欧洲成年人杂合子或纯合子 AAT Pi∗Z 变异（Pi∗MZ 与 Pi∗ZZ 基因型）与非携带者的肝脏表型。
Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.
机构信息
Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; Coordinating Center for alpha-1 antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha-1 Liver," University Hospital Aachen, Aachen, Germany.
出版信息
Gastroenterology. 2020 Aug;159(2):534-548.e11. doi: 10.1053/j.gastro.2020.04.058. Epub 2020 May 4.
BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease.
METHODS
We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank.
RESULTS
In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals.
CONCLUSIONS
Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.
背景与目的
编码α-1 抗胰蛋白酶肽（AAT）的基因的 Pi∗Z 变体纯合子（称为 Pi∗ZZ 基因型）导致一种称为α-1 抗胰蛋白酶缺乏症的肝肺疾病。杂合子（Pi∗MZ 基因型）是肝病患者发生肝硬化的危险因素。多达 4%的欧洲人具有 Pi∗MZ 基因型；我们比较了无先存肝病的人群中具有和不具有 Pi∗MZ 基因型的成年人的特征。
方法
我们分析了来自欧洲α-1 肝脏队列的 419 名 Pi∗MZ 基因型成年人、309 名 Pi∗ZZ 基因型成年人和 284 名无变异体（非携带者）成年人的数据。所有成年人都接受了全面评估；使用瞬时弹性成像进行肝硬度测量（LSM）。肝活检分析用于定义与 Pi∗Z 变异相关的组织学和生化特征。来自英国生物银行的 444642 名参与者的血清转氨酶水平被检索。
结果
在英国生物银行数据库中，与非携带者相比，Pi∗MZ 基因型受试者的血清转氨酶水平升高。在α-1 肝脏队列中，Pi∗MZ 基因型的成年人的血清γ-谷氨酰转移酶水平较低，LSM 低于 Pi∗ZZ 变异体的成年人，但高于非携带者。10%的 Pi∗MZ 基因型受试者与 4%的非携带者的 LSM 为 7.1kPa 或更高（调整后的优势比，4.8；95%置信区间，2.0-11.8）。肥胖和糖尿病是 Pi∗MZ 基因型受试者 LSM≥7.1kPa 的最重要相关因素。Pi∗MZ 基因型受试者的肝活检中有 63%检测到 AAT 包涵体，而 Pi∗ZZ 基因型受试者的肝活检中有 97%检测到 AAT 包涵体，且随肝纤维化阶段增加。Pi∗MZ 基因型受试者的肝脏 AAT 水平没有增加，而可溶性 AAT 水平在个体之间有所不同。
结论
Pi∗MZ 基因型的成年人的血清转氨酶水平较低，肝内 AAT 包涵体较少，LSM 低于 Pi∗ZZ 基因型的成年人，但高于无 Pi∗Z 变异体的成年人。这些发现应该有助于确定 Pi∗MZ 基因型受试者的风险，并有助于提供咨询。
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