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Page 14 of 22 Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75

restricted to patients with more severe NAFLD or applies to all patients with NAFLD is relevant given the
disease burden of NAFLD. However, additional studies are needed to establish if NAFLD can increase the
risk of developing distal symmetric polyneuropathy and to elucidate if improvement in NAFLD is able to
prevent the development and progression of distal symmetric polyneuropathy in patients with diabetes.

Putative mechanisms linking NAFLD to vascular complications in patients with diabetes
mellitus
The detailed description of the putative mechanisms linking NALFD to vascular complications in patients
with diabetes mellitus is beyond the purpose of this narrative review. Therefore, we refer the reader to other
reviews for this topic [1,2,134,142,156] .

When common diseases coexist and share common risk factors, it might be difficult to separate pivotal
relationships and understand the role of potential confounders. Indeed, T2DM or MetS are examples of
confounding diseases linking NAFLD to cardiovascular complications.

However, there are many potential underlying mechanisms that can link NAFLD to the development
and progression of vascular complications [134] . As several studies have clearly demonstrated in the last
decade, NAFLD (mainly in its more severe histological forms) can worsen hepatic and systemic insulin
resistance [156] . Insulin resistance is linked to an excessive fat accumulation in ectopic tissues, including
the liver, as well as with increased circulating free fatty acids [156] . All these factors can strongly promote
endoplasmic reticulum stress and inflammation [156] . In addition, they aggravate and maintain the insulin
resistant state, thereby leading to a vicious cycle [156] . In fact, inhibition of insulin signaling pathways
associated with NAFLD can occur by various mechanisms, including inflammatory, many kinase proteins
[156]
and several lipid-derived by-products . NAFLD and its more severe histological forms can also contribute
to the release into the bloodstream of several proinflammatory, profibrogenic and vasoactive mediators
(such as C‐reactive protein, tumor necrosis factor alpha, interleukin‐6, transforming growth factor-
beta, factor VIII, plasminogen activator inhibitor-1 and endothelin-1). All these mediators can promote
important cardiac and arrhythmic complications [134] . Hence, it is possible that the reduction of chronic
inflammation in NAFLD patients might be a potential intervention to reduce the risk of cardiac disease and
arrhythmias [134] . Accumulating experimental and clinical data also indicate that NAFLD may contribute to
the activation of multiple pathways implicated in the pathophysiology of CKD [1,2,134,142] . Impaired activation
of the renin-angiotensin system (RAS) may indeed contribute to the renovascular injury by inflammation
and coagulation pathways [1,2,134,142] . Atherogenic dyslipidemia, insulin resistance, oxidative stress and
pro-inflammatory factors can contribute to renal damage [1,2,134,142] . However, in spite of the large body of
evidence linking NAFLD to cardiac, arrhythmic and renal complications, it has not been conclusively
established if a cause‐effect relationship exists [134] .

Not only are many traditional risk factors combined between NAFLD, micro and macrovascular disease,
CKD and T2DM/MetS, but novel risk factors are also emerging in each of these conditions. These novel
risk factors include perturbation of the intestinal microbiota (dysbiosis) with associated inflammation,
intestinal dysfunction and platelet activation.

Recently, the role of dysbiosis in NAFLD and in the development of its complications has gained
[134]
scientific interest . Dysbiosis is associated with increased production of lipopolysaccharide from gram-
negative bacteria, which can damage the intestinal barrier and, consequently, can increase permeability
and contribute to the release of endotoxins into the systemic circulation, thereby determining a chronic
inflammation and oxidative stress, mainly due to the release of pro-inflammatory cytokines [134,157] .