Mortality and Cardiovascular Outcomes in Patients with MAFLD Compared with Patients with MASLD: A Systematic Review and Meta-Analysis (original) (raw)

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Jiwon Yang1 , Ye Rim Kim1 , Seong Kyun Na2 , Seonok Kim3 , Jihyun An4 , Ju Hyun Shim1

1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Gastroenterology, Inje University Sanggye Paik Hospital, Seoul, Korea; 3Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 4Department of Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Korea

Received: June 7, 2025; Revised: July 15, 2025; Accepted: July 20, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS
• References

Background/Aims: Although metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) represent the updated nomenclature and diagnostic criteria for nonalcoholic fatty liver disease, studies comparing the prognostic implications of these conditions remain limited. This meta-analysis aimed to quantify the associations among MAFLD, MASLD, and long-term clinical outcomes.
Methods: A comprehensive literature search was performed to identify cohort studies that assessed the association of MASLD and MAFLD with all-cause mortality, cause-specific (cardiovascular and cancer-related) mortality, and the incidence of cardiovascular disease in the PubMed, Embase, Web of Science, CINAHL, and CENTRAL databases from inception through October 31, 2024. Pooled hazard ratios (HRs) were calculated for relevant outcomes.
Results: We identified 18 cohort studies, comprising 10,653,666 patients with MAFLD from 13 studies and 3,202,447 patients with MASLD from nine studies. MAFLD was significantly associated with an increased risk of overall mortality (pooled HR [95% confidence interval], 1.30 [1.16 to 1.47]) and cardiovascular mortality (1.31 [1.08 to 1.60]; both p<0.01), but not with cancer-related mortality (1.10 [0.97 to 1.24]; p=0.130). Conversely, MASLD was associated with a higher risk for all mortality outcomes: overall mortality (1.34 [1.12 to 1.61]), cardiovascular mortality (1.17 [1.07 to 1.27]), and cancer-related mortality (1.24 [1.19 to 1.29]; all p<0.01). The risk of cardiovascular disease was increased in patients with both MAFLD (1.48 [1.31 to 1.66]) and MASLD (1.33 [1.21 to 1.46]; both p<0.001).
Conclusions: MAFLD and MASLD were both associated with increased risks of mortality and cardiovascular outcomes. Notably, a significant association with cancer-related mortality was observed for MASLD, but not for MAFLD.

Keywords: Metabolic dysfunction-associated steatotic liver disease, Metabolic dysfunction-associated fatty liver disease, Mortality, Cardiovascular diseases

INTRODUCTION

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• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS
• References

Metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) represent updated nomenclature and diagnostic frameworks that have been proposed to replace the term nonalcoholic fatty liver disease (NAFLD).1-3 These terms were developed to eliminate the potential stigmatization associated with the words “fatty” and “alcoholic” in NAFLD, while also reflecting the diverse etiologies of steatotic liver diseases (SLDs).4 However, they have distinct diagnostic criteria. MAFLD is diagnosed based on the presence of hepatic steatosis along with at least one of the following metabolic risk factors: overweight/obesity, type 2 diabetes mellitus (T2DM), or metabolic dysfunction.2,5 Importantly, MAFLD allows for coexistence with other liver diseases including viral hepatitis and alcohol-related liver disease. In contrast, MASLD is defined as part of a broader classification under SLD and emphasizes cardiometabolic dysfunction. It also requires the presence of hepatic steatosis but maintains the historical exclusion of significant alcohol consumption (>140 g/week for women and 210 g/week for men) and other chronic liver diseases.1,3 In other words, MAFLD permits overlap with other liver diseases based on metabolic criteria, while MASLD adheres to stricter exclusions, preserving NAFLD's traditional definition.

In addition to an elevated risk of liver-related events and hepatocellular carcinoma,6,7 individuals with NAFLD have been shown to exhibit higher risks of all-cause mortality, extrahepatic malignancies, and cardiovascular diseases (CVDs) compared to those without NAFLD or general populations.8-12 In line with findings from NAFLD studies, several investigations have demonstrated that MAFLD and MASLD are significantly associated with increased risks of mortality and cardiovascular (CV) outcomes.13-30 These findings underscore the importance of carefully assessing mortality and CV risk in individuals with MAFLD or MASLD and support the development of surveillance strategies targeting high-risk populations. Nonetheless, the associations between these disease entities and prognostic outcomes vary across studies, likely due to differences in covariate adjustment, study design, and geographic region.13,23,27,31-34 For instance, a large population-based study using data from the United Kingdom Biobank reported that both MASLD and MAFLD were significantly associated with increased risks of all-cause and CV mortality, even after adjusting for potential confounders.27 However, data from the United States Third National Health and Nutrition Examination Survey, which included 13,856 adults with available ultrasonographic data, showed that CV mortality was significantly increased in MAFLD but not in MASLD, and neither condition was associated with cancer-related mortality.35

Therefore, it is essential to clarify the association between MAFLD or MASLD and prognostic outcomes to improve surveillance and prevention strategies. This meta-analysis aims to evaluate and quantify the risk of mortality and CVDs in MASLD and MAFLD, respectively, and to determine which definition more accurately predicts the long-term hard outcomes through a systematic review of pertinent clinical studies.

1. Search strategy and selection criteria

This meta-analysis was performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol has been registered in the International Prospective Register of Systematic Reviews database (PROSPERO registration number: CRD42024548216). The Institutional Review Board of Asan Medical Center approved this meta-analysis and waived the requirement for informed consent from individual patients (approval number: 2024-0681).

We conducted a search for human cohort studies published from inception to October 31, 2024, using scholarly databases such as PubMed, Embase, Web of Science, CINAHL, and the CENTRAL. The detailed search strategy is presented in Supplementary Table 1. Two authors (Y.R.K. and J.A.) independently reviewed the titles and abstracts of the studies identified through the search to exclude those that did not address the research question of interest. Subsequently, the full texts of the remaining articles, along with their references, were thoroughly examined to confirm the inclusion of relevant information. In cases of discrepancies, consensus was achieved through discussion with another author (J.H.S.).

To be eligible, studies had to meet the following criteria: (1) include patients diagnosed with MAFLD or MASLD; (2) report the incidence of overall mortality, CV mortality, cancer-related mortality, and incident CVD; (3) use a longitudinal design; (4) follow-up duration of more than 1 year; (5) include a control arm, such as non-MASLD, non-MAFLD, or non-SLD for comparison; and (6) provide data on hazard ratio (HR) with 95% confidence interval (CI). Given that the terminology for MASLD was introduced recently, we did not impose restrictions on the types of articles included. Thus, abstracts and letters were included in the literature search and screening process. When we found multiple publications based on the same study population, we included only the most recent and informative one. Studies were excluded if they met any of the following criteria: (1) published in a non-English language; (2) focused on pediatric populations (aged <19 years); and (3) classified as preclinical studies, case reports, case series, case-control studies, systematic reviews, or meta-analyses. The flow diagram summarizing the study identification and selection process is presented in Fig. 1.

Figure 1.PRISMA checklist. WOS, Web of Science; CINAHL, Cumulative Index to Nursing and Allied Health Literature; SLD, steatotic liver disease; MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CV, cardiovascular; CVD, cardiovascular disease; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. *Four studies13,18,22,27 assessed both MASLD and MAFLD outcomes.

2. Definition of MAFLD and MASLD

MAFLD was defined as the presence of hepatic steatosis with metabolic dysfunction, which includes being overweight or obese, having T2DM, or exhibiting a combination of at least two of the seven metabolic risk factors.2 MASLD was defined as the presence of hepatic steatosis along with at least one of the five cardiometabolic criteria in adults.1 The detailed criteria for MAFLD and MASLD are presented in Supplementary Table 2.

3. Data extraction

Data were independently extracted by two reviewers (Y.R.K. and J.A.) using a pre-established form. In addition to the standard bibliometric variables, information on the following variables was also collected: category of hepatic steatosis (MAFLD or MASLD); study design; year of publication; median follow-up duration; study region; methods of steatosis assessment (fatty liver index [FLI], abdominal ultrasound [US], or liver biopsy); age; sex; prevalence of T2DM; total number of participants; cases of overall mortality, cancer-related mortality, CV mortality, or CVD; HR and 95% CI; and adjusted covariates. Any discrepancies in data extraction were resolved by consensus, with reference to the original articles for clarification.

4. Outcomes of interest

The primary outcome was the overall mortality of individuals classified according to the definitions of MASLD and MAFLD (Supplementary Table 2). The secondary outcomes included CV mortality, cancer-related mortality, and incident CVD. The definitions of CV mortality, cancer-related mortality, and CVD were derived from the original studies included in this meta-analysis (Supplementary Table 3). The comparison groups included those without SLD or those who did not meet the diagnostic criteria for the respective conditions (i.e., non-SLD, non-MASLD, or non-MAFLD).

