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Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75 Page 9 of 22

Table 2. Principal observational studies that assessed the association between NAFLD and risk of liver-related disease and
extrahepatic complications (cardiovascular diseases)
NAFLD
Author Study characteristics Complication Results Country
diagnosis
De Marco et al. [115] Population-based study: Mortality US The highest SMRs in the Italy
7,148 T2DM patients diabetic cohort were for
(3,366 men and 3,782 diabetes, liver cirrhosis and
women) followed for a cardiovascular diseases
period of 5 years
Zoppini et al. [116] Retrospective study: Mortality US T2DM patients had a higher Italy
167,621 T2DM patients, risk of dying from chronic
aged 30-89 years (54.6% liver diseases, in particular
men), followed from 2008 NAFLD
to 2010
Adams et al. [117] Community-based study: Mortality US Overall mortality was USA
337 T2DM patients significantly associated
from Olmsted County, with a diagnosis of NAFLD,
Minnesota, presence of ischemic heart
followed for 11 years; 116 of disease and duration of
them had NAFLD diabetes
Bertot et al. [119] Prospective study: 284 Death/transplantation, Biopsy, T2DM patients had a Australia
patients (53% with decompensation, HCC Hepascore, greater risk of liver-related
T2DM, 15% with cirrhosis) NAFLD fibrosis death/transplantation
followed up for a median score (NFS), (HR 3.4, 95%CI: 1.2-9.1)
period of 51 months APRI and FIB-4 decompensation (HR 4.7,
95%CI: 2.0-11.3) and HCC
(HR 2.9, 95%CI: 1.2-7.3)
Sanyal et al. [121] Prospective study: using a HCC Radiological The incidence of HCC in the USA
health care claims database imaging database was 0.4 per 1,000
from Thomas Reuters persons. NAFLD/NASH
covering 18 million lives (59%) and T2DM (36%),
yearly and all USA census along with hepatitis C virus
regions from 2002 to infection (22%), were the
2008, 4,406 HCC patients main etiologic risk factors
were identified associated with HCC
Ertle et al. [122] Cross-sectional study: 162 HCC Radiological Patients with NAFLD/ Germany
adults with HCC enrolled imaging NASH-associated HCC
between February 2007 exhibited a higher prevalence
and March 2008 of T2DM, hypertension,
dyslipidemia, coronary
artery disease, when
compared to non-NAFLD/
NASH-HCC
Targher et al. [123] Cross-sectional study: Coronary heart disease, US NAFLD was associated Italy
2,893 T2DM outpatients; myocardial infarction, with a greater risk of
1,974 had NAFLD angina, cerebrovascular prevalent CVD, independent
disease and peripheral of classical risk factors,
vascular disease glycemic control,
medications and metabolic
syndrome features
Cassidy et al. [124] Case-control study: 19 Cardiac structure, function Magnetic Changes in cardiac structure United
adults with T2DM, 19 and metabolism resonance were evident in adults with Kingdom
adults with NAFLD and 19 imaging T2DM and NAFLD
healthy controls
Mantovani et al. [45] Cross-sectional study: 222 Left ventricular dysfunction US NAFLD was associated Italy
T2DM outpatients with no with an increased risk of
previous history of CVD mild and/or moderate
left ventricular diastolic
dysfunction
Mantovani et al. [125] Cross-sectional study: Cardiac calcification on US NAFLD was independently Italy
247 consecutive T2DM echocardiography associated with cardiac
outpatients with no calcification both aortic and
previous history of heart mitral valves
failure, valvular heart
diseases and hepatic
diseases