Introduction: Crigler-Najjar syndrome, type I, is a disease characterized by complete absence of hepatic bilirubin glucuronidation. The congenital indirect hyperbilirubinemia is due to an autosomal recessive deficiency of the enzyme, uridine diphosphate glucuronosyl transferase (UDPGT). The inbred homozygous Gunn rat is also deficient in UDPGT, exhibits unconjugated hyperbilirubinemia, and is an excellent animal model of the Crigler-Najjar syndrome. This study was performed to test the ability of transplanted intestine from normal Wistar rat donors to correct the deficiency in hepatic bilirubin conjugation.
Materials and methods: In phase 1, Gunn rats underwent 40-cm heterotopic small-bowel transplants from either Wistar (experimental) or Gunn (control) rats. In phase 2, 15- to 20-cm Wistar-to-Gunn jejunal transplants were placed either heterotopically or orthotopically (in intestinal continuity). All rats were treated with cyclosporin A (CsA), 5 mg/kg per day. Serum bilirubin levels were determined spectrophotometrically at weekly intervals posttransplantation. In phase 2, UDPGT activity was quantitated at 0, 2, 4, and 8 weeks using known quantities of bilirubin as substrate.
Results: Total bilirubin levels decreased significantly in the 40-cm heterotopic transplant recipient rats. From the initial values of 7.12 +/- 0.59 mg/dL, levels reached the nadir of 4.23 +/- 0.27 mg/dL. A parallel drop in serum levels of indirect bilirubin was noted (5.04 +/- 0.54 mg/dL to 2.74 +/- 0.23 mg/dL). After 6 weeks, bilirubin levels began to rise toward pretransplant values. In contrast, there was no significant change in bilirubin levels in the control Gunn-to-Gunn rats. Fifteen- to 20-cm heterotopic Wistar-to-Gunn transplants caused a qualitatively similar drop in total and indirect bilirubin levels. Orthotopic (in continuity) Wistar-to-Gunn transplants lowered serum bilirubin levels more rapidly, and the effect was sustained throughout the 8-week study period. By 1 week posttransplantation, total bilirubin levels dropped from 5.11 +/- 0.48 mg/dL to 2.41 +/- 0.16 mg/dL (P < 0.05); data at 8 weeks averaged 1.84 +/- 0.35 mg/dL. Respective data for indirect bilirubin levels were 4.81 +/- 0.45 mg/dL, 2.26 +/- 0.18 mg/dL, and 1.35 +/- 0.39 mg/dL. Wistar rat UDPGT activity in intestine and liver averaged 0.61 +/- 0.05 and 1.88 +/- 0.06 mg bilirubin conjugated/mg tissue per hour, respectively. Enzyme activity in the transplanted intestine persisted throughout the course of the study.
Conclusion: Transplants of small intestine with known UDPGT activity partially corrected the deficiency in Gunn rats and allayed the hyperbilirubinemia. Since the small intestine is known to contain small but significant amounts of a large number of predominantly hepatic enzymes, bowel transplantation may be an appropriate treatment for this and other similar genetic enzyme deficiencies.