Extrahepatic morbidities and mortality of NAFLD: an umbrella review of meta-analyses.

Background: Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions currently and may contribute to multiple extrahepatic outcomes.

Aim: To comprehensively summarise evidence of associations between NAFLD and risk of extrahepatic outcomes.

Methods: We conducted an umbrella review. We searched PubMed, Web of Science and Cochrane database from inception to 27 November 2021.

Results: We included 22 meta-analyses with 374 original studies in our analysis. Subjects with NAFLD had an increased risk of mortality, multiple cardiovascular complications, extrahepatic cancers, diabetes and chronic kidney disease (CKD) than those without NAFLD. Excess risks of several other extrahepatic outcomes including hypothyroidism, urolithiasis, gastro-oesophageal reflux disease, gallstones, depression and worse maternal and foetal outcomes were also observed in this population. However, associations were not significant for prostate cancer, female organ genital cancer, haematological cancer, diabetic retinopathy or osteoporotic fracture. The risks of CVD, diabetes and CKD were similar in obese and non-obese patients. Most associations were heterogeneous across regions; significantly, Europeans with NAFLD were more prone to all-cause mortality than North Americans. The certainty of evidence was graded from only very low to moderate as all included studies were observational.

Conclusions: Patients with NAFLD are at heightened risk of extrahepatic outcomes. However, the certainty of evidence is only from very low to moderate. Further studies at low risk of bias are required to support the evidence and elucidate any causal associations.