Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impairs the production or secretion of this hepatocellular protein and leads to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2 to 10% of carriers as neonatal cholestasis and 20 to 35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

Alpha-1 抗胰蛋白酶缺乏症 (AATD) 是由于SERPINA1的遗传变异引起的，SERPINA1 是 AAT 基因，会损害这种肝细胞蛋白的产生或分泌，并导致肝脏蛋白毒性功能获得性。纯合 Pi*Z 致病性变异（Pi*ZZ 基因型）是严重 AATD 的主要原因。2%至10%的携带者表现为新生儿胆汁淤积，20%至35%的成人表现为明显的肝纤维化。儿童和成人都可能出现需要肝移植的终末期肝病。杂合 Pi*Z 致病变异（Pi*MZ 基因型）构成了一种已确定的疾病调节剂。我们的综述总结了儿童和成人 AATD 相关肝病受试者的自然史和治疗。目前 2 期临床试验的结果表明，RNA 沉默可能构成成人 AATD 的可行治疗方法。总之，AATD 是一种日益受到重视的儿童和成人肝脏疾病，正在成为现代药理学策略的一个有吸引力的目标。