Long-Term Outcomes After Living-Donor Liver Transplantation for Alagille Syndrome: A Single Center 20-Year Experience in Japan

Abstract

To the Editor: Alagille syndrome (AS) was described in 1969 (1Alagille D, Habib E, Thomassin N. L'atrésie des voies biliaires intrahépatiques avec voies biliaires extra-hépatiques perméables chez l'enfant (à propos de 25 observations). Paris: Flammarion, 1969: 301–318.Google Scholar) and was defined as syndromic paucity of the intrahepatic bile ducts (BD), associated with at least three of the following five clinical features: cholestasis, heart disease, characteristic face (i.e. widely spaced eyes, long straight nose, thinned mandible, prominent forehead, large ears and high-pitched voice), butterfly-like vertebrae and posterior embryotoxon (2Alagille D Estrada A Hadchouel M Gautier M Odievre M Dommergues JP Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (544) Google Scholar). AS is autosomal-dominant, and mutations in Jagged1, which is crucial for the development of the biliary epithelium, were detected in 1997 (3Oda T Elkahloun AG Pike BL et al.Mutations in the human Jagged1 gene are responsible for Alagille syndrome.Nat Genet. 1997; 16: 235-242Crossref PubMed Scopus (937) Google Scholar). The incidence is estimated as one in 70 000–100 000 live births. Though AS is rare, AS patients show a wide variety of congenital and life-threatening abnormalities (e.g. hepatic, cardiac, vascular, renal, cranial, neural, skeletal and ocular disorders) (2Alagille D Estrada A Hadchouel M Gautier M Odievre M Dommergues JP Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases.J Pediatr. 1987; 110: 195-200Abstract Full Text PDF PubMed Scopus (544) Google Scholar). Kyoto University Hospital performed 656 pediatric living-donor liver transplantations (LDLT) from 1990. This report focused on the long-term outcomes of AS recipients after LDLT, as a follow-up to our previous analysis in 2002 (4Kasahara M Kiuchi T Inomata Y et al.Living-related liver transplantation for Alagille syndrome.Transplantation. 2003; 75: 2147-2150Crossref PubMed Scopus (55) Google Scholar). The 24 AS recipients comprised 15 males and 9 females, and ranged 0.7–13.0 years of age at LDLT. At the time point of LDLT, all 24 cases kept cardiac function after treatments, though mild pulmonary arterial hypertensions were observed in 21 cases. Eleven of twenty-four patients received the gene investigations, and Jagged1 mutations were confirmed in all these cases. Donor relatives were 13 fathers and 11 mothers, though parental mosaicism of Jagged1 mutations in the AS family was documented. Eleven living donors received magnetic resonance cholangiopancreatography and liver needle biopsy before LDLT to exclude inappropriate allografts with BD paucity. ABO blood group analysis found 13 identical, eight compatible and three incompatible. Graft type consisted of 19 lateral-segment, four left-lobe and one reduced mono-segment graft. The graft-to-recipient weight ratio was 2.20 ± 1.01. Four patients eventually died: cause of death and postoperative day (POD) of death were multiple organ failure triggered by intraperitoneal bleeding (POD 40), graft dysfunction as a result of an allograft with unsuspected BD paucity (POD 217), cardiac failure associated with progressive pulmonary arterial stenosis (PAS) (POD 467) and intracranial infarction and pulmonary embolism (POD 3226). Only two patients died from cardiovascular disorders, although 21 of the 24 cases had cardiovascular abnormalities including PAS and tetralogy of Fallot. One patient had a history of hepatocellular carcinoma, and recurrence was not detected. The 20 surviving patients were followed up for 10.0 ± 4.7 years, and survival rates at 5 years and 10 years were 84.3% and 80.9%, respectively (Figure 1). In contrast to other pediatric liver diseases, the indication of LDLT for AS is difficult to establish, because the safety of LDLT for AS is still controversial. However, a manifestation of AS is progressive liver cirrhosis, and survival rates of AS patients with no liver transplant were 51% and 38% at 10 and 20 years, respectively (5Lykavieris P Hadchouel M Chardot C Bernard O Outcome of liver disease in children with Alagille syndrome: A study of 163 patients.Gut. 2001; 49: 431-435Crossref PubMed Scopus (179) Google Scholar). AS worsens during the wait for deceased donor LT, because deceased donor donation is limited in Japan. The donor shortage in deceased donor LT and donor safety in LDLT are crucial in the world. Left-side grafts are safe in living donors, and present an adequate hepatic volume for pediatric recipients. Catch-up growth in AS recipients after LDLT has been confirmed, though with slower growth-velocity than after whole-liver transplantation (4Kasahara M Kiuchi T Inomata Y et al.Living-related liver transplantation for Alagille syndrome.Transplantation. 2003; 75: 2147-2150Crossref PubMed Scopus (55) Google Scholar). The safety of LDLT for AS is controversial due to the risk in donor selection, our AS recipients showed similar overall outcomes after LDLT compared with other pediatric recipients (Figure 1). We suggest that LDLT can further improve AS prognosis and that the indications for LDLT in AS patients may be extended, with careful evaluation of the donor's BD and the recipient's extra-hepatic disorders. This work was partially supported by a grant from the Uehara Memorial Foundation (No. 200940051, Tokyo, 171-0033, Japan). The authors have no financial conflicts of interest. The protocol of this study was approved by the Ethics Review Committee for Clinical Studies of Kyoto University Graduate School of Medicine. T. Hori wrote the paper and performed this research. F. Oike, M. Kasahara, Y. Ogura, S. Sakamoto, K. Ogawa and Y. Yonekawa provided important opinions based on their specialized experiences. H. Doi and M. Ueno assessed cardiac function in AS patients. Prof. S. Uemoto, Prof. Y. Takada and Prof. H. Egawa designed this research. Prof. S. Uemoto and Prof. JH. Nguyen supervised this research.