Growth Differentiation Factor 15 (GDF-15) as a modulator of hepatic steatosis and fibrosis: insights from a 6-year retrospective cohort study

TL;DR

This study shows that GDF-15 may help protect the liver from fat buildup and scarring, especially in people with metabolic or lifestyle risk factors.

Contribution

The study reveals GDF-15's potential protective role in liver disease through interactions with fibrosis, alcohol, and insulin resistance.

Findings

Higher GDF-15 levels were linked to increased liver stiffness in those with elevated baseline fibrosis.

GDF-15 interacted with alcohol intake to reduce liver stiffness.

GDF-15 was associated with increased steatosis, but its interaction with insulin resistance reduced it.

Abstract

Liver diseases represent a major global health burden. Growth Differentiation Factor 15 (GDF-15), a stress-induced cytokine, has been suggested to protect against fibrosis progression through neuro-metabolic-immunologic pathways and to regulate energy and lipid homeostasis, potentially influencing hepatic steatosis. This study evaluated the role of GDF-15 in steatosis and fibrosis, considering prior liver injury, alcohol intake, insulin resistance, and obesity.

In this retrospective cohort study, 626 participants from a large population-based cohort were analyzed. Associations of baseline GDF-15, alcohol intake, FIB-4 score, and metabolic risk factors with hepatic steatosis and fibrosis over 6 years were examined using linear regression models.

In participants with elevated baseline FIB-4, the interaction of GDF-15 and FIB-4 was positively associated with follow-up liver stiffness (β = 0.47, p = 0.045). Interactions between GDF-15 and higher alcohol intake (3rd/4th quantiles) were negatively associated with stiffness (β = −1.68, p = 0.002; β = −1.43, p = 0.038). GDF-15 was positively associated with follow-up steatosis (β = 37.14, p = 0.006). Higher HOMA-IR (3rd/4th quantile) was linked to increased steatosis (β = 31.15, p = 0.032; β = 38.15, p = 0.023), whereas interactions of HOMA-IR × GDF-15 were inversely associated (β = −38.98, p = 0.008; β = −38.54, p = 0.019), suggesting a protective modulation.

GDF-15 appears to modulate hepatic steatosis and fibrosis in individuals with metabolic or lifestyle risk factors, supporting its potential as a therapeutic target and warranting further investigation of the neuro-metabolic-immunologic axis.

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