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96 De novo autoimmune hepatitis after liver transplantation in children: a single centre experience
202A
AASLD ABSTRACTS
HEPATOLOGY, October 2003
95
96
HEPATIC PATHOLOGY OF NEONATAL INTRAHEPATIC CHOLESTASIS CAUSED BY CITRIN DEFICIENCY. Masayoshi
DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER
Kage, Kojiro Masamichi, Akihiko Kimura, Kurume University, Kurume, Japan; Keiko Kobayashi, Takeyori Saheki, Kagoshima University, Kagoshima, Japan [Objective] Neonatal intrahepatic cholestasis associated with SLC25A13 gene mutations is referred to as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Most NICCD patients develop hypoproteinemia, galactosemia, maltipleaminoacidemia including citrullinemia, and tyrosinemia, cholestasis, and fatty liver. However the hepatic pathology of NICCD has not b e e n clarified. Therefore, the present study was designed to characterize the liver histologic features of patients with NICCD. [Patients and Methods] We studied the histologic findings of liver biopsy specimens taken from 30 patients (aged, 2.9 months; range, 1 - 7 months; 17 males) who h a d diagnosed as NICCD by genetic analysis of the SLC25A13 gene, including 22 patients with heterozygote NICCD. Moreover, mutations in SLC25A13 were detected in both alleles of 24 patients and in a single allele of 6 patients. Mutation detection and DNA diagnosis of SLC25A13 gene were performed as described previously by Kobayashi K (Nat genet 1999;22:159-163). Degree of hepatic inflammation and fibrosis was evaluated according to the Inuyama Classification. Inflammation ( A):none 0, mild 1, moderate 2, severe 3. Fibrosis (F):none 0, mild portal fibrosis 1, moderate fibrosis 2, bridging fibrosis 3, cirrhosis 4. Results: Patients Two patients developed to liver failure at 6 m o n t h s and 7 months of age and I patient developed to behavioral aberration, which included shouting and episodes of violence, at 16 years of age. Two patients, patient with liver failure and patient with mental derangement, received living-related liver transplant. Serum levels of citrulline, a-fetoproteine, ferritin, and pancreatic secretory trypsin inhibiter were generally increased. We also detected high serum levels of total and direct bilirubin, asparate (AST) and/or alanine aminotransferase (ALT), total bile acids, and g-glutamyl transpeptidase. Pathological findings Histological examination showed fat deposits in liver cells in all specimens except one, 20 (67%) of which h a d severe fatty liver. In 25 (83%) specimens, fatty liver was characterized by a mixture of liver cells containing large droplets of fat and those containing microvesicular fat deposits with a centrally located nucleus. Cholestasis was observed in 23 (77%) specimens, 17 (57%) of which showed marked cholestasis with bile thrombi. Necro-inflammatory reaction such as focal necrosis with lymphocytic infiltration of portal tracts and acidophilic bodies was seen in all specimens. According to the Inuyama Classification, at least moderate inflammatory findings were observed in approximately half of the specimens: A1(14 specimens), A2(10), and A3(5). Eighty percents of the specimens showed fatty liver and necro-inflammatory reaction to be interpreted as steatohepatitis. A wide spectrum of fibrosis was found: F0 (10 specimens), F1 (6), F2 (8), F3 (4), and F4 (1). A case contained no portal tract in the specimen. Hemosiderin deposits mainly in periportal areas were observed in 14 (47%) specimens. Conclusion: The hepatic pathology of NICCD was characterized by fatty change, necro-inflammatory reaction, cholestasis and hemosiderin deposition. Although each histological finding may not be pathognomonic, combination of these findings and microvesicular fat deposits with a centrally located nucleus found in the same liver is very unique. Liver biopsy seems to have an important role in diagnosis and evaluation of progression of NICCD. Disclosures: Masayoshi Kage - No relationships to disclose Akihiko Kimura - No relationships to disclose Keiko Kobayashi - No relationships to disclose Kojiro Masamichi - No relationships to disclose Takeyori Saheki - No relationships to disclose
TRANSPLANTATION IN CHILDREN; A SINGLE CENTRE EXPERIENCE. Nedim Hadzic, Ramesh Srinivasan, Mohamed Rela,
