Circulating and hepatic levels of growth differentiation factor 15 in patients with metabolic dysfunction-associated steatotic liver disease

Aim: Increased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow-up (n = 276). Methods: Participants were evaluated clinically and histologically in both cohorts. Fibrosis severity was classified as no/mild (F0/F1) or significant (F2–4). Plasma GDF15 was measured by enzyme-linked immunosorbent assays and the SOMAScan platform. Hepatic GDF15 mRNA expression was analyzed by RNA in situ hybridization and bulk RNA-sequencing. In addition, we used data from public single-nucleus RNA-sequencing datasets. Results: In both cohorts, plasma GDF15 was increased in MASLD compared with healthy controls (p < 0.0001) with the highest levels in patients with significant fibrosis (area under the curve 0.83; 95% confidence interval [CI], 0.76–0.91). The GDF15 levels were unaffected by a standardized meal and there was no difference in peripheral or hepatic venous concentrations. After 2 years, the increase in GDF15 levels was reduced in patients treated with glucagon-like peptide receptor agonists (GLP-1-RA) compared to patients receiving lifestyle advice (−28%; 95% CI, −44 to −8; p = 0.01). Plasma GDF15 was associated with circulating insulin-like growth factor 1 and related proteins. Hepatic GDF15 mRNA was mainly expressed in hepatocytes and in cholangiocytes in fibrotic areas and was increased in MASLD (p = 0.02) with the highest expression in the group with steatohepatitis (p = 0.009). Conclusions: Increased hepatic and circulating GDF15 are found in MASLD. Treatment with GLP-1-RA may reduce GDF15, possibly reflecting beneficial metabolic and inflammatory effects.