We read with great interest the recent paper by Jeong et al. [1], which found a significant association between changes in metabolic dysfunction-associated steatotic liver disease (MASLD) status and the risk of hepatocellular carcinoma in a nationwide cohort. This finding provides important evidence for a deeper understanding of the role of MASLD in liver disease progression. Notably, non-alcoholic fatty liver disease (NAFLD) has undergone two name changes, first being renamed to metabolic-associated fatty liver disease (MAFLD) [2] and then to MASLD [3]. These renamings are not merely changes in nomenclature but involve adjustments in diagnostic criteria and management populations. In this context, it is crucial to comprehensively compare the differences in various clinical outcomes between MAFLD and MASLD populations to assess the impact of the new standards on disease management.

In our study, the clinical outcomes of steatotic liver disease are categorized into liver-related and extrahepatic outcomes, as well as all-cause and cause-specific mortality. Specifically, liver-related outcomes encompass the progression of steatotic liver disease, fibrosis, cirrhosis, as well as other related complications, including portal hypertension, ascites, hepatic encephalopathy, hepatorenal syndrome, liver cancer, liver faliure and more. These conditions are further defined by corresponding International Classification of Disease version 10 (ICD-10) codes, including G93.4, G94.3, I85, I86.4, I98.2, I98.3, K70.0, K70.3, K72, K74, K76.6, K76.7, R17, R18, and C22 [4]. On the other hand, extrahepatic outcomes include cardiovascular events and cancer. Cardiovascular outcomes involve conditions such as hypertensive heart disease, ischemic heart disease, heart failure, cerebrovascular events like strokes, and retinal vascular disorders. Cancer outcomes encompass a broad range of malignancies. These conditions are further defined by ICD-10 codes, with cardiovascular outcomes identified using I11.0, I13.0, I13.2, I20–I25, I50, I60–I69, H34, and cancer outcomes defined by codes C00–C97. However, most current studies primarily focus on cardiovascular events and all-cause mortality in MAFLD and MASLD populations [5-7], with insufficient comparisons of intrahepatic outcomes and cause-specific mortality. Therefore, it is essential to delve deeper into these differences, especially regarding liver-related outcomes, to evaluate the impact of the new diagnostic criteria on disease management.

To achieve this goal, we conducted a study based on the large-scale prospective cohort data from the UK Biobank, including 459,211 British adults aged 40 to 69 years. Since the UK Biobank lacks imaging data such as liver ultrasound, we used the fatty liver index to define fatty liver and classified the population accordingly [8,9]. The overall prevalence rates of MAFLD and MASLD were 38.14% (n=175,156) and 32.95% (n=151,327), respectively. According to the two diagnostic criteria, we divided the population into four groups: MAFLD-ONLY (n=24,132), MASLD-ONLY (n=303), overlap group (n=151,024), and non-MAFLD/MASLD group (n=283,752) (Fig. 1). We systematically compared the baseline characteristics (Supplementary Table 1) and clinical outcomes (Table 1) of these four groups. As shown in Supplementary Table 1, firstly, the overlap group had the largest number of participants, indicating that despite changes in diagnostic criteria, most patients are simultaneously covered by both standards. Secondly, the number of individuals in the MAFLD-ONLY group far exceeded that in the MASLD-ONLY group, demonstrating the limitations of the MASLD diagnostic criteria in population coverage. Finally, individuals in the MASLD-ONLY group were generally lean at baseline and had worse liver-related indicators than the other groups, suggesting that this subgroup may have a higher risk of liver disease progression.

As shown in Table 1, our multivariate Cox regression models revealed that both MAFLD and MASLD populations are associated with significantly higher risks for liver-related, cardiovascular, cancer, all-cause and cause-specific mortality outcomes. After adjusting for three models, the liver-related outcome risk for the MASLD-ONLY group (hazard ratio [HR] 3.22, 95% confidence interval [CI] 2.00–5.19; P<0.001) and the liver-related mortality risk (HR 17.62, 95% CI 8.66–35.83; P<0.001) remained significantly higher than those in other groups, whereas the cardiovascular disease risk (HR 1.29, 95% CI 1.23–1.35; P<0.001), cancer risk (HR 1.33, 95% CI 1.24–1.42; P<0.001), all-cause mortality risk (HR 1.50, 95% CI 1.42–1.58; P<0.001), cardiovascular-related mortality risk (HR 1.45, 95% CI 1.26–1.66; P<0.001), and cancer-related mortality risk (HR 1.36, 95% CI 1.26–1.47; P<0.001) for the MAFLD-ONLY group were all higher than those in the MASLD-ONLY group. Given that the MASLD-ONLY group has a relatively small sample size (n=303), with even fewer cases in Table 1, caution is needed when interpreting the outcomes, particularly the extremely high hazard ratio for liver outcomes. Nevertheless, similar findings have been observed in the study by Jeong et al. [1], where the overall MASLD population consistently demonstrated progression in liver-related outcomes. In contrast, the MAFLD-ONLY group was more focused on extrahepatic outcomes but did not emphasize liver risks. In terms of cardiovascular outcomes, we found that the overlapping group exhibited the highest risk (HR 1.32, 95% CI 1.29–1.35; P<0.001). Additionally, along with other research [6,7], similar to the study by Zhao and Deng [7], our population analysis shows that the mortality risk for MAFLD is higher than that for MASLD. However, our study takes a more comprehensive approach to outcome selection, including not only liver, cardiovascular, and cancer outcomes, but also expanding to related mortalities in these areas. While a recent article noted that the AIC value of MAFLD in all-cause mortality risk models was higher, indicating lower predictive accuracy compared to NAFLD and MASLD [10]. This suggests that there are certain limitations in the definitions of both MAFLD and MASLD.

In conclusion, our study demonstrates that regarding clinical outcomes and mortality risks, MAFLD focuses more on cardiovascular and other extrahepatic events, while MASLD emphasizes liver-related issues. Whether MAFLD or MASLD, the differing emphases on clinical outcomes pose challenges for patient management. Additionally, the current diagnostic criteria for MASLD may overlook many individuals, affecting management for this group. These differences require clinicians to consider the specific circumstances of patients when formulating treatment plans to ensure comprehensive and personalized care. Furthermore, understanding the distinct characteristics of these two diseases in terms of clinical outcomes can help optimize intervention strategies and improve treatment effectiveness.