Characteristics and long-term mortality of individuals with MASLD, MetALD, and ALD, and the utility of SAFE score

Abstract

Background & aims: The new nomenclature of steatotic liver disease (SLD) was recently launched with sub-classifications of metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD). Herein, we aimed to evaluate the characteristics and long-term outcomes associated with these subgroups and the utility of non-invasive biomarkers.

Methods: Using NHANES III (the third National Health and Nutrition Examination Survey) and linked mortality data, all adult participants with available ultrasonographic liver steatosis status were included. Those with viral hepatitis, incomplete data on alcohol consumption, cardiometabolic risk, and missing data that hindered Steatosis-associated Fibrosis Estimator (SAFE) score calculation were excluded. The characteristics of those without SLD (no steatosis on ultrasound), MASLD, MetALD, and ALD were compared. Overall survival (OS) was determined and SAFE score strata were applied to SLD subgroups.

Results: A total of 9,939 participants were eligible; 64% had no SLD, while 30%, 2.3%, and 1% had MASLD, MetALD, and ALD, respectively. A higher proportion of men, as well as active smokers, was observed in the MetALD and ALD groups compared to the MASLD group. Diabetes was more prevalent in the MASLD group than in the MetALD and ALD groups. The ALD subgroup had significantly lower OS than the MASLD group (p = 0.004), but the MetALD did not (p = 0.165). SAFE score strata meaningfully differentiated OS of all SLD subgroups.

Conclusions: MASLD accounted for the largest proportion of SLD. MetALD shared the characteristics of both MASLD and ALD. The ALD subgroup had a significantly lower OS than the MASLD subgroup but there was no difference between MetALD and MASLD. The SAFE score can be used to stratify long-term outcomes in all SLD subgroups.

Impact and implications: "Steatotic liver disease (SLD)" is a recently introduced term covering three subgroups: MASLD (metabolic dysfunction-associated SLD), MetALD (MASLD with increased alcohol intake), and ALD (alcohol-related liver disease). We explored the characteristics and outcomes of these subgroups among the US population. We found that MASLD was far more common than MetALD and ALD, but all subgroups shared cardiometabolic risk factors. The ALD subgroup has the worst survival, pointing to the synergistic effect of alcohol and metabolic dysfunction. In addition, the SAFE (Steatosis-associated Fibrosis Estimator) score might be a useful non-invasive test to stratify long-term risk in all three SLD subgroups.

Keywords: MAFLD; NAFLD; Nomenclature; fatty liver disease; steatotic liver disease.

Graphical abstract

Fig. 1

Kaplan-Meier survival curves of all four groups of participants according to the new nomenclature. Level of significance: p <0.0001 (log-rank test). ALD, alcohol-related liver disease; MASLD, metabolic dysfunction-associated SLD; MetALD, MASLD and increased alcohol intake; SLD, steatotic liver disease.

Fig. 2

The adjusted hazard ratios for long-term mortality of participants in each group, using Cox proportional hazard regressions. Levels of significance as shown in the table. ALD, alcohol-related liver disease; MASLD, metabolic dysfunction-associated SLD; MetALD, MASLD and increased alcohol intake; NH, non-Hispanic; SLD, steatotic liver disease.

Fig. 3

Kaplan-Meier survival curves of MASLD, MetALD, and ALD subgroups categorized by SAFE score strata. (A) MASLD; level of significance: p <0.0001 (log-rank test); (B) MetALD; level of significance: p <0.0001 (log-rank test); (C) ALD; level of significance: p = 0.00013 (log-rank test). ALD, alcohol-related liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, MASLD and increased alcohol intake; NH, non-Hispanic; SAFE, Steatosis-associated Fibrosis Estimator.

Fig. 4

Survival stratified by SAFE and FIB-4 scores. (A) SAFE score stratification but not (B) FIB-4 stratification is significantly associated with survival after adjustment with age, sex, ethnicity, and smoking status in individuals with steatotic liver disease (using Cox proportional hazard regressions; levels of significance as shown in the table). ALD, alcohol-related liver disease; FIB-4, Fibrosis-4; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, MASLD and increased alcohol intake; SAFE, Steatosis-associated Fibrosis Estimator.

Fig. 5

Cumulative incidences of cardiovascular, cancer, and other cause of death among individuals with SLD, using competing risk analyses. Levels of significance as shown in the table (Grey’s test). ALD, alcohol-related liver disease; MASLD, metabolic dysfunction-associated SLD; MetALD, MASLD and increased alcohol intake; SLD, steatotic liver disease.