RESUMO
AIM: To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen. METHODS: This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-ß (TGF-ß), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages. RESULTS: A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-α, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-ß [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-ß1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-ß1, P = 0.009; HA: P = 0.01), according to time since LT (> than 5 years, TFG-ß1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications (HA: P = 0.01) and HCV recurrence (HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-ß y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was non-significant but trends towards the lower expression of TFG-ß1 in the everolimus group. Mammalian target of rapamycin (mTOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their active profibrotic state, and experimental models have demonstrated the potential activity of mTOR inhibition in attenuating fibrogenesis. CONCLUSION: This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft.
RESUMO
AIM: Identification of predictors in the natural history of cirrhosis is based on determinations at a fixed time point. However, changes of these predictors may offer more information. To evaluate the predictive value of Model for End Stage Liver Disease (MELD) and hepatic venous pressure gradient (HVPG) and their changes in cirrhosis. METHODS: Patients with repeat HVPG measurements between January 2000 and December 2008 were considered for inclusion. Patients were followed until decompensation/death or July 2009. Multivariate Cox regression was used to analyze the predictive value of a single measurement of MELD and HVPG, and changes between measurements. Compensated and decompensated patients were analyzed separately. RESULTS: One hundred and seventeen patients were included (51 compensated, 66 decompensated). Median time between measurements and follow-up was 13 (2-24) and 11 (6-38) months in compensated and 8 (1-16) and 10 (3-21) months in decompensated patients, respectively. Fifteen compensated patients developed decompensation while twelve decompensated patients died. On multivariate analysis, MELD (HR 1.12 (95% CI 1-1.24)) and HVPG (HR 1.16 (95% CI 1.04-1.29)) were independent predictors of decompensation in compensated, while MELD (HR 1.18 (95% CI 1.09-1.27)) was the only predictor of death in the decompensated. CONCLUSION: Single and repeat measurements of MELD and HVPG are associated to outcomes in cirrhosis. Use of repeat measurements does not seem to add further information.
