Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
Clin Gastroenterol Hepatol. 2024 Feb;22(2):283-294.e5. doi: 10.1016/j.cgh.2023.08.038. Epub 2023 Sep 15.
BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown.
Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation.
Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted.
The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.
α1-抗胰蛋白酶（AAT）是由肝细胞产生的主要蛋白酶抑制剂。导致 AAT 缺乏症（AATD）的最相关 AAT 突变，即“Pi∗Z”变体，导致有害的 AAT 蛋白在肝脏中积累，全身循环中的 AAT 短缺，从而易导致肝脏和肺部损伤。虽然静脉内 AAT 增强构成了 AATD 相关肺部疾病的既定治疗方法，但它对肝脏的影响尚不清楚。
在一个由 760 名患有严重 AATD（Pi∗ZZ 基因型）的成年人组成的多国家队列中评估了与肝脏相关的参数，这些成年人有可用的肝脏表型，并接受了增强治疗（n=344）或未接受增强治疗（n=416）。通过血清天门冬氨酸转氨酶与血小板比值指数和基于瞬时弹性成像的肝硬度测量来非侵入性地评估肝纤维化。在 15 名接受增强治疗和 35 名未接受增强治疗的 Pi∗ZZ 成年人中比较了组织学参数。
与未增强的个体相比，接受增强治疗的 Pi∗ZZ 个体的血清肝酶水平较低（天冬氨酸转氨酶 71% vs 正常上限的 75%，P <.001；胆红素 49% vs 正常上限的 58%，P=.019），纤维化的替代标志物也较低（AST 与血小板比值指数 0.34 vs 0.38，P <.001；肝硬度测量值 6.5 vs 7.2 kPa，P=.005）。在接受活检的参与者中，接受增强治疗的个体肝纤维化程度较轻，炎症灶较少，但未发现 AAT 积累的差异。
这是首次评估 AAT 增强治疗对 Pi∗ZZ 相关肝病的影响，表明广泛用于治疗 AATD 相关肺部疾病的治疗方法对肝脏是安全的。需要进行前瞻性研究以确认其有益效果，并证明外源性 AAT 在 Pi∗ZZ 相关肝病患者中的潜在疗效。