5. Quality assessment and publication bias

The methodological quality of the cohort studies was independently assessed by two authors (J.Y. and J.A.) using the Newcastle-Ottawa Scale.36 Within this scale, studies were evaluated across three categories: selection of study groups (four items), comparability of study groups (two items), and ascertainment of the outcome of interest (three items). Each item was assigned a score of one point, except in the comparability category, where additional points were awarded for controlling for age and/or sex, allowing for a maximum of 2 points in this category. Publication bias was assessed quantitatively using Egger’s rank correlation regression test and qualitatively through the visualization of funnel plots depicting the logarithmic HRs against their standard errors.37

6. Statistical analysis

A random-effects meta-analysis model was employed to calculate pooled HR and 95% CI. Heterogeneity among study-specific estimates was assessed using two complementary methods. First, Cochran’s Q statistic was calculated to determine whether the observed variations in study results exceeded what would be expected by chance. This was accomplished by summing the weighted squared deviations of each study’s estimate from the overall weighted mean effect size. Second, to quantify the proportion of total variation attributable to heterogeneity rather than chance, the I² statistic was computed. In this analysis, an I² value greater than 50% indicated significant heterogeneity.38 Specifically, I² values of approximately 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively, while a p-value greater than 0.10 was considered to indicate homogeneity.39

To mitigate the impact of heterogeneity across included studies on outcomes assessment, we performed subgroup analyses stratified by the following parameters: diagnostic modality for steatosis (US vs FLI), geographical region (Eastern populations vs Western populations), study methodology (prospective design vs retrospective design), mean or median age of participants (≥50 years vs <50 years vs not reported), sex distribution (≥60% male participants vs <60% male participants vs not reported), T2DM prevalence at baseline (≥15% vs <15% vs not reported), comparator group (non-MAFLD vs non-MASLD vs non-SLD), and median follow-up duration (≥10 years vs <10 years). Threshold values for stratification were determined based on previously established criteria by Ha et al.40 Additionally, we employed random-effects meta-regression models to evaluate the impact of these baseline covariates on the observed heterogeneity.

All statistical analyses were conducted using the “meta” packages in R software (Version 4.4.2, R Foundation for Statistical Computing, Vienna, Austria). All tests were two-sided, and a p_-_value <0.05 was considered statistically significant.

RESULTS

Go to

• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS
• References

1. Summary of the literature search

As shown in the PRISMA flow diagram, our literature search yielded 4,055 articles after the removal of duplicates. We screened 4,055 potentially relevant articles and subsequently reviewed the full text of 210 articles. Of these, 192 articles were excluded for the following reasons: (1) studies originating from overlapping cohorts (n=7); (2) irrelevant study population (n=10); (3) use of a comparator other than non-MAFLD, non-MASLD or non-SLD (n=22); (4) absence of a comparator (n=37); (5) irrelevant outcomes (n=97); and (6) insufficient data on the outcome of interest (n=19). Ultimately, 18 studies were included in this meta-analysis, comprising 16 peer-reviewed original articles13-26,29,30 and two conference abstracts (Fig. 1).27,28 Among these, nine studies exclusively focused on MAFLD,16,17,20,21,23,25,26,28,29 five studies on MASLD,14,15,19,24,30 and four studies examined both MAFLD and MASLD in the same population.13,18,22,27 Overall, data from 13 studies comprising 10,653,666 patients classified as having MAFLD13,16-18,20-23,25-29 and from nine studies comprising 3,202,447 patients diagnosed with MASLD13-15,18,19,22,24,27,30 were analyzed.

The baseline characteristics of the included studies are summarized in Table 1. Among the studies, eight articles (44.4%) assessed steatosis using abdominal US,13,17,19,20,26,28-30 while 10 articles utilized the FLI;14-16,18,21-25,27 one study diagnosed steatosis using abdominal US, liver biopsy or controlled attenuated parameter.19 The study population primarily consisted of Asian patients, accounting for 14 articles (77.8%).15-18,20-26,28-30 Excluding one study that lacked data on sex,28 the proportion of male patients exceeded 60% in most studies (10 articles).14,16,19-26 The mean or median age of the study populations across all included studies ranged between 41.9 and 61.6 years, except for two studies that did not report age data.28,30 Of the included studies, eight reported a prevalence of T2DM greater than 15%,13,15,18,19,21,23,25,29 while two studies did not provide data on T2DM status.27,28 The median follow-up duration ranged from 3.99 to 26.9 years. The detailed definitions of comparison groups used in the included studies are presented in Supplementary Table 4.

Table 1. Baseline Characteristics of the Included Studies

T2DM, type 2 diabetes mellitus; MAFLD, metabolic dysfunction-associated fatty liver disease; FLI, fatty liver index; CV, cardiovascular; CVD, cardiovascular disease; BMI, body mass index; US, ultrasound; NR, not reported; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; SLD, steatotic liver disease; CCI, Charlson Comorbidity Index; HDL-C, high-density lipoprotein cholesterol; MASLD, metabolic dysfunction-associated steatotic liver disease.

*Data are presented as the mean or median; †Data were derived from the group with MAFLD combined with nonalcoholic fatty liver disease; ‡Data were derived from the general population; §T2DM was defined as the use of glucose-lowering drugs; ‖The steatosis assessment method included biopsy, US, or controlled attenuated parameters; ¶T2DM was defined as a fasting glucose level ≥5·6 mmol/L, a glycated hemoglobin level ≥39 mmol/mol, a diagnosis of T2DM, or the use of anti-diabetic treatment.

2. Risk of mortality outcomes and CVDs in patients with MAFLD

Among the 13 articles focusing on patients with MAFLD, five studies examined the overall mortality as an outcome, involving a total of 265,446 MAFLD patients (Supplementary Table 5).13,18,20,23,27 In the pooled analysis, MAFLD was significantly associated with an increased risk of overall mortality compared to its comparators (pooled HR, 1.30; 95% CI, 1.16 to 1.47; p<0.001 with I2=76%) (Fig. 2A). Assessment of CV mortality from six studies including 467,715 MAFLD patients demonstrated similarly elevated risk (HR, 1.31; 95% CI, 1.08 to 1.60; p=0.006 with I2=85%) (Fig. 2B, Supplementary Table 6).13,20,23,26-28

Figure 2.Forest plot and pooled estimates of the clinical effect of MAFLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MAFLD, metabolic dysfunction-associated fatty liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Three studies investigated the association between MAFLD and cancer-related mortality in 2,835,883 MAFLD patients (Supplementary Table 7).13,16,23 Notably, the risk of cancer-related mortality showed no significant difference between MAFLD patients and comparators, despite exhibiting low-to-moderate heterogeneity (HR, 1.10; 95% CI, 0.97 to 1.24; p=0.130 with I2=27%) (Fig. 2C). Evaluation of incident CVD from seven studies with 7,500,134 MAFLD revealed substantially higher risk in MAFLD patients versus those without SLD or MAFLD (HR, 1.48; 95% CI, 1.31 to 1.66; p<0.001; I²=97%) (Fig. 2D, Supplementary Table 8).17,21-23,25,27,29

3. Risk of mortality and CVDs in patients with MASLD

Among all the articles on patients with MASLD, six studies investigated the association between MASLD and overall mortality in 238,571 MASLD patients (Supplementary Table 5).13-15,18,19,30 In the pooled analysis, patients with MASLD showed a significantly higher risk of overall mortality compared to those without SLD or MASLD (HR, 1.34; 95% CI, 1.12 to 1.61; p=0.001 with I2=94%) (Fig. 3A). CV mortality was assessed in five studies encompassing 2,926,708 MASLD patients (Supplementary Table 6).13,15,22,27,30 Results demonstrated a significant increase in CV mortality risk among MASLD patients versus comparators (HR, 1.17; 95% CI, 1.07 to 1.27; p<0.001; I²=84%) (Fig. 3B). For cancer-related mortality, pooled data from three studies with 108,027 MASLD patients indicated a significantly heightened risk with remarkable consistency across studies (HR, 1.24; 95% CI, 1.19 to 1.29; p<0.001; I²=0%) (Fig. 3C, Supplementary Table 7).13-15

Figure 3.Forest plot and pooled estimates of the clinical effect of MASLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MASLD, metabolic dysfunction-associated steatotic liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Four studies evaluated the risk of incident CVD in 2,967,518 patients with MASLD (Supplementary Table 8).15,22,24,27 The incidence risk of CVD was significantly higher in patients with MASLD compared to non-SLD or non-MASLD controls (HR, 1.33; 95% CI, 1.21 to 1.46; p<0.001 with I2=96%) (Fig. 3D).

4. Subgroup analyses of mortality and CV events in MAFLD and MASLD

Subgroup analyses were performed to assess effect modification across study characteristics and explore sources of heterogeneity for the outcomes of overall mortality, CV mortality, and incident CVD, as shown in Supplementary Figs 1 and 2. Subgroup analysis for cancer-related mortality was not conducted due to low heterogeneity observed in the overall meta-analysis for both MAFLD and MASLD individuals.

For MAFLD, subgroup findings were largely consistent with the main results, although significant effect size differences were observed based on methods of steatosis assessment for overall mortality and T2DM prevalence for both overall mortality and incident CVD (all p for group difference <0.05) (Table 2, Supplementary Fig. 1). Study design demonstrated a significant effect on the association between MAFLD and CV mortality, with prospective studies revealing a higher risk compared to retrospective designs (HR, 1.52; 95% CI, 1.45 to 1.60 vs HR, 1.13; 95% CI, 1.02 to 1.25; p for group difference <0.001), accompanied by reduced heterogeneity (overall: I²=85% vs prospective design: I²=16%; retrospective design: I²=50%).

Table 2. Subgroup Analyses of Mortality and Cardiovascular Diseases in Patients with MAFLD and MASLD

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; HR, hazard ratio; CI, confidence interval; FLI, fatty liver index; T2DM, type 2 diabetes mellitus; SLD, steatotic liver disease; NA, not applicable.

*One study (Israelsen 2024)19 that included patients diagnosed with steatosis using biopsy, ultrasound, or controlled attenuation parameters was categorized as the ultrasound group.

For MASLD, the elevated risks of overall mortality and CV mortality remained consistent across most subgroups (Table 2, Supplementary Fig. 2). Notably, MASLD patients aged ≥50 years (HR, 1.54; 95% CI, 1.18 to 2.00) and those with a median follow-up duration <10 years (HR, 2.11; 95% CI, 1.59 to 2.81) demonstrated significantly higher overall mortality risk compared to their counterparts (p for group difference=0.024 and <0.001, respectively), with substantially reduced heterogeneity (overall: I²=94% vs age ≥50 years: I²=75%; follow-up <10 years: I²=0%). The method of steatosis assessment and study design exhibited significant modification effects on the association between MASLD and CV mortality (all p for group difference <0.001), resulting in improved heterogeneity (overall: I²=84% vs both FLI ≥30 and US: I²=0%; both study designs: I²=0%). For CVD incidence, the estimated effect size for MASLD varied by comparator type. When non-MASLD individuals were used as the reference group, MASLD was associated with CVD (HR, 1.42; 95% CI, 1.36 to 1.48), whereas the HR was 1.20 (95% CI, 1.15 to 1.26) when non-SLD comparators were used. The test for subgroup differences was statistically significant (p<0.001), indicating that comparator type influences the magnitude of the observed association.

