Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Saint Louis University, St Louis, Missouri, USA.
Department of Health and Clinical Outcomes Research AHEAD Institute, Saint Louis University, St Louis, Missouri, USA.
Liver Int. 2024 Dec;44(12):3204-3213. doi: 10.1111/liv.16094. Epub 2024 Sep 12.
The course of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined.
A prospective cohort, including protocol liver biopsies, was enrolled to address these questions.
We enrolled 96 homozygous ZZ AATD adults prospectively at three US sites with standardized clinical evaluations, and protocol liver biopsies. Fibrosis was scored using Ishak (stages 0-6). Also, 51% of the 96 subjects had Ishak score >1 fibrosis (49% Ishak 0-1, 36% Ishak 2-3 and 15% ≥4). Elevated aspartate aminotransferase (AST) more than alanine aminotransferase (ALT), high body mass index (BMI), obesity, AST platelet ratio index and elevated serum Z alpha 1 antitrypsin (AAT) polymer levels were associated with increased fibrosis. Steatosis did not correlate to fibrosis. Increased fibrosis was associated with increased mutant Z polymer globular inclusions (p = .002) and increased diffuse cytoplasmic Z polymer on biopsy (p = .0029) in a direct relationship. Increased globule Z polymer was associated with increased serum AST (p = .007) and increased periportal inflammation on histopathology (p = .004), but there was no relationship of Z polymer hepatocellular accumulation with ALT, gamma glutamine transferase, inflammation in other parts of the lobule, necrosis or steatosis. Serum Z polymer levels were directly correlated to hepatic Z protein polymer content. Lung function, smoking and alcohol consumption patterns were not associated with fibrosis.
In AATD high BMI, obesity and elevated AST are associated with increased fibrosis. Liver biopsy features are correlated to some serum tests. Serum Z AAT polymer levels could be a future biomarker to detect fibrosis early and is directly correlated to liver Z content.
成人 ZZ 型α-1-抗胰蛋白酶缺乏症（AATD）肝脏疾病的病程是不可预测的。包括肝活检在内的标志物的效用尚未确定。
通过前瞻性队列研究，包括协议肝活检，来解决这些问题。
我们前瞻性地在三个美国地点招募了 96 名纯合子 ZZ AATD 成年人，进行了标准化的临床评估和协议肝活检。纤维化使用 Ishak 评分（0-6 级）进行评分。此外，96 名受试者中有 51%的 Ishak 评分>1 纤维化（49%Ishak 0-1，36%Ishak 2-3，15%≥4）。天门冬氨酸氨基转移酶（AST）高于丙氨酸氨基转移酶（ALT）、高体重指数（BMI）、肥胖、AST 血小板比值指数和血清 Z 型α 1 抗胰蛋白酶（AAT）聚合物水平升高与纤维化增加相关。脂肪变性与纤维化不相关。增加的纤维化与肝活检中增加的突变 Z 聚合物球状包涵物（p=0.002）和弥漫性细胞质 Z 聚合物（p=0.0029）呈直接相关。球蛋白 Z 聚合物增加与血清 AST 增加（p=0.007）和肝组织病理学上门管区周围炎症增加（p=0.004）相关，但 Z 聚合物在肝细胞内的积累与 ALT、γ-谷氨酰转移酶、小叶其他部位的炎症、坏死或脂肪变性无关。血清 Z 聚合物水平与肝内 Z 蛋白聚合物含量直接相关。肺功能、吸烟和饮酒模式与纤维化无关。
在 AATD 中，高 BMI、肥胖和 AST 升高与纤维化增加有关。肝活检特征与某些血清检测相关。血清 Z AAT 聚合物水平可能是一种早期检测纤维化的未来生物标志物，并且与肝内 Z 含量直接相关。
