Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.
Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.
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DOI：
10.1016/j.jhepr.2022.100483
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发表时间：
2022-06
期刊：
影响因子：
8.3
通讯作者：
Speliotes, Elizabeth K.
中科院分区：
文献类型：
--
作者：
Chen, Vincent L.;Burkholder, Daniel A.;Moran, Isabel J.;V. DiBattista, Jacob;Miller, Matthew J.;Chen, Yanhua;Du, Xiaomeng;Oliveri, Antonino;Cushing, Kelly C.;Lok, Anna S.;Speliotes, Elizabeth K.
α-1抗胰蛋白酶缺乏症是由SERPINA 1突变引起的，最常见的是Pi β Z变体的纯合性，并且可以表现为肝脏疾病。虽然Pi Z（Pi MZ）的杂合性与肝硬化风险增加有关，但Pi MZ基因型是否与已经患有代偿性肝硬化的患者的失代偿率增加有关尚不清楚。这是一项对密歇根基因组计划参与者基线代偿性肝硬化的回顾性研究。主要预测因子是Pi MZ或Pi MS基因型（与Pi MM相比）。主要结局为肝失代偿伴腹水、肝性脑病或静脉曲张出血，或肝脏相关死亡或肝移植的联合终点，均采用Fine-Gray竞争风险模型建模。我们纳入了576例基线代偿性肝硬化患者，他们接受了基因分型，其中474例为Pi MM，49例为Pi MZ，52例为Pi MS基因型。与Pi MM基因型相比，Pi MZ与肝失代偿（风险比1.81; 95% CI 1.22-2.69; p = 0.003）和肝移植或肝脏相关死亡（风险比2.07; 95% CI 1.21-3.52; p = 0.078）的发生率增加相关。在调整基础肝脏疾病的严重程度后，这些相关性仍然显着，并且在基于病因、性别、肥胖和糖尿病状态的亚组分析中表现出稳健性。PI/MS与失代偿或死亡/移植无关。SERPINA 1 Pi MZ基因型与基线代偿性肝硬化患者的肝失代偿率增加和无移植存活率降低相关。SERPINA 1基因中有一种称为Pi MZ的突变，会增加肝瘢痕形成（肝硬化）的风险;然而，如果有人已经患有肝硬化，则不知道Pi MZ有什么影响。在这项研究中，我们发现患有肝硬化和Pi MZ的人比那些没有突变的人更快地发生肝硬化并发症。我们评估了SERPINA Pi PIMZ在代偿性肝硬化队列中的影响。SERPINA 1 Pi MZ与失代偿风险增加相关。Pl-MZ与肝脏相关死亡或肝移植的风险增加有关。在几项敏感性分析中，结果均稳健。
Alpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known. This was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models. We included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation. The SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis. There is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation. We evaluated the impact of SERPINA Pi∗MZ in a compensated cirrhosis cohort. SERPINA1 Pi∗MZ was associated with an increased risk of decompensation vs. Pi∗MM. Pi∗MZ was associated with an increased risk of liver-related death or liver transplant. Findings were robust across several sensitivity analyses.
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