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Characteristics and Outcome of Liver Transplantation in Children with Alagille Syndrome: A Single-center Experience
Pediatrics and Neonatology (2014) 55, 135e138
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ScienceDirect journal homepage: http://www.pediatr-neonatol.com
ORIGINAL ARTICLE
Characteristics and Outcome of Liver Transplantation in Children with Alagille Syndrome: A Single-center Experience Chi-Ning Lee a,b,y, Mao-Meng Tiao a,*,y, Hung-Jen Chen a, Allan Concejero c, Chao-Long Chen c, Ying-Hsien Huang a a Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan b Department of Pediatrics, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan c Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Received Jun 25, 2012; received in revised form Jun 24, 2013; accepted Sep 2, 2013 Available online 8 October 2013
Key Words Alagille syndrome; children; liver disease; living donor liver transplant; outcome
Background: This study was carried out in Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, with the aim of reviewing the characteristics and the outcome of liver transplantation (LT) in children with Alagille syndrome (AGS). Methods: We performed a retrospective analysis of transplant records of children diagnosed with AGS and undergoing LT between 1987 and 2010. Results: Nine patients underwent living donor LT. Cholestasis and characteristic facies were seen in all patients. Posterior embryotoxon was seen in 4/9 (44.4%), butterfly vertebrae in 3/9 (33.3%), heart defect (pulmonary stenosis in 2) in 3/9 (33.3%), and renal disease in 2/9 (22.2%) patients. Five cases had cholestasis prior to the age of 60 days, whereas four cases had cholestasis after 60 days of age. Iminodiacetic acid scans showed no excretion of isotope into the bowel in four cases and suggested a false diagnosis of biliary atresia. All patients underwent diagnostic laparotomy and liver biopsy. Results of liver biopsy showed characteristic features of paucity of interlobular bile ducts in all patients. Kasai portoenterostomy was not performed in any patient prior to being referred for LT. The mean age at the time of LT was 4.6 years. The 5-year overall survival rate after living donor LT was 88.9%.
* Corresponding author. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 83305, Taiwan. E-mail address: [email protected] (M.-M. Tiao). y C.-N.L. and M.-M.T. contributed equally to this work. 1875-9572/$36 Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.pedneo.2013.09.001
136
C.-N. Lee et al Conclusion: Our conclusion is that the clinical features of AGS are informative. In addition, histological confirmation is important in the diagnosis. AGS children with severe liver disease had good prognoses with LT. Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction Alagille syndrome (AGS), biliary atresia, choledochal cysts, and gallbladder disease can be associated with similar clinical symptoms, laboratory findings, and radiographic findings that make accurate diagnosis difficult.1 All of these conditions/diseases can be associated with high morbidity and mortality if the diagnosis and treatment are not accurately provided or they are delayed.1 AGS is an autosomal dominant disorder.2 In addition to the liver, AGS is also associated with abnormalities involving the heart, eye, skeleton, and kidney, and the increasing importance of abnormalities in the central nervous system is being recognized.2,3 Cholestasis associated with AGS may, in a few cases, be extremely severe and result in a major impairment in the quality of life during early childhood, eventually resulting in cirrhosis.4 It is reported that pruritus and xanthomata disappear and results of liver function tests are normal in 83.3% of AGS children after living donor liver transplantation (LDLT).4 The overall 20-year average survival rate is 70% after LDLT.5 These results indicate that the quality of life can be improved after LT in children with a severe hepatic form of AGS.4 In this study, we reviewed our experience with AGS, its signs and symptoms, diagnostic modalities, and outcome after LDLT.
