Page 918 - Read Online

Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75 Page 15 of 22

Altered production of short-chain fatty acids, such as acetate, propionate and butyrate, can influence
hepatic gluconeogenesis and liponeogenesis [158] . Short-term probiotic treatments should have a beneficial
[158]
effect on insulin resistance by increasing butyrate production .
Another consequence of dysbiosis is an increase in the uremic toxins that are associated with
atherosclerosis and hypertension. There is a demonstrated relationship between trimethylamine oxide
(TMAO) and atherosclerosis [159] . Circulating levels of TMAO, an early biomarker of adipose dysfunction,
are high in obese NAFLD patients [159] . TMAO is produced from the oxidation of trimethylamine in
the liver, which is derived from bacteria-dependent metabolism of dietary choline [159] . TMAO leads to
atherosclerosis acting on reverse cholesterol transport, inducing platelet aggregation, the formation of foam
cells and the increased expression of scavenger receptors [159] .

Cardiovascular tissue cells, such as endothelial cells, vascular smooth cells and cardiac cells, express bile
acid receptors [160] . Gut microbiota influence the production of secondary bile acids, such as deoxycholic
acid, ursodeoxycholic acid and lithocholic acid [160] . The alteration of bile acid metabolism seems to be
associated with an increased risk of CVD, because of increased LDL cholesterol levels, vasomotor tone and
[160]
blood pressure .
Several experimental studies also suggest that mitochondrial dysfunction may be closely associated
with insulin resistance and atherosclerosis [161] , thereby indicating a potential mechanistic link between
[134]
mitochondrial dysfunction, T2DM, NAFLD and CVD .

Recently, Malehmir et al. [162] showed that platelet number, platelet activation and platelet aggregation are
increased in NASH, but not in simple steatosis, pointing to novel mechanisms that should be studied.

We suggest that future prospective and interventional studies be carried out in well-characterised cohorts
of patients that can clarify mechanisms linking NALFD to vascular complications.

CONCLUSION
The concept that NAFLD is a benign condition has changed over the last decades. At present, NAFLD is
the most common chronic liver disease observed in clinical practice, especially in patients with T2DM
and those with obesity, thereby becoming a relevant health care problem worldwide [1,86,135] . In fact, NAFLD
is a leading cause of liver-related and cardiovascular mortality and morbidity . Convincing evidence
[1]
clearly shows that NAFLD is strongly linked to clinical and subclinical alterations in cardiac structure
and function, independent of the coexistence of established cardiovascular risk factors and metabolic
syndrome [134] . These findings may partly explain the increased risk of cardiovascular death found in T2DM
patients with NAFLD. Given the available data and as suggested by European and American clinical
practice guidelines [143,144] , a careful assessment of cardiometabolic risk factors and regular monitoring of
liver and cardiovascular complications is mandatory in patients with NAFLD, especially if they are obese
or have T2DM. Some authors suggest repeating the assessments every 1 or 2 years, based on the CVD risk
[4]
factors . The clinical and laboratory data that should be obtained, along with sex and age, are as follows:
body weight, height, body mass index, waist circumference, cigarette smoking, alcohol consumption,
blood pressure, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, fasting plasma glucose,
hemoglobin A1c (HbA1c), estimated glomerular filtration rate (or serum creatinine), albuminuria,
75-g oral glucose tolerance test (in patients with impaired fasting glycaemia and/or obesity), CVD risk
[4]
estimation (by using risk calculators), and carotid artery ultrasonography . In addition, seeing that the
prevalence of NAFLD and significant or advanced liver fibrosis is relatively high in T2DM patients (most
[1]
of whom have normal serum levels of liver enzymes) , FibroScan® may be useful not only for assessing
the severity of liver fibrosis, which is the strongest predictor of long-term adverse clinical outcomes in