5. Meta-regression analysis for overall mortality in MAFLD and MASLD

We performed meta-regression to identify associations between study-level characteristics and overall mortality, as shown in Table 3. In brief, age, the proportion of male, study region, and the length of follow-up did not have significant effects on all-cause mortality in MAFLD and MASLD patients. Only steatosis assessment using FLI was associated with increased risk of overall mortality in MAFLD, whereas this significance was not observed in MASLD. In terms of MASLD, a significant positive association between the proportion of patients with pre-existing T2DM and increased overall mortality was observed (Supplementary Fig. 3).

Table 3. Meta-Regression Analysis of the Effects of Covariates on Overall Mortality in Patients with MAFLD and MASLD

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CI, confidence interval; T2DM, type 2 diabetes mellitus.

6. Quality assessment

The quality assessment of the included articles and PRISMA checklist are provided in Supplementary Tables 9 and 10, respectively. All included studies demonstrated good methodological quality, with Newcastle-Ottawa Scale scores ranging from 7 to 9 points.

7. Publication bias

Despite the limited number of studies included for each outcome, neither the rank correlation test nor Egger's test showed statistically significant evidence of publication bias for overall mortality (p=0.805), CV mortality (p=0.564), cancer-related mortality (p=0.312), and CVD (p=0.480) in studies with MAFLD (Supplementary Fig. 4). Similarly, for the MASLD, no significant publication bias was observed for these same outcomes: overall mortality (p=0.458), CV mortality (p=0.631), cancer-related mortality (p=0.509), and CVD (p=0.589) (Supplementary Fig. 5).

DISCUSSION

Go to

• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS
• References

With the introduction of MAFLD and MASLD as alternative nomenclatures for NAFLD, the differences in their diagnostic criteria have sparked ongoing debate regarding whether they accurately reflect prognostic outcomes consistent with existing NAFLD-related data. In this meta-analysis, both MAFLD and MASLD demonstrated a strong association with an increased risk of overall mortality, CV mortality, and CVD. Notably, MASLD was significantly associated with a poor prognosis for cancer-related mortality, whereas MAFLD did not exhibit a significant association. To the best of our knowledge, our study is the first meta-analysis to comprehensively evaluate prognostic outcomes in MAFLD and MASLD employing rigorous subgroup and meta-regression methodologies to address inter-study heterogeneity. By integrating data from large cohort studies across both Asian and Western populations, our analysis provides valuable insights into mortality and CV outcomes associated with these evolving diagnostic frameworks.

Compared to MASLD, MAFLD exhibited higher HRs for CV mortality (HR: 1.31 vs 1.17) and CVD (HR: 1.48 vs 1.33). This discrepancy may be attributed to the broader inclusion criteria of MAFLD, which encompasses significant alcohol consumption and various etiologies of liver disease. Although our meta-analysis did not directly compare MAFLD and MASLD due to the limited number of original studies, a recent large-scale prospective study on CV mortality between the two classifications demonstrated that MAFLD had a significantly higher risk of CV mortality than MASLD.27 However, the variables adjusted for CV mortality in MAFLD varied across studies (Supplementary Table 6); in the study by Song et al.,13 statistical significance was lost after multiple adjustments. In our meta-analysis, we observed high heterogeneity among studies examining CV mortality. Subgroup analysis revealed that study design significantly influenced CV mortality outcomes, reducing heterogeneity in both MASLD and MAFLD. Notably, prospective studies showed a higher risk of CV mortality but demonstrated lower heterogeneity compared to retrospective studies. This finding may be explained by the potential for missing outcomes and inaccuracies in self-reported data inherent in retrospective study designs. Regarding MASLD specifically, participants aged ≥50 years demonstrated a higher HR (1.30; 95% CI, 1.23 to 1.37) compared to those under 50 years (1.13; 95% CI, 1.11 to 1.15), with minimal heterogeneity observed in both age groups. These findings reinforce the well-established association between advancing age, increased cardiometabolic burden, and adverse CV outcomes in MASLD,41 highlighting the critical need for age-specific risk stratification in clinical practice. Additionally, while diagnostic methods for hepatic steatosis assessment contributed to heterogeneity in the overall analysis, both FLI and US consistently demonstrated increased CV mortality risk in MASLD patients.

Interestingly, MASLD was significantly associated with increased cancer-related mortality, whereas MAFLD was not. This discrepancy may be partly explained by their differing diagnostic frameworks and the resulting population characteristics. MAFLD includes individuals with coexisting liver diseases, potentially introducing competing causes of death that attenuate the observed association with cancer-related mortality. Additionally, MAFLD's broader diagnostic criteria may result in a more heterogeneous population with variable metabolic risk profiles, potentially diluting the cancer-specific mortality signal. In contrast, MASLD excludes individuals with coexisting chronic liver diseases, resulting in a more homogeneous study population with a consistent burden of metabolic dysfunction. MASLD specifically requires the presence of cardiometabolic risk factors such as obesity, T2DM, hypertension, and dyslipidemia—conditions that are well established to increase cancer risk. This more uniform metabolic burden likely strengthens the observed association with cancer-related mortality. A recently published nationwide Swedish cohort study (2002 to 2020) found that both hepatocellular carcinoma-related mortality (HR, 35.0; 95% CI, 17.0 to 72.1) and non-hepatocellular carcinoma cancer mortality (HR, 1.47; 95% CI, 1.32 to 1.63) were significantly increased in MASLD patients compared to controls.42 These findings from an independent large-scale cohort further support our meta-analysis results, reinforcing that MASLD identifies a population at elevated cancer risk due to its distinct metabolic and etiologic characteristics. The excessive cancer-related mortality in MASLD suggests that early multidisciplinary care should be prioritized, involving primary care physicians, hepatologists, endocrinologists, and oncologists for comprehensive risk stratification and management.43 Additionally, lifestyle modifications including weight reduction, healthy diet, and regular physical activity should be reinforced as important measures to treat underlying liver disease and potentially reduce cancer risk.44 These efforts should be supported by public health initiatives that recognize MASLD as a major global health challenge.

In the present meta-analysis, both MASLD and MAFLD were significantly associated with increased overall mortality. Despite overall consistency in the direction of effect estimates, substantial heterogeneity was observed across studies. Subgroup analyses revealed that certain study-level characteristics contributed to this heterogeneity in overall mortality estimates, particularly in the MASLD population. Stratification by steatosis assessment methods, study region, participant age characteristics, and median follow-up duration notably reduced heterogeneity while maintaining a consistent significant association between MASLD and overall mortality. Furthermore, meta-regression analysis demonstrated that the prevalence of T2DM significantly influenced mortality outcomes in MASLD patients, suggesting that MASLD patients with concurrent diabetes may require more intensive therapeutic interventions to reduce mortality risk.

Our study has some limitations. First, given that the design of the included studies was an observational cohort study, establishing a definitive causal link between clinical outcomes and either MAFLD or MASLD remains challenging. Second, due to the limited number of studies with shared control groups, direct comparisons or network meta-analyses between MAFLD and MASLD were not feasible. As a result, the current comparisons are based on indirect evidence rather than head-to-head analyses within the same populations. This limitation introduces the possibility that observed differences reflect variations in study design, patient characteristics, comparator groups, or covariate adjustments, rather than true differences in prognostic value. To investigate potential sources of heterogeneity, we performed subgroup and meta-regression analyses where feasible; however, given the indirect nature of the comparisons, effect size estimates should be interpreted with caution. Third, patient numbers were unevenly distributed across studies, with a few large-scale studies disproportionately influencing the pooled estimates, particularly for cancer-related mortality. Additionally, most included studies failed to adequately account for competing risks, especially CV mortality, which represents a leading cause of death in these populations. This methodological limitation may have resulted in underestimation of cancer-related mortality, particularly in MAFLD populations where higher rates of early CV death could mask cancer outcomes. Future studies employing balanced sample sizes and appropriate competing risk analyses are warranted to validate these findings. Fourth, hepatic steatosis was assessed using either US or FLI, which differs in diagnostic performance and population applicability. FLI demonstrates moderate accuracy (area under the receiver operating characteristic curve, 0.84) for detecting hepatic steatosis (FLI <30: 87% sensitivity; FLI ≥60: 86% specificity),45 but may underestimate steatosis in lean Asian individuals due to their typically lower BMI distribution, potentially leading to misclassification.46 In contrast, US demonstrates higher accuracy (area under the receiver operating characteristic curve, 0.93; sensitivity, 84.8%; specificity, 93.6%) for detecting moderate-to-severe hepatic steatosis, but it is operator-dependent.47 Despite these differences in diagnostic modalities, stratified analyses by assessment method of hepatic steatosis consistently demonstrated significant associations between both MAFLD and MASLD and mortality outcomes. Fifth, we were unable to evaluate the degree of fibrosis—an important factor associated with outcomes in both MASLD and MAFLD—because the original studies did not report these values. Additionally, we could not analyze liver-related mortality and events for either condition, as only one study in each diagnostic group reported these relevant outcomes,14,23 preventing meaningful comparative analysis.

In conclusion, our meta-analysis demonstrated that both MAFLD and MASLD were significantly associated with increased risks of overall mortality, CV mortality, and CVD. Distinctively, MASLD showed an additional significant association with cancer-related mortality that was not observed with MAFLD. Given the rising prevalence of SLD in conjunction with metabolic dysfunction-related conditions, our findings may provide valuable insights into determining the most clinically relevant nomenclature for classifying individuals with SLD, potentially improving prevention strategies for mortality and CV risk. These results could inform the development of more refined and targeted surveillance approaches. However, as our analysis was based on indirect comparisons across heterogeneous studies, the observed differences between MAFLD and MASLD should be interpreted with caution. Prospective, head-to-head studies are warranted to validate and further elucidate these associations.

This study was supported by grants from the National Research Foundation of Korea funded by the Ministry of Science and ICT (NRF-2022R1A2C3008956 and NRF-2021R1A6A1A03040260), Asan Institute for Life Sciences (grant number: 2022IP0046), and the Elimination of Cancer Project Fund from the Asan Cancer Institute of Asan Medical Center.

No potential conflict of interest relevant to this article was reported.

Study concept and design; Data acquisition; Data analysis and interpretation: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: J.Y., Y.R.K., S.K.N., J.A., J.H.S. Statistical analysis: all authors. Obtained funding: J.H.S. Study supervision: J.A., J.H.S. Approval of final manuscript: all authors.

Data sharing is not applicable as no new data were created or analyzed in this study. All articles referenced in this manuscript are publicly accessible through PubMed, Embase, CINAHL, the Cochrane Library, and Web of Science.

References

Go to

• Abstract
• Graphical Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS
• References

1. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023;79:1542-1556.
   
2. Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158:1999-2014.e1.
   
3. European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
   
4. Kim GA, Moon JH, Kim W. Critical appraisal of metabolic dysfunction-associated steatotic liver disease: Implication of Janus-faced modernity. Clin Mol Hepatol 2023;29:831-843.
   
5. Eslam M, George J. Two years on, a perspective on MAFLD. eGastroenterology 2023;1:e100019.
   
6. Younossi ZM, Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep 2021;3:100305.
   
7. Petta S, Sebastiani G, Viganò M, et al. Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease. Clin Gastroenterol Hepatol 2021;19:806-815.e5.
   
8. Bisaccia G, Ricci F, Khanji MY, et al. Cardiovascular morbidity and mortality related to non-alcoholic fatty liver disease: a systematic review and meta-analysis. Curr Probl Cardiol 2023;48:101643.
   
9. Mantovani A, Petracca G, Beatrice G, et al. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut 2022;71:778-788.
   
10. Thomas JA, Kendall BJ, El-Serag HB, Thrift AP, Macdonald GA. Hepatocellular and extrahepatic cancer risk in people with non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2024;9:159-169.
    
11. Alvarez CS, Graubard BI, Thistle JE, Petrick JL, McGlynn KA. Attributable fractions of nonalcoholic fatty liver disease for mortality in the United States: results from the Third National Health and Nutrition Examination Survey with 27 years of follow-up. Hepatology 2020;72:430-440.
    
12. Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study. Hepatology 2018;67:1726-1736.
    
13. Song R, Li Z, Zhang Y, Tan J, Chen Z. Comparison of NAFLD, MAFLD and MASLD characteristics and mortality outcomes in United States adults. Liver Int 2024;44:1051-1060.
    
14. Bao X, Zhang X, Kang L, Xu B, Yin S, Zhang X. Association of MASLD with liver-related and extrahepatic outcomes: a prospective cohort study [Preprint]. Posted 2024 Feb 21. SSRN. https://doi.org/10.2139/ssrn.4731176
    
15. Choe HJ, Moon JH, Kim W, Koo BK, Cho NH. Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: a community-dwelling cohort study with 20-year follow-up. Metabolism 2024;153:155800.
    
16. Chung GE, Yu SJ, Yoo JJ, et al. Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients with metabolic dysfunction-associated fatty liver disease: a population-based cohort study with 9.7 million Korean subjects. Cancer Commun (Lond) 2023;43:863-876.
    
17. Guo Y, Yang J, Ma R, et al. Metabolic dysfunction-associated fatty liver disease is associated with the risk of incident cardiovascular disease: a prospective cohort study in Xinjiang. Nutrients 2022;14:2361.
    
18. Han E, Lee BW, Kang ES, et al. Mortality in metabolic dysfunction-associated steatotic liver disease: a nationwide population-based cohort study. Metabolism 2024;152:155789.
    
19. Israelsen M, Torp N, Johansen S, et al. Validation of the new nomenclature of steatotic liver disease in patients with a history of excessive alcohol intake: an analysis of data from a prospective cohort study. Lancet Gastroenterol Hepatol 2024;9:218-228.
    
20. Kim KS, Hong S, Ahn HY, Park CY. Metabolic dysfunction-associated fatty liver disease and mortality: a population-based cohort study. Diabetes Metab J 2023;47:220-231.
    
21. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol Hepatol 2021;19:2138-2147.e10.
    
22. Lee HH, Lee HA, Kim EJ, et al. Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease. Gut 2024;73:533-540.
    
23. Moon JH, Kim W, Koo BK, Cho NH. Metabolic dysfunction-associated fatty liver disease predicts long-term mortality and cardiovascular disease. Gut Liver 2022;16:433-442.
    
24. Moon JH, Jeong S, Jang H, Koo BK, Kim W. Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study. EClinicalMedicine 2023;65:102292.
    
25. Yoneda M, Yamamoto T, Honda Y, et al. Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan. J Gastroenterol 2021;56:1022-1032.
    
26. Yoo TK, Lee MY, Kim SH, et al. Comparison of cardiovascular mortality between MAFLD and NAFLD: a cohort study. Nutr Metab Cardiovasc Dis 2023;33:947-955.
    
27. Zhang X, Bao X, Xu B. Association of MASLD and MAFLD with cardiovascular and mortality outcomes: a prospective study of the UK biobank cohort. J Am Coll Cardiol 2024;83(13 Suppl):1729.
    
28. Cheng WC, Li CY. Metabolic dysfunction-associated fatty liver disease is associated with increased cardiovascular disease mortality: a cohort study. Hepatology International 2023;17:S101-102.
29. Liang Y, Chen H, Liu Y, et al. Association of MAFLD With diabetes, chronic kidney disease, and cardiovascular disease: a 4.6-year cohort study in China. J Clin Endocrinol Metab 2022;107:88-97.
    
30. Chen YT, Chen TI, Yin SC, et al. Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease. J Gastroenterol Hepatol 2024;39:1939-1949.
    
31. Younossi ZM, Paik JM, Al Shabeeb R, Golabi P, Younossi I, Henry L. Are there outcome differences between NAFLD and metabolic-associated fatty liver disease?. Hepatology 2022;76:1423-1437.
    
32. Nguyen VH, Le MH, Cheung RC, Nguyen MH. Differential clinical characteristics and mortality outcomes in persons with NAFLD and/or MAFLD. Clin Gastroenterol Hepatol 2021;19:2172-2181.e6.
    
33. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol 2021;75:1284-1291.
    
34. van Kleef LA, de Knegt RJ, Brouwer WP. Metabolic dysfunction-associated fatty liver disease and excessive alcohol consumption are both independent risk factors for mortality. Hepatology 2023;77:942-948.
    
35. Zhao Q, Deng Y. Comparison of mortality outcomes in individuals with MASLD and/or MAFLD. J Hepatol 2024;80:e62-e64.
    
36. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-605.
    
37. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.
    
38. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558.
    
39. Higgins JPT, Thomas James, Chandler Jacqueline, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. The Cochrane Collaboration, 2019.
    
40. Ha J, Yim SY, Karagozian R. Mortality and liver-related events in lean versus non-lean nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2023;21:2496-2507.e5.
    
41. He QJ, Li YF, Zhao LT, Lin CT, Yu CY, Wang D. Recent advances in age-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol 2024;30:652-662.
    
42. Issa G, Shang Y, Strandberg R, Hagström H, Wester A. Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden. J Hepatol 2025;83:643-651.
    
43. Lazarus JV, Mark HE, Allen AM, et al. A global action agenda for turning the tide on fatty liver disease. Hepatology 2024;79:502-523.
    
44. Cheraghpour M, Hatami B, Singal AG. Lifestyle and pharmacologic approaches to prevention of metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2025;23:685-694.e6.
    
45. Bedogni G, Bellentani S, Miglioli L, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6:33.
    
46. Li J, Zou B, Yeo YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2019;4:389-398.
    
47. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011;54:1082-1090.
    

Article

Original Article

Mortality and Cardiovascular Outcomes in Patients with MAFLD Compared with Patients with MASLD: A Systematic Review and Meta-Analysis

Jiwon Yang1 , Ye Rim Kim1 , Seong Kyun Na2 , Seonok Kim3 , Jihyun An4 , Ju Hyun Shim1

1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Gastroenterology, Inje University Sanggye Paik Hospital, Seoul, Korea; 3Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 4Department of Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Korea

Received: June 7, 2025; Revised: July 15, 2025; Accepted: July 20, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Although metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) represent the updated nomenclature and diagnostic criteria for nonalcoholic fatty liver disease, studies comparing the prognostic implications of these conditions remain limited. This meta-analysis aimed to quantify the associations among MAFLD, MASLD, and long-term clinical outcomes.
Methods: A comprehensive literature search was performed to identify cohort studies that assessed the association of MASLD and MAFLD with all-cause mortality, cause-specific (cardiovascular and cancer-related) mortality, and the incidence of cardiovascular disease in the PubMed, Embase, Web of Science, CINAHL, and CENTRAL databases from inception through October 31, 2024. Pooled hazard ratios (HRs) were calculated for relevant outcomes.
Results: We identified 18 cohort studies, comprising 10,653,666 patients with MAFLD from 13 studies and 3,202,447 patients with MASLD from nine studies. MAFLD was significantly associated with an increased risk of overall mortality (pooled HR [95% confidence interval], 1.30 [1.16 to 1.47]) and cardiovascular mortality (1.31 [1.08 to 1.60]; both p<0.01), but not with cancer-related mortality (1.10 [0.97 to 1.24]; p=0.130). Conversely, MASLD was associated with a higher risk for all mortality outcomes: overall mortality (1.34 [1.12 to 1.61]), cardiovascular mortality (1.17 [1.07 to 1.27]), and cancer-related mortality (1.24 [1.19 to 1.29]; all p<0.01). The risk of cardiovascular disease was increased in patients with both MAFLD (1.48 [1.31 to 1.66]) and MASLD (1.33 [1.21 to 1.46]; both p<0.001).
Conclusions: MAFLD and MASLD were both associated with increased risks of mortality and cardiovascular outcomes. Notably, a significant association with cancer-related mortality was observed for MASLD, but not for MAFLD.

