Serum growth differentiation factor 15 is a novel biomarker with high predictive capability for liver cancer occurrence in patients with MASLD regardless of liver fibrosis

Summary Background and Aims Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels of growth differentiation factor‐15 (GDF15), a cell stress‐responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods Serum GDF15 levels were measured in 518 biopsy‐performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results In the biopsy‐MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib‐4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high‐GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib‐4 index <1.3 or low‐GDF15 rarely developed liver cancer, high‐GDF15 patients with a Fib‐4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high‐GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low‐GDF15 patients, whether limited to high‐Fib‐4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib‐4 index >1.3, 2.7% had a Fib‐4 index >1.3 and >1.75 ng/mL GDF15. Conclusions Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance.