未经证实:α-1抗胰蛋白酶(AAT)缺乏导致/易使个体患晚期慢性肝病(ACLD)。然而,SERPINA1Pi*Z等位基因在已经进展为ACLD的患者中的作用尚不清楚。因此,我们的目的是评估Pi*Z等位基因对ACLD患者肝移植/肝脏相关死亡风险的影响,同时调整纳入时肝脏疾病的严重程度。
UNASSIGNED:共有1,118例ACLD患者在维也纳肝脏血流动力学实验室进行了肝静脉压力梯度(HVPG)测量和Pi*Z/Pi*S等位基因基因分型。感兴趣的结果是肝移植/肝脏相关死亡,而非肝脏相关死亡和去除/抑制主要病因被认为是竞争风险。
未经证实:病毒性肝炎是最常见的病因(44%),其次是酒精相关(31%)和非酒精性脂肪性肝病(11%)。42(4%)和46(4%)名患者携带Pi*Z和Pi*S变体,分别。Pi*Z携带者的门静脉高压症(HVPG:19±6vs.15±7mmHg;p<0.001)和肝功能异常(Child-Turcotte-Pugh:7.1±1.9vs.6.5±1.9分;p=0.050)在夹杂物,与非运营商相比。相反,Pi*S等位基因与肝病严重程度无关。在竞争风险回归分析中,携带Pi*Z等位基因与肝移植/肝脏相关死亡的概率增加显着相关,即使在纳入时调整了肝脏疾病的严重程度。常见Pi*MZ基因型的有害影响(调整后的子分布风险比:≈1.56与Pi*MM)在完全调整的亚组分析中得到证实。相比之下,Pi*S携带者的事件风险没有增加。
UASSIGNED:Pi*Z等位基因的基因分型可识别ACLD患者的不良肝脏相关结局风险增加,从而改善预后。针对异常AAT积累的疗法应评估为具有ACLD的Pi*Z等位基因携带者的疾病改善治疗。
UNASSIGNED:α-1抗胰蛋白酶缺乏症是一种影响肺部和肝脏的遗传性疾病。携带两个功能失调的基因拷贝会导致晚期肝病。携带一个功能失调的副本会增加患有其他肝病的患者的疾病严重程度。然而,这种遗传缺陷在已经患有晚期肝病的患者中的意义尚不清楚。我们的研究发现,携带至少一个功能失调的α-1抗胰蛋白酶基因拷贝会增加需要肝移植或死于肝病的风险。这表明需要旨在治疗这种遗传缺陷的肝脏后果的医学疗法。
UNASSIGNED: Alpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi∗Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi∗Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion.
UNASSIGNED: A total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi∗Z/Pi∗S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks.
UNASSIGNED: Viral hepatitis was the most common etiology (44%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi∗Z and Pi∗S variants, respectively. Pi∗Z carriers had more severe portal hypertension (HVPG: 19±6 vs.15±7 mmHg; p <0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1±1.9 vs. 6.5±1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi∗S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi∗Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi∗MZ genotype (adjusted subdistribution hazard ratio: ≈1.56 vs. Pi∗MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi∗S carriers had no increased risk of events.
UNASSIGNED: Genotyping for the Pi∗Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease-modifying treatments in Pi∗Z allele carriers with ACLD.
UNASSIGNED: Alpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect.