Excessive production and cleavage of fibroblast growth factor 23 in decompensated cirrhosis: pathophysiological and clinical implications

Background The pleiotropic functions of fibroblast growth factor 23 (FGF23) beyond as phosphate hormone are increasingly recognized. Recently, the C-terminal proteolytic fragment of FGF23 (Cter-FGF23), previously considered inactive, has been shown to ameliorate inflammation-induced anemia by inhibiting hepcidin secretion. In the present study we assessed if FGF23 and Cter-FGF23 are also regulated in liver cirrhosis.

Methods Olink analysis was used to identify plasma proteins and mediators associated with decompensated cirrhosis and acute-on-chronic liver failure (ACLF). In two independent cohorts of hospitalized patients with cirrhosis, we quantified intact and Cter-FGF23 and assessed associations with clinical outcomes of cirrhosis, parameters of iron metabolism and inflammation.

Results FGF23 was one of the most strongly upregulated mediators in a panel of 76 plasma proteins (quantified by Olink analysis) in acute decompensation (AD) and acute-on-chronic liver failure (ACLF) compared to compensated cirrhosis. Cter-FGF23 concentrations exceeded intact FGF23 concentrations substantially in many patients, in particular in those with decompensated cirrhosis or ACLF, suggesting increased FGF23 cleavage and excessive production of the cleaved Cter-FGF23 in these patients. Notably, Cter-FGF23, but not intact FGF23, was a strong predictor of 30-day and 1-year mortality. Anemia was a frequent complication of AD and ACLF (92% and 95%, respectively). Cter-FGF23 (but not intact FGF23) was an independent predictor of anemia, and Cter-FGF23 correlated with hepcidin concentration and other determinants of iron metabolism.

Conclusion Cter-FGF23 might be a promising prognostic biomarker in patients with advanced liver cirrhosis and seems to play a role in iron metabolism in cirrhosis.

Publication History

Article published online:
20 January 2025