Hepatic, Extra-hepatic Outcomes and Causes of Mortality in NAFLD - An Umbrella Overview of Systematic Review of Meta-Analysis

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. While the prevalence, impact, and causes of mortality have been described in various meta-analyses, a systematic all-encompassing umbrella review has yet to be conducted to consolidate the evidence on outcomes associated with NAFLD.

Methods: Search was conducted on Medline and Embase for meta-analysis investigating associated complications and causes of mortality in NAFLD patients. Summary estimates were presented with original units, sample size, and I² for heterogeneity. The Assessment of Multiple Systematic Reviews 2 was employed for article selection.

Results: 25 meta-analyses were included in the present review. NAFLD increased the risks of systemic complications, including cardiovascular diseases, systemic malignancies, diabetes, and chronic kidney disease. Regarding hepatic outcomes, the incidence of hepatocellular carcinoma in NAFLD was 2.39 per 100 person years (CI: 1.40 to 4.08). Individuals with NAFLD were also found to have an increased likelihood of cholangiocarcinoma (OR: 1.88, CI: 1.25 to 2.83) and gallstone disease (OR: 1.55, CI: 1.31 to 1.82) compared to individuals without NAFLD. NAFLD was associated with a higher risk of fatal and non-fatal CVD events (HR: 1.45, CI: 1.31 to 1.61) compared to individuals without NAFLD. Coronary heart disease and subclinical and clinical coronary heart disease were also significantly elevated in NAFLD individuals compared to individuals without NAFLD. Additionally, NAFLD was associated with an increased risk of all-cause mortality (HR: 1.34, CI: 1.17 to 1.54) and cardiovascular (HR: 1.30, CI: 1.08 to 1.56) but not cancer-related mortality.

Conclusion: The study summarizes high-level evidence from published meta-analyses to provide a much-needed update on the outcomes in patients with NAFLD. The significant systemic burden associated with NAFLD and impending fatty liver epidemic requires prompt action from multidisciplinary providers, policy providers, and stakeholders to reduce the burden of NAFLD.

Keywords: epidemiology; extra-hepatic complications; hepatic complications; non-alcoholic fatty liver disease.

Figure 1

PRISMA flow diagram.

Figure 2

Forest plot of hepatic complications. Legend: 100PY, 100 person years; OR, odds ratio; 95% CI, 95% confidence interval.

Figure 3

Forest plot of cardiovascular diseases. Legend: CVD, cardiovascular; PVC/PAC, premature ventricular contractions/premature atrial contractions; CAD, coronary artery disease; HR, hazard ratio; MD, mean difference; OR, odds ratio; RR, risk ratio; 95% CI, 95% confidence interval.

Figure 5

Forest plot of other complications associated with NAFLD and forest plot of other clinical and biometric measurements. Legend: COPD, chronic obstructive pulmonary disease; OSA, obstructive sleep apnea; GERD, gastroesophageal reflux disease; BMD, bone mineral density; LVEF, left ventricle ejection fraction; E, peak E wave; A, peak A wave; LVM, left ventricular mass; LVEDD, left ventricle end-diastolic diameter; LVESD, left ventricle end-systolic diameter; LAD, left atrial diameter; PWT, posterior wall; EAT, epicardial adipose thickness; HR, hazard ratio; 95% CI, 95% confidence interval; OR, odds ratio; WMD, weighted mean difference; MD, mean difference.

Figure 4

Forest plot of systemic malignancies. Legend: HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 6

Cause of mortality in patients with NAFLD. Legend: CVD, cardiovascular; HR, hazard ratio; 95% CI, 95% confidence interval.