Noninvasive SAFE Score Stratifies Long-Term Outcomes in Steatotic Liver Disease

Pimsiri Sripongpun, MD

Credit: ResearchGate

New research is providing clinicians with an overview of the characteristics and long-term outcomes of steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD).¹

Study results showed MASLD accounted for the largest proportion of SLD, additionally revealing the ALD subgroup had significantly lower overall survival than MetALD or MASLD and suggesting a synergistic effect of alcohol and metabolic dysfunction. Further analysis with the Steatosis-associated Fibrosis Estimator (SAFE) score pointed to the utility of the noninvasive test for stratifying long-term risk in all 3 SLD subgroups.¹

To encourage a better understanding of liver disease etiologies and pathophysiology as well as to avoid stigmatization, new nomenclature from a multi-society consensus was recently proposed and accepted in 2023, changing nonalcoholic fatty liver disease (NAFLD) to MASLD and adding SLD as an overarching term to encompass the various etiologies of steatosis.²

“The characteristics and long-term outcomes of these new subclasses, as well as the potential benefits of employing non-invasive biomarkers within these subgroups, remain uncertain,” Pimsiri Sripongpun, MD, an associate professor in the department of internal medicine at Prince of Songkla University in Thailand, and colleagues wrote.¹

To assess the characteristics and long-term outcomes associated with MASLD, MetALD, and ALD, as well as the utility of non-invasive biomarkers, investigators examined National Health and Nutrition Examination Survey (NHANES) 1988-1994 data and linked mortality data for adults ≥ 18 years of age with available data on ultrasonographic determination of hepatic steatosis. Those with viral hepatitis, incomplete data on alcohol consumption, cardiometabolic risk, and missing data that hindered SAFE score calculation were excluded from the study.¹

Individuals with hepatic steatosis present on ultrasonography either mild, moderate, or severe grade were classified as having SLD. Among those with SLD, participants with ≥ 1 of the following cardiometabolic criteria were categorized as having MASLD:

• BMI ≥25 kg/m2
• Waist circumference ≥80/90 cm in women and men, respectively
• Diagnosis of hypertension, diabetes, or fasting serum glucose >5.6 mmol/L or HbA1c >5.7%
• Hyperlipidemia/plasma triglyceride >1.7 mmol/L/plasma HDL-cholesterol <1.0 mmol/L plus history of alcohol intake <20/30 gm/day in women/men

Participants with SLD who had ≥1 of the aforementioned cardiometabolic criteria and reported alcohol consumption of 20-50 g/day in women or 30-60 g/day in men were categorized into the MetALD group.¹

Investigators then calculated the SAFE score in eligible participants. The participants with SAFE scores <0, 0-100, and ≥100 were categorized into low-, intermediate-, and high-risk groups for long-term mortality, respectively.¹

A total of 9939 individuals were included in the study. Hepatic steatosis was found in 3592 (36.1%) patients, of whom 2980 (30.0% of the entire cohort), 230 (2.3%), and 97 (1.0%) were categorized into MASLD, MetALD, and ALD groups, respectively. The remaining 285 participants with steatosis but no cardiometabolic factors or significant alcohol consumption were grouped as ‘uncategorized’.¹

Investigators observed a greater proportion of men and active smokers in the MetALD and ALD groups compared to the MASLD group. Additionally, they pointed out the prevalence of diabetes and dyslipidemia was lower in the MetALD and ALD groups.¹

Individuals without SLD had the best survival, followed by those with MASLD, MetALD, and ALD. After adjustment for age, sex, race-ethnicity, and smoking status, MASLD, MetALD, and ALD were associated with 16%, 33%, and 75% higher mortality, respectively, compared to no SLD. Of note, the ALD subgroup had significantly lower overall survival than the MASLD group (P = .004), but the MetALD subgroup did not (P = .165).¹

Investigators noted the SAFE score strata meaningfully differentiated overall surival of all SLD subgroups. Compared with low-risk SAFE scores, intermediate- and high-risk SAFE scores were associated with a 31% and 90% increase in mortality, respectively. However, when the analysis was repeated for FIB-4, only the highest stratum (FIB-4 ≥2.67) was significantly associated with increased mortality risk, with a 53% risk increase.¹

Investigators outlined multiple limitations to these findings, including the fact that ultrasonography was not highly sensitive or specific for the diagnosis of steatosis during the study period (1988-1994), likely leading to misclassifications; the small number of individuals with ALD provided barely sufficient power in the survival analysis, potentially due to underreporting of alcohol consumption in the survey; and the study was based on data collected at a single time point to predict long-term outcomes.¹

“These data obtained in the sample of US adults generalizable to the population enhance our knowledge of the epidemiology and impact of the entities defined in the recent nomenclature,” investigators concluded.¹ “The continuous impact of alcohol on future mortality and the high prevalence of cardiometabolic factors in individuals with ALD highlight the need for further research focused on the individuals subject to liver injury from concomitant alcohol use and insulin resistance.”

References

1. ^{Sripongpun P, Kaewdech A, Udompap P, et al. Characteristics and long-term mortality of individuals with MASLD, MetALD, and ALD, and the utility of SAFE score. JHEP Reports. doi:10.1016/j.jhepr.2024.101127}
2. ^{Brooks, A. From NAFLD to MASLD: 2023 Brings New Liver Disease Nomenclature. HCPLive. December 13, 2023. Accessed September 18, 2024. https://www.hcplive.com/view/from-nafld-to-masld-2023-new-liver-disease-nomenclature}