2. Patients and Methods The medical records of patients diagnosed as AGS and those AGS patients who underwent LDLT at Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, between 1987 and 2010 were retrospectively reviewed. This study was approved by the Technical Review Board and Ethics Committee of Chang Gung Memorial Hospital. All patients had at least three of the five major clinical features (chronic cholestasis, congenital heart disease, “butterfly-like” vertebrae, posterior embryotoxon, and peculiar facies). End-stage liver disease was clinically defined by the following laboratory tests: serum bilirubin concentration >17.0 mg/dL and prolonged prothrombin time despite judicious treatment with parenteral vitamin K. Investigations for portal hypertension included ultrasonography and computed tomography angiography and/or conventional angiography. Therapy included various antipruritus drugs over time and supplementation as necessary with parenteral or oral fat-soluble vitamins. Baseline immunosuppression involved cyclosporine (Neoral) administration (600 mg/m2/day for pediatric patients and 15 mg/kg/day for adults). The C2 concentrations were aimed at 800e1200 ng/mL during the first 6 months, 640e960 ng/mL for up to 1 year, and 480e720 ng/mL
thereafter. Intravenous methylprednisolone or oral prednisolone was administered when tolerated, and azathioprine (2 mg/kg/day) was discontinued when the patient had not experienced an episode of severe rejection in the preceding 6 months. All of the acute rejections were reversed with steroid pulse therapy.6 Mycophenolate (Roche, Basel, Switzerland) was used in recipients whose indications included a more potent immunosuppression and renal-sparing benefits.7
2.1. Statistical analyses Data were expressed as mean standard deviation or median (range). Survival rates were calculated according to the KaplaneMeier method and the results were compared using the log-rank test. All significance tests were two tailed and differences were considered to be statistically significant at p < 0.05. Statistical analyses were performed using SPSS version 10 (SPSS Inc., Chicago, IL, USA).
3. Results Twelve cases were diagnosed with AGS. Nine of the 12 underwent LDLT. Two were brothers who underwent LDLT and received partial liver allograft. Cholestasis and characteristic facies were seen in all of the patients. Posterior embryotoxon was seen in 4/9 (44.4%) patients and butterfly vertebrae in 3/9 (33.3%) patients. Heart defect (2 with peripheral pulmonary stenosis and 1 with atrial septal defect) was seen in 3/9 (33.3%) patients and hepatopulmonary syndrome in 2/9 (22.2%) prior to LDLT. Upper gastrointestinal bleeding was observed in 3/9 (33.3%) and one had hepatic artery occlusion. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 4/9 cases (44.4%). Four cases had cholestasis after 60 days of age, whereas five cases had cholestasis prior to 60 days of age. A small gallbladder on ultrasonography (<1.5 cm length) was noted in 3/9 cases (33.3%); 4/9 cases (44.4%) showed no excretion of isotope into the bowel, which suggested a false diagnosis of biliary atresia. Liver biopsy is needed in all cholestasis cases especially in those cases where biliary atresia cannot be excluded. All underwent diagnostic laparotomy and liver biopsy. Liver biopsy showed characteristic features of paucity of interlobular bile ducts in all patients. Kasai portoenterostomy was not performed in any patient prior to being referred for LT. The mean age at the time of LDLT was 4.6 years (range: 1.0e10.6 years). The total serum bilirubin ranged from 2.0 mg/dL to 15.1 mg/dL. Indications for LT in patients with AGS were refractory pruritus in all of the nine children, decompensated cirrhosis in seven patients, recurrent
LDLT for Alagille syndrome upper gastrointestinal bleeding in four patients, and hepatopulmonary syndrome in two patients. Four cases had somatic growth retardation prior to LDLT and one died after LDLT; the other three cases caught up in lineal growth after LDLT. The first one weighed 11.8 kg (3e10 percentile) at 3 years of age; at 4 years and 5 months of age, the child’s height was 103 cm (10e25 percentile) and weight was 16 kg (10e25 percentile). The second child weighed 9.0 kg (<3 percentile) at 2 years and 9 months of age; at 12 years of age, the patient’s height was 141.6 cm (10e25 percentile) and weight was 34 kg (10e25 percentile).The third one was 8 kg (<3 percentile) at 1 year, and 153 cm (10e25 percentile) in length with 45 kg (10e25 percentile) at 16 years 5 months old. Renal disease prior to LDLT existed in 2/9 (22.2%) patients. The 5-year and 20-year overall survival rates after LDLT were 88.9% and 77.8%, respectively. Patient follow-up ranged from 4.3 years to 25.7 years after transplant (Figure 1). The two deaths occurred within the first 30 days after LDLT. One case died due to hepatic artery thrombosis, whereas the other died from gastrointestinal bleeding and intracranial bleeding complicated with brain herniation.
