Multi-Society Expert Panel Consensus Guidance Regarding Clinical Assessment and Clinical Trial Endpoints in Adults With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease.

Lack of standardized definitions, diagnostic criteria, and staging impedes timely diagnosis and therapeutic development.

缺乏标准化的定义、诊断标准和分期阻碍了及时诊断和治疗开发。

To address these gaps, a multi-disciplinary expert panel convened under the auspices of the American Gastroenterological Association in collaboration with the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Alpha-1 Foundation to develop consensus recommendations for nomenclature, diagnosis, staging, and clinical trial endpoints in AATD-LD.

为了填补这些空白，美国胃肠病学会在美国肝病研究协会、欧洲肝病研究协会和Alpha-1基金会的协助下，召集了一个多学科专家小组，制定了关于AATD-LD的命名、诊断、分期和临床试验终点的共识建议。

Methods

An international multi-disciplinary expert consensus synthesized data from recent epidemiologic, histopathologic, and noninvasive biomarker studies related to AATD-LD.

一个国际多学科专家共识综合了最近关于AATD-LD的流行病学、组织病理学和非侵入性生物标志物研究的数据。

Expert opinion was integrated with published evidence to establish case definitions, staging algorithms, and clinical trial endpoint criteria.

综合专家意见与已发表的证据，建立了病例定义、分期算法和临床试验终点标准。

Results

AATD-LD is defined by the presence of liver enzyme (ie, aspartate aminotransferase, alanine aminotransferase, or γ-glutamyl transferase) elevations-which may be episodic-and/or liver fibrosis (≥F2) in adults with AATD, particularly those with the PiZZ genotype.

AATD-LD的定义是基于成人AATD患者（特别是PiZZ基因型患者）存在肝酶（即天冬氨酸氨基转移酶、丙氨酸氨基转移酶或γ-谷氨酰转移酶）升高-可能是间歇性的-和/或肝纤维化（≥F2）。

Liver stiffness measurement by means of noninvasive elastography (eg, vibration-controlled transient elastography and magnetic resonance elastography) was identified as the preferred method for staging fibrosis, with liver stiffness measurement ≥8 kPa by means of vibration-controlled transient elastography as a threshold for clinically significant fibrosis.

通过非侵入性弹性成像技术（例如，振动控制瞬时弹性成像和磁共振弹性成像）测量的肝脏硬度被确定为分期纤维化的首选方法，振动控制瞬时弹性成像测量的肝脏硬度≥8 kPa作为临床显著纤维化的阈值。

Aspartate aminotransferase-to-platelet ratio (<0.5) and fibrosis-4 index (<1.3) (low risk for advanced liver disease) were endorsed for risk stratification, although their sensitivity is limited.

尽管其敏感性有限，但还是推荐使用天冬氨酸氨基转移酶与血小板比率（<0.5）和纤维化-4指数（<1.3）（低风险的晚期肝病）来进行风险分层。

A foundational, tiered algorithm was developed to guide longitudinal monitoring and staging, incorporating serial noninvasive testing and timely referral for liver transplantation evaluation.

开发了一套基础的分层算法，用于指导纵向监测和分期，包括连续的非侵入性检测和及时转诊进行肝脏移植评估。

For clinical trial design, adults with F2-F4 fibrosis were recommended for inclusion in phase 3 trials; earlier stages (eg, F1) may be appropriate for phase 1-2 safety studies and patients with cirrhosis may be excluded, depending on therapeutic class.

在临床试验设计方面，建议将F2-F4期纤维化的成人纳入III期试验；更早的阶段（例如，F1期）可能适合纳入I-II期的安全性研究，而根据治疗类别，可能需要排除肝硬化患者。

Preservation of pulmonary function was not deemed necessary for inclusion in trials of therapies that increase AAT levels via DNA or RNA editing.

通过DNA或RNA编辑提高AAT水平的治疗试验中，不认为必须保留肺功能。

The consensus primary efficacy endpoint is a ≥1-stage improvement in fibrosis.

共识的主要疗效终点是纤维化改善≥1级。

Conclusions

These consensus statements provide a unified framework for diagnosing, staging, and studying AATD-LD.

这些共识声明为诊断、分期和研究AATD-LD提供了一个统一的框架。

Broad adoption will improve disease recognition, optimize clinical management, and facilitate therapeutic development.

广泛采用将提高疾病识别，优化临床管理，并促进治疗开发。