Zibert Andree, Hüsing-Kabar Anna, Schmidt Hartmut
Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster.
Dtsch Med Wochenschr. 2019 Oct;144(20):1438-1443. doi: 10.1055/a-0848-9610. Epub 2019 Oct 8.
Rare, progressive, and fatal is a short description for autosomal dominant hereditary transthyretin (TTR) amyloidosis (ATTR). In the absence of a family background, delays in diagnosis are common. ATTR is often represented by a progressive, axonal fiber-length-dependent polyneuropathy (motor, autonomic, sensory). Cardiovascular, gastrointestinal, renal and ocular manifestations are frequently observed. ATTR is caused by mutated serum protein transthyretin (TTRm), which results in amyloid deposits.The three current concepts of ATTR treatment aim to replace, stabilize and reduce TTR synthesis. (i) The mutant TTRm is almost completely replaced in the peripheral blood after orthotopic liver transplantation by the synthesis of the wild-type (TTRwt) in the donor liver. (ii) Low molecular weight compounds stabilize the TTR tetramer and thereby minimize the formation of amyloid precursors. (iii) Gene silencers (mRNA-inhibiting oligonucleotides) reduce liver-secreted TTRm and TTRwt.Liver transplantation (LTx) is an established procedure in ATTR patients. LTx significantly prolongs survival, especially in early stage patients (< 50 years) with variant ATTRV30M. Some non-ATTRV30M variants show a higher mortality after LTx. The progression of the disease can be slowed down but not prevented by LTx. Diflunisal is a low-cost, off-label drug from the NSAID group. Similar to Tafamidis, it stabilizes the TTR tetramer. Tafamidis has been approved for the treatment of stage 1 ATTR since 2011. It is administered orally and used in patients with polyneuropathy and more recently with cardiomyopathy. Inotersen represents an antisense oligonucleotide that is administered subcutaneously (s. c.) once a week. Patisiran acts as a siRNA oligonucleotide administered intravenously (i. v.) every three weeks in combination with premedication. Both gene silencers were approved in 2018 for the treatment of ATTR stages 1 and 2. The new era of TTR gene silencers now affords an update of algorithms used for treatment of ATTR.
罕见、进行性且致命，这是常染色体显性遗传性转甲状腺素蛋白（TTR）淀粉样变性（ATTR）的简要描述。在没有家族背景的情况下，诊断延迟很常见。ATTR通常表现为进行性、轴突纤维长度依赖性多神经病（运动、自主神经、感觉）。心血管、胃肠道、肾脏和眼部表现也经常出现。ATTR由突变的血清蛋白转甲状腺素蛋白（TTRm）引起，会导致淀粉样蛋白沉积。目前ATTR治疗的三个理念旨在替代、稳定和减少TTR合成。（i）原位肝移植后，供体肝脏中野生型（TTRwt）的合成几乎可将外周血中的突变型TTRm完全替代。（ii）低分子量化合物可稳定TTR四聚体，从而最大限度减少淀粉样前体的形成。（iii）基因沉默剂（抑制mRNA的寡核苷酸）可减少肝脏分泌的TTRm和TTRwt。肝移植（LTx）是治疗ATTR患者的既定方法。肝移植可显著延长生存期，尤其是对于携带变异型ATTRV30M的早期患者（<50岁）。一些非ATTRV30M变异型在肝移植后死亡率更高。肝移植可减缓疾病进展，但无法阻止。双氟尼酸是一种非甾体抗炎药组的低成本、未按批准说明书用药的药物。与塔非酰胺类似，它可稳定TTR四聚体。自2011年以来，塔非酰胺已被批准用于治疗1期ATTR。它通过口服给药，用于患有多神经病以及最近患有心肌病的患者。依诺特森是一种反义寡核苷酸，每周皮下注射一次。帕替拉韦是一种小干扰RNA寡核苷酸，每三周静脉注射一次，并需进行预处理。这两种基因沉默剂在2018年都被批准用于治疗1期和2期ATTR。现在，TTR基因沉默剂的新时代为用于治疗ATTR的算法提供了更新。
