Diverse outcome of liver transplantation in children with Niemann-Pick Disease type C cannot be predicted by mutation analysis

Abstract

Objectives and Study: Liver transplantation remains a controversial treatment strategy for patients with Niemann-Pick type C (NPC) disease, as it does not prevent neurological disease progression. The aim was to report on clinical presentation, morbidity and mortality of children who underwent liver transplantation (LTx) and were subsequently diagnosed to have NPC. Methods: We report a retrospective, descriptive, multi-centre review of clinical and laboratory features of children who underwent LTx between 2003 and 2018 diagnosed with NPC. Patients were identified by personal communication (n=8) and a review of European liver transplant registry data (n=1). Included were children in whom diagnosis was confirmed by positive filipin staining of skin fibroblasts and/or genetic testing. Results: A total of 9 (6 male) patients born between 2003-2012 underwent LTx at one of six centres in Germany, UK, Canada, Spain, Australia and USA (listed in table 1). Neonatal acute liver failure was the most common indication, occurring in 7 children. The most prevalent presenting symptoms were jaundice (8/9) and hepatosplenomegaly (8/9) followed by ascites (6/9), pulmonary symptoms (5/9) and hypoglycaemia (5/9). Total bilirubin levels were high with a median of 277 (range: 100-477) microgram/L at time of presentation. Elevated alanine aminotransferase (ALT) was reported in 7/9 patients with median values of 75 (range: 10-164) U/L; furthermore high median aspartate aminotransferase (AST) levels of 325 (range: 66-531) U/L were reported. Prothrombin time (PT) was prolonged in all children with a median value of 46.5 (range: 13-110) seconds. Overall, 8/9 children had a LTx before the diagnosis of NPC while one patient had LTx 6 years after the initial diagnosis of NPC. Genetic testing revealed mutations in NPC1 that in many cases correlate with a severe biochemical phenotype, such as p. Ile1061Thr, p. Arg1077X, p. Pro887Leu and a deletion mutant in exon 23. It has been proposed that severe biochemical phenotypes are associated with severe clinical manifestations. In fact, explant liver histology showed signs of acute and subacute liver damage ranging from massive necrosis to cirrhosis with regenerative nodules, mixed macro and microvascular cirrhosis and focal fatty changes. In contrast to the primary presentation of liver disease long term outcome after liver transplantation does not correlate with genotype. Persistent post LTx splenomegaly or deranged transaminases led to further investigations including skin biopsy with filipin staining (7/9) and/or bone marrow aspiration (5/9). Chitotriosidase levels were reported elevated in 2/5 children. All 9 children survived beyond early infancy and 7 children are still alive with a median follow-up time of 9 years (range: 6-13). Conclusion: Early diagnosis of NPC continues to be a challenge and a definitive diagnosis can often be reached only after LTx. Neurological disease is not prevented in the majority of patients but prolonged symptom free survival has been observed survival between 6-9 years has been observed 33% of cases. Genotype does not appear to predict neurological outcome after transplantation. Liver transplantation remains controversial in Niemann-Pick C. (Table Presented) .L6280936332019-06-18 <br />