Keywords: Metabolic dysfunction-associated steatotic liver disease, Metabolic dysfunction-associated fatty liver disease, Mortality, Cardiovascular diseases

INTRODUCTION

Metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) represent updated nomenclature and diagnostic frameworks that have been proposed to replace the term nonalcoholic fatty liver disease (NAFLD).1-3 These terms were developed to eliminate the potential stigmatization associated with the words “fatty” and “alcoholic” in NAFLD, while also reflecting the diverse etiologies of steatotic liver diseases (SLDs).4 However, they have distinct diagnostic criteria. MAFLD is diagnosed based on the presence of hepatic steatosis along with at least one of the following metabolic risk factors: overweight/obesity, type 2 diabetes mellitus (T2DM), or metabolic dysfunction.2,5 Importantly, MAFLD allows for coexistence with other liver diseases including viral hepatitis and alcohol-related liver disease. In contrast, MASLD is defined as part of a broader classification under SLD and emphasizes cardiometabolic dysfunction. It also requires the presence of hepatic steatosis but maintains the historical exclusion of significant alcohol consumption (>140 g/week for women and 210 g/week for men) and other chronic liver diseases.1,3 In other words, MAFLD permits overlap with other liver diseases based on metabolic criteria, while MASLD adheres to stricter exclusions, preserving NAFLD's traditional definition.

In addition to an elevated risk of liver-related events and hepatocellular carcinoma,6,7 individuals with NAFLD have been shown to exhibit higher risks of all-cause mortality, extrahepatic malignancies, and cardiovascular diseases (CVDs) compared to those without NAFLD or general populations.8-12 In line with findings from NAFLD studies, several investigations have demonstrated that MAFLD and MASLD are significantly associated with increased risks of mortality and cardiovascular (CV) outcomes.13-30 These findings underscore the importance of carefully assessing mortality and CV risk in individuals with MAFLD or MASLD and support the development of surveillance strategies targeting high-risk populations. Nonetheless, the associations between these disease entities and prognostic outcomes vary across studies, likely due to differences in covariate adjustment, study design, and geographic region.13,23,27,31-34 For instance, a large population-based study using data from the United Kingdom Biobank reported that both MASLD and MAFLD were significantly associated with increased risks of all-cause and CV mortality, even after adjusting for potential confounders.27 However, data from the United States Third National Health and Nutrition Examination Survey, which included 13,856 adults with available ultrasonographic data, showed that CV mortality was significantly increased in MAFLD but not in MASLD, and neither condition was associated with cancer-related mortality.35

Therefore, it is essential to clarify the association between MAFLD or MASLD and prognostic outcomes to improve surveillance and prevention strategies. This meta-analysis aims to evaluate and quantify the risk of mortality and CVDs in MASLD and MAFLD, respectively, and to determine which definition more accurately predicts the long-term hard outcomes through a systematic review of pertinent clinical studies.

MATERIALS AND METHODS

1. Search strategy and selection criteria

This meta-analysis was performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol has been registered in the International Prospective Register of Systematic Reviews database (PROSPERO registration number: CRD42024548216). The Institutional Review Board of Asan Medical Center approved this meta-analysis and waived the requirement for informed consent from individual patients (approval number: 2024-0681).

We conducted a search for human cohort studies published from inception to October 31, 2024, using scholarly databases such as PubMed, Embase, Web of Science, CINAHL, and the CENTRAL. The detailed search strategy is presented in Supplementary Table 1. Two authors (Y.R.K. and J.A.) independently reviewed the titles and abstracts of the studies identified through the search to exclude those that did not address the research question of interest. Subsequently, the full texts of the remaining articles, along with their references, were thoroughly examined to confirm the inclusion of relevant information. In cases of discrepancies, consensus was achieved through discussion with another author (J.H.S.).

To be eligible, studies had to meet the following criteria: (1) include patients diagnosed with MAFLD or MASLD; (2) report the incidence of overall mortality, CV mortality, cancer-related mortality, and incident CVD; (3) use a longitudinal design; (4) follow-up duration of more than 1 year; (5) include a control arm, such as non-MASLD, non-MAFLD, or non-SLD for comparison; and (6) provide data on hazard ratio (HR) with 95% confidence interval (CI). Given that the terminology for MASLD was introduced recently, we did not impose restrictions on the types of articles included. Thus, abstracts and letters were included in the literature search and screening process. When we found multiple publications based on the same study population, we included only the most recent and informative one. Studies were excluded if they met any of the following criteria: (1) published in a non-English language; (2) focused on pediatric populations (aged <19 years); and (3) classified as preclinical studies, case reports, case series, case-control studies, systematic reviews, or meta-analyses. The flow diagram summarizing the study identification and selection process is presented in Fig. 1.

Figure 1. PRISMA checklist. WOS, Web of Science; CINAHL, Cumulative Index to Nursing and Allied Health Literature; SLD, steatotic liver disease; MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CV, cardiovascular; CVD, cardiovascular disease; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. *Four studies13,18,22,27 assessed both MASLD and MAFLD outcomes.

2. Definition of MAFLD and MASLD

MAFLD was defined as the presence of hepatic steatosis with metabolic dysfunction, which includes being overweight or obese, having T2DM, or exhibiting a combination of at least two of the seven metabolic risk factors.2 MASLD was defined as the presence of hepatic steatosis along with at least one of the five cardiometabolic criteria in adults.1 The detailed criteria for MAFLD and MASLD are presented in Supplementary Table 2.

3. Data extraction

Data were independently extracted by two reviewers (Y.R.K. and J.A.) using a pre-established form. In addition to the standard bibliometric variables, information on the following variables was also collected: category of hepatic steatosis (MAFLD or MASLD); study design; year of publication; median follow-up duration; study region; methods of steatosis assessment (fatty liver index [FLI], abdominal ultrasound [US], or liver biopsy); age; sex; prevalence of T2DM; total number of participants; cases of overall mortality, cancer-related mortality, CV mortality, or CVD; HR and 95% CI; and adjusted covariates. Any discrepancies in data extraction were resolved by consensus, with reference to the original articles for clarification.

4. Outcomes of interest

The primary outcome was the overall mortality of individuals classified according to the definitions of MASLD and MAFLD (Supplementary Table 2). The secondary outcomes included CV mortality, cancer-related mortality, and incident CVD. The definitions of CV mortality, cancer-related mortality, and CVD were derived from the original studies included in this meta-analysis (Supplementary Table 3). The comparison groups included those without SLD or those who did not meet the diagnostic criteria for the respective conditions (i.e., non-SLD, non-MASLD, or non-MAFLD).

5. Quality assessment and publication bias

The methodological quality of the cohort studies was independently assessed by two authors (J.Y. and J.A.) using the Newcastle-Ottawa Scale.36 Within this scale, studies were evaluated across three categories: selection of study groups (four items), comparability of study groups (two items), and ascertainment of the outcome of interest (three items). Each item was assigned a score of one point, except in the comparability category, where additional points were awarded for controlling for age and/or sex, allowing for a maximum of 2 points in this category. Publication bias was assessed quantitatively using Egger’s rank correlation regression test and qualitatively through the visualization of funnel plots depicting the logarithmic HRs against their standard errors.37

6. Statistical analysis

A random-effects meta-analysis model was employed to calculate pooled HR and 95% CI. Heterogeneity among study-specific estimates was assessed using two complementary methods. First, Cochran’s Q statistic was calculated to determine whether the observed variations in study results exceeded what would be expected by chance. This was accomplished by summing the weighted squared deviations of each study’s estimate from the overall weighted mean effect size. Second, to quantify the proportion of total variation attributable to heterogeneity rather than chance, the I² statistic was computed. In this analysis, an I² value greater than 50% indicated significant heterogeneity.38 Specifically, I² values of approximately 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively, while a p-value greater than 0.10 was considered to indicate homogeneity.39

To mitigate the impact of heterogeneity across included studies on outcomes assessment, we performed subgroup analyses stratified by the following parameters: diagnostic modality for steatosis (US vs FLI), geographical region (Eastern populations vs Western populations), study methodology (prospective design vs retrospective design), mean or median age of participants (≥50 years vs <50 years vs not reported), sex distribution (≥60% male participants vs <60% male participants vs not reported), T2DM prevalence at baseline (≥15% vs <15% vs not reported), comparator group (non-MAFLD vs non-MASLD vs non-SLD), and median follow-up duration (≥10 years vs <10 years). Threshold values for stratification were determined based on previously established criteria by Ha et al.40 Additionally, we employed random-effects meta-regression models to evaluate the impact of these baseline covariates on the observed heterogeneity.

All statistical analyses were conducted using the “meta” packages in R software (Version 4.4.2, R Foundation for Statistical Computing, Vienna, Austria). All tests were two-sided, and a p_-_value <0.05 was considered statistically significant.

