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

<div><p>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.</p></div

Multivariate analysis of prognostic factors on the waiting list.

<p>Analyses were performed with the use of a Cox proportional-hazard analysis considering transplant as a censor.</p>*<p>HR for an increase of one unit of the variable.</p><p>GFR: glomerular filtration rate.</p

FGF23 concentration according to glomerular filtration rate (GFR) in patients with end-stage liver disease (ESLD).

<p>Dashed lines indicate upper and normal values of FGF23 and GFR respectively. FGF23 concentration was above normal values in most of subjects with ESLD and normal renal function (GFR>70 ml/min).</p

Univariate analysis of prognostic factors on the waiting list.

<p>Analyses were performed with the use of a Cox proportional-hazard analysis considering transplant as a censor.</p>*<p>HR for an increase of one unit of the variable.</p><p>GFR: glomerular filtration rate.</p

Comparison of FGF23 concentration between patients with end-stage liver disease (ESLD) or normal liver function (control).

<p>(A) Glomerular filtration rate (GFR) was not different between patients with ESLD and controls. (B) FGF23 concentration was significantly higher in patients with ESLD than in control subjects (p<0.0001). Results are mean ± SD.</p

FGF23 plasma concentration and FGF23 mRNA level quantification in control and DEN- treated mice.

<p>(A) FGF23 plasma concentration in control mice (n = 6) and in DEN-treated mice (n = 6). The bars represent the means, and the circles the individual sample values. Samples were compared with the median test, p<0.005. (B) FGF23 mRNA expression was measured by qRT-PCR in the liver of control (untreated) mice and DEN-treated mice at 3 (n = 5) and 9 (n = 5) months after DEN injection. Since FGF23 mRNA was undetectable in control mice the fold of increase were expressed by comparison to 3 month DEN-treated mice. The bars represent the means, and the circles the individual sample values. Samples from DEN-treated mice were compared with the median test, p<0.005.</p

Correlation of FGF23 concentration.

*<p>correlation coefficients are indicated except for gender (mean ±sd).</p

Characteristics of the patients on the liver-transplant waiting list.

<p>Characteristics of the patients on the liver-transplant waiting list.</p

Correlation of plasma FGF23 concentration with liver FGF23 mRNA expression in DEN treated mice at month 9.

<p>Plasma FGF23 concentration and FGF23 mRNA expression were measured in 5 mice 9 month after a single injection of DEN. The best fitting was obtained with a second order polynomial curve (R² = 0.9993). The best fitting equation was determined by GraphPad Prism 5 for mac.</p

Meta-analysis of the standardized area under the ROC curves (AUROC) assessed in published studies of Fibrotest diagnostic value

<p><b>Copyright information:</b></p><p>Taken from "Meta-analyses of FibroTest diagnostic value in chronic liver disease"</p><p>http://www.biomedcentral.com/1471-230X/7/40</p><p>BMC Gastroenterology 2007;7():40-40.</p><p>Published online 15 Oct 2007</p><p>PMCID:PMC2175505.</p><p></p> There was no significant difference between the different liver diseases