Mortality and Liver-Related Events in Lean Versus Non-Lean Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis

Background & Aims: Although approximately 40% of patients with nonalcoholic fatty liver disease (NAFLD) are nonobese or lean, little is known about the long-term clinical outcomes of lean NAFLD. We aimed to estimate the risk of mortality and adverse liver-related events in patients with lean NAFLD compared with those with non-lean NAFLD. Methods: We searched the PubMed, Embase, and Cochrane Library databases through May 2022 for articles reporting mortality and/or development of cirrhosis among lean and non-lean NAFLD patients. The relative risks (RRs) of all-cause mortality, cardiovascular mortality, liver-related mortality, and occurrence of decompensated cirrhosis or hepatocellular carcinoma were pooled using the random-effects model. We also performed subgroup analysis according to characteristics of the study population, methods of NAFLD diagnosis, study design, study region, and length of follow-up. Results: We analyzed 10 cohort studies involving 109,151 NAFLD patients. Patients with lean NAFLD had comparable risks for all-cause mortality (RR, 1.09; 95% confidence interval [CI], 0.66–1.90), cardiovascular mortality (RR, 1.12; 95% CI, 0.66–1.90), and adverse liver events including decompensated cirrhosis and hepatocellular carcinoma (RR, 0.81; 95% CI, 0.50–1.30). However, the risk of liver-related mortality was higher in patients with lean than non-lean NAFLD (RR, 1.88; 95% CI, 1.02–3.45). Conclusions: This study highlights a higher risk of liver-related mortality in patients with lean NAFLD than those with non-lean NAFLD. This finding indicates that further understanding of the pathophysiology, risk factors of adverse outcomes, and genetic and ethnic variabilities of lean NAFLD phenotype is warranted for individualized treatment strategies in lean NAFLD patients.