Novel treatment strategies for unconjugated hyperbilirubinemia

PhD ceremony: Mr. F.J.C. Cuperus, 11.00 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Novel treatment strategies for unconjugated hyperbilirubinemia

Promotor(s): prof. H.J. Verkade

Faculty: Medical Sciences

In this thesis a refined treatment strategy for severe unconjugated hyperbilirubinemia was developed in the Gunn rat model. Severe unconjugated hyperbilirubinemia occurs in Crigler-Najjar disease and neonatal hemolytic jaundice. It is associated with brain damage and death. Routine treatment mainly consists of phototherapy, which converts bilirubin into more readily excretable photo-isomers. Although generally effective, phototherapy has some disadvantages. The lifelong phototherapy in Crigler-Najjar patients, who suffer from inherited jaundice, may last up to 16h per day but fails to prevent brain damage in ~25% of these patients. Neonatal phototherapy, although mostly efficient and safe, sometimes fails to decrease plasma bilirubin levels sufficiently, which may also lead to permanent brain damage. Thus, there is a need for alternative treatment strategies for unconjugated hyperbilirubinemiea.

In this thesis we demonstrated that administration of the bile salt ursodeoxycholate, the laxative polyethylene glycol, and polyethylene glycol combined with phototherapy, effectively treat unconjugated hyperbilirubinemia in Gunn rats. These therapies bind unconjugated bilirubin in the intestinal lumen, which stimulates the excretion of bilirubin with the feces. In addition we showed that albumin infusion synergizes the therapeutic effect of phototherapy in these animals.

Ursodeoxycholic acid, polyethylene glycol, and albumin infusion may serve as an alternative for routine treatment, and may well prevent bilirubin-induced brain damage in hyperbilirubinemic patients. The results of this thesis can be used as a framework for the development of clinical controlled trials in Crigler-Najjar patients and in severely jaundiced neonates.