Balcar Lorenz, Fromme Malin, Kappe Naomi, Schaefer Benedikt, Fraňková Soňa, van Melkebeke Lukas, Stolk Jan, Jachs Mathias, Semmler Georg, Hofer Benedikt S, Tergast Tammo L, Rieland Hannah, Karl Anna Sophie, Sperl Jan, Wagner Martin, Pons Mònica, Hofer Harald, Peck-Radosavljevic Markus, Trauner Michael, Reiberger Thomas, Maasoumy Benjamin, Zoller Heinz, van Hoek Bart, Verbeek Jef, Strnad Pavel, Mandorfer Mattias
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
JHEP Rep. 2025 Mar 20;7(6):101398. doi: 10.1016/j.jhepr.2025.101398. eCollection 2025 Jun.
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) causes/predisposes to advanced chronic liver disease. However, the role of the Pi∗ZZ genotype in patients with decompensated cirrhosis is unclear. Thus, we evaluated the impact of the Pi∗ZZ genotype on the disease course after the first hepatic decompensation event.
We retrospectively included 59 adults with decompensated cirrhosis and severe AATD (Pi∗ZZ) from 12 European tertiary care centres. First decompensation was considered as baseline. To compare the course of AATD to other cirrhosis aetiologies, we applied propensity score matching for Child-Turcotte-Pugh (CTP) score as well as age/sex. Patients were followed until further decompensation, liver transplantation or liver-related death.
Most patients were male (74.6%), with a mean age of 55 years. The most common type of first decompensation was ascites (n = 40; 67.8%), followed by variceal bleeding (n = 13; 22.0%) and overt hepatic encephalopathy (n = 6; 10.2%). Median CTP and MELD (model for end-stage liver disease) scores at first decompensation were 8 and 14, respectively. Median MELD scores were 16 and 20 points at listing and liver transplantation (median time on list: 2.9 [IQR 1.1-7.2] months), respectively. Patients with other aetiologies (subdistribution hazard ratio: steatotic liver disease: 0.62, 95% CI 0.44-0.88, 0.007; abstinent alcohol-associated liver disease: 0.50, 95% CI 0.35-0.71, <0.001; hepatitis C virus-associated cirrhosis: 0.56, 95% CI 0.37-0.83, 0.004) had a significantly lower risk of further hepatic decompensation, liver transplantation, or liver-related death, compared to those with Pi∗ZZ. Exchanging further decompensation with acute-on-chronic liver failure yielded similar results.
Our study defines the course of decompensated cirrhosis in patients with severe AATD (Pi∗ZZ), who are particularly prone to complications of cirrhosis and exhibit a more progressive disease course than those with cirrhosis of other aetiologies.
Alpha-1 antitrypsin deficiency is an inherited disease that affects the lung and the liver. Carrying two severely dysfunctional copies of the alpha-1 antitrypsin gene may cause advanced chronic liver disease/cirrhosis. Affected individuals with a first complication of cirrhosis are more prone to developing further liver-related events (including multiorgan dysfunction) and requiring liver transplantation (which cures the inherited liver disease) compared to patients who have similarly advanced liver disease. These findings should prompt the development of disease-modifying treatments and early listing for liver transplantation.
α-1抗胰蛋白酶缺乏症（AATD）可导致/易引发晚期慢性肝病。然而，PiZZ基因型在失代偿期肝硬化患者中的作用尚不清楚。因此，我们评估了PiZZ基因型对首次肝失代偿事件后疾病进程的影响。
我们回顾性纳入了来自12个欧洲三级医疗中心的59例失代偿期肝硬化且患有严重AATD（Pi*ZZ）的成年人。首次失代偿被视为基线。为了将AATD的病程与其他肝硬化病因进行比较，我们对Child-Turcotte-Pugh（CTP）评分以及年龄/性别应用了倾向得分匹配。对患者进行随访，直至出现进一步失代偿、肝移植或肝相关死亡。
大多数患者为男性（74.6%），平均年龄55岁。首次失代偿最常见的类型是腹水（n = 40；67.8%），其次是静脉曲张出血（n = 13；22.0%）和明显的肝性脑病（n = 6；10.2%）。首次失代偿时CTP和终末期肝病模型（MELD）评分的中位数分别为8分和14分。列入名单和肝移植时MELD评分的中位数分别为16分和20分（名单上的中位时间：2.9[IQR 1.1 - 7.2]个月）。与Pi*ZZ患者相比，其他病因的患者（亚分布风险比：脂肪性肝病：0.62，95%CI 0.44 - 0.88，P = 0.007；戒酒相关肝病：0.50，95%CI 0.35 - 0.71，P < 0.001；丙型肝炎病毒相关性肝硬化：0.56，95%CI 0.37 - 0.83，P = 0.004）发生进一步肝失代偿、肝移植或肝相关死亡的风险显著更低。用慢加急性肝衰竭替代进一步失代偿得到了类似结果。
我们的研究明确了严重AATD（Pi*ZZ）患者失代偿期肝硬化的病程，这些患者特别容易发生肝硬化并发症，并且与其他病因的肝硬化患者相比，疾病进展更为迅速。
α-1抗胰蛋白酶缺乏症是一种影响肺和肝脏的遗传性疾病。携带两个严重功能失调的α-1抗胰蛋白酶基因拷贝可能导致晚期慢性肝病/肝硬化。与具有相似晚期肝病的患者相比，首次出现肝硬化并发症的受影响个体更容易发生进一步的肝相关事件（包括多器官功能障碍），并且需要进行肝移植（这可治愈遗传性肝病）。这些发现应促使开发改善疾病的治疗方法，并尽早将患者列入肝移植名单。
