Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia.

Omid Madadi-Sanjani,Julia Andruszkow,Claus Petersen,Reinhard Von Wasielewski,Heike Bantel,Gunnar Bohlen,Karim Khelif,Fabian Wehrmann

doi:10.3390/jcm10122718

Abstract

In biliary atresia (BA), apoptosis is part of the pathomechanism, which results in progressive liver fibrosis. There is increasing evidence suggesting that apoptotic liver injury can be non-invasively detected by measuring the caspase activity in the serum. The purpose of this study was to investigate whether serological detection of caspase activation mirrors apoptotic liver injury in the infective murine BA-model and represents a suitable biomarker for BA in humans. Analysis showed increased caspase-3 activity and apoptosis in the livers of cholestatic BALB/c mice, which correlated significantly with caspase activation in the serum. We then investigated caspase activation and apoptosis in liver tissues and sera from 26 BA patients, 23 age-matched healthy and 11 cholestatic newborns, due to other hepatopathies. Compared to healthy individuals, increased caspase activation in the liver samples of BA patients was present. Moreover, caspase-3 activity was significantly higher in sera from BA infants compared to patients with other cholestatic diseases (sensitivity 85%, specificity 91%). In conclusion, caspase activation and hepatocyte apoptosis play an important role in experimental and human BA. We demonstrated that serological detection of caspase activation represents a reliable non-invasive biomarker for monitoring disease activity in neonatal cholestatic liver diseases including BA.

Highlights

During the last few decades, the overall outcome of patients with biliary atresia (BA)has been stabilized in industrial nations [1,2]
The 192 pups were the basis of a multitude of studies from our department, using the Rhesus rotavirus (RRV)-BALB/c mice model, which is the reason for the number of animals
We observed experimental BA in 69% of BALB/c and 22% of C57BL/6 mice (p < 0.001). It remains unclear far, whether the development of BA in this mouse model depends on the presence of the virus, or if RRV only acts as an initial trigger resulting in immune-response mechanisms that lead to bile duct destruction

Summary

Introduction

During the last few decades, the overall outcome of patients with biliary atresia (BA)has been stabilized in industrial nations [1,2]. The survival rate with the patient’s native liver is still low and the complications and sequelae of liver transplantation (LTx), as well as the financial burden, are unsolved problems [3]. Clinical research focuses on effective screening, timely and appropriate diagnosis, surgery for BA, as well as postoperative care in order to extend the survival of both native and transplanted livers [6,7,8,9]. BA, which is solely simulated in the Rhesus rotavirus (RRV) driven mouse model [10]. Under these circumstances, the translation of findings from the animal model to the human disease and to clinical application is of the highest interest [11]

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Results