Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation
Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation
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DOI：
10.1053/j.gastro.2019.05.013
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发表时间：
2019-09-01
期刊：
影响因子：
29.4
通讯作者：
Strnad, Pavel
中科院分区：
文献类型：
--
作者：
Hamesch, Karim;Mandorfer, Mattias;Strnad, Pavel
背景与目的：α-1抗胰蛋白酶缺乏症（AATD）是最常见的遗传性疾病之一.严重的AATD是由编码Glu 342 Lys取代的SERPINA 1基因中的纯合突变（称为Pi*Z突变，Pi*ZZ基因型）引起的。Pi*ZZ携带者可能会发生肺部和肝脏疾病。突变相关的肺部疾病已经得到了很好的研究，但对肝脏的影响知之甚少。我们评估了这种形式的AATD成人的肝脏疾病负担和相关特征。方法：我们收集了来自9个欧洲国家的554名Pi*ZZ成年人（403名在探索性队列中，151名在确证性队列中）的数据，这些成年人患有Pi*Z突变纯合子的AATD，以及234名没有Pi*Z突变的成年人（对照组），所有人都没有预先存在的肝脏疾病。我们收集了有关人口统计学参数、合并症、肺和肝脏相关健康状况的数据，以及用于实验室分析的血液样本。肝纤维化通过血清检测门冬氨酸转氨酶与血小板比率指数和HepaScore以及瞬时弹性成像进行非侵入性评估。通过基于瞬时弹性成像的受控衰减参数确定肝脏脂肪变性。我们对过表达AATD相关Pi*Z变体的转基因小鼠的肝脏进行了组织学分析。结果：Pi*ZZ携带者血清肝酶水平显著高于对照组。基于肝纤维化的非侵入性测试，在20%-36%的Pi*ZZ携带者中怀疑有显著的纤维化，而与非携带者相比，Pi*ZZ携带者中晚期纤维化的体征是非携带者的9- 20倍。男性;年龄大于50岁;丙氨酸氨基转移酶、天冬氨酸氨基转移酶或γ-谷氨酰转移酶水平升高;血小板数量减少与较高的肝纤维化负荷相关。我们没有发现肺功能和肝纤维化之间存在关系的证据。控制衰减参数>= 280 dB/m，表明严重的脂肪变性，在39%的Pi*ZZ携带者和31%的对照中检测到。Pi*ZZ携带者血清甘油三酯、低密度脂蛋白和极低密度脂蛋白胆固醇浓度低于对照组，表明肝脏脂质分泌受损。来自Pi* Z过表达小鼠的肝脏具有脂肪变性和参与脂质分泌的基因的下调。结论：在对具有Pi*ZZ突变的AATD成人和Pi* Z过表达小鼠的研究中，我们发现了肝脏脂肪变性和脂质分泌受损的证据。我们确定了与患者显著肝纤维化相关的因素，这有助于对携带Pi*ZZ突变的个体进行肝脏评估和咨询。ClinicalTrials.gov编号NCT 02929940。
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung-and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9-to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter >= 280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low-and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.