| In Crigler-Najjar type I patients absent activity of the liver enzyme UDP- glucuronosyltransferase results in a permanent unconjugated hyperbilirubinemia. Severe unconjugated hyperbilirubinemia can lead to bilirubin-induced neurological dysfunction (BIND), kernicterus and death. Patients are treated life-long with daily phototherapy. Phototherapy however becomes less effective with age, has a negative impact on social life and induces DNA damage to human cells in vitro. Eventually, many Crigler-Najjar disease type I patients undergo liver transplantation to prevent brain damage. In our laboratory, an alternative treatment strategy has been studied, based on oral administration of compounds that lead to capturing of unconjugated bilirubin in the intestinal lumen, and its subsequent exctretion into the feces. Unconjugated bilirubin can, in addition to its secretion in bile, also be disposed from the body by transepithelial transport (diffusion?) from the blood into the intestinal lumen. Prevention of intestinal reabsorption with the lipase inhibitor orlistat decreased plasma bilirubin levels equally effective as continuous phototherapy in Gunn rats, the well-established animal model of Crigler-Najjar disease. Both orlistat treatment and phototherapy increase the availability of unconjugated bilirubin in the intestine for its subsequent metabolisation by the microflora. The intestinal microflora thus seems to play a crucial role in bilirubin metabolism by inhibiting its enterohepatic circulation. We speculate that manipulation of the metabolising capacity (probiotics/ antibiotics) of the intestinal microflora has a profound impact on the hypobilirubinemic effect of orlistat treatment and photoherapy in the jaundiced Gunn rat. Also, a major effect of orlistat on the metabolic activity of the bacterial flora may be of interest for patients treated with this drug in the light of weight control. |
