Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, affects an estimated 30% of the global population, and its prevalence continues to rise alongside obesity and type 2 diabetes [1]. As the disease often develops without specific symptoms [2], and routine liver enzymes can remain normal as it advances, many patients are identified late.
Limitations of current assessment
Liver biopsy remains the reference standard for assessing inflammation and fibrosis, but it is invasive, operator-dependent and subject to sampling variability, and impractical for large at-risk populations [2]. Imaging and scoring tools such as FIB-4 are valuable, imaging is limited in primary care by cost and technical requirements, and FIB-4 is less able to separate significant fibrosis (F2 or above) from early-stage disease [2]. Tracking change over time is harder still, as repeated biopsy is difficult to justify and the sensitivity of FIB-4 for monitoring progression is limited [2]. There is a clear need for blood-based markers that reflect underlying liver pathology.
FGF21 as a marker of hepatic stress
Fibroblast growth factor 21 (FGF21) is a signalling protein produced primarily by the liver, where it helps regulate energy, glucose and lipid metabolism. Its production increases under metabolic stress. FGF21 expression is significantly elevated in liver tissue from MASLD patients, and liver cells exposed to high concentrations of fatty acids upregulate its production [3].
Circulating levels appear to follow disease severity. Higher FGF21 has been reported in steatohepatitis than in simple steatosis [3], and in patients with significant fibrosis (F2-F4) than in those with minimal fibrosis (F0-F1) [2]. In a study of 125 MASLD patients, combining FGF21 with FIB-4 improved the detection of significant fibrosis (AUC 0.806), outperforming FIB-4 (0.743) or FGF21 (0.735) alone [2].
Potential clinical value
These findings suggest FGF21 could support risk stratification by helping identify individuals with metabolic dysfunction who are more likely to progress. Serial measurement may also offer a practical way to monitor disease trajectory and response to lifestyle intervention, complementing existing tools rather than replacing them.
The evidence base is still developing, and longitudinal studies are needed to confirm FGF21’s role in predicting progression and guiding management. As liver care moves towards more personalised, biomarker-informed approaches, FGF21 represents a promising addition to the diagnostic landscape.
References
- Younossi, Z.M. et al. (2023) ‘The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review’, Hepatology, 77, pp. 1335-1347.
- Cao, Y., Zhang, X. and Zhang, Q. (2026) ‘Diagnostic value of serum fibroblast growth factor 21 combined with fibrosis-4 index for hepatic fibrosis in metabolic dysfunction-associated steatotic liver disease’, Turkish Journal of Gastroenterology, 37(7), pp. 782-792. doi: 10.5152/tjg.2026.25740.
- Gallego-Durán, R. et al. (2024) ‘Fibroblast growth factor 21 is a hepatokine involved in MASLD progression’, United European Gastroenterology Journal, 12(8), pp. 1056-1068. doi: 10.1002/ueg2.12534.