Evans Helen M, Kelly Deirdre A, McKiernan Patrick J, Hübscher Stefan
Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom.
Hepatology. 2006 May;43(5):1109-17. doi: 10.1002/hep.21152.
The long-term histological outcome after pediatric liver transplantation (OLT) is not yet fully understood. De novo autoimmune hepatitis, consisting of histological chronic hepatitis associated with autoantibody formation and allograft dysfunction, is increasingly recognized as an important complication of liver transplantation, particularly in the pediatric population. In this study, 158 asymptomatic children with 5-year graft survival underwent protocol liver biopsies (113, 135, and 64 at 1, 5, and 10 years after OLT, respectively). Histological changes we re correlated with dinical,biochemical, and serological findings. All patients received cydosporine A as primary immunosuppression with withdrawal of corticosteroids at 3 months post OLT. Normal or near-normal histology was reported in 77 of 113 (68%), 61 of 135 (45%), and 20 of 64 (31%) at 1, 5, and 10 years, respectively. The commonest histological abnormality was chronic hepatitis (CH), the incidence of which increased with time [25/113 (22%), 58/135 (43%), and 41/64 (64%) at 1, 5, and 10 years, respectively) (P < .0001)]. The incidence of fibrosis associatedwith CH increasedwith time [13/25 (52%), 47/58 (81%), and 37/41 (91%) at 1, 5, and 10 years, respectively) (P < .0001)]. The severity of fibrosis associated with CH also increased with time, such that by 10 years 15% had progressed to cirrhosis. Aspartate aminotransfemse (AST) levels were slightly elevated in children with CH (median levels 52 IU/L, 63 IU/L, and 48 IU/L at 1, 5, and 10 years, respectively), but this did not reach statistical significance compared with those with normal histology. On multivariate analysis, the only factor predictive of chronic hepatitis was autoantibody positivity (present in 13% and 10% of children with normal biopsies at 5 and 10 years, respectively, and 72% and 80% of those with CH at 5 and 10 years, respectively) (P < .0001). Four children with CH and autoantibodies, who also had raised immunoglobulin G (IgG) levels and AST greater than 1.5 x normal fulfilled the diagnostic criteria for de novo autoimmune hepatitis (AIH). Another two were found to be hepatitis C positive. No definite cause for CH could be identified in the other cases. In condusion, chronic hepatitis is a common finding in children after liver transplantation and is associated with a high risk of developing progressive fibrosis, leading to cirrhosis. Standard liver biochemical tests cannot be relied on either in the diagnosis or in the monitoring of progress of chronic allograft hepatitis. In contrast, the presence ofautoantibodies is strongly associated with the presence of CH. The cause of chronic hepatitis in transplanted allografts is uncertain but may be immune mediated, representing a hepatitic form of chronic rejection.
小儿肝移植（OLT）后的长期组织学转归尚未完全明了。新发自身免疫性肝炎，表现为与自身抗体形成及移植物功能障碍相关的组织学慢性肝炎，日益被视为肝移植的一种重要并发症，尤其在小儿群体中。在本研究中，158例移植肝存活5年的无症状儿童接受了定期肝活检（OLT后1年、5年和10年分别有113例、135例和64例）。组织学改变与临床、生化及血清学检查结果相关。所有患者均接受环孢素A作为初始免疫抑制治疗，OLT后3个月停用皮质类固醇。分别在1年、5年和10年时，113例中的77例（68%）、135例中的61例（45%）和64例中的20例（31%）报告组织学正常或接近正常。最常见的组织学异常为慢性肝炎（CH），其发生率随时间增加[1年、5年和10年时分别为25/113（22%）、58/135（43%）和41/64（64%）]（P<0.0001）。与CH相关的纤维化发生率随时间增加[1年、5年和10年时分别为13/25（52%）、47/58（81%）和37/41（91%）]（P<0.0001）。与CH相关的纤维化严重程度也随时间增加，至10年时已有15%进展为肝硬化。CH患儿的天冬氨酸氨基转移酶（AST）水平略有升高（1年、5年和10年时中位数水平分别为52 IU/L、63 IU/L和48 IU/L），但与组织学正常者相比无统计学意义。多因素分析显示，预测慢性肝炎的唯一因素是自身抗体阳性（5年和10年时活检正常的儿童中分别有13%和10%存在自身抗体，5年和10年时CH患儿中分别有72%和80%存在自身抗体）（P<0.0001）。4例CH且有自身抗体的患儿，同时伴有免疫球蛋白G（IgG）水平升高及AST大于正常上限1.5倍，符合新发自身免疫性肝炎（AIH）的诊断标准。另外2例被发现丙型肝炎病毒阳性。其他病例中未明确CH的病因。总之，慢性肝炎是小儿肝移植后常见的表现，且与发生进行性纤维化进而发展为肝硬化的高风险相关。标准的肝脏生化检查无论是在诊断还是在监测慢性移植肝肝炎进展方面均不可靠。相反，自身抗体的存在与CH密切相关。移植肝中慢性肝炎的病因尚不确定，但可能是免疫介导的，代表一种慢性排斥反应的肝炎形式。
