1/30. Bilirubin adsorption therapy and subsequent liver transplantation cured severe bilirubin encephalopathy in a long-term survival patient with Crigler-Najjar disease type I.Crigler-Najjar disease (CN) type I is characterized by persistent unconjugated hyperbilirubinemia from birth. The male patient here was diagnosed with this disease as a neonate and had been treated by phototherapy. At age 16 he suddenly developed generalized convulsions, followed by impaired cognitive function. The serum level of bilirubin was extremely high (total bilirubin: 41.7 mg/dl) and there were no other detectable causes responsible for the metabolic encephalopathy. He received bilirubin adsorption therapy several times, and the bilirubin encephalopathy improved in response to the fall in the serum level of bilirubin. After this he underwent a successful liver transplantation in australia, and recovery of his mental faculties was satisfactory. Within the subsequent 3 years epileptic abnormal discharges on the electroencephalogram disappeared. phototherapy alone can not prevent the rise in the serum level of bilirubin in adolescent or adult patients with CN type I, therefore such patients tend to experience life-threatening bilirubin encephalopathy. To save patients with the acute onset type of bilirubin encephalopathy, sufficient bilirubin adsorption followed by liver transplantation appears to be the most recommended therapeutic approach.- - - - - - - - - - ranking = 1keywords = liver (Clic here for more details about this article) |
2/30. Successful liver transplantation of two brothers with crigler-najjar syndrome type 1 using a single cadaveric organ.Crigler-Najjar type 1 disease (CNS1) is the result of a genetic defect, leading to complete functional loss of an enzyme which glucuronidates bilirubin. As a consequence, unconjugated bilirubin accumulates and may cause kernicterus, the most serious complication in adolescents. phototherapy effectively adjusts bilirubin levels less than critical concentrations over many years but become less effective in elder children. Therefore, liver transplantation must be performed as definite therapy in these patients to avoid irreversible neurological deficits. Two brothers with CNS1, one without neurological deficits and one with moderate brain injury underwent orthotopic split liver transplantation from the same donor. The intra- and postoperative course of both patients was uneventful. Bilirubin levels normalized after transplantation in both recipients. Furthermore, mental and physical development considerably improved upon transplantation in the brother with neurological dysfunction. Therefore, orthotopic liver transplantation in CNS1 patients should be performed early enough to avoid irreversible brain damage, i.e., as a prophylactic procedure.- - - - - - - - - - ranking = 1.1666666666667keywords = liver (Clic here for more details about this article) |
3/30. A novel intronic mutation results in the use of a cryptic splice acceptor site within the coding region of UGT1A1, causing crigler-najjar syndrome type 1.crigler-najjar syndrome type 1 (CN-1) is characterized by severe unconjugated hyperbilirubinemia due to an inherited deficiency of hepatic bilirubin uridinediphosphoglucuronate glucuronosyltransferase (UGT1A1), inherited as an autosomal recessive characteristic. CN-1 is potentially lethal because of the risk of bilirubin encephalopathy (kernicterus). Genetic lesions of the coding region of the UGT1A1 gene are known to cause CN-1. Here, we report a CN-1 patient who has a novel G > A mutation at the splice acceptor site in intron 4 (IVS4-1 G > A) on one allele, and a T > A substitution followed by a 13-nt deletion in exon 2 (877T > A 878-890del) of the other allele. As the UGT1A1 gene is expressed specifically in the liver, structural analysis of the expressed UGT1A1 mRNA requires liver biopsy. To use a noninvasive approach to determine the effect of the splice site mutation on splicing of the rna transcript, we amplified the relevant region of the genomic dna by long-range polymerase chain reaction (PCR). The amplicon was cloned in an expression plasmid and transfected into COS-7 cells. The expressed mRNA was amplified by reverse-transcription-primed PCR. Nucleotide sequence determination of the amplicon showed that the splice acceptor site mutation caused splicing of the 3'-end of exon 4 to a cryptic splice site within exon 5. This resulted in deletion of the first 7 nucleotides of exon 5, causing a frameshift and premature truncation of UGT1A1, with consequent inactivation of the enzyme.- - - - - - - - - - ranking = 0.48459960738717keywords = liver, hepatic (Clic here for more details about this article) |