RESULTS

1. Summary of the literature search

As shown in the PRISMA flow diagram, our literature search yielded 4,055 articles after the removal of duplicates. We screened 4,055 potentially relevant articles and subsequently reviewed the full text of 210 articles. Of these, 192 articles were excluded for the following reasons: (1) studies originating from overlapping cohorts (n=7); (2) irrelevant study population (n=10); (3) use of a comparator other than non-MAFLD, non-MASLD or non-SLD (n=22); (4) absence of a comparator (n=37); (5) irrelevant outcomes (n=97); and (6) insufficient data on the outcome of interest (n=19). Ultimately, 18 studies were included in this meta-analysis, comprising 16 peer-reviewed original articles13-26,29,30 and two conference abstracts (Fig. 1).27,28 Among these, nine studies exclusively focused on MAFLD,16,17,20,21,23,25,26,28,29 five studies on MASLD,14,15,19,24,30 and four studies examined both MAFLD and MASLD in the same population.13,18,22,27 Overall, data from 13 studies comprising 10,653,666 patients classified as having MAFLD13,16-18,20-23,25-29 and from nine studies comprising 3,202,447 patients diagnosed with MASLD13-15,18,19,22,24,27,30 were analyzed.

The baseline characteristics of the included studies are summarized in Table 1. Among the studies, eight articles (44.4%) assessed steatosis using abdominal US,13,17,19,20,26,28-30 while 10 articles utilized the FLI;14-16,18,21-25,27 one study diagnosed steatosis using abdominal US, liver biopsy or controlled attenuated parameter.19 The study population primarily consisted of Asian patients, accounting for 14 articles (77.8%).15-18,20-26,28-30 Excluding one study that lacked data on sex,28 the proportion of male patients exceeded 60% in most studies (10 articles).14,16,19-26 The mean or median age of the study populations across all included studies ranged between 41.9 and 61.6 years, except for two studies that did not report age data.28,30 Of the included studies, eight reported a prevalence of T2DM greater than 15%,13,15,18,19,21,23,25,29 while two studies did not provide data on T2DM status.27,28 The median follow-up duration ranged from 3.99 to 26.9 years. The detailed definitions of comparison groups used in the included studies are presented in Supplementary Table 4.

Table 1 . Baseline Characteristics of the Included Studies.

T2DM, type 2 diabetes mellitus; MAFLD, metabolic dysfunction-associated fatty liver disease; FLI, fatty liver index; CV, cardiovascular; CVD, cardiovascular disease; BMI, body mass index; US, ultrasound; NR, not reported; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; SLD, steatotic liver disease; CCI, Charlson Comorbidity Index; HDL-C, high-density lipoprotein cholesterol; MASLD, metabolic dysfunction-associated steatotic liver disease..

*Data are presented as the mean or median; †Data were derived from the group with MAFLD combined with nonalcoholic fatty liver disease; ‡Data were derived from the general population; §T2DM was defined as the use of glucose-lowering drugs; ‖The steatosis assessment method included biopsy, US, or controlled attenuated parameters; ¶T2DM was defined as a fasting glucose level ≥5·6 mmol/L, a glycated hemoglobin level ≥39 mmol/mol, a diagnosis of T2DM, or the use of anti-diabetic treatment..

2. Risk of mortality outcomes and CVDs in patients with MAFLD

Among the 13 articles focusing on patients with MAFLD, five studies examined the overall mortality as an outcome, involving a total of 265,446 MAFLD patients (Supplementary Table 5).13,18,20,23,27 In the pooled analysis, MAFLD was significantly associated with an increased risk of overall mortality compared to its comparators (pooled HR, 1.30; 95% CI, 1.16 to 1.47; p<0.001 with I2=76%) (Fig. 2A). Assessment of CV mortality from six studies including 467,715 MAFLD patients demonstrated similarly elevated risk (HR, 1.31; 95% CI, 1.08 to 1.60; p=0.006 with I2=85%) (Fig. 2B, Supplementary Table 6).13,20,23,26-28

Figure 2. Forest plot and pooled estimates of the clinical effect of MAFLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MAFLD, metabolic dysfunction-associated fatty liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Three studies investigated the association between MAFLD and cancer-related mortality in 2,835,883 MAFLD patients (Supplementary Table 7).13,16,23 Notably, the risk of cancer-related mortality showed no significant difference between MAFLD patients and comparators, despite exhibiting low-to-moderate heterogeneity (HR, 1.10; 95% CI, 0.97 to 1.24; p=0.130 with I2=27%) (Fig. 2C). Evaluation of incident CVD from seven studies with 7,500,134 MAFLD revealed substantially higher risk in MAFLD patients versus those without SLD or MAFLD (HR, 1.48; 95% CI, 1.31 to 1.66; p<0.001; I²=97%) (Fig. 2D, Supplementary Table 8).17,21-23,25,27,29

3. Risk of mortality and CVDs in patients with MASLD

Among all the articles on patients with MASLD, six studies investigated the association between MASLD and overall mortality in 238,571 MASLD patients (Supplementary Table 5).13-15,18,19,30 In the pooled analysis, patients with MASLD showed a significantly higher risk of overall mortality compared to those without SLD or MASLD (HR, 1.34; 95% CI, 1.12 to 1.61; p=0.001 with I2=94%) (Fig. 3A). CV mortality was assessed in five studies encompassing 2,926,708 MASLD patients (Supplementary Table 6).13,15,22,27,30 Results demonstrated a significant increase in CV mortality risk among MASLD patients versus comparators (HR, 1.17; 95% CI, 1.07 to 1.27; p<0.001; I²=84%) (Fig. 3B). For cancer-related mortality, pooled data from three studies with 108,027 MASLD patients indicated a significantly heightened risk with remarkable consistency across studies (HR, 1.24; 95% CI, 1.19 to 1.29; p<0.001; I²=0%) (Fig. 3C, Supplementary Table 7).13-15

Figure 3. Forest plot and pooled estimates of the clinical effect of MASLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MASLD, metabolic dysfunction-associated steatotic liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Four studies evaluated the risk of incident CVD in 2,967,518 patients with MASLD (Supplementary Table 8).15,22,24,27 The incidence risk of CVD was significantly higher in patients with MASLD compared to non-SLD or non-MASLD controls (HR, 1.33; 95% CI, 1.21 to 1.46; p<0.001 with I2=96%) (Fig. 3D).

4. Subgroup analyses of mortality and CV events in MAFLD and MASLD

Subgroup analyses were performed to assess effect modification across study characteristics and explore sources of heterogeneity for the outcomes of overall mortality, CV mortality, and incident CVD, as shown in Supplementary Figs 1 and 2. Subgroup analysis for cancer-related mortality was not conducted due to low heterogeneity observed in the overall meta-analysis for both MAFLD and MASLD individuals.

For MAFLD, subgroup findings were largely consistent with the main results, although significant effect size differences were observed based on methods of steatosis assessment for overall mortality and T2DM prevalence for both overall mortality and incident CVD (all p for group difference <0.05) (Table 2, Supplementary Fig. 1). Study design demonstrated a significant effect on the association between MAFLD and CV mortality, with prospective studies revealing a higher risk compared to retrospective designs (HR, 1.52; 95% CI, 1.45 to 1.60 vs HR, 1.13; 95% CI, 1.02 to 1.25; p for group difference <0.001), accompanied by reduced heterogeneity (overall: I²=85% vs prospective design: I²=16%; retrospective design: I²=50%).

Table 2 . Subgroup Analyses of Mortality and Cardiovascular Diseases in Patients with MAFLD and MASLD.

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; HR, hazard ratio; CI, confidence interval; FLI, fatty liver index; T2DM, type 2 diabetes mellitus; SLD, steatotic liver disease; NA, not applicable..

*One study (Israelsen 2024)19 that included patients diagnosed with steatosis using biopsy, ultrasound, or controlled attenuation parameters was categorized as the ultrasound group..

For MASLD, the elevated risks of overall mortality and CV mortality remained consistent across most subgroups (Table 2, Supplementary Fig. 2). Notably, MASLD patients aged ≥50 years (HR, 1.54; 95% CI, 1.18 to 2.00) and those with a median follow-up duration <10 years (HR, 2.11; 95% CI, 1.59 to 2.81) demonstrated significantly higher overall mortality risk compared to their counterparts (p for group difference=0.024 and <0.001, respectively), with substantially reduced heterogeneity (overall: I²=94% vs age ≥50 years: I²=75%; follow-up <10 years: I²=0%). The method of steatosis assessment and study design exhibited significant modification effects on the association between MASLD and CV mortality (all p for group difference <0.001), resulting in improved heterogeneity (overall: I²=84% vs both FLI ≥30 and US: I²=0%; both study designs: I²=0%). For CVD incidence, the estimated effect size for MASLD varied by comparator type. When non-MASLD individuals were used as the reference group, MASLD was associated with CVD (HR, 1.42; 95% CI, 1.36 to 1.48), whereas the HR was 1.20 (95% CI, 1.15 to 1.26) when non-SLD comparators were used. The test for subgroup differences was statistically significant (p<0.001), indicating that comparator type influences the magnitude of the observed association.

5. Meta-regression analysis for overall mortality in MAFLD and MASLD

We performed meta-regression to identify associations between study-level characteristics and overall mortality, as shown in Table 3. In brief, age, the proportion of male, study region, and the length of follow-up did not have significant effects on all-cause mortality in MAFLD and MASLD patients. Only steatosis assessment using FLI was associated with increased risk of overall mortality in MAFLD, whereas this significance was not observed in MASLD. In terms of MASLD, a significant positive association between the proportion of patients with pre-existing T2DM and increased overall mortality was observed (Supplementary Fig. 3).

Table 3 . Meta-Regression Analysis of the Effects of Covariates on Overall Mortality in Patients with MAFLD and MASLD.

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CI, confidence interval; T2DM, type 2 diabetes mellitus..

