Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1

Abstract

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 x 10(9) hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean +/- SD bilirubin level was 530 +/- 38 micromol/L before and 359 +/- 46 micromol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

DMSO modulates the pathway of apoptosis triggering

“…There have been attempts to use hepatocytes as substitutes to orthotopic liver transplantation to increase the availability of donor material [1]. For example, hepatocyte transplantations were used as a treatment for acute liver failure [2][3][4] and for some metabolic diseases in adults and children, such as urea cycle defects [5,6], glycogen storage disease types 1a and 1b [7,8], and CriglerNajjar syndrome type 1 [9,10]. Nevertheless, the metabolism of isolated hepatocytes somewhat differs to that within tissue.…”

Liver Regeneration and Bioengineering - The Emergence of Whole Organ Scaffolds

“…However, not all the patients treated had a clear benefit from the procedure (23). Since then, several other metabolic diseases have been treated with hepatocyte transplantation with different degrees of success (24)(25)(26)(27)(28). It has also been used as a support treatment to acute (29)(30)(31) and chronic liver diseases (30)(31)(32)(33) in bridging severely ill patients to orthotopic liver transplantation (OLT).…”

Clinical applications of hepatocyte transplantation

“…HT can potentially support liver function until an organ becomes available or the liver regenerates. In a 1994 study [3] , fetal hepatocytes Crigler-Najjar type 1 6 1.5-7.5 × 10 9 -/3 [11][12][13][14] Hypercholesterolemia 5 1.0-3.2 × 10 9 -/- [15] Factor Ⅶ deficiency…”