CORRECTION OF CONGENITAL INDIRECT HYPERBILIRUBINEMIA BY SMALL-INTESTINAL TRANSPLANTATION

INTRODUCTION: Crigler-Najjar syndrome, type I, is a disease characteri zed by complete absence of hepatic bilirubin glucuronidation. The cong enital indirect hyperbilirubinemia is due to an autosomal recessive de ficiency of the enzyme, uridine diphosphate glucuronosyl transferase ( UDPGT). The inbred homozygous Gunn rat is also deficient in UDPGT, exh ibits unconjugated hyperbilirubinemia, and is an excellent animal mode l of the Crigler-Najjar syndrome. This study was performed to test the ability of transplanted intestine from normal Wistar rat donors to co rrect the deficiency in hepatic bilirubin conjugation. MATERIALS AND M ETHODS: In phase 1, Gunn rats underwent 40-cm heterotopic small-bowel transplants front either Wistar (experimental) or Gunn (control) rats. In phase 2, 15- to 20-cm Wistar-to-Gunn jejunal transplants were plac ed either heterotopically or orthotopically (in intestinal continuity) . Ah rats were treated with cyclosporin A (CsA), 5 mg/kg per day. Seru m bilirubin levels were determined spectrophotometrically at weekly in tervals posttransplantation. In phase 2, UDPGT activity was quantitate d at 0, 2, 4, and 8 weeks using known quantities of bilirubin as subst rate. RESULTS: Total bilirubin levels decreased significantly in the 4 0-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 leve ls began to rise toward pretransplant values. In contrast, there was n o significant change in bilirubin levels in the control Gunn-to-Gunn r ats, Fifteen- to 20-cm heterotopic Wistar-to-Gunn transplants caused a qualitatively similar drop in total and indirect bilirubin levels. Or thotopic (in continuity) Wistar-to-Gunn transplants lowered serum bili rubin levels more rapidly, and the effect was sustained throughout the 8-week study period. By 1 week posttransplantation, total bilirubin l evels 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 i ndirect 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: T ransplants of small intestine with known UDPGT activity partially corr ected the deficiency in Gunn rats and allayed the hyperbilirubinemia. Since the small intestine is known to contain small but significant am ounts of a large number of predominantly hepatic enzymes, bowel transp lantation may be an appropriate treatment for this and other similar g enetic enzyme deficiencies.