Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.
Neurology Department, AP-HP, Lariboisière University Hospital, Paris, France; National Reference Centre for Wilson's Disease, AP-HP, Lariboisière University Hospital, Paris, France.
Clin Res Hepatol Gastroenterol. 2018 Dec;42(6):512-520. doi: 10.1016/j.clinre.2018.03.007. Epub 2018 Apr 4.
Wilson's disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of "free copper", or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08μmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), and the disease will be more clinically and radiologically severe as values rise. The use of FibroScan is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness of Fibroscan in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy.
威尔逊病（WD）的特征是肝脏和大脑中铜的有害积累。它是受益于有效和终身治疗的罕见遗传疾病之一，这些治疗方法极大地改变了疾病的预后。在欧洲，其临床患病率估计在每 10 万人中有 1.2 到 2 人，但遗传患病率更高，约为每 7000 人中有 1 人。基因不完全外显或修饰基因的存在可能导致计算出的遗传患病率与被诊断为 WD 的患者人数之间存在差异。WD 的临床表现更为广泛，因为在 6%的患者中，临床表现较轻，疾病在 40 岁以后才出现。当血清铜蓝蛋白和血清铜水平降低，24 小时尿铜排泄增加时，通常会怀疑 WD。最近，随着“游离铜”或可交换铜（CuEXC）的直接测定的实施，取得了一项重大的诊断进展。相对可交换铜（REC）是 CuEXC 与总血清铜之间的比值，当 REC>18.5%时，可以高度敏感和特异性地诊断 WD。此外，诊断时的 CuEXC 值是肝外受累及其严重程度的标志物。值>2.08μmol/L 提示角膜和脑受累（Se=86%，Sp=94%），值升高表明疾病在临床上和影像学上更为严重。现在越来越多地使用 FibroScan 来评估 WD 患者的肝脏硬度测量值。6.6kPa 被认为是轻度和中度纤维化之间的阈值，而高于 8.4 则表明严重纤维化。需要更多的研究来证实 Fibroscan 在管理 WD 患者慢性治疗中的有用性。这种疾病的治疗基于初始的积极和延长的螯合阶段（使用 D-青霉胺或曲恩汀），然后用曲恩汀或锌盐维持。可能遇到的两个主要问题是初始阶段的神经恶化和维持治疗期间的不遵医嘱。对于急性肝衰竭或终末期肝硬化的 WD，肝移植是推荐的治疗选择；尽管有效螯合，但如果神经状态迅速恶化，应考虑进行肝移植。定期进行临床、生物学和肝脏超声随访对于评估疗效、耐受性和治疗依从性至关重要，但也需要检测肝硬化肝脏上肝细胞癌的发生。随着新型螯合剂和铜吸收抑制剂四硫钼酸盐（TTM）的引入以及基因治疗的发展，在不久的将来有望取得进展。
