Overall Mortality and Cardiovascular Mortality Associated With MAFLD+/NAFLD− Versus MAFLD−/NAFLD+: A Secondary Analysis

Recent shift in nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) reflects the crucial role of metabolic dysfunction in steatotic liver diseases. Under this context, Dr. Pennisi et al. [1] performed an important meta-analysis comparing outcomes between NAFLD versus MAFLD and found that MAFLD were associated significantly with a 12% higher risk of overall mortality and a 15% high risk of cardiovascular mortality compared to NAFLD. As Dr. Pennisi et al. [1] acknowledged, the most important limitation of their meta-analysis was the comparison of NAFLD and MAFLD, instead of MASLD. To further explore the impact of metabolic dysfunction on overall and cardiovascular mortality in hepatic steatosis, we conducted a secondary data synthesized analysis comparing outcomes in patients with MAFLD+/NAFLD− versus those with MAFLD−/NAFLD+. All seven and six cohort studies reporting data on all-cause mortality and cardiovascular mortality, respectively, that were included in the original meta-analysis by Dr. Pennisi et al. [1] met the eligibility criteria for this secondary analysis because these studies provided comparative data on outcomes in patients diagnosed exclusively with MAFLD but not with NAFLD (defined as MAFLD+/NAFLD−) versus those diagnosed only with NAFLD but not with MAFLD (defined as MAFLD−/NAFLD+). Pooled analysis of seven cohort studies, including 27 676 MAFLD+/NAFLD− and 8007 MAFLD−/NAFLD+ patients, showed that MAFLD+/NAFLD− was significantly associated with a 107% higher risk of overall mortality compared to MAFLD−/NAFLD+ (random-effect risk ratio [RR] 2.07, 95% CI 1.36–3.16, p = 0.001; Figure 1A). Consistent results were obtained using different random-effect pooling models [2, 5-7] (Figure 1A). Similarly, pooled analysis of six cohort studies, including 52 243 MAFLD+/NAFLD− and 18 794 MAFLD−/NAFLD+ patients, revealed a 225% higher risk of cardiovascular mortality in MAFLD+/NAFLD− compared with MAFLD−/NAFLD+ (random-effect RR 3.25, 95% CI 2.37–4.47, p < 0.001; Figure 1B). Different random-effect pooling models yielded almost identical results (Figure 1B). Our secondary analysis demonstrates a 107% higher risk of all-cause mortality and a 225% high risk of cardiovascular mortality in patients with MAFLD+/NAFLD− compared to those with MAFLD−/NAFLD+. These findings provide further support for the recent MASLD definition, highlight the importance of metabolic dysfunction in hepatic steatosis outcomes and facilitate the translation of these findings into the recent MASLD definition. Additionally, during conducting of this secondary analysis, we noted that included studies originally referenced as Numbers 6 and 11 need to be replaced with others [3, 4], to ensure reproducibility and credibility. The authors declare no conflicts of interest. All raw data for this secondary analysis have been presented in Figure 1. References for all included studies in this secondary analysis can be found in the primary analysis of reference 1. Codes for pooling analysis could be available from the corresponding authors based on reasonable requests.