Ronca Vincenzo, Parente Alessandro, Lytvyak Ellina, Hansen Bettina E, Hirschfield Gideon, Bonder Alan, Ebadi Maryam, Elwir Saleh, Alsaed Mohamad, Milkiewicz Piotr, Janik Maciej K, Marschall Hanns-Ulrich, Burza Maria Antonella, Efe Cumali, Rıza Calışkan Ali, Harputluoglu Murat, Kabaçam Gökhan, Terrabuio Débora, de Quadros Onofrio Fernanda, Selzner Nazia, Parés Albert, Llovet Laura, Akyıldız Murat, Arikan Cigdem, Manns Mihael P, Taubert Richard, Weber Anna-Lena, Schiano Thomas D, Haydel Brandy, Czubkowski Piotr, Socha Piotr, Ołdak Natalia, Akamatsu Nobuhisa, Tanaka Atsushi, Levy Cynthia, Martin Eric F, Goel Aparna, Sedki Mai, Jankowska Irena, Ikegami Toru, Rodriguez Maria, Sterneck Martina, Sebode Marcial, Schramm Christoph, Donato Maria Francesca, Colapietro Francesca, Lohse Ansgar, Andrade Raul J, Patwardhan Vilas R, van Hoek Bart, Biewenga Maaike, Kremer Andreas E, Ueda Yoshihide, Deneau Mark, Pedersen Mark, Mayo Marlyn J, Floreani Annarosa, Burra Patrizia, Secchi Maria Francesca, Terziroli Beretta-Piccoli Benedetta, Sciveres Marco, Maggiore Giuseppe, Jafri Syed-Mohammed, Debray Dominique, Girard Muriel, Lacaille Florence, Heneghan Michael, Mason Andrew L, Oo Ye, Montano-Loza Aldo J
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.
IRCCS Humanitas Research Hospital, Rozzano, Italy.
JHEP Rep. 2025 Mar 10;7(5):101332. doi: 10.1016/j.jhepr.2025.101332. eCollection 2025 May.
BACKGROUND & AIMS: A significant proportion of patients with variant syndromes (VSs), namely autoimmune hepatitis/primary biliary cholangitis or autoimmune hepatitis/primary sclerosing cholangitis, require liver transplantation (LT) despite treatment. The frequency of disease recurrence and the effect on graft survival are yet to be clarified. The aim of this international, multicentric, retrospective study is to evaluate the risk factors associated with recurrence and the impact of the disease recurrence after LT on graft and patient survival.
We evaluated 166 patients undergoing LT for VS in 33 centers in North America, South America, Europe, and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients with a higher risk of recurrence of autoimmune disease based on a histological and radiological diagnosis. Cumulative probabilities of graft and overall survival after LT were calculated using a semi-Markov model.
The autoimmune pattern of recurrence resembled the original VS in 19 cases (61%). Recurrence of autoimmune liver disease (ALD) after LT was observed in 23% and 33% of patients after 5 and 10 years, respectively. Increased alkaline phosphatase (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.13-2.25, <0.01) and alanine aminotransferase (HR 1.25, 95% CI 1.01-1.53, = 0.03) at 12 months after LT and acute rejection (HR 3.58, 95% CI 1.60-7.73, <0.01) were associated with a higher risk of VS recurrence, whereas the use of predniso(lo)ne was associated with a reduced risk (HR 0.30, 95% CI 0.14-0.64, <0.01). After adjusting for alanine aminotransferase and alkaline phosphatase at 12 months, the use of predniso(lo)ne was found to be independently and negatively associated with recurrent disease. The ALD was found to be significantly associated with graft loss and patient survival in the multivariate Cox regression analysis with a time-dependent covariate. The 5- and 10-year probabilities of graft survival were 68% and 41% in patients with recurrent VS compared with 83% and 60% in patients without recurrent disease, respectively ( = 0.01). The overall survival was significantly reduced in patients with recurrent disease ( = 0.01), with event probability at 5 and 10 years of 75% and 49% . 84% and 60% in patients without recurrence, respectively.
ALD after LT is frequent and is associated with elevation in liver enzymes within the first year after LT and rejection episodes. According to our data, VS recurrence appears to be associated with poorer graft and patient survival. Further studies are needed to explore strategies that can prevent VS recurrence or mitigate its potential impact.
This study investigated the recurrence of autoimmune liver diseases (rALD) in patients transplanted for variant syndromes (VSs) and its effect on graft and patient survival. The findings reveal a significant association between ALD and poorer graft and overall survival, highlighting the need for preventive strategies. This research is crucial for transplant physicians and healthcare providers, as it underscores the impact of early liver enzyme monitoring and tailored immunosuppressive therapy on long-term outcomes. These insights can inform more effective post-LT management protocols, potentially improving patient prognosis.
相当一部分患有变异综合征（VSs）的患者，即自身免疫性肝炎/原发性胆汁性胆管炎或自身免疫性肝炎/原发性硬化性胆管炎，尽管接受了治疗仍需要肝移植（LT）。疾病复发的频率及其对移植物存活的影响尚待阐明。这项国际多中心回顾性研究的目的是评估与复发相关的危险因素以及LT后疾病复发对移植物和患者存活的影响。
我们评估了北美、南美、欧洲和亚洲33个中心接受LT治疗VS的166例患者。分析LT前后的临床数据、LT后前12个月的生化数据以及LT后的免疫抑制情况，以根据组织学和放射学诊断确定自身免疫性疾病复发风险较高的患者。使用半马尔可夫模型计算LT后移植物和总体存活的累积概率。
19例（61%）患者的自身免疫复发模式与原始VS相似。LT后自身免疫性肝病（ALD）复发在5年和10年后分别见于23%和33%的患者。LT后12个月碱性磷酸酶升高（风险比[HR]1.60，95%置信区间[CI]1.13 - 2.25，P<0.01）和丙氨酸氨基转移酶升高（HR 1.25，95% CI 1.01 - 1.53，P = 0.03）以及急性排斥反应（HR 3.58，95% CI 1.60 - 7.73，P<0.01）与VS复发风险较高相关，而使用泼尼松（龙）与风险降低相关（HR 0.30，95% CI 0.14 - 0.64，P<0.01）。在调整LT后12个月的丙氨酸氨基转移酶和碱性磷酸酶后，发现使用泼尼松（龙）与复发性疾病独立且呈负相关。在多变量Cox回归分析中，ALD与移植物丢失和患者存活显著相关，具有时间依赖性协变量。复发性VS患者的5年和10年移植物存活概率分别为68%和41%，而无复发性疾病患者分别为83%和60%（P = 0.01）。复发性疾病患者的总体存活显著降低（P = 0.01），5年和10年事件概率分别为75%和49%，无复发患者分别为84%和60%。
LT后ALD很常见，并且与LT后第一年肝酶升高和排斥反应发作相关。根据我们的数据，VS复发似乎与较差的移植物和患者存活相关。需要进一步研究探索能够预防VS复发或减轻其潜在影响的策略。
本研究调查了因变异综合征（VSs）接受移植患者的自身免疫性肝病复发（rALD）及其对移植物和患者存活的影响。研究结果揭示了ALD与较差的移植物和总体存活之间存在显著关联，凸显了预防策略的必要性。这项研究对移植医生和医疗服务提供者至关重要，因为它强调了早期肝酶监测和定制免疫抑制治疗对长期结局的影响。这些见解可为更有效的LT后管理方案提供依据，可能改善患者预后。
