LS performed the best in predicting liver fibrosis, whereas APRi had the highest predictive accuracy for esophageal varices. An LS value over 7.7 kPa identified significant liver fibrosis with high accuracy, whereas low APRi ascertained the absence of esophageal varices.
Background
Subclinical graft inflammation and fibrosis after pediatric liver transplantation (LT) are common. Biomarkers are needed that precede and are associated with these changes and graft outcome.
Material/Methods
We evaluated immunohistochemical expression of 6 biomarkers [α-smooth muscle actin (α-SMA), collagen I, decorin, vimentin, P-selectin glycoprotein ligand-1 (PSGL-1), and CD34] in biopsies taken intraoperatively at LT (baseline) (n=29) and at 11.3 years after LT (first follow-up) (n=51). Liver biochemistry and graft histology were assessed at the first follow-up and at final assessment (19.6 years after LT) (n=48). Second follow-up biopsies for histology were available from 24 patients. The immunostainings were correlated with liver histology, biochemistry, and outcome at these time-points.
Results
Baseline levels of the biomarkers were unrelated to presence of fibrosis at follow-up. Increased α-SMA, collagen I levels, decorin, and vimentin were associated with simultaneous fibrosis at the first follow-up (p=0.001–0.027). Increased SMA, collagen I, decorin, vimentin, PSGL-1, and CD34 expression at first follow-up were associated with simultaneous portal inflammation (p=0.001–0.025). α-SMA, decorin, and vimentin expression were increased in patients without fibrosis at the first follow-up but who developed fibrosis in second follow-up (p=0.014 p=0.024 and p=0.024). Significant fibrosis (F2) and markedly increased α-SMA, collagen I, decorin, and vimentin levels at first follow-up were associated with suboptimal liver status at the final assessment (p=0.002–0.042).
Conclusions
The expression of the biomarkers at LT was unrelated to later development of graft fibrosis. α-SMA, decorin, and vimentin were associated with later graft fibrosis and suboptimal liver status.
We related hepatic gene and serum expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) to liver histology in pediatric LT recipients. Liver biopsies and serum samples were obtained from 52 patients 10.6 years post-LT and age-matched controls for analyses of MMPs and TIMPs. Patients with fibrosis had significantly higher hepatic gene expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 than patients without. Expression of these genes correlated with graft Metavir fibrosis stage (r = 0.494-0.684, P ≤ 0.006 for all). Gene expression of MMP-1, MMP-3, MMP-8, TIMP-3, and TIMP-4 was undetectable in both patients and controls. Portal inflammation and cytokeratin 7 correlated positively with gene expression of TIMP-1. Gene expression of MMP-2, MMP-9, and TIMP-2 correlated negatively with the time of low-dose cortisone usage (r = -0.448 to -0.422, P < 0.05 for all). Serum concentrations of MMP-8 and TIMP-1 were significantly increased and MMP-9 decreased among patients compared with controls, but no correlations to graft histology or gene expression were observed. Hepatic gene expression of certain MMPs and TIMPs is increased in stable pediatric LT recipients displaying graft fibrosis, but this did not reflect to their serum concentrations. Increased hepatic gene expression of TIMP-1 correlated with graft fibrosis stage, inflammation, and chronic cholestasis.
The long-term survival of patients after liver transplantation (LT) has improved during the last decades. 1 The focus of interest has shifted from the early events to long-term patient health and graft survival.Several centers have reported the development of subclinical fibrosis and inflammation in long-term follow-up studies. 2 The etiology and mechanism of this slow process remain unclear.
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