6. Quality assessment

The quality assessment of the included articles and PRISMA checklist are provided in Supplementary Tables 9 and 10, respectively. All included studies demonstrated good methodological quality, with Newcastle-Ottawa Scale scores ranging from 7 to 9 points.

7. Publication bias

Despite the limited number of studies included for each outcome, neither the rank correlation test nor Egger's test showed statistically significant evidence of publication bias for overall mortality (p=0.805), CV mortality (p=0.564), cancer-related mortality (p=0.312), and CVD (p=0.480) in studies with MAFLD (Supplementary Fig. 4). Similarly, for the MASLD, no significant publication bias was observed for these same outcomes: overall mortality (p=0.458), CV mortality (p=0.631), cancer-related mortality (p=0.509), and CVD (p=0.589) (Supplementary Fig. 5).

DISCUSSION

With the introduction of MAFLD and MASLD as alternative nomenclatures for NAFLD, the differences in their diagnostic criteria have sparked ongoing debate regarding whether they accurately reflect prognostic outcomes consistent with existing NAFLD-related data. In this meta-analysis, both MAFLD and MASLD demonstrated a strong association with an increased risk of overall mortality, CV mortality, and CVD. Notably, MASLD was significantly associated with a poor prognosis for cancer-related mortality, whereas MAFLD did not exhibit a significant association. To the best of our knowledge, our study is the first meta-analysis to comprehensively evaluate prognostic outcomes in MAFLD and MASLD employing rigorous subgroup and meta-regression methodologies to address inter-study heterogeneity. By integrating data from large cohort studies across both Asian and Western populations, our analysis provides valuable insights into mortality and CV outcomes associated with these evolving diagnostic frameworks.

Compared to MASLD, MAFLD exhibited higher HRs for CV mortality (HR: 1.31 vs 1.17) and CVD (HR: 1.48 vs 1.33). This discrepancy may be attributed to the broader inclusion criteria of MAFLD, which encompasses significant alcohol consumption and various etiologies of liver disease. Although our meta-analysis did not directly compare MAFLD and MASLD due to the limited number of original studies, a recent large-scale prospective study on CV mortality between the two classifications demonstrated that MAFLD had a significantly higher risk of CV mortality than MASLD.27 However, the variables adjusted for CV mortality in MAFLD varied across studies (Supplementary Table 6); in the study by Song et al.,13 statistical significance was lost after multiple adjustments. In our meta-analysis, we observed high heterogeneity among studies examining CV mortality. Subgroup analysis revealed that study design significantly influenced CV mortality outcomes, reducing heterogeneity in both MASLD and MAFLD. Notably, prospective studies showed a higher risk of CV mortality but demonstrated lower heterogeneity compared to retrospective studies. This finding may be explained by the potential for missing outcomes and inaccuracies in self-reported data inherent in retrospective study designs. Regarding MASLD specifically, participants aged ≥50 years demonstrated a higher HR (1.30; 95% CI, 1.23 to 1.37) compared to those under 50 years (1.13; 95% CI, 1.11 to 1.15), with minimal heterogeneity observed in both age groups. These findings reinforce the well-established association between advancing age, increased cardiometabolic burden, and adverse CV outcomes in MASLD,41 highlighting the critical need for age-specific risk stratification in clinical practice. Additionally, while diagnostic methods for hepatic steatosis assessment contributed to heterogeneity in the overall analysis, both FLI and US consistently demonstrated increased CV mortality risk in MASLD patients.

Interestingly, MASLD was significantly associated with increased cancer-related mortality, whereas MAFLD was not. This discrepancy may be partly explained by their differing diagnostic frameworks and the resulting population characteristics. MAFLD includes individuals with coexisting liver diseases, potentially introducing competing causes of death that attenuate the observed association with cancer-related mortality. Additionally, MAFLD's broader diagnostic criteria may result in a more heterogeneous population with variable metabolic risk profiles, potentially diluting the cancer-specific mortality signal. In contrast, MASLD excludes individuals with coexisting chronic liver diseases, resulting in a more homogeneous study population with a consistent burden of metabolic dysfunction. MASLD specifically requires the presence of cardiometabolic risk factors such as obesity, T2DM, hypertension, and dyslipidemia—conditions that are well established to increase cancer risk. This more uniform metabolic burden likely strengthens the observed association with cancer-related mortality. A recently published nationwide Swedish cohort study (2002 to 2020) found that both hepatocellular carcinoma-related mortality (HR, 35.0; 95% CI, 17.0 to 72.1) and non-hepatocellular carcinoma cancer mortality (HR, 1.47; 95% CI, 1.32 to 1.63) were significantly increased in MASLD patients compared to controls.42 These findings from an independent large-scale cohort further support our meta-analysis results, reinforcing that MASLD identifies a population at elevated cancer risk due to its distinct metabolic and etiologic characteristics. The excessive cancer-related mortality in MASLD suggests that early multidisciplinary care should be prioritized, involving primary care physicians, hepatologists, endocrinologists, and oncologists for comprehensive risk stratification and management.43 Additionally, lifestyle modifications including weight reduction, healthy diet, and regular physical activity should be reinforced as important measures to treat underlying liver disease and potentially reduce cancer risk.44 These efforts should be supported by public health initiatives that recognize MASLD as a major global health challenge.

In the present meta-analysis, both MASLD and MAFLD were significantly associated with increased overall mortality. Despite overall consistency in the direction of effect estimates, substantial heterogeneity was observed across studies. Subgroup analyses revealed that certain study-level characteristics contributed to this heterogeneity in overall mortality estimates, particularly in the MASLD population. Stratification by steatosis assessment methods, study region, participant age characteristics, and median follow-up duration notably reduced heterogeneity while maintaining a consistent significant association between MASLD and overall mortality. Furthermore, meta-regression analysis demonstrated that the prevalence of T2DM significantly influenced mortality outcomes in MASLD patients, suggesting that MASLD patients with concurrent diabetes may require more intensive therapeutic interventions to reduce mortality risk.

Our study has some limitations. First, given that the design of the included studies was an observational cohort study, establishing a definitive causal link between clinical outcomes and either MAFLD or MASLD remains challenging. Second, due to the limited number of studies with shared control groups, direct comparisons or network meta-analyses between MAFLD and MASLD were not feasible. As a result, the current comparisons are based on indirect evidence rather than head-to-head analyses within the same populations. This limitation introduces the possibility that observed differences reflect variations in study design, patient characteristics, comparator groups, or covariate adjustments, rather than true differences in prognostic value. To investigate potential sources of heterogeneity, we performed subgroup and meta-regression analyses where feasible; however, given the indirect nature of the comparisons, effect size estimates should be interpreted with caution. Third, patient numbers were unevenly distributed across studies, with a few large-scale studies disproportionately influencing the pooled estimates, particularly for cancer-related mortality. Additionally, most included studies failed to adequately account for competing risks, especially CV mortality, which represents a leading cause of death in these populations. This methodological limitation may have resulted in underestimation of cancer-related mortality, particularly in MAFLD populations where higher rates of early CV death could mask cancer outcomes. Future studies employing balanced sample sizes and appropriate competing risk analyses are warranted to validate these findings. Fourth, hepatic steatosis was assessed using either US or FLI, which differs in diagnostic performance and population applicability. FLI demonstrates moderate accuracy (area under the receiver operating characteristic curve, 0.84) for detecting hepatic steatosis (FLI <30: 87% sensitivity; FLI ≥60: 86% specificity),45 but may underestimate steatosis in lean Asian individuals due to their typically lower BMI distribution, potentially leading to misclassification.46 In contrast, US demonstrates higher accuracy (area under the receiver operating characteristic curve, 0.93; sensitivity, 84.8%; specificity, 93.6%) for detecting moderate-to-severe hepatic steatosis, but it is operator-dependent.47 Despite these differences in diagnostic modalities, stratified analyses by assessment method of hepatic steatosis consistently demonstrated significant associations between both MAFLD and MASLD and mortality outcomes. Fifth, we were unable to evaluate the degree of fibrosis—an important factor associated with outcomes in both MASLD and MAFLD—because the original studies did not report these values. Additionally, we could not analyze liver-related mortality and events for either condition, as only one study in each diagnostic group reported these relevant outcomes,14,23 preventing meaningful comparative analysis.

In conclusion, our meta-analysis demonstrated that both MAFLD and MASLD were significantly associated with increased risks of overall mortality, CV mortality, and CVD. Distinctively, MASLD showed an additional significant association with cancer-related mortality that was not observed with MAFLD. Given the rising prevalence of SLD in conjunction with metabolic dysfunction-related conditions, our findings may provide valuable insights into determining the most clinically relevant nomenclature for classifying individuals with SLD, potentially improving prevention strategies for mortality and CV risk. These results could inform the development of more refined and targeted surveillance approaches. However, as our analysis was based on indirect comparisons across heterogeneous studies, the observed differences between MAFLD and MASLD should be interpreted with caution. Prospective, head-to-head studies are warranted to validate and further elucidate these associations.

ACKNOWLEDGEMENTS

This study was supported by grants from the National Research Foundation of Korea funded by the Ministry of Science and ICT (NRF-2022R1A2C3008956 and NRF-2021R1A6A1A03040260), Asan Institute for Life Sciences (grant number: 2022IP0046), and the Elimination of Cancer Project Fund from the Asan Cancer Institute of Asan Medical Center.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design; Data acquisition; Data analysis and interpretation: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: J.Y., Y.R.K., S.K.N., J.A., J.H.S. Statistical analysis: all authors. Obtained funding: J.H.S. Study supervision: J.A., J.H.S. Approval of final manuscript: all authors.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable as no new data were created or analyzed in this study. All articles referenced in this manuscript are publicly accessible through PubMed, Embase, CINAHL, the Cochrane Library, and Web of Science.

