A potential age-independent MASLD-related liver fibrosis index based on metabolic profiling

Abstract

The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is of immediate concern, as its prevalence is increasing worldwide. MASLD often progresses to liver fibrosis, posing significant health risks. Age-independent, noninvasive tools to evaluate fibrosis are needed to improve diagnostic accuracy across all age groups. Eighty-four inflammatory, hematological, and metabolic variables were quantified in the blood of 63 individuals with MASLD, with varying degrees of fibrosis, and 22 age-matched controls. Linear regression models were used to identify markers strongly correlated with liver fibrosis that were not influenced by age. Logistic regression models were used to evaluate the ability of various indices to discriminate between no/mild and severe liver fibrosis. Glutamine and propionate levels were identified as strongly correlated with fibrosis but not with age and were combined to form the GP index. The GP index demonstrated superior predictive power for liver fibrosis compared to existing scores, like FIB-4 and FIB-3. The study introduces the GP index, a novel metabolite-based score for diagnosing and monitoring liver fibrosis in patients with MASLD, which demonstrated robust performance irrespective of patient age in this cohort. By excluding age-dependent markers, the GP index can potentially reduce false positives and improve diagnostic accuracy, particularly in older populations. The combination of glutamine and propionate in this index represents a novel approach, capturing both intrinsic hepatic metabolic changes and extrinsic influences from the gut microbiota, providing a simple yet effective solution for liver fibrosis staging.

Keywords: Fibrosis; Glutamine; Glutaminolysis; Gut-liver axis; Metabolic associated steatotic liver disease; Propionate.

Fig. 1

Multiple linear regression coefficient (b) and regression p-value in logarithmic scale of the 83 variables with liver fibrosis (A) and age x fibrosis interaction (B). Variables with labels are the only ones that show a significant correlation. Variables in red show a significant association with fibrosis even after a Bonferroni correction. Venn diagram of the variables significantly correlated with the three conditions (C). The variables in red in (A) and (C) significantly correlate with fibrosis progression independently of age. Abbreviations are defined in Table 2.

Fig. 2

Concentrations of metabolites significantly correlated with fibrosis progression independently of age and already proposed with their average and standard deviation values [mM] measured as a function of the fibrosis scale. The change in metabolite concentrations was compared to the previous value on the scale to determine its significance. *p < 0.05, **p < 0.01.

Fig. 3

Scatter plots of the measured values of three MASLD-related Liver Fibrosis prognostic indexes: BTR, Glu/Gln, SCFA s, and the new proposed MASLD-related liver fibrosis index (GP) scatter plot. The change in index values was compared to the previous value on the scale to determine its significance. *p < 0.05, **p < 0.01.