with other authors [113] , we strongly believe that future observational studies
should have sex-specific analyses.

Liver complications in NAFLD patients with diabetes mellitus
Liver involvement in patients with T2DM is recognized in the form of simple steatosis, nonalcoholic
steatohepatitis (NASH), advanced fibrosis, cirrhosis, hepatocellular carcinoma, glycogenic hepatopathy and
hepatic arteriolosclerosis [114] . That said, some histological analysis suggests that simple steatosis is a benign
condition, while NASH with different degrees of hepatic fibrosis is closely associated with liver-related
morbidity and mortality. As previously mentioned, T2DM patients have a greater prevalence of NASH
and advanced fibrosis when compared to the general adult population [114] . In addition, many observational
studies have clearly demonstrated that T2DM, along with obesity and severe degrees of insulin resistance,
is one of the main clinical risk factors implicated in the progression of NAFLD to NASH, advanced fibrosis
or cirrhosis [1,2,4] . Conversely, it is also reported that the presence of NAFLD may also adversely influence
the prognosis of diabetes [1,2,4] . Among various observational studies [115-127] published so far [Table 2], the
Verona Diabetes Study was one of first observational studies demonstrating that the risk of mortality from
liver causes was higher in a large cohort of T2DM patients when compared to the general population [115] .
These findings were subsequently replicated in other case-control studies. For instance, in a retrospective
study that used the administrative database of the Veneto region, Zoppini et al. [116] observed that Italian
T2DM individuals had a roughly 3-fold higher risk of dying from chronic liver diseases due to a non-
virus and non-alcohol-related etiology. In another community-based cohort study involving nearly 340
T2DM patients, Adams et al. [117] showed that the presence of NAFLD, as detected by imaging or biopsy, was
associated with a higher risk of all-cause mortality (mainly due to cardiovascular disease, malignancy and
liver-related complications) during a mean follow-up of 11 years.

An association between T2DM and liver cirrhosis is also currently known. In patients with cirrhosis,
indeed, diabetes mellitus can be due to the presence of T2DM or as a direct consequence of liver
insufficiency (namely hepatogenous diabetes mellitus) [114] . In this context, several observational studies
have documented an elevated prevalence of cirrhosis in patients with T2DM and NAFLD, especially if they
are older or have cardiovascular complications [114,118] . Cirrhosis is also associated with reduced hepatic mass
and portosystemic shunts; two conditions able to alter insulin clearance, thereby contributing to systemic
insulin resistance [119] . In addition, cirrhosis is associated with increased levels of hypoxia-inducible factors
and advanced glycation end products, which play a role in the development of T2DM [119,120] . T2DM is an