Aims/hypothesis Clinical data regarding circulating leptin levels in patients with non-alcoholic fatty liver disease (NAFLD) are conflicting. The purpose of this meta-analysis was to compare leptin levels between the following groups: patients with biopsy-proven NAFLD vs controls; simple steatosis (SS) patients vs controls; non-alcoholic steatohepatitis (NASH) patients vs controls and NASH patients vs SS patients. Methods We performed a systematic search in PubMed, Scopus and the Cochrane Library. We analysed 33 studies, published between 1999 and 2014, including 2,612 individuals (775 controls and 1,837 NAFLD patients). Results Higher circulating leptin levels were observed in NAFLD patients vs controls (standardised mean difference [SMD] 0.640; 95% CI 0.422, 0.858), SS patients vs controls (SMD 0.358; 95% CI 0.043, 0.673), NASH patients vs controls (SMD 0.617; 95% CI 0.403, 0.832) and NASH patients vs SS patients (SMD 0.209; 95% CI 0.023, 0.395). These results remained essentially unchanged after excluding studies involving paediatric or adolescent populations and/or individuals undergoing bariatric surgery. There was moderate-tosevere heterogeneity among studies in all comparisons, but no significant publication bias was detected. Meta-regression analysis demonstrated that BMI was inversely associated with leptin SMD and accounted for 26.5% (p=0.014) and 32.7% (p=0.021) of the between-study variance in the comparison between NASH patients and controls and NAFLD patients and controls, respectively. However, when bariatric studies were excluded, BMI did not significantly explain the between-study variance. Conclusions/interpretation Circulating leptin levels were higher in patients with NAFLD than in controls. Higher levels of circulating leptin were associated with increased severity of NAFLD, and the association remained significant after the exclusion of studies involving paediatric or adolescent populations and morbidly obese individuals subjected to bariatric surgery.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.