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.
Highlights
The liver expresses several fibroblast growth factors including FGF1, FGF2, FGF19, FGF21, Fibroblast growth factor 23 (FGF23) [1,2,3,4]
FGF23 Plasma Concentration and Mortality Since the increase in FGF23 plasma concentration was significantly associated with two known prognostic markers of survival (MELD score and hyponatremia) in patients with liver diseases, we examined the association between FGF23 plasma levels and the risk of death in the patients on the transplant waiting list
In this study we report for the first time that plasma FGF23 concentration is increased in patients with end stage liver disease and we show that FGF23 plasma levels predict the risk of death in patients on the liver-transplant waiting list
Summary
The liver expresses several fibroblast growth factors including FGF1, FGF2, FGF19, FGF21, FGF23 [1,2,3,4]. In many countries the allocation of livers from deceased donors for transplantation uses the Model for End-Stage Liver Disease (MELD) score This score is based on objective laboratory tests: the international normalized ration (INR) for the prothrombin time and the total bilirubin concentration, which assess the severity of liver cell dysfunction, and the serum creatinine concentration as an estimation of renal function. FGF23 concentration can be measured quite by enzyme link immunosorbent assay (ELISA) and should be enter in routine in many diagnosis laboratories in the few years In this context we measured FGF23 levels in patients with end-stage liver disease on a liver transplantation waiting list and found that FGF23 concentration was increased even in the absence of renal insufficiency and was associated with the risk of death on the waiting list. The levels of FGF23 mRNA expression in the liver and plasma FGF23 concentration increased with the severity of the liver lesion in mice, which may explain that FGF23 was the best predictor of mortality in human
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