4. Discussion Neonatal cholestatic jaundice is mostly caused by neonatal giant cell hepatitis. Biliary atresia and AGS also present as neonatal cholestatic jaundice (8% and 6%, respectively).8 Persistent cholestatic jaundice is associated with poorer survival with native liver.9 The correct treatment for each of these clinical entities is different and can significantly reduce morbidity and mortality from these diseases.1 The findings of microcornea, posterior embryotoxon, and anomalous optic discs should suggest the diagnosis of AGS.10 Liver biopsy shows characteristic features of paucity of interlobular bile ducts in 76.6%.11 In our nine cases, 44.4% had abnormal findings in the eye, but all showed the
Figure 1 Overall survival rates after liver transplantation (KaplaneMeier method).
137 paucity of interlobular bile ducts and peculiar facies. This suggests that performing careful physical examination looking for peculiar characteristics and liver biopsy findings of interlobular bile duct paucity are important to diagnose AGS. Four cases had cholestasis after 60 days of age. The other five AGS cases had cholestasis prior to the age of 60 days with three children having small gallbladders and four patients without excretion of isotope into the bowel, making it difficult to exclude biliary atresia from the diagnosis of AGS. The Kasai procedure, although appropriate for children with biliary atresia, does not benefit children with AGS and actually appears to worsen outcomes.12,13 None of our patients had Kasai’s operation. A correct diagnosis can avoid an unnecessary Kasai portoenterostomy.11 It is reported that mutations in JAG1 can be identified in 70% of AGS patients.3,14 However, we did not do genetic profiling studies. We emphasized the importance of the peculiar facies and liver pathology in the diagnosis of AGS. In a large series of AGS, heart defects were present in 107 of 117 (91.5%) patients with peripheral pulmonary stenosis as the most common condition.11 Complex congenital heart disease and hepatic disease with or without LT contribute significantly to AGS mortality.5 There were reported cases of mitral valve regurgitation requiring valvuloplasty,15 anomalous origin of the left coronary artery from the pulmonary artery,15 and severe aortic stenosis.16 As reported previously, the frequency of complex cardiac anomalies was lower in the LT group with AGS compared with published AGS series (5% and 13%, respectively).17 We did not see these complex heart conditions in our cases with routine two-dimensional trans-thoracic echocardiography evaluation prior to LT.18 The lower prevalence of complex cardiac anomalies in LT could result from selection criteria for transplantation candidates17 or the small number of AGS patients in our study. This needs further study to be clarified. We had three congenital heart disease patients, one atrial septal defect and two peripheral pulmonary stenosis cases. The causes of death of our patients were without cardiac manifestations of AGS disease, which is different from previous reports.5,11,15 Actuarial survival rates with the native liver were 51% and 38% at 10 years and 20 years, respectively.9 The common factors contributing to the decision for LT were bone fractures, pruritus, and severe xanthomata.19,20 In our cases, cholestasis and pruritus with end-stage liver disease was the most common presentation. We did not find bone fracture cases. Most AGS patients die as a result of the complications related to surgery and heart failure caused by progressive pulmonary artery stenosis.4,21 One study reported that deaths in the AGS group mostly occurred within the first 30 days,17 which is consistent with our study where two cases died after LDLT within 30 days. LDLT is an efficacious treatment modality for AGS.21 The overall survival rate was 80.4% at 5 years and 62% at 20 years.9,21 Tannuri et al22 reported that AGS constituted 3.3% of all indications for LDLT in Brazil. Most patients undergo LT at a median age of 6.5 years.4,19,21 Liver dysfunction improved in all successful cases. We should also be careful when procuring partial liver grafts from close family relatives of AGS patients as these donors may be AGS patients who were diagnosed. In a
138 previous study, the donor operation had to be aborted because of a liver biopsy that showed paucity of bile ducts during the operation.23 However, such a finding was not found in liver pathological analysis in this study. In summary, we report the clinical characteristics of nine AGS patients with severe liver disease who had a good 5-year overall survival rate after LT. The clinical features of AGS are informative. Histological confirmation is important in the diagnosis.
Conflicts of Interest The authors have no conflicts of interest relevant to this article.
