Plasma Fibroblast Growth Factor 23 Concentration Is Increased and Predicts Mortality in Patients on the Liver-Transplant Waiting List

Abstract

High plasma fibroblast growth factor-23 (FGF23) concentration predicts the risk of death and poor outcomes in patients with chronic kidney disease or chronic heart failure. We checked if FGF23 concentration could be modified in patients with end stage liver disease (ESLD) and predict mortality. We measured plasma FGF23 in 200 patients with ESLD registered on a liver transplant waiting list between January 2005 and October 2008. We found that median plasma FGF23 concentration was above normal values in 63% of the patients. Increased FGF23 concentration was not explained by its classical determinants: hyperphosphataemia, increased calcitriol concentration or decreased renal function. FGF23 concentration correlated with the MELD score, serum sodium concentration, and GFR. Forty-six patients died before being transplanted and 135 underwent liver transplantation. We analyzed the prognostic value of FGF23 levels. Mortality was significantly associated with FGF23 levels, the MELD score, serum sodium concentration and glomerular filtration rate. On multivariate analyses only FGF23 concentration was associated with mortality. FGF23 levels were independent of the cause of the liver disease. To determine if the damaged liver can produce FGF23 we measured plasma FGF23 concentration and liver FGF23 mRNA expression in control and diethyl-nitrosamine (DEN)-treated mice. FGF23 plasma levels increased with the apparition of liver lesions in DEN-treated mice and that FGF23 mRNA expression, which was undetectable in the liver of control mice, markedly increased with the development of liver lesions. The correlation between FGF23 plasma concentration and FGF23 mRNA expression in DEN-treated mice suggests that FGF23 production by the liver accounts for the increased plasma FGF23 concentration. In conclusion chronic liver lesions can induce expression of FGF23 mRNA leading to increased FGF23 concentration, which is associated with a higher mortality in patients on a liver-transplant waiting list. In these patients FGF23 concentration was the best predictor of mortality.

Up-regulation of FGF23 release by aldosterone

“…According to the present observations, the high FGF23 plasma concentration in heart failure [10,11], acute renal failure [12], chronic kidney disease [11,13,14], diabetic nephropathy [15] and hepatic failure [16] could at least in part be secondary to the hyperaldosteronism associated with these diseases. The effect of aldosterone may at least partially be mediated by the serum & glucocorticoid inducible kinase SGK1, which is up-regulated by aldosterone and during diabetes [36] and is known to up-regulate Orai1 [23].…”

“…Excessive plasma FGF23 levels are observed and are associated with accelerated disease progression, morbidity and/or mortality in several clinical disorders including cardiac failure [10,11], acute renal failure [12], chronic kidney disease [11,13,14], diabetic nephropathy [15] and hepatic failure [16]. The pathophysiological significance of enhanced FGF23 formation, has, however, remained ill-defined [17,18] and little is known about mechanisms accounting for the up-regulation of FGF23 release in these clinical disorders.…”

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

“…In patients with cardiac failure [16,17], acute renal failure [18], chronic kidney disease [7,17,19], diabetic nephropathy [20] and hepatic failure [21], plasma FGF23 concentrations are high and associated with accelerated disease progression, morbidity and/or mortality. Mechanisms up-regulating FGF23 in those disorders are still ill-defined.…”

Alcoholism, Fibroblast Growth Factor 23 and Cardiovascular Risk

“…In these patients, high FGF-23 levels were not explained by decreased renal function. They also found in an experimental model that the damaged liver of diethyl-nitrosamine-treated mice expressed FGF-23 mRNA whereas healthy livers of control mice did not [40]. Additionally, in a more recent study by Wasserman et al high FGF-23 levels were described in 2 infants with liver disease due to biliary atresia who had developed a form of hypophosphatemic rickets.…”

“…Nafi di et al, (2009) reported that partial hepatectomy led to increased FGF-23 levels [38], and later, Raimann et al, (2013) showed that liver tissue could express mRNA for FGF-23 [39]. In the same year Prie et al found that high FGF-23 levels predict the risk of death in patients with end stage liver disease on a liver transplant waiting list [40]. In these patients, high FGF-23 levels were not explained by decreased renal function.…”