原位肝移植(OLT)是第一个能够改变遗传性甲状腺素运载蛋白(ATTRv)淀粉样变性自然病程的治疗方法,这是一种罕见且致命的疾病,由不同器官和组织中错误折叠的甲状腺素运载蛋白(TTR)变体的积累引起,并导致进行性和多系统功能障碍。因为肝脏是TTR的主要来源,OLT大大降低了致病性TTR变体的产生,这应该防止淀粉样蛋白形成并阻止疾病进展。然而,由于野生型TTR沉积,OLT后可能发生淀粉样变性进展,尤其是神经和心脏.在这次审查中,我们讨论了影响OLT结局的疾病特征和OLT后ATTRv淀粉样变性进展的临床表现,以提高我们对OLT后疾病恶化的认识,并优化这些患者的随访和临床管理.通过对PubMed数据库进行文献综述,我们确定了与OLT后不良结局相关的患者特征,包括晚发性V50M和非V50M变体,年龄>40岁,疾病持续时间长,晚期神经病和自主神经功能障碍,和营养不良。关于OLT后死亡率,OLT后第一年内的死亡主要与致命的移植物并发症和传染病有关,而心血管相关的死亡通常发生在较晚的时候.考虑到OLT后ATTRv淀粉样变性进展的不同临床表现,包括恶化的神经病和/或心肌病,自主神经功能障碍,和眼膜受累,我们就评估OLT后疾病进展的最相关测试提出建议.最后,我们讨论了基于TTR稳定剂和TTRmRNA沉默剂的新疗法用于治疗OLT后ATTRv淀粉样变性患者。
Orthotopic liver transplantation (OLT) was the first treatment able to modify the natural course of hereditary transthyretin (ATTRv) amyloidosis, which is a rare and fatal disorder caused by the accumulation of misfolded transthyretin (
TTR) variants in different organs and tissues and which leads to a progressive and multisystem dysfunction. Because the liver is the main source of TTR, OLT dramatically reduces the production of the pathogenic
TTR variant, which should prevent amyloid formation and halt disease progression. However, amyloidosis progression may occur after OLT due to wild-type TTR deposition, especially in the nerves and heart. In this
review, we discuss the disease features influencing OLT outcomes and the clinical manifestations of ATTRv amyloidosis progression post-OLT to improve our understanding of disease worsening after OLT and optimize the follow-up and clinical management of these patients. By conducting a literature
review on the PubMed database, we identified patient characteristics that have been associated with worse post-OLT outcomes, including late-onset V50M and non-V50M variants, age >40 years, long disease duration, advanced neuropathy and autonomic dysfunction, and malnutrition. Regarding post-OLT mortality, deaths occurring within the first year after OLT were mainly associated with fatal graft complications and infectious diseases, whereas cardiovascular-related deaths usually occurred later. Considering the diverse clinical manifestations of ATTRv amyloidosis progression post-OLT, including worsening neuropathy and/or cardiomyopathy, autonomic dysfunction, and oculoleptomeningeal involvement, we present advice on the most relevant tests for assessing disease progression post-OLT. Finally, we discuss the use of new therapies based on
TTR stabilizers and
TTR mRNA silencers for the treatment of ATTRv amyloidosis patients post-OLT.