References 1. Goldman M, Pranikoff T. Biliary disease in children. Curr Gastroenterol Rep 2011;13:193e201. 2. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152e7. 3. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001;21:525e34. 4. Cardona J, Houssin D, Gauthier F, Devictor D, Losay J, Hadchouel M, et al. Liver transplantation in children with Alagille syndromeda study of twelve cases. Transplantation 1995;60:339e42. 5. Hadchouel M. Alagille syndrome. Indian J Pediatr 2002;69: 815e8. 6. Chiu KW, Chen YS, de Villa VH, Wang CC, Eng HL, Wang SH, et al. Characterization of liver enzymes on living related liver transplantation patients with acute rejection. Hepatogastroenterology 2005;52:1825e7. 7. Chen CL, Concejero A, Wang CC, Wang SH, Lin CC, Liu YW, et al. Living donor liver transplantation for biliary atresia: a single-center experience with first 100 cases. Am J Transplant 2006;6:2672e9. 8. Torbenson M, Hart J, Westerhoff M, Azzam RK, Elgendi A, Mziray-Andrew HC, et al. Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010;34: 1498e503. 9. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001;49:431e5.
C.-N. Lee et al 10. Brodsky MC, Cunniff C. Ocular anomalies in the alagille syndrome (arteriohepatic dysplasia). Ophthalmology 1993;100: 1767e74. 11. Subramaniam P, Knisely A, Portmann B, Qureshi SA, Aclimandos WA, Karani JB, et al. Diagnosis of Alagille syndromed25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr 2011;52:84e9. 12. Kaye AJ, Rand EB, Munoz PS, Spinner NB, Flake AW, Kamath BM. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr 2010;51: 319e21. 13. Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr 2010;50: 580e6. 14. Krantz ID, Piccoli DA, Spinner NB. Clinical and molecular genetics of Alagille syndrome. Curr Opin Pediatr 1999;11:558e64. 15. Lemoine TJ, Kaza AK, Gray R, Day RW, Tani LY, Poss WB. Anomalous origin of the left coronary artery from the pulmonary artery in Alagille syndrome. Congenit Heart Dis 2010;5: 462e4. 16. Funk M, Cohen M, Santana O. Alagille syndrome: an unusual presentation of an uncommon disease. South Med J 2010;103: 1049e51. 17. Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl 2012;18:940e8. 18. Liang CD, Concejero A, Ko SF, Chen CC, Wang CC, Chen CL. The impact of intrapulmonary shunting after liver transplantation in pediatric patients. J Formos Med Assoc 2012;111:315e9. 19. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220e4. 20. Bales CB, Kamath BM, Munoz PS, Nguyen A, Piccoli DA, Spinner NB, et al. Pathologic lower extremity fractures in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 2010;51:66e70. 21. Kasahara M, Kiuchi T, Inomata Y, Uryuhara K, Sakamoto S, Ito T, et al. Living-related liver transplantation for Alagille syndrome. Transplantation 2003;75:2147e50. 22. Tannuri AC, Gibelli NE, Ricardi LR, Santos MM, MaksoudFilho JG, Pinho-Apezzato ML, et al. Living related donor liver transplantation in children. Transplant Proc 2011;43:161e4. 23. Gurkan A, Emre S, Fishbein TM, Brady L, Millis M, Birnbaum A, et al. Unsuspected bile duct paucity in donors for living-related liver transplantation: two case reports. Transplantation 1999; 67:416e8.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
ORIGINAL ARTICLE
Characteristics and Outcome of Liver Transplantation in Children with Alagille Syndrome: A Single-center Experience Chi-Ning Lee a,b,y, Mao-Meng Tiao a,*,y, Hung-Jen Chen a, Allan Concejero c, Chao-Long Chen c, Ying-Hsien Huang a a Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan b Department of Pediatrics, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan c Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Received Jun 25, 2012; received in revised form Jun 24, 2013; accepted Sep 2, 2013 Available online 8 October 2013
Key Words Alagille syndrome; children; liver disease; living donor liver transplant; outcome
Background: This study was carried out in Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, with the aim of reviewing the characteristics and the outcome of liver transplantation (LT) in children with Alagille syndrome (AGS). Methods: We performed a retrospective analysis of transplant records of children diagnosed with AGS and undergoing LT between 1987 and 2010. Results: Nine patients underwent living donor LT. Cholestasis and characteristic facies were seen in all patients. Posterior embryotoxon was seen in 4/9 (44.4%), butterfly vertebrae in 3/9 (33.3%), heart defect (pulmonary stenosis in 2) in 3/9 (33.3%), and renal disease in 2/9 (22.2%) patients. Five cases had cholestasis prior to the age of 60 days, whereas four cases had cholestasis after 60 days of age. Iminodiacetic acid scans showed no excretion of isotope into the bowel in four cases and suggested a false diagnosis of biliary atresia. All patients underwent diagnostic laparotomy and liver biopsy. Results of liver biopsy showed characteristic features of paucity of interlobular bile ducts in all patients. Kasai portoenterostomy was not performed in any patient prior to being referred for LT. The mean age at the time of LT was 4.6 years. The 5-year overall survival rate after living donor LT was 88.9%.
