Table 1.

Selected studies of metabolic consequences in patients with NAFLD.

Type of consequences	Authors	Study population	Country	Main findings
Insulin resistance	Lonardo et al. [13]	A systematic review of 47 longitudinal studies which provided evidence for NAFLD as a risk factor for the future development of diabetes and metabolic syndrome	Italy	NAFLD is a strong determinant for the development of diabetes and metabolic syndrome.
	Khan et al. [23]	A systematic review of insulin resistance in NAFLD	Multi countries	There is a close relationship between insulin resistance (IR) and NAFLD, with the prevalence of NAFLD being 5-fold higher in patients with diabetes compared to those without.
	Li et al. [25]	A systematic review of twenty-one cohort studies including 13 prospective studies and 8 retrospective studies with 381,655 total patients	China	Obese individuals have a 3.5-fold increased risk of developing NAFLD.
Cirrhosis/HCC	Alexander et al. [54]	Cohort study of 136,703 patients with diagnosis of NAFLD or NASH (NAFLD/NASH) were followed up about incident cirrhosis and HCC diagnosis	Multi countries	NAFLD/NASH increases risk of life-threatening liver outcomes. Diabetes is an independent predictor of advanced liver disease.
	Piscagila et al. [58]	Observational prospective study of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611)	Italy	HCC secondary to NAFLD is usually detected at a later tumor stage and could arise in the absence of cirrhosis.
ASCVD	Targher et al. [60]	Observational, prospective, and retrospective studies with 34,043 total adult patients	Multi countries	NAFLD is associated with an increased risk of fatal and non-fatal CVD events.
	Zeb et al. [69]	Prospective cohort study of 4119 adult participants who were free of CVD and known liver diseases at baseline	United States	NAFLD was independently associated with incident CHD events (HR 1.42, 95% CI 1.00 to 2.03)
	Mantovani et al. [70]	Retrospective cohort of 286 adults with type 1 diabetes without known liver diseases	Italy	NAFLD was independently associated with an increased risk of non-fatal CVD events (HR 6.73, 95% CI 1.2 to 38
	Targher et al. [64]	Prospectively cohort of 400 patients with type 2 diabetes, who were free from Atrial fibrillation at baseline	Italy	NAFLD is strongly associated with an increased incidence of AF in patients with type 2 diabetes.
CKD	Musso et al. [65]	Meta-analysis of thirty-three studies (63,902 participants, 16 population-based, 17 hospital-based, 20 cross-sectional, and 13 longitudinal)	Multi countries	NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
	Yasui et al. [66]	A cross-sectional study of 174 patients	Japan	CKD was present in 24 (14%) of 174 NAFLD patients. The prevalence of CKD was significantly higher in NASH patients (19 of 92; 21%) than non-NASH patients (5 of 82; 6%).
	Machado et al. [67]	Prospective and consecutive recruitment of 148 morbidly obese patients undergoing bariatric surgey	Portugal	NASH patients were older, with higher body mass index and had more frequent metabolic syndrome and lower eGFR ((97 ± 22 vs 106 ± 16 ml/min/1.73 (2), p = 0.035)
All-cause and liver-related mortality	Kim et al. [49]	Cohort of 726,736 individuals with NAFLD who underwent a health examination	Korea	Body weight variability was associated with increased risks of MI, stroke, and all-cause mortality in NAFLD patients.
	Matteoni et al. [7]	Retrospective cohort of 132 patients with NAFLD and elevated serum liver enzymes	United States	Patients with NASH had higher rates of all-cause and liver-related mortality than those without. CVD death rate did not differ between the groups.
	Polyzos et al. [47]	A systematic review of obesity and nonalcoholic fatty liver disease	Multi countries	Obesity increases liver-specific mortality in NAFLD patients.