Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno‐associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune‐mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre‐existing liver conditions. Liver biopsy data conducted years post‐gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug‐induced liver injury (DILI) based on Hy's Law criteria. Essential pre‐therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non‐invasive fibroscans, while novel blood‐based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long‐term effects on the liver, providing insights for optimising gene therapy for haemophilia.

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基因治疗后肝炎，可能的原因有哪些？

肝炎是血友病基因治疗后常见的不良事件，通常与转基因表达的丧失有关。调查其潜在原因和影响对于治疗的整体成功至关重要。使用腺相关病毒 (AAV) 载体的基因治疗试验已显示出可喜的结果，其特点是因子 FVIII 和 FIX 水平增加以及出血次数减少。然而，已注意到以丙氨酸转氨酶 (ALT) 升高为特征的肝细胞损伤。这种肝损伤通常是短暂的且无症状，这给确定其临床意义带来了挑战。提出的原因包括免疫介导的反应，特别是对 AAV 载体的 T 细胞细胞毒性、病毒衣壳或转录蛋白通过未折叠蛋白反应和预先存在的肝脏状况造成的直接肝损伤。基因治疗输注后数年进行的肝活检数据显示，肝窦浸润，无明显炎症。基因治疗的总体安全性仍然良好，根据海氏定律标准没有药物性肝损伤（DILI）的证据。基本的治疗前监测和识别肝损伤高风险患者应包括肝功能测试和非侵入性纤维扫描，同时新的基于血液的生物标志物正在探索中。需要进一步的研究来理解转氨炎、转基因表达缺失和对肝脏的长期影响的机制，为优化血友病基因治疗提供见解。