TABLE 1.

NAFLD as a multisystem disease: recent meta‐analyses describing the increased risk of incident diabetes, incident cardiovascular disease, incident chronic kidney disease and incident extra‐hepatic cancers with NAFLD

Publication	Study aims	Study characteristics	Summary estimate of risk (e.g., HR (95% CIs) of outcome associated with NAFLD	Comments and interpretation
Mantovani et al. 25	To ascertain the risk of incident diabetes associated with NAFLD	33 studies (501,022 individuals), 30.8% with NAFLD 27,953 cases of incident diabetes over a median of 5 years (IQR: 4.0–19 years) were included Meta‐analysis was performed using random‐effects modelling	Patients with NAFLD had a higher risk of incident diabetes than those without NAFLD (n = 26 studies; random‐effects HR 2.19, 95% CI 1.93 to 2.48; I 2  = 91.2%). Patients with more ‘severe’ NAFLD were also more likely to develop incident diabetes (n = 9 studies; random‐effects HR 2.69, 95% CI 2.08 to 3.49; I 2  = 69%). This risk markedly increased across the severity of liver fibrosis (n = 5 studies; random‐effects HR 3.42, 95% CI 2.29 to 5.11; I 2 = 44.6%). All risks were independent of age, sex, adiposity measures and other common metabolic risk factors. Sensitivity analyses did not alter these findings. The funnel plots did not reveal any significant publication bias	PubMed, Scopus and Web of Science databases from January 2000 to June 2020 using predefined keywords to identify observational studies with a follow‐up duration of at least 1 year, in which NAFLD was diagnosed by imaging techniques or biopsy The meta‐analysis shows that NAFLD is associated with a ~ 2.2‐fold increased risk of incident diabetes. This risk parallels the underlying severity of NAFLD The results support those by the authors in an earlier and smaller meta‐analysis in 2018 (Diabetes Care. 2018 Feb;41[2]:372–382)
Mantovani et al. 29	A meta‐analysis of observational studies to quantify the magnitude of the association between NAFLD and the risk of incident CVD events	36 longitudinal studies with aggregate data on 5,802,226 middle‐aged individuals (mean age 53 years [SD 7]) and 99,668 incident cases of fatal and non‐fatal CVD events over a median follow‐up of 6·5 years (IQR 5·0–10·2) Meta‐analysis was performed using random‐effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool	NAFLD was associated with a moderately increased risk of fatal or non‐fatal CVD events (pooled random‐effects HR 1·45, 95% CI 1·31–1·61; I 2 = 86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random‐effects HR 2·50, 95% CI 1·68–3·72; I 2 = 73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors Sensitivity analyses did not modify these results	PubMed, Scopus and Web of Science searched from database inception to July 1st 2021 NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy The primary outcomes were CVD death, non‐fatal CVD events, or both NAFLD is associated with an increased long‐term risk of fatal or non‐fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality N.B. Univariable meta‐regression analyses to examine the effect of potential moderator variables showed a significant positive association between the proportion of patients with pre‐existing type 2 diabetes (p = 0·001) or mean plasma LDL‐cholesterol concentrations (p = 0·041) and the risk of NAFLD‐related CVD event.
Mantovani et al. 27	A meta‐analysis of observational studies to quantify the magnitude of the association between non‐alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers	10 cohort studies with 182,202 middle‐aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow‐up of 5.8 years Meta‐analysis was performed using random‐effects modelling	NAFLD was significantly associated with a nearly 1.5‐fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2‐fold to 1.5‐fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias	PubMed, Scopus and Web of Science databases searched from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy‐proven NAFLD were available for the analysis This large meta‐analysis suggests that NAFLD is associated with a moderately increased long‐term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development
Mantovani et al. 26	A meta‐analysis of observational studies to quantify the magnitude of the association between NAFLD and the risk of incident chronic kidney disease (CKD)	13 studies with 1,222,032 individuals (28.1% with NAFLD) and 33,840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2, with or without accompanying overt proteinuria) over a median follow‐up of 9.7 years were included Meta‐analysis was performed using random‐effects modelling	NAFLD was associated with a moderately increased risk of incident CKD (n = 10 studies; random‐effects HR 1.43, 95% CI 1.33 to 1.54; I 2  = 60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias	PubMed, Web of Science and Scopus were searched from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow‐up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy This large and updated meta‐analysis indicates that NAFLD is significantly associated with a ~ 1.45‐fold increased long‐term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD