Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA.
Department of Medicine, University of Florida, Gainesville, Florida, USA.
Aliment Pharmacol Ther. 2024 May;59(10):1183-1195. doi: 10.1111/apt.17967. Epub 2024 Mar 22.
Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD.
To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments.
This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic.
AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies.
This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.
α-1 抗胰蛋白酶肝疾病（AATLD）发生于α-1 抗胰蛋白酶缺乏症患者中的一部分人群。疾病进展的危险因素以及特定的病理生理特征尚不清楚，缺乏用于评估疾病严重程度的非侵入性评估方法。目前，尚无针对 AATLD 的获批治疗方法。
概述对 AATLD 的现有认识，并确定对改善临床试验设计和开发新疗法至关重要的知识空白。
本报告是在由 α-1 抗胰蛋白酶缺乏相关肝病专家小组组织的一次多利益相关者论坛之后编写的，专家在该论坛上介绍了该主题现有文献的概述。
AATLD 是由“获得毒性功能”引起的，主要表现为纯合子 Pi*ZZ 基因型的患者。错误折叠的“Z”AAT 蛋白在肝细胞中的积累触发细胞内肝细胞损伤，最终可能导致肝纤维化。男性、年龄大于 50 岁、持续升高的肝酶、乙型或丙型肝炎病毒感染并存以及代谢综合征（包括肥胖和 2 型糖尿病）是成人 AATLD 的已知危险因素。虽然评估 AATLD 疾病活动度的金标准是肝组织学，但需要具有低内在和观察者间变异性的非侵入性措施。肝硬度测量具有前景；正在开发用于分期 AATLD 的验证阈值。这些进展将通过能够进行风险分层和个性化监测，以及简化新疗法的开发过程，为患者带来帮助。
此次首次论坛提出了一系列建议，以解决 AATLD 领域的未满足需求。
