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Page 12 of 22 Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75

With regard to cardiac arrhythmias, many observational studies and some meta-analyses have reported that
NAFLD (as detected by ultrasound or computed tomography) is associated with prevalent and incident
atrial fibrillation in patients with and without T2DM [134] . Atrial fibrillation is a frequent arrhythmia seen in
clinical practice and it is closely related to cardiovascular morbidity and mortality [134] . In a meta‐analysis of
[141]
5 observational studies enrolling approximately 240,000 middle‐aged and elderly individuals, Mantovani et al.
documented that NAFLD was associated with higher prevalence and incidence of AF. Other studies have
documented that in T2DM patients, NAFLD (on ultrasound) was associated with an increased risk of
prolonged QTc, ventricular arrhythmias or other conduction defects [56,126,127,134,142] .

Collectively, these data strongly support the assertion that, as also recommended by the European and
American guidelines on the management of NAFLD [143,144] , a multidisciplinary approach to NAFLD patients
is necessary, based on careful assessment of cardiometabolic risk factors.

Increased risk of CKD in NAFLD patients with T2DM
Recently, several studies and some meta-analyses have demonstrated that in T2DM patients, NAFLD,
as detected by liver ultrasound or biopsy, is linked to an increased risk of prevalent and incident CKD,
above and beyond established cardiometabolic risk factors [145] . For instance, regarding the association
between NAFLD and prevalence of CKD, recently, in an observational study of 169 T2DM patients with
NAFLD and 169 T2DM patients without NAFLD, Jia et al. [146] reported that NAFLD (on ultrasound) was
2
independently associated with an increased risk of prevalent CKD (defined as eGFR < 60 mL/min/1.73 m
and/or albuminuria). Accumulating data now suggest that the association between NAFLD and risk
of prevalent CKD may be even bidirectional [145] . For example, in an observational study enrolling
[73]
approximately 2,000 Taiwanese patients with T2DM, Lee et al. confirmed an independent association
between imaging-diagnosed NAFLD and CKD (adjusted odds ratio 1.59, 95% confidence interval 1.12-2.25).
Interestingly, when the authors performed a structural equation model analysis to test the effects of NAFLD
on CKD and the potential role of CKD on NAFLD, they found the existence of a bidirectional relationship
[73]
between NAFLD and CKD .

Accumulating data also indicate that the risk of CKD may be higher in patients with advanced forms of
NAFLD (mostly liver fibrosis) as compared to patients with simple steatosis [145] . In an observational cross-
[71]
sectional study enrolling nearly 400 Italian patients with T2DM, Lombardi et al. reported that CKD
2
(defined by the presence of eGFR CKD-EPI < 60 mL/min/1.73 m and/or abnormal albuminuria) was present
in 36% of NAFLD patients with liver fibrosis (as detected by Fibroscan®) as compared to 21% of NAFLD
[65]
patients without liver fibrosis (P < 0.001). Recently, Mantovani et al. documented that, after adjusting for
established risk factors and potential confounders, LSM was significantly associated with an approximately
3-fold higher risk of prevalent CKD (adjusted odds ratio 3.28, 95% confidence interval 1.22-8.90) in a
[62]
sample of nearly 140 T2DM outpatients. Interestingly, Yeung et al. in 2018 also reported that advanced
fibrosis, as detected by Fibroscan®, but not liver steatosis on US, was independently associated with a
higher risk of prevalent albuminuria in nearly 1,800 patients with T2DM (belonging to the Hong Kong
Diabetes Registry). Additionally, in a cross-sectional study of 100 Indian patients with NAFLD (on US),
Nampoothiri et al. [147] reported that patients with impaired renal function (defined as eGFR Cockcroft–Gault <
2
80 mL/min/1.73 m and/or presence of proteinuria) had higher proportion of significant liver fibrosis and
advanced fibrosis on Fibroscan®, when compared to those with normal renal function. Importantly, in the
multivariate analyses, the authors found that T2DM and advanced fibrosis were two independent predictors
of impaired renal function in patients with NAFLD. In particular, advanced fibrosis had the best diagnostic
accuracy and specificity in predicting impaired renal function in these patients (diagnostic accuracy: 81%;
sensitivity: 58%; specificity: 90%) [147] .

Regarding the association between NAFLD and incidence of CKD, to date, there are still few data in
patients with T2DM [148] . In 2008, the Valpolicella Heart Diabetes Study demonstrated that patients with