Nigel Heaton, Diego Vergani, Giorgina Mieli-Vergani, Institute of Liver Studies, King's College Hospital, London, UK INTRODUCTION: Post-transplant de novo autoimmune hepatitis (dn-AIH) is a novel form of late liver graft dysfunction defined by hypergammaglobulinaemia, elevated titres of serum autoantibodies, and histological findings of chronic hepatitis with portal and periportal infiltrate with plasma ceils and lymphocytes in the absence of other causes. AIM/METHODS: To establish the prevalence and m e d i u m term outcome of dn-AIH we have retrospectively reviewed medical records of 377 children transplanted at our centre between 1990 and 2002. Since 1995 we have routinely monitored emergence of serum antibodies (titre > 1/20 was considered significant), dnAIH treatment included reduction of CyA/tacrolimus dose by 20-30%, prednisolone 1-2 mg/kg/day tapered to a maintenance dose of 2.5-5 m g / d and azathioprine (2 mg/kg/d) or mycophenolate mofetil (40 mg/kg/d). The children transplanted for autoimm u n e conditions have b e e n excluded. RESULTS: 157 children (41.6% of total)(84 girls) h a d significant autoantibody titres during follow up. Eighty-nine patients h a d SMA (titres range: 1/20 to 1/640), 43 SMA and ANA (SMA: 1/20 to 1/640, ANA: 1/20 to 1/2560), 13 ANA (1/40 to 1/2560), 4 LKM (1/160 to 1/640), while 4 were positive for anti-mitochondrial, 3 for gastric parietal cell and I for p-ANCA. Simultaneous biochemical graft dysfunction has b e e n observed in 54 (34%) of these patients. Twenty of t h e m (5.3% of total)(11 girls) satisfied the diagnostic criteria for dn-AIH. Their indications for liver transplant were: biliary atresia (9), alpha-l-antitrypsin deficiency (3), Alagille syndrome (2), cryptogenic cirrhosis (2), and hepatitis A-related acute liver failure, drug-induced acute liver failure, BSEP deficiency and Crigler-Najjar syndrome, I each. All patients responded to the treatment over a median of 8 weeks (range 1-32). Five episodes of histologically-proven relapses occurred in 4 patients during follow up. One child n e e d e d retransplantation for persistent graft dysfunction; the explanted liver showed chronic rejection. No patient died after a median follow up of 4.72 years (range 0.44-8.2).CONCLUSIONS: Serum autoantibodies are frequently detected in children after liver transplant, dn-AIH occurs in around 5% of transplanted children and in 12% of those with demonstrable autoantibodies. The standard treatment of autoimmune hepatitis combined with reduction of the calcineurin-inhibitor dose is highly effective, inducing prolonged biochemical remission and a good m e d i u m term prognosis. Disclosures: N e d i m Hactzic - No relationships to disclose Nigel Heaton - No relationships to disclose Giorgina Mieli-Vergani - No relationships to disclose M o h a m e d Rela - No relationships to disclose Ramesh Srinivasan - No relationships to disclose Diego Vergani - No relationships to disclose
AASLD ABSTRACTS
HEPATOLOGY, October 2003
95
96
HEPATIC PATHOLOGY OF NEONATAL INTRAHEPATIC CHOLESTASIS CAUSED BY CITRIN DEFICIENCY. Masayoshi
DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER
Kage, Kojiro Masamichi, Akihiko Kimura, Kurume University, Kurume, Japan; Keiko Kobayashi, Takeyori Saheki, Kagoshima University, Kagoshima, Japan [Objective] Neonatal intrahepatic cholestasis associated with SLC25A13 gene mutations is referred to as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Most NICCD patients develop hypoproteinemia, galactosemia, maltipleaminoacidemia including citrullinemia, and tyrosinemia, cholestasis, and fatty liver. However the hepatic pathology of NICCD has not b e e n clarified. Therefore, the present study was designed to characterize the liver histologic features of patients with NICCD. [Patients and Methods] We studied the histologic findings of liver biopsy specimens taken from 30 patients (aged, 2.9 months; range, 1 - 7 months; 17 males) who h a d diagnosed as NICCD by genetic analysis of the SLC25A13 gene, including 22 patients with heterozygote NICCD. Moreover, mutations in SLC25A13 were detected in both alleles of 24 patients and in a single allele of 6 patients. Mutation detection and DNA diagnosis of SLC25A13 gene were performed as described previously by Kobayashi K (Nat genet 1999;22:159-163). Degree of hepatic inflammation and fibrosis was evaluated according to the Inuyama Classification. Inflammation ( A):none 0, mild 1, moderate 2, severe 3. Fibrosis (F):none 0, mild portal fibrosis 1, moderate fibrosis 2, bridging fibrosis 3, cirrhosis 4. Results: Patients Two patients developed to liver failure at 6 m o n t h s and 7 months of age and I patient developed to behavioral aberration, which included shouting and episodes of violence, at 16 years of age. Two patients, patient with liver failure and patient with mental derangement, received living-related liver transplant. Serum levels of citrulline, a-fetoproteine, ferritin, and pancreatic secretory trypsin inhibiter were generally increased. We also detected high serum levels of total and direct bilirubin, asparate (AST) and/or alanine aminotransferase (ALT), total bile acids, and g-glutamyl transpeptidase. Pathological findings Histological examination showed fat deposits in liver cells