Cystic fibrosis liver disease and the enterohepatic circulation of bile acids

Cystic fibrosis (CF) is one of the most frequently occurring life threatening congenital diseases. This progressive disease manifests itself in several organ systems. The disease is caused by a mutation in the CFTR protein.The studies in the thesis focused on the development and treatment of CF in the liver and intestine, in particular the role of bile salts. Bile salts are essential in metabolism and play a crucial role in intestinal dietary fat and vitamin absorption in the gut. The experiments were performed in mice models with a mutation in the CFTR protein. With respect to CF disease in the gut we found that a disturbance in the bile salt metabolism, together with e.g. changes in the intestinal microbial flora, could be related to the clinical finding of persistent decrease of intestinal fat absorption in CF, despite adequate medication. These findings could be related to the decreased growth in CF conditions.With respect to CF disease in the liver we found that the currently used treatment for CF related liver disease (Ursodeoxycholaat or UDCA) can potentially be effective. We were particularly interested to investigate whether the severe form of cirrhotic CF related liver disease is caused by the altered bile salt metabolism. This was not the case. We did however find that normal liver growth is impaired in CF. This is most likely due to the important interaction between the mutated CFTR protein, the intestinal microbial flora, and the altered bile metabolism