Advanced treatment of severe hyperbilirubinemia and cholestasis

In the first part of this thesis we show that adeno-associated virus mediated gene therapy is a viable option for the curative treatment of patients with Crigler-Najjar syndrome. Still, a careful patient selection and consideration of the impact of the immune system during and after the therapy are warranted before the initiation of a clinical trial. We also demonstrate that biliverdin reductase is a potential new target in the treatment of severe unconjugated hyperbilirubinemia. In addition, we showed that HNF1α plays an important role in modulating UGT1A1 activity in vivo.
In the second part of the thesis we show that the potent PXR agonist rifampicin is effective and safe for the treatment of patients with persistent hepatocellular secretory failure, and that mutations in PFIC and BRIC genes could be part of the underlying cause of the development of PHSF. We also show that increased serum ATX activity is associated with cholestasis-associated pruritus, but not with other forms of pruritus and that it closely correlates with effectiveness of antipruritic treatment strategies. Notably, in vitro findings show that the antipruritic activity of rifampicin may be explained, at least in part, by PXR-dependent transcriptional inhibition of ATX expression.