in all specimens except one, 20 (67%) of which h a d severe fatty liver. In 25 (83%) specimens, fatty liver was characterized by a mixture of liver cells containing large droplets of fat and those containing microvesicular fat deposits with a centrally located nucleus. Cholestasis was observed in 23 (77%) specimens, 17 (57%) of which showed marked cholestasis with bile thrombi. Necro-inflammatory reaction such as focal necrosis with lymphocytic infiltration of portal tracts and acidophilic bodies was seen in all specimens. According to the Inuyama Classification, at least moderate inflammatory findings were observed in approximately half of the specimens: A1(14 specimens), A2(10), and A3(5). Eighty percents of the specimens showed fatty liver and necro-inflammatory reaction to be interpreted as steatohepatitis. A wide spectrum of fibrosis was found: F0 (10 specimens), F1 (6), F2 (8), F3 (4), and F4 (1). A case contained no portal tract in the specimen. Hemosiderin deposits mainly in periportal areas were observed in 14 (47%) specimens. Conclusion: The hepatic pathology of NICCD was characterized by fatty change, necro-inflammatory reaction, cholestasis and hemosiderin deposition. Although each histological finding may not be pathognomonic, combination of these findings and microvesicular fat deposits with a centrally located nucleus found in the same liver is very unique. Liver biopsy seems to have an important role in diagnosis and evaluation of progression of NICCD. Disclosures: Masayoshi Kage - No relationships to disclose Akihiko Kimura - No relationships to disclose Keiko Kobayashi - No relationships to disclose Kojiro Masamichi - No relationships to disclose Takeyori Saheki - No relationships to disclose
TRANSPLANTATION IN CHILDREN; A SINGLE CENTRE EXPERIENCE. Nedim Hadzic, Ramesh Srinivasan, Mohamed Rela,
Nigel Heaton, Diego Vergani, Giorgina Mieli-Vergani, Institute of Liver Studies, King's College Hospital, London, UK INTRODUCTION: Post-transplant de novo autoimmune hepatitis (dn-AIH) is a novel form of late liver graft dysfunction defined by hypergammaglobulinaemia, elevated titres of serum autoantibodies, and histological findings of chronic hepatitis with portal and periportal infiltrate with plasma ceils and lymphocytes in the absence of other causes. AIM/METHODS: To establish the prevalence and m e d i u m term outcome of dn-AIH we have retrospectively reviewed medical records of 377 children transplanted at our centre between 1990 and 2002. Since 1995 we have routinely monitored emergence of serum antibodies (titre > 1/20 was considered significant), dnAIH treatment included reduction of CyA/tacrolimus dose by 20-30%, prednisolone 1-2 mg/kg/day tapered to a maintenance dose of 2.5-5 m g / d and azathioprine (2 mg/kg/d) or mycophenolate mofetil (40 mg/kg/d). The children transplanted for autoimm u n e conditions have b e e n excluded. RESULTS: 157 children (41.6% of total)(84 girls) h a d significant autoantibody titres during follow up. Eighty-nine patients h a d SMA (titres range: 1/20 to 1/640), 43 SMA and ANA (SMA: 1/20 to 1/640, ANA: 1/20 to 1/2560), 13 ANA (1/40 to 1/2560), 4 LKM (1/160 to 1/640), while 4 were positive for anti-mitochondrial, 3 for gastric parietal cell and I for p-ANCA. Simultaneous biochemical graft dysfunction has b e e n observed in 54 (34%) of these patients. Twenty of t h e m (5.3% of total)(11 girls) satisfied the diagnostic criteria for dn-AIH. Their indications for liver transplant were: biliary atresia (9), alpha-l-antitrypsin deficiency (3), Alagille syndrome (2), cryptogenic cirrhosis (2), and hepatitis A-related acute liver failure, drug-induced acute liver failure, BSEP deficiency and Crigler-Najjar syndrome, I each. All patients responded to the treatment over a median of 8 weeks (range 1-32). Five episodes of histologically-proven relapses occurred in 4 patients during follow up. One child n e e d e d retransplantation for persistent graft dysfunction; the explanted liver showed chronic rejection. No patient died after a median follow up of 4.72 years (range 0.44-8.2).CONCLUSIONS: Serum autoantibodies are frequently detected in children after liver transplant, dn-AIH occurs in around 5% of transplanted children and in 12% of those with demonstrable autoantibodies. The standard treatment of autoimmune hepatitis combined with reduction of the calcineurin-inhibitor dose is highly effective, inducing prolonged biochemical remission and a good m e d i u m term prognosis. Disclosures: N e d i m Hactzic - No relationships to disclose Nigel Heaton - No relationships to disclose Giorgina Mieli-Vergani - No relationships to disclose M o h a m e d Rela - No relationships to disclose Ramesh Srinivasan - No relationships to disclose Diego Vergani - No relationships to disclose