SUPPLEMENTARY MATERIALS

• Abstract
• INTRODUCTION
• MATERIALS AND METHODS
• RESULTS
• DISCUSSION
• ACKNOWLEDGEMENTS
• CONFLICTS OF INTEREST
• AUTHOR CONTRIBUTIONS
• DATA AVAILABILITY STATEMENT
• SUPPLEMENTARY MATERIALS

Fig 1.

Figure 1.PRISMA checklist. WOS, Web of Science; CINAHL, Cumulative Index to Nursing and Allied Health Literature; SLD, steatotic liver disease; MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CV, cardiovascular; CVD, cardiovascular disease; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses. *Four studies13,18,22,27 assessed both MASLD and MAFLD outcomes.

Fig 2.

Figure 2.Forest plot and pooled estimates of the clinical effect of MAFLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MAFLD, metabolic dysfunction-associated fatty liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Fig 3.

Figure 3.Forest plot and pooled estimates of the clinical effect of MASLD on mortality and CVD. (A) Overall mortality, (B) CV mortality, (C) cancer-related mortality, and (D) incident CVD. MASLD, metabolic dysfunction-associated steatotic liver disease; CVD, cardiovascular disease; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Table 1 Baseline Characteristics of the Included Studies

T2DM, type 2 diabetes mellitus; MAFLD, metabolic dysfunction-associated fatty liver disease; FLI, fatty liver index; CV, cardiovascular; CVD, cardiovascular disease; BMI, body mass index; US, ultrasound; NR, not reported; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; SLD, steatotic liver disease; CCI, Charlson Comorbidity Index; HDL-C, high-density lipoprotein cholesterol; MASLD, metabolic dysfunction-associated steatotic liver disease.

*Data are presented as the mean or median; †Data were derived from the group with MAFLD combined with nonalcoholic fatty liver disease; ‡Data were derived from the general population; §T2DM was defined as the use of glucose-lowering drugs; ‖The steatosis assessment method included biopsy, US, or controlled attenuated parameters; ¶T2DM was defined as a fasting glucose level ≥5·6 mmol/L, a glycated hemoglobin level ≥39 mmol/mol, a diagnosis of T2DM, or the use of anti-diabetic treatment.

Table 2 Subgroup Analyses of Mortality and Cardiovascular Diseases in Patients with MAFLD and MASLD

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; HR, hazard ratio; CI, confidence interval; FLI, fatty liver index; T2DM, type 2 diabetes mellitus; SLD, steatotic liver disease; NA, not applicable.

*One study (Israelsen 2024)19 that included patients diagnosed with steatosis using biopsy, ultrasound, or controlled attenuation parameters was categorized as the ultrasound group.

Table 3 Meta-Regression Analysis of the Effects of Covariates on Overall Mortality in Patients with MAFLD and MASLD

MAFLD, metabolic dysfunction-associated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; CI, confidence interval; T2DM, type 2 diabetes mellitus.

References

1. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023;79:1542-1556.
   
2. Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158:1999-2014.e1.
   
3. European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.
   
4. Kim GA, Moon JH, Kim W. Critical appraisal of metabolic dysfunction-associated steatotic liver disease: Implication of Janus-faced modernity. Clin Mol Hepatol 2023;29:831-843.
   
5. Eslam M, George J. Two years on, a perspective on MAFLD. eGastroenterology 2023;1:e100019.
   
6. Younossi ZM, Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep 2021;3:100305.
   
7. Petta S, Sebastiani G, Viganò M, et al. Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease. Clin Gastroenterol Hepatol 2021;19:806-815.e5.
   
8. Bisaccia G, Ricci F, Khanji MY, et al. Cardiovascular morbidity and mortality related to non-alcoholic fatty liver disease: a systematic review and meta-analysis. Curr Probl Cardiol 2023;48:101643.
   
9. Mantovani A, Petracca G, Beatrice G, et al. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut 2022;71:778-788.
   
10. Thomas JA, Kendall BJ, El-Serag HB, Thrift AP, Macdonald GA. Hepatocellular and extrahepatic cancer risk in people with non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2024;9:159-169.
    
11. Alvarez CS, Graubard BI, Thistle JE, Petrick JL, McGlynn KA. Attributable fractions of nonalcoholic fatty liver disease for mortality in the United States: results from the Third National Health and Nutrition Examination Survey with 27 years of follow-up. Hepatology 2020;72:430-440.
    
12. Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study. Hepatology 2018;67:1726-1736.
    
13. Song R, Li Z, Zhang Y, Tan J, Chen Z. Comparison of NAFLD, MAFLD and MASLD characteristics and mortality outcomes in United States adults. Liver Int 2024;44:1051-1060.
    
14. Bao X, Zhang X, Kang L, Xu B, Yin S, Zhang X. Association of MASLD with liver-related and extrahepatic outcomes: a prospective cohort study [Preprint]. Posted 2024 Feb 21. SSRN.
    https://doi.org/10.2139/ssrn.4731176
    
15. Choe HJ, Moon JH, Kim W, Koo BK, Cho NH. Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: a community-dwelling cohort study with 20-year follow-up. Metabolism 2024;153:155800.
    
16. Chung GE, Yu SJ, Yoo JJ, et al. Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients with metabolic dysfunction-associated fatty liver disease: a population-based cohort study with 9.7 million Korean subjects. Cancer Commun (Lond) 2023;43:863-876.
    
17. Guo Y, Yang J, Ma R, et al. Metabolic dysfunction-associated fatty liver disease is associated with the risk of incident cardiovascular disease: a prospective cohort study in Xinjiang. Nutrients 2022;14:2361.
    
18. Han E, Lee BW, Kang ES, et al. Mortality in metabolic dysfunction-associated steatotic liver disease: a nationwide population-based cohort study. Metabolism 2024;152:155789.
    
19. Israelsen M, Torp N, Johansen S, et al. Validation of the new nomenclature of steatotic liver disease in patients with a history of excessive alcohol intake: an analysis of data from a prospective cohort study. Lancet Gastroenterol Hepatol 2024;9:218-228.
    
20. Kim KS, Hong S, Ahn HY, Park CY. Metabolic dysfunction-associated fatty liver disease and mortality: a population-based cohort study. Diabetes Metab J 2023;47:220-231.
    
21. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol Hepatol 2021;19:2138-2147.e10.
    
22. Lee HH, Lee HA, Kim EJ, et al. Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease. Gut 2024;73:533-540.
    
23. Moon JH, Kim W, Koo BK, Cho NH. Metabolic dysfunction-associated fatty liver disease predicts long-term mortality and cardiovascular disease. Gut Liver 2022;16:433-442.
    
24. Moon JH, Jeong S, Jang H, Koo BK, Kim W. Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study. EClinicalMedicine 2023;65:102292.
    
25. Yoneda M, Yamamoto T, Honda Y, et al. Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan. J Gastroenterol 2021;56:1022-1032.
    
26. Yoo TK, Lee MY, Kim SH, et al. Comparison of cardiovascular mortality between MAFLD and NAFLD: a cohort study. Nutr Metab Cardiovasc Dis 2023;33:947-955.
    
27. Zhang X, Bao X, Xu B. Association of MASLD and MAFLD with cardiovascular and mortality outcomes: a prospective study of the UK biobank cohort. J Am Coll Cardiol 2024;83(13 Suppl):1729.
    
28. Cheng WC, Li CY. Metabolic dysfunction-associated fatty liver disease is associated with increased cardiovascular disease mortality: a cohort study. Hepatology International 2023;17:S101-102.
29. Liang Y, Chen H, Liu Y, et al. Association of MAFLD With diabetes, chronic kidney disease, and cardiovascular disease: a 4.6-year cohort study in China. J Clin Endocrinol Metab 2022;107:88-97.
    
30. Chen YT, Chen TI, Yin SC, et al. Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease. J Gastroenterol Hepatol 2024;39:1939-1949.
    
31. Younossi ZM, Paik JM, Al Shabeeb R, Golabi P, Younossi I, Henry L. Are there outcome differences between NAFLD and metabolic-associated fatty liver disease?. Hepatology 2022;76:1423-1437.
    
32. Nguyen VH, Le MH, Cheung RC, Nguyen MH. Differential clinical characteristics and mortality outcomes in persons with NAFLD and/or MAFLD. Clin Gastroenterol Hepatol 2021;19:2172-2181.e6.
    
33. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol 2021;75:1284-1291.
    
34. van Kleef LA, de Knegt RJ, Brouwer WP. Metabolic dysfunction-associated fatty liver disease and excessive alcohol consumption are both independent risk factors for mortality. Hepatology 2023;77:942-948.
    
35. Zhao Q, Deng Y. Comparison of mortality outcomes in individuals with MASLD and/or MAFLD. J Hepatol 2024;80:e62-e64.
    
36. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-605.
    
37. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.
    
38. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558.
    
39. Higgins JPT, Thomas James, Chandler Jacqueline, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. The Cochrane Collaboration, 2019.
    
40. Ha J, Yim SY, Karagozian R. Mortality and liver-related events in lean versus non-lean nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2023;21:2496-2507.e5.
    
41. He QJ, Li YF, Zhao LT, Lin CT, Yu CY, Wang D. Recent advances in age-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol 2024;30:652-662.
    
42. Issa G, Shang Y, Strandberg R, Hagström H, Wester A. Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden. J Hepatol 2025;83:643-651.
    
43. Lazarus JV, Mark HE, Allen AM, et al. A global action agenda for turning the tide on fatty liver disease. Hepatology 2024;79:502-523.
    
44. Cheraghpour M, Hatami B, Singal AG. Lifestyle and pharmacologic approaches to prevention of metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2025;23:685-694.e6.
    
45. Bedogni G, Bellentani S, Miglioli L, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6:33.
    
46. Li J, Zou B, Yeo YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2019;4:389-398.
    
47. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011;54:1082-1090.
    

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