* Corresponding author. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 83305, Taiwan. E-mail address: [email protected] (M.-M. Tiao). y C.-N.L. and M.-M.T. contributed equally to this work. 1875-9572/$36 Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.pedneo.2013.09.001
136
C.-N. Lee et al Conclusion: Our conclusion is that the clinical features of AGS are informative. In addition, histological confirmation is important in the diagnosis. AGS children with severe liver disease had good prognoses with LT. Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction Alagille syndrome (AGS), biliary atresia, choledochal cysts, and gallbladder disease can be associated with similar clinical symptoms, laboratory findings, and radiographic findings that make accurate diagnosis difficult.1 All of these conditions/diseases can be associated with high morbidity and mortality if the diagnosis and treatment are not accurately provided or they are delayed.1 AGS is an autosomal dominant disorder.2 In addition to the liver, AGS is also associated with abnormalities involving the heart, eye, skeleton, and kidney, and the increasing importance of abnormalities in the central nervous system is being recognized.2,3 Cholestasis associated with AGS may, in a few cases, be extremely severe and result in a major impairment in the quality of life during early childhood, eventually resulting in cirrhosis.4 It is reported that pruritus and xanthomata disappear and results of liver function tests are normal in 83.3% of AGS children after living donor liver transplantation (LDLT).4 The overall 20-year average survival rate is 70% after LDLT.5 These results indicate that the quality of life can be improved after LT in children with a severe hepatic form of AGS.4 In this study, we reviewed our experience with AGS, its signs and symptoms, diagnostic modalities, and outcome after LDLT.
2. Patients and Methods The medical records of patients diagnosed as AGS and those AGS patients who underwent LDLT at Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, between 1987 and 2010 were retrospectively reviewed. This study was approved by the Technical Review Board and Ethics Committee of Chang Gung Memorial Hospital. All patients had at least three of the five major clinical features (chronic cholestasis, congenital heart disease, “butterfly-like” vertebrae, posterior embryotoxon, and peculiar facies). End-stage liver disease was clinically defined by the following laboratory tests: serum bilirubin concentration >17.0 mg/dL and prolonged prothrombin time despite judicious treatment with parenteral vitamin K. Investigations for portal hypertension included ultrasonography and computed tomography angiography and/or conventional angiography. Therapy included various antipruritus drugs over time and supplementation as necessary with parenteral or oral fat-soluble vitamins. Baseline immunosuppression involved cyclosporine (Neoral) administration (600 mg/m2/day for pediatric patients and 15 mg/kg/day for adults). The C2 concentrations were aimed at 800e1200 ng/mL during the first 6 months, 640e960 ng/mL for up to 1 year, and 480e720 ng/mL
thereafter. Intravenous methylprednisolone or oral prednisolone was administered when tolerated, and azathioprine (2 mg/kg/day) was discontinued when the patient had not experienced an episode of severe rejection in the preceding 6 months. All of the acute rejections were reversed with steroid pulse therapy.6 Mycophenolate (Roche, Basel, Switzerland) was used in recipients whose indications included a more potent immunosuppression and renal-sparing benefits.7
2.1. Statistical analyses Data were expressed as mean standard deviation or median (range). Survival rates were calculated according to the KaplaneMeier method and the results were compared using the log-rank test. All significance tests were two tailed and differences were considered to be statistically significant at p < 0.05. Statistical analyses were performed using SPSS version 10 (SPSS Inc., Chicago, IL, USA).
