Patients with
Crigler-Najjar syndrome and Gunn rats cannot form
bilirubin glucuronides owing to a lack of
bilirubin UDP-glucuronosyltransferase activity. Because increased serum and tissue
bilirubin levels remain constant, an alternative excretory route has to substitute for this deficiency. Gunn rats excrete in bile only 2-13% of the bilirubins eliminated in Wistar rats. In contrast, the biliary excretion rate of
urobilinogen in Gunn and Wistar rats is comparable. The sum of bilirubins and
urobilinogen excreted in the bile of Gunn rats amounts to 10-30% of pigments excreted in Wistar rats. Despite this low biliary excretion, the intestinal content and fecal excretion of
bile pigments in Gunn and Wistar rats were similar. These data support an extrabiliary entrance of unconjugated
bilirubin into the intestine. Additional proof for this was found in that the intestinal lumen of Gunn rats still contains a high amount of bilirubins and
urobilinogen after 3 d of external biliary drainage. A similar procedure in Wistar rats resulted in the complete disappearance of
bile pigments from the intestine. The direct transmural transport of
bilirubin from blood to all parts of the intestinal lumen was demonstrated by injecting 14C-bilirubin i.v. into Gunn rats with isolated parts of small and large intestine. In Crigler-Najjar and
Gilbert's syndrome patients, the biliary excretion of
bile pigments has previously been shown to be strongly reduced. Their stools, however, contained approximately the same amount of
bile pigments as in normal subjects. Although only traces of unconjugated
bilirubin were detected in the stool of normal persons (4 +/- 3% of total
bile pigments), higher amounts were found in patients with Crigler-Najjar disease (20 +/- 12&). These results suggest a direct intestinal permeation of unconjugated
bilirubin in severe unconjugated
hyperbilirubinemia both in man and rats.