4/30. The effect of repeated phlebotomy on bilirubin turnover, bilirubin clearance and unconjugated hyperbilirubinaemia in the crigler-najjar syndrome and the jaundiced Gunn rat: application of computers to experimental design.1. A multicompartmental model of erythrokinetics and bilirubin production has been developed to predict the consequences of chronic phlebotomy on daily bilirubin turnover. 2. Control values for four physiological variables including bilirubin turnover were determined in a 20-year-old woman with type I congenital nonhaemolytic jaundice (crigler-najjar syndrome). With these base-line data, the model predicted the following changes during phlebotomy: a 34% fall in bilirubin turnover; a 240% increase in the haemoglobin content of bone-marrow erythroid precursors; a 25% fall in the half-life of 51Cr-labelled erythrocytes; a characteristic alteration of the erythrocyte survival curve after labelling with [2-14C]glycine. 3. On the assumption, previously validated in normal volunteer subjects and patients with Gilbert's syndrome, that hepatic bilirubin clearance was independent of turnover and would therefore remain unchanged, a fall in plasma unconjugated bilirubin concentration during phlebotomy from 436 to 282 mumol/1 was expected. 4. Accordingly, the patient underwent phlebotomy 350 ml/week for 2 months, and 500 ml/week during an additional 3 months. Appropriate studies during phlebotomy confirmed each of the predictions in paragraph 2 above. In particular, turnover fell by 31%. Unexpectedly, plasma unconjugated bilirubin remained essentially unchanged. Analogous results were observed in phlebotomized jaundiced Gunn rats. 5. Kinetic studies in both the patient and the rats demonstrated that the failure of plasma unconjugated bilirubin to fall in parallel with bilirubin turnover resulted from a prolongation of the terminal half-life of radioactively labelled bilirubin and a fall in bilirubin clearance in every instance. 6. These studies indicate that (a) in congenital non-haemolytic jaundice, bilirubin clearance is uniquely influenced by bilirubin turnover and (b) compartmental modelling and kinetic studies are useful for predicting and interpreting the results of both physiological experiments and experimental therapeutic regimens.- - - - - - - - - - ranking = 0.15126627405383keywords = hepatic (Clic here for more details about this article) |
5/30. Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder.OBJECTIVE: Transplantation of isolated hepatocytes in animal models has been shown to correct inborn errors of metabolism. Based on these studies and our experience with hepatocyte transplantation in a child with crigler-najjar syndrome, isolated hepatocyte transplantation was performed to attempt metabolic reconstitution in a male infant with severe ornithine transcarbamylase (OTC) deficiency. methods: An infant with an antenatal diagnosis of OTC deficiency was managed intensively to prevent hyperammonemia. Isolated hepatocytes were obtained by collagenase perfusion of donated livers not used for transplantation. hepatocytes were infused in batches over the first 4 weeks of life via an umbilical venous catheter positioned in the portal vein. immunosuppression consisted of tacrolimus and corticosteroids. RESULTS: Over 4 billion viable hepatocytes were transplanted during the first 3.5 weeks of life. A period of metabolic stability was achieved between days 20 and 31 during which normal protein intake was tolerated while phenylbutyrate was weaned. During this time, plasma ammonia and glutamine remained within normal limits. hyperammonemia reappeared abruptly on day 31 of life. Protein tolerance diminished to baseline; metabolic stability was subsequently reattained only following successful liver transplantation at 6 months of age. CONCLUSIONS: Isolated hepatocyte transplantation appeared to result in temporary relief of hyperammonemia and protein intolerance attributable to OTC deficiency. The metabolic stability achieved was lost after 11 days presumably because of rejection of the transplanted cells because of insufficient immunosuppression. Future attempts at isolated hepatocyte transplantation for inborn errors of metabolism in humans should include adequate immunosuppression and a liver biopsy as a means of proving hepatocyte engraftment and function.- - - - - - - - - - ranking = 0.5keywords = liver (Clic here for more details about this article) |