3. Results Twelve cases were diagnosed with AGS. Nine of the 12 underwent LDLT. Two were brothers who underwent LDLT and received partial liver allograft. Cholestasis and characteristic facies were seen in all of the patients. Posterior embryotoxon was seen in 4/9 (44.4%) patients and butterfly vertebrae in 3/9 (33.3%) patients. Heart defect (2 with peripheral pulmonary stenosis and 1 with atrial septal defect) was seen in 3/9 (33.3%) patients and hepatopulmonary syndrome in 2/9 (22.2%) prior to LDLT. Upper gastrointestinal bleeding was observed in 3/9 (33.3%) and one had hepatic artery occlusion. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 4/9 cases (44.4%). Four cases had cholestasis after 60 days of age, whereas five cases had cholestasis prior to 60 days of age. A small gallbladder on ultrasonography (<1.5 cm length) was noted in 3/9 cases (33.3%); 4/9 cases (44.4%) showed no excretion of isotope into the bowel, which suggested a false diagnosis of biliary atresia. Liver biopsy is needed in all cholestasis cases especially in those cases where biliary atresia cannot be excluded. All underwent diagnostic laparotomy and liver biopsy. Liver biopsy showed characteristic features of paucity of interlobular bile ducts in all patients. Kasai portoenterostomy was not performed in any patient prior to being referred for LT. The mean age at the time of LDLT was 4.6 years (range: 1.0e10.6 years). The total serum bilirubin ranged from 2.0 mg/dL to 15.1 mg/dL. Indications for LT in patients with AGS were refractory pruritus in all of the nine children, decompensated cirrhosis in seven patients, recurrent
LDLT for Alagille syndrome upper gastrointestinal bleeding in four patients, and hepatopulmonary syndrome in two patients. Four cases had somatic growth retardation prior to LDLT and one died after LDLT; the other three cases caught up in lineal growth after LDLT. The first one weighed 11.8 kg (3e10 percentile) at 3 years of age; at 4 years and 5 months of age, the child’s height was 103 cm (10e25 percentile) and weight was 16 kg (10e25 percentile). The second child weighed 9.0 kg (<3 percentile) at 2 years and 9 months of age; at 12 years of age, the patient’s height was 141.6 cm (10e25 percentile) and weight was 34 kg (10e25 percentile).The third one was 8 kg (<3 percentile) at 1 year, and 153 cm (10e25 percentile) in length with 45 kg (10e25 percentile) at 16 years 5 months old. Renal disease prior to LDLT existed in 2/9 (22.2%) patients. The 5-year and 20-year overall survival rates after LDLT were 88.9% and 77.8%, respectively. Patient follow-up ranged from 4.3 years to 25.7 years after transplant (Figure 1). The two deaths occurred within the first 30 days after LDLT. One case died due to hepatic artery thrombosis, whereas the other died from gastrointestinal bleeding and intracranial bleeding complicated with brain herniation.
4. Discussion Neonatal cholestatic jaundice is mostly caused by neonatal giant cell hepatitis. Biliary atresia and AGS also present as neonatal cholestatic jaundice (8% and 6%, respectively).8 Persistent cholestatic jaundice is associated with poorer survival with native liver.9 The correct treatment for each of these clinical entities is different and can significantly reduce morbidity and mortality from these diseases.1 The findings of microcornea, posterior embryotoxon, and anomalous optic discs should suggest the diagnosis of AGS.10 Liver biopsy shows characteristic features of paucity of interlobular bile ducts in 76.6%.11 In our nine cases, 44.4% had abnormal findings in the eye, but all showed the
Figure 1 Overall survival rates after liver transplantation (KaplaneMeier method).
