Extrahepatic Morbidities and Mortality of NAFLD

An Umbrella Review of Meta-analyses

Mengshi Yi; Wei Peng; Xi Feng; Fei Teng; Youyin Tang; Qingyan Kong; Zheyu Chen


Aliment Pharmacol Ther. 2022;56(7):1119-1130. 

In This Article

Abstract and Introduction


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.


Non-alcoholic fatty liver disease (NAFLD), estimated to affect approximately one-quarter of the global adult population,[1] has become a major cause of chronic liver disease and a growing cause of liver transplantation, especially in the United States and Europe.[2] It is closely link to underlying obesity, T2DM and related disorders, ranging from simple NASH with varying amounts of fibrosis and cirrhosis.[3] Due to the high prevalence of NAFLD, it has been suggested as the most rapidly growing cause of liver-related mortality worldwide[4] and an emerging contributor to the burden of end-stage liver disease.[5] More than that, growing evidence proposed that NAFLD is more like a "multi-system" disease, and potentially associated with multiple extra-hepatic chronic complications, such as cardiovascular disease (CVD), extra-hepatic cancers, diabetes and chronic kidney disease (CKD).[6] More importantly, epidemiological evidence indicated that patients with NAFLD more frequently died from extra-hepatic complications than the liver related events of NAFLD,[6] especially from CVD, which has been suggested as the leading cause of death in large cohort studies of individuals with NAFLD.[7] Keeping up with trends, several systematic reviews and meta-analyses of observational studies have been published to focus on associations between NAFLD and risk of extra-hepatic outcomes.

An umbrella review is an increasing popular approach that systematic collects and evaluates information from systematic reviews and meta-analyses, which is used to consolidate the highest level of evidence on a given topic (usually clinical associations), and inform clinical practice as well as public health policies.[8] Previously, several umbrella reviews related to NAFLD have been published to summarise the quality of evidence regarding the associations between nutritional, lifestyle, metabolic factors and NAFLD,[9–11] and effects of sodium glucose co-transporter 2 (SLGT2)[12] and resveratrol supplementation[13] in patients with NAFLD. However, no umbrella review was conducted for issue of the extra-hepatic morbidities and mortality of NAFLD currently.

Following the large number of published systematic reviews and meta-analyses that investigated associations between NAFLD and related extra-hepatic outcomes, we, therefore, conducted a novel umbrella review to assess the breadth, strength, and validity of the associations between NAFLD and risk of extra-hepatic morbidities and mortality. This work may help interpreting these epidemiological associations more reliably and help guiding clinical management of NAFLD for clinical workers, especially during the current worldwide pandemic of this disease.