Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies.
Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies.
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DOI：
10.1007/s40120-020-00210-7
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发表时间：
2020-12
影响因子：
3.7
通讯作者：
Katsuno M
中科院分区：
文献类型：
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作者：
Koike H;Katsuno M
ATTR淀粉样变性是由全身性的转甲状腺蛋白(TTR)沉积引起的，包括ATTRUPT(野生型)淀粉样变性、ATTRv(v变异型)淀粉样变性和多米诺骨牌肝移植后获得性ATTR淀粉样变性。ATTRUT淀粉样变性被经典地认为是在老年人中发现的心肌病，而腕管综合征也成为主要的首发症状。ATTRv淀粉样变性的表型多种多样，主要表现为神经病变、心肌病和眼脑膜受累，具体取决于突变和发病年龄。除了变异型Ttr外，野生型Ttr的沉积也起着重要作用，甚至在ATTRv淀粉样变性患者中也是如此。淀粉样蛋白纤维的形成往往与基底膜有关。在ATTRv淀粉样变性中观察到神经内膜微血管周围的基底膜增厚或重复，这类似于糖尿病神经病变，提示共同的机制，如晚期糖基化终产物的积累，可能参与了疾病过程。除了淀粉样蛋白纤维引起的直接损伤外，最近的研究表明，非纤维TTRs的毒性，如TTR寡聚体，参与了组织损伤的过程。虽然自1990年以来，ATTRv淀粉样变性患者一直接受肝移植治疗，但发病较晚的患者没有资格接受这种治疗。然而，随着口服他法米迪和二氟尼柳稳定TTR四聚体的疗效在2010年代初被提出，这类晚发患者也成为疾病修正治疗的目标。此外，最近对小干扰RNA(Patisiran)和反义寡核苷酸(Inotersen)疗法的研究已经证明了这些基因沉默药物的有效性。应该建立一种监测患者的战略，使其能够从全面和长期的角度选择适当的治疗方法。由于许多Attr淀粉样变性患者年龄较大，并有心力衰竭，如果他们感染SARS-CoV2，他们病情恶化的风险会增加。评估的最佳间隔也应该被考虑，特别是在这个新冠肺炎时代。
ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end products, may participate in the disease process. In addition to direct damage caused by amyloid fibrils, recent studies have suggested that the toxicity of nonfibrillar TTRs, such as TTR oligomers, participates in the process of tissue damage. Although liver transplantation has been performed for patients with ATTRv amyloidosis since 1990, late-onset patients were not eligible for this treatment. However, as the efficacy of orally administered tafamidis and diflunisal, which stabilize TTR tetramers, was suggested in the early 2010s, such late-onset patients have also become targets for disease-modifying therapies. Additionally, recent studies of small interfering RNA (patisiran) and antisense oligonucleotide (inotersen) therapies have demonstrated the efficacy of these gene-silencing agents. A strategy for monitoring patients that enables the choice of an appropriate treatment from comprehensive and long-term viewpoints should be established. As many patients with ATTR amyloidosis are aged and have heart failure, they are at increased risk of aggravation if they are infected by SARS-CoV2. The optimal interval of evaluation should also be considered, particularly in this COVID-19 era.