Elevated serum growth differentiation factor 15 and decorin predict the fibrotic progression of metabolic dysfunction-associated steatotic liver disease

Abstract

Mitochondrial dysfunction with oxidative stress contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. We aimed to evaluate the fibrosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. From a population-based general cohort, 144 subjects with MASLD were recruited in the development group and underwent magnetic resonance imaging-based liver examinations, anthropometric and laboratory tests. As an external validation group, 41 patients enrolled in a biopsy-evaluated MASLD cohort participated in this study. Liver fat content and stiffness were measured by magnetic resonance (MR) imaging-proton density fat fraction and MR elastography (MRE), respectively. Serologic stress biomarkers were quantitated by ELISA. Multivariate regression showed that waist-to-height ratio, growth differentiation factor-15 (GDF15), γ-glutamyltransferase, decorin, and alkaline-phosphatase were independent predictors of hepatic fibrosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95% CI)) of the metabolic stress index for fibrosis (MSI-F) was 0.912 (0.85‒0.98) and 0.977 (0.92‒1.00) in development and validation groups, respectively. MSI-F also had better diagnostic accuracy (82.6‒92.4%) than other fibrosis indices in the both study cohorts. MSI-F consistently differentiated fibrosis severities across cohorts of MRE-evaluated general population and biopsy-proven patients with MASLD, while other indices showed no or less discrimination. MSI-F, as a novel non-invasive index based on a stress-stimulated protective hormone GDF15 and decorin, effectively predicted hepatic fibrosis. Furthermore, MSI-F may serve as pre-screening tool to increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.

Keywords: Decorin; Growth differentiation factor-15; Hepatic fibrosis; Mitochondrial stress; Serum biomarker.

Fig. 1

Predictive ability of MSI-F for liver stiffness compared with other fibrosis indices. (A) Non-invasive prediction scores according to liver stiffness grades (Kruskal–Wallis [KW] test with post hoc Dunnett’s T3 test). (B) ROC curves of non-invasive scores for predicting hepatic fibrosis. *p < 0.05, **p < 0.01 vs. MSI-F (DeLong’s tests). MSI-F metabolic stress index of liver fibrosis, APRI AST to platelet ratio index, FIB-4 Fibrosis-4 index, NFS nonalcoholic fatty liver disease fibrosis score, MRE magnetic resonance elastography, AUROC area under the ROC (receiver operating characteristic) curve.

Fig. 2

Validation of MSI-F in patients with biopsy-proven MASLD. (A) Non-invasive prediction scores according to histological fibrosis stages (Kruskal–Wallis [KW] test with post hoc Dunnett’s T3 test). Bars and circles represent the mean with standard error of the mean and individual values, respectively. (B) ROC curves of non-invasive scores for predicting significant fibrosis. *p < 0.05, **p < 0.01 vs. MSI-F (DeLong’s tests).

Fig. 3

The potential clinical utility model of MSI-F. (A) Clinical utility of MSI-F and other indices predicting hepatic fibrosis with sensitivity and specificity of 90% in the development cohort. (B) Clinical utility of the indices in the validation cohort by applying the thresholds derived from the development cohort. Blue, true positive and true negative; red, indeterminate; grey, false positive and false negative. MSI-F metabolic stress index of liver fibrosis, APRI AST to platelet ratio index, FIB-4 Fibrosis-4 index, NFS nonalcoholic fatty liver disease fibrosis score, AUROC area under the ROC (receiver operating characteristic) curve.

Fig. 4

Flow chart of participant recruitment and analyzed subgroups in this study. KoGES-ARIRANG Korean Genome and Epidemiology Study on the Atherosclerosis Risk of Rural Areas in the Korean General Population, MASLD metabolic dysfunction-associated steatotic liver disease, MRI-PDFF magnetic resonance imaging-proton density fat fraction, MRE magnetic resonance elastography.