Microvesicles and Monocytes to Predict Mortality of Patients with Cirrhosis
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 335
- 试验地点
- 5
- 主要终点
- Compare the prognostic performance for the cumulative incidence of death at 6 months of a composite score including MELD, hepatocyte microvesicle concentration and IFN score to that of the MELD alone, considering LT as a competitive risk
研究概览
简要总结
Chronic liver diseases related to viral hepatitis, metabolic syndrome or excessive alcohol consumption can evolve towards cirrhosis. Cirrhosis is responsible for 170 000 deaths per year in Europe. Initially asymptomatic and called "compensated" it can become "decompensated" with the developement of acute complications such as infections, ascites or variceal bleeding. The transition from compensated to decompensated cirrhosis is associated with a reduction in survival from 95 to 55% at 1 year.
The only curative treatment for cirrhosis is liver transplantation (LT). Liver transplants are allocated according to the severity of the patients. Despite a modest prognostic value (area under the ROC curve = 0.7 to predict the risk of death), graft allocation is based on the MELD (Model for End-Stage Liver Disease) score including INR, bilirubin and serum creatinine. In 2014, 11.5% of registered patients died on the liver transplant waiting list, illustrating the need for biomarkers that predict death and improve MELD-based prediction.
Microvesicles are membrane vesicles released in extracellular space during cell activation or apoptosis. Our team showed that circulating levels of hepatocyte microvesicles increase with the severity of cirrhosis and predict survival at 6 months independently of MELD score in a cohort of 242 patients with cirrhosis.
Type 1 interferons (IFN-1) are mediators of inflammation, which is excessively activated in cirrhosis. Our team has shown that a gene signature (IFN score) measured in the immune cells of 101 patients with cirrhosis is able to predict 6 month-survival independently of the MELD score.
Thus, the investigators hypothesize that a composite score combining the level of circulating hepatocyte microvesicles, the IFN score and the MELD score could improve the prediction of survival in patients with severe cirrhosis.
The aim of this study is to compare the prognostic performance for the cumulative incidence of death at 6 months of a composite score including MELD, hepatocyte microvesicle level and IFN score with that of the MELD score alone, in patients with Child B or C cirrhosis, considering liver transplantation as a competitive risk.
To address this question, peripheral blood from 335 patients with Child B or C cirrhosis will be obtained and hepatocyte microvesicle levels and IFN score will be measured using ELISA/filtration and Real Time-quantitative PCR.
详细描述
Natural history of cirrhosis
Cirrhosis is the end stage form of chronic liver disease. It is estimated that 200,000 to 500,000 people in France have cirrhosis. Cirrhosis is responsible for more than 170,000 deaths per year in Europe.
The main causes of cirrhosis include excessive alcohol consumption, the leading cause in Europe, and chronic viral hepatitis B and C, which are the leading causes in Asia and Africa. In addition, the current epidemic of obesity and type 2 diabetes worldwide has led to a sharp increase in the incidence of non-alcoholic steatohepatitis associated with metabolic syndrome, particularly in North America.
Cirrhosis is defined histologically as a diffuse alteration in the architecture of the liver by annular fibrosis associated with regeneration nodules. With the emergence of non-invasive tests allowing fibrosis measurement, cirrhosis is now considered highly probable when the liver elasticity measured by Fibroscan® is > 15 kPa.