6/30. Removal of protein-bound and unbound unconjugated bilirubin by perfusion of plasma through an anion-exchange resin in a case of crigler-najjar syndrome type I.BACKGROUND: patients with crigler-najjar syndrome, type I (CNS-I) have an inherited absence of hepatocellular bilirubin uridine diphosphate-glucuronosyltransferase activity, which results in severe unconjugated hyperbilirubinaemia, often causing kernicterus and death in infancy or childhood. methods: Our patient is a 19-year-old Japanese man with CNS-I diagnosed by the complete absence of the hepatocellular enzyme in a liver biopsy and genotyping. The efficacies of the removal of protein-bound (PBB) and unbound (UB) unconjugated bilirubin by phototherapy, plasma perfusion and liver transplantation were compared in the patient. RESULTS: At the age of 5 years, phototherapy treatment reduced the patient's PBB by 21% and UB by 34%, and 98% of the bilirubin produced daily was removed. At the age of 16 years, plasma perfusion combined with nightly phototherapy completely removed the daily production of bilirubin; however, by 24 h post-treatment, the PBB and UB were again increased. Apparently, these treatments were effective in reducing PBB and UB, but the effect was only temporary. Following liver transplantation, PBB and UB decreased to normal concentrations. CONCLUSIONS: liver transplantation as a potential cure should be performed at a younger age, particularly in confirmed CNS-I cases for which reliable effects of phototherapy cannot be guaranteed.- - - - - - - - - - ranking = 0.5keywords = liver (Clic here for more details about this article) |
7/30. Permanent access to the portal system for cellular transplantation using an implantable port device.A novel application of the implantable Port-a-Cath (PAC) system is described in the context of cellular transplantation. A silicone catheter was inserted in a collateral branch of the portal vein and connected to a port device positioned subcutaneously on the left thoracic cage. This permanent vascular access allowed iterative intraportal infusions of allogenic hepatocytes without the need of repeated transhepatic catheterization of the portal vein. Using this technique, repeated infusions of cryopreserved and / or fresh hepatocytes were successfully carried out in 3 children with inborn errors of liver metabolism, with the aim of progressively providing a sufficient mass of transplanted liver cells to stabilize the metabolic condition of the patients. We suggest that this technique might also be valuable in pancreatic islet cell transplantation.- - - - - - - - - - ranking = 0.48459960738717keywords = liver, hepatic (Clic here for more details about this article) |
8/30. Isolated hepatocyte transplantation for crigler-najjar syndrome type 1.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.- - - - - - - - - - ranking = 0.48459960738717keywords = liver, hepatic (Clic here for more details about this article) |
9/30. Severe hyperbilirubinaemia in a Chinese girl with type I crigler-najjar syndrome: first case ever reported in Mainland china.jaundice is common in ethnic Chinese infants, but to our knowledge crigler-najjar syndrome (CN syndrome) type I has never been reported in china. A Chinese girl with severe jaundice was recently diagnosed to have CN syndrome type I by analyzing the bilirubin-uridinediphospho (UDP)-glucuronosyltransferase gene (UGT1A1). The patient was homozygous for a nonsense mutation that replaced glutamine (CAG, amino acid 239) with stop codon (TAG) at nucleotide number 715 (715C-->T) in exon 1. No mutation was found in exons 2-5. Her parents were heterozygous for the same mutant. The patient had an average bilirubin level of 300-500 mumol/L and a peak of 701 mumol/L. Daily phototherapy for 15 h was required to keep the bilirubin levels within 280-320 mumol/L. The unconjugated hyperbilirubinaemia apparently resulted from homozygous nonsense mutation of UGT1A1, which could completely abolish the UGT activity towards bilirubin (hepatic glucuronidation) and result in CN syndrome type I. Identification of the genetic defect is very useful for gene therapy, especially for dna/rna chimera therapy, and can be used as an antenatal screening test to identify the affected offsprings.- - - - - - - - - - ranking = 0.15126627405383keywords = hepatic (Clic here for more details about this article) |
10/30. Overcoming the portal steal phenomenon in auxiliary partial orthotopic liver transplantation by modulation of the venous outflow of the native liver.The main drawback of auxiliary partial orthotopic liver transplantation (APOLT) is the competition of the portal flow between the graft and the native liver, leading to graft failure. In two patients with crigler-najjar syndrome type I, the intrahepatic resistance of the native liver was increased by occluding the recipients middle hepatic vein during parenchymal transection, leading the portal flow towards the graft. This new surgical technique could encourage centers to recommence APOLT.- - - - - - - - - - ranking = 2.135865881441keywords = liver, hepatic (Clic here for more details about this article) |
| | Next -> |