Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency
Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency
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DOI：
10.1136/gutjnl-2020-323729
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发表时间：
2021-02-25
期刊：
影响因子：
24.5
通讯作者：
Strnad, Pavel
中科院分区：
文献类型：
--
作者：
Fromme, Malin;Schneider, Carolin, V;Strnad, Pavel
目的α 1抗胰蛋白酶缺乏症（AATD）是一种常见的、潜在致死性的先天性疾病，由α 1抗胰蛋白酶（AAT）基因突变引起。AAT的“Pi*Z”变体的纯合性（Pi*ZZ基因型）导致肺和肝脏疾病，而杂合的“Pi*Z”携带（Pi*MZ基因型）易患胆结石和肝纤维化。更常见的“Pi*S”变异的临床意义在很大程度上仍不明确，也没有关于AATD肝肿瘤患病率的可靠数据。设计AATD个体和非携带者的基线表型在英国生物库的482380名参与者中进行了分析。多国队列的1104名参与者（586名Pi*ZZ，239名Pi*SZ，279名非携带者）接受了全面的临床评估。相关性根据年龄、性别、体重指数、糖尿病和饮酒量进行了调整。结果在英国生物样本库的参与者中，Pi*ZZ个体显示出最高的肝酶值，肝纤维化/肝硬化（校正OR（aOR）=21.7（8.8-53.7））和原发性肝癌（aOR=44.5（10.8-183.6））的发生率最高。具有Pi*MZ基因型的受试者肝酶轻微升高，肝纤维化/肝硬化（aOR=1.7（1.2-2.2））和胆石症（aOR=1.3（1.2-1.4））的几率中度增加。具有纯合子Pi*S突变（Pi*SS基因型）的个体具有最低限度的丙氨酸氨基转移酶值升高，但没有其他肝胆异常。Pi*SZ受试者的肝酶水平较高，肝纤维化/肝硬化（aOR=3.1（1.1-8.2））和原发性肝癌（aOR=6.6（1.6-26.9））发生率较高。在多国队列中证实了较高的纤维化负荷。男性、年龄>= 50岁、肥胖和糖尿病与严重的肝纤维化相关。结论：我们的研究定义了最相关的AATD基因型个体的肝胆表型，包括他们对肝脏肿瘤的易感性，从而允许基于证据的建议和个性化的肝病监测。
Objective Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. Design Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. Results Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age >= 50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. Conclusion Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.