Teckman Jeffrey H, Buchanan Paula, Blomenkamp Keith Steven, Heyer-Chauhan Nina, Burling Keith, Lomas David A
Department of Pediatrics and Biochemistry and Molecular Biology, St. Louis University School of Medicine, Cardinal Glennon Children's Hospital, St. Louis, Missouri.
Department of Health and Clinical Outcomes Research, St. Louis University School of Medicine, St. Louis, Missouri.
Gastro Hep Adv. 2024 Apr 26;3(6):842-850. doi: 10.1016/j.gastha.2024.04.010. eCollection 2024.
Children with alpha-1-antitrypsin deficiency (AATD) exhibit a wide range of liver disease outcomes from portal hypertension and transplant to asymptomatic without fibrosis. Individual outcomes cannot be predicted. Liver injury in AATD is caused by the accumulation in hepatocytes of the mutant Z alpha-1-antitrypsin (AAT) protein, especially the toxic, intracellular polymerized conformation. AATD patients have trace Z polymer detectable in serum with unknown significance.
The Childhood Liver Disease Research Network is an NIH consortium for the study of pediatric liver diseases, including AATD. We obtained data and samples with the aim of identifying biomarkers predictive of severe AATD liver disease.
We analyzed prospective AATD Childhood Liver Disease Research Network data and serum samples in 251 subjects from 2007 to 2015 for outcomes and Z polymer levels. Fifty-eight of 251 had clinically evident portal hypertension (CEPH) at enrollment, and 10 developed CEPH during follow-up. Higher Z AAT polymer levels were associated with existing CEPH ( = .01). In infants without CEPH, higher polymer levels were associated with future CEPH later in childhood, but total AAT was not predictive. Higher gamma-glutamyl transferase (GGT) in the first few months of life was also significantly associated with future CEPH, and risk-threshold GGT levels can be identified. A model was constructed to identify subjects at high risk of future CEPH by combining clinical GGT and polymer levels (area under the curve of 0.83; 95% confidence interval: 0.656-1.00, = .019).
High circulating Z polymer levels and high GGT early in life are associated with future CEPH in AATD, and the use of predictive cutoffs may assist in future clinical trial design.
α-1抗胰蛋白酶缺乏症（AATD）患儿的肝病结局范围广泛，从门静脉高压和肝移植到无纤维化的无症状状态。个体结局无法预测。AATD中的肝损伤是由突变的Z型α-1抗胰蛋白酶（AAT）蛋白在肝细胞中积累所致，尤其是有毒的细胞内聚合构象。AATD患者血清中可检测到微量Z聚合物，其意义不明。
儿童肝病研究网络是美国国立卫生研究院（NIH）下属的一个研究儿童肝病（包括AATD）的联盟。我们获取数据和样本，旨在识别预测严重AATD肝病的生物标志物。
我们分析了2007年至2015年儿童肝病研究网络中251名AATD受试者的前瞻性数据和血清样本，以了解结局和Z聚合物水平。251名受试者中有58名在入组时患有临床明显的门静脉高压（CEPH），10名在随访期间出现CEPH。较高的Z AAT聚合物水平与现有的CEPH相关（P = 0.01）。在无CEPH的婴儿中，较高的聚合物水平与儿童期后期发生的未来CEPH相关，但总AAT无预测价值。出生后最初几个月较高的γ-谷氨酰转移酶（GGT）水平也与未来CEPH显著相关，且可确定风险阈值GGT水平。通过结合临床GGT和聚合物水平构建了一个模型，以识别未来发生CEPH的高危受试者（曲线下面积为0.83；95%置信区间：0.656 - 1.00，P = 0.019）。
高循环Z聚合物水平和生命早期高GGT水平与AATD患者未来发生CEPH相关，使用预测临界值可能有助于未来临床试验设计。