137 paucity of interlobular bile ducts and peculiar facies. This suggests that performing careful physical examination looking for peculiar characteristics and liver biopsy findings of interlobular bile duct paucity are important to diagnose AGS. Four cases had cholestasis after 60 days of age. The other five AGS cases had cholestasis prior to the age of 60 days with three children having small gallbladders and four patients without excretion of isotope into the bowel, making it difficult to exclude biliary atresia from the diagnosis of AGS. The Kasai procedure, although appropriate for children with biliary atresia, does not benefit children with AGS and actually appears to worsen outcomes.12,13 None of our patients had Kasai’s operation. A correct diagnosis can avoid an unnecessary Kasai portoenterostomy.11 It is reported that mutations in JAG1 can be identified in 70% of AGS patients.3,14 However, we did not do genetic profiling studies. We emphasized the importance of the peculiar facies and liver pathology in the diagnosis of AGS. In a large series of AGS, heart defects were present in 107 of 117 (91.5%) patients with peripheral pulmonary stenosis as the most common condition.11 Complex congenital heart disease and hepatic disease with or without LT contribute significantly to AGS mortality.5 There were reported cases of mitral valve regurgitation requiring valvuloplasty,15 anomalous origin of the left coronary artery from the pulmonary artery,15 and severe aortic stenosis.16 As reported previously, the frequency of complex cardiac anomalies was lower in the LT group with AGS compared with published AGS series (5% and 13%, respectively).17 We did not see these complex heart conditions in our cases with routine two-dimensional trans-thoracic echocardiography evaluation prior to LT.18 The lower prevalence of complex cardiac anomalies in LT could result from selection criteria for transplantation candidates17 or the small number of AGS patients in our study. This needs further study to be clarified. We had three congenital heart disease patients, one atrial septal defect and two peripheral pulmonary stenosis cases. The causes of death of our patients were without cardiac manifestations of AGS disease, which is different from previous reports.5,11,15 Actuarial survival rates with the native liver were 51% and 38% at 10 years and 20 years, respectively.9 The common factors contributing to the decision for LT were bone fractures, pruritus, and severe xanthomata.19,20 In our cases, cholestasis and pruritus with end-stage liver disease was the most common presentation. We did not find bone fracture cases. Most AGS patients die as a result of the complications related to surgery and heart failure caused by progressive pulmonary artery stenosis.4,21 One study reported that deaths in the AGS group mostly occurred within the first 30 days,17 which is consistent with our study where two cases died after LDLT within 30 days. LDLT is an efficacious treatment modality for AGS.21 The overall survival rate was 80.4% at 5 years and 62% at 20 years.9,21 Tannuri et al22 reported that AGS constituted 3.3% of all indications for LDLT in Brazil. Most patients undergo LT at a median age of 6.5 years.4,19,21 Liver dysfunction improved in all successful cases. We should also be careful when procuring partial liver grafts from close family relatives of AGS patients as these donors may be AGS patients who were diagnosed. In a
138 previous study, the donor operation had to be aborted because of a liver biopsy that showed paucity of bile ducts during the operation.23 However, such a finding was not found in liver pathological analysis in this study. In summary, we report the clinical characteristics of nine AGS patients with severe liver disease who had a good 5-year overall survival rate after LT. The clinical features of AGS are informative. Histological confirmation is important in the diagnosis.
Conflicts of Interest The authors have no conflicts of interest relevant to this article.
References 1. Goldman M, Pranikoff T. Biliary disease in children. Curr Gastroenterol Rep 2011;13:193e201. 2. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152e7. 3. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001;21:525e34. 4. Cardona J, Houssin D, Gauthier F, Devictor D, Losay J, Hadchouel M, et al. Liver transplantation in children with Alagille syndromeda study of twelve cases. Transplantation 1995;60:339e42. 5. Hadchouel M. Alagille syndrome. Indian J Pediatr 2002;69: 815e8. 6. Chiu KW, Chen YS, de Villa VH, Wang CC, Eng HL, Wang SH, et al. Characterization of liver enzymes on living related liver transplantation patients with acute rejection. Hepatogastroenterology 2005;52:1825e7. 7. Chen CL, Concejero A, Wang CC, Wang SH, Lin CC, Liu YW, et al. Living donor liver transplantation for biliary atresia: a single-center experience with first 100 cases. Am J Transplant 2006;6:2672e9. 8. Torbenson M, Hart J, Westerhoff M, Azzam RK, Elgendi A, Mziray-Andrew HC, et al. Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010;34: 1498e503. 9. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001;49:431e5.
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