Due to the close collaboration of the MHH- Pediatric Clinic with the research group of Marie Riepenhoff-Talty in Buffalo, USA, our focus was already in the early 1990s on the hepatotropic (liver-related) effect of the rhesus rotavirus (RRV) in newborn mice. Assuming that this could be a suitable animal model for studies of biliary atresia, we have validated this model and are now able to induce experimental BA in > 80% of postnatally infected Balb/c mice. Meanwhile, this model has become a standard in basic research on BA and is used by leading research groups worldwide in this field (Cincinnatti, Denver, Housten (USA) Groningen (NL) and others).
With the validation of the above mentioned mouse model we aim to better understand the cause and early course of biliary atresia. Together with the other BARG research groups we favor the following hypothesis today:
The biliary atresia is probably due to a genetic disposition and is probably triggered after birth by a (viral?) infection. Contact with the previously unknown pathogen then induces an inadequate immune response that resembles the pattern of an autoimmune response.
The mouse model:
Mice of the Balb/c strain become infected with rhesus rotavirus (RRV) within 24h after birth and develop biliary atresia within the next 3 weeks. At defined points in time the animals are killed and their blood and organs are collected for further examinations. The livers and bile ducts are histologically processed or used for immunological questions.
Serum, plasma as well as blood cells can be isolated from the blood and in cell cultures we can examine certain processes of the immune system.
We use the methods qRT-PCR, ELISA, FACS, fluorescence microscopy, CBA, iCBC, sequencing and many more.
All animal experiments are checked and approved by the competent authority and are of course limited to the absolute necessary extent.
Our research laboratory is closely linked to clinical processes. This enables us to build a unique and comprehensive biobank of patient material. Since 1994 more than 300 patients with biliary atresia have been treated and their samples (biopsies of liver, gallbladder and bile ducts, intestine, lymph nodes and blood) have been stored. We also have the possibility to obtain samples (mainly blood) from immunologically healthy children who have undergone surgical operations (e.g. inguinal hernia). These samples provide important reference data for research.
Of course, all samples are only taken if the parents have given their explicit written consent to this procedure after a detailed information meeting. Parents or patients have an unlimited legal right to the elimination of stored biological material. In addition, biological samples from patients are only used for research projects if a written consent of the ethics committee is available.
The intensive study of this particular disease has led to an increase in the number of new patients treated at the MHH from initially 3-4/year to between 12 and 15 per year today. This enables us to pursue important questions and thus improve the treatment of each individual. For example, we have been able to show that routine ERCP (endoscopy of the duodenum with imaging of the bile ducts) can save about 25% of all newborns with suspected BA from surgery. Furthermore, we were able to show that contrary to the minimally invasive procedure that we also propagated, open surgery shows better results.
EBAR European Biliary Atresia Registry
The possibilities for research in the field of biliary atresia are generally limited by two factors:
- Patients come to us only at a time when the disease is already well advanced.
- Biliary atresia is so rare that no center has a large enough patient population to conduct successful research on its own. In addition, the treatment of biliary atresia patients always requires several disciplines to work together (pediatric hepatologists, pediatric and transplant surgeons, etc.).
In order to solve these problems, we organized the first international and interdisciplinary workshop in Hannover in 1999. Under the slogan "Innovation by cooperation" about 200 colleagues from more than 20 countries took part. The title was "biliary atresia - new clues from etiology to therapy" and became the program for the coming years. This also included the "starting shot" for the European BA Register (EBAR). Over a period of 5 years, data from more than 100 clinics from 20 countries were reported from about 1000 patients. Finally, we were able to evaluate 600 data sets and discuss the results at a 2nd Hanover BA Symposium in 2006.
The register was then closed for financial reasons. In 2014, a new initiative was started and presented at a congress in Berlin: BARD -Online.
The Online Register
The central registration of patient data reaches its limits at the latest when the number of data records, including follow-up, increases exponentially. To solve this problem, it is possible to use the Internet and register patients decentrally. Once these data sets are then structured identically, they can be combined and evaluated as required. We are taking this path with the BARD-online project, a registry that documents an unlimited number of patients and their progressions who suffer from biliary atresia or other neonatal cholestasis.
The international and interdisciplinary congress BARD-Berlin-2014 has set a new milestone for scientific collaboration. A summary of the congress was published in 2016.
The follow-up congress was planned for 2020 and has to be postponed to the following year due to the corona pandemic. Under the title BARD-Bruges-2021, the members of the 2014 faculty will, in an extended circle, deal with the following 6 topics in addition to scientific questions:
- Neonatal Cholestasis (Diagnostic Algorithm)
- Biliary atresia (surgery / adjuvant therapy / transition)
- Choledochus cyst (diagnosis, treatment / surgery)
- Cholangitis (definition / treatment)
- Portal hypertension (diagnosis / shunt surgery)
- Pediatric Liver Surgery
As part of the EU-wide initiative to create competence centers for rare diseases, the ERN-rare-liver network was founded for the liver. And since many rare liver diseases start at an early age, this network has a pediatric focus. The diseases grouped under the generic term BARD (biliary atresia and related diseases) are coordinated Europe-wide by the Hannover working group.