Patients with cirrhosis may be perfectly asymptomatic and have normal liver function. In this case, the Child-Pugh score, which rates the severity of cirrhosis, is "A". However, the severity of cirrhosis may increase, resulting in the development of signs of liver failure, such as jaundice, decreased coagulation factors and hypoalbuminemia, and/or ascites or hepatic encephalopathy. Cirrhosis is then classified as Child-Pugh B or C.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 18 and 90 years
- •Child-Pugh B or Child-Pugh C cirrhosis diagnosed on the basis of one or several of the following elements :
- •Liver Biopsy
- •Liver stiffness>15kPa measured by Fibroscan
- •Combination of clinical, laboratory and imaging criteria characteristic of cirrhosis (association of signs of portal hypertension, liver failure and abnormal liver morphology in a patient with at least one cause of cirrhosis)
排除标准
- •Acute renal failure (increase in serum creatinin level by more than 1.5 times the baseline value or by more than 26 μmol/l from the baseline value) within 15 days before inclusion
- •Bacterial infection proven or highly suspected on the basis of clinical-laboratory features within 15 days of inclusion
- •Digestive bleeding within 15 days before inclusion
- •Alcoholic hepatitis in the previous month
- •History of porto-systemic shunt or liver transplant
- •Primary sclerosing cholangitis
- •Primary biliary cirrhosis
- •Budd-Chiari Syndrome
- •Hepatocellular carcinoma outside the Milan criteria contraindicating transplantation
- •Active extrahepatic neoplasia
- •HIV or known immune deficiency or immunosuppressive treatment
- •Pregnant or breastfeeding woman
- •Protected populations: persons under guardianship or curatorship
- •Patient not affiliated to social security
- •Patient who did not signed consent
- •Ongoing participation in an intervention research whose protocol could, according to the literature, modify the release of hepatocyte microvesicles or the IFN score
结局指标
主要结局
Compare the prognostic performance for the cumulative incidence of death at 6 months of a composite score including MELD, hepatocyte microvesicle concentration and IFN score to that of the MELD alone, considering LT as a competitive risk
时间窗: 6 months
AUROC of the composite score including MELD, hepatocyte microvesicle and IFN score for predicting the cumulative incidence of death at 6 months (considering liver transplantation (LT) as a competitive risk) compared to the AUROC of the MELD score alone
次要结局
- Compare the prognostic performance for the cumulative incidence of death at 12 months of a composite MELD-microvesicles-IFN score to that of the MELD alone, considering liver transplantation as a competitive risk(12 months)
- Compare the prognostic performance for the cumulative incidence of death post-LT, of the composite MELD-microvesicles-IFN score to that of the MELD alone, in patients with Child B or C cirrhosis transplanted during the 12 months following the inclusion(One month post LT)
- Compare the prognostic performance for episodes of "Acute on Chronic Liver Failure", of the composite MELD-microvesicles-IFN score to the MELD score alone, considering LT and death as competitive risks at 6 and 12 months(6 months and 12 months)
- Determine whether this composite score improves prediction of the cumulative incidence of death of patients with Child B or C cirrhosis, compared to the MELD score alone, using the continuous version of the Net Reclassification Index (NRI)(6 months and 12 months)
- Compare the prognostic performance for the cumulative incidence of death of a MELD-microvesicles-IFN score to that of the MELD-Na score, considering LT as a competitive event at 6 and 12 months(6 months and 12 months)
- Compare the prognostic performance for the cumulative incidence of death due to infection of the composite MELD-microvesicles-IFN score to that of the MELD alone, considering LT as a competitive risk(12 months)
- Compare the prognostic performance for the cumulative incidence of death due to infection of the MELD-IFN composite score to that of the MELD alone, considering LT as a competitive risk(12 months)
- Compare the prognostic performance for the cumulative incidence of death due to infection of the composite MELD-microvesicles score to that of the MELD score alone, considering LT as a competitive risk(6 months)
- Compare the prognostic performance for the cumulative incidence of death of a composite MELD-hepatocyte microvesicles score to that of the MELD alone, considering LT as a competitive risk(6 months)
- Compare the prognostic performance for the cumulative incidence of death of a composite MELD-IFN score with that of the MELD score alone, considering liver transplantation as a competitive risk(6 months)
- Compare the prognostic performance for the cumulative incidence death due to infection of the composite MELD-microvesicles-IFN score to that of the MELD alone, considering LT as a competitive risk(6 months)
- Compare the prognostic performance for the cumulative incidence of death due to infection of the composite MELD-IFN score to that of the MELD alone, considering LT as a competitive risk(6 months)
- Compare the prognostic performance for the cumulative incidence of death due to infection of the composite MELD-microvesicles score with that of the MELD score alone, considering LT as a competitive risk(12 months)
- Compare the performance of MELD-microvesicles-IFN, MELD-microvesicles and MELD-IFN versus MELD alone to predict cirrhosis progression.(6 and 12 months)
- Consider whether the difference between the prognostic performance of the composite MELD-microvesicles-IFN score and the MELD alone is associated with CHC status at the inclusion(6 and 12 months)
- Investigate whether the difference between the prognostic performance of the composite MELD-microvesicles-IFN score and the MELD alone could be explained by transplants performed outside MELD(6 and 12 months)