Ryan Aidan, Nevitt Sarah J, Tuohy Orla, Cook Paul
University Hospital Southampton NHS Foundation Trust, Department of Clinical Biochemistry, 17 Tremona Road, Southampton, UK, SO16 6YD.
University of Liverpool, Department of Biostatistics, Block F, Waterhouse Building, 1-5 Brownlow Hill, Liverpool, UK, L69 3GL.
Cochrane Database Syst Rev. 2019 Nov 19;2019(11):CD012267. doi: 10.1002/14651858.CD012267.pub2.
Wilson's disease, first described by Samuel Wilson in 1912, is an autosomal recessive metabolic disorder resulting from mutations in the ATP7B gene. The disease develops as a consequence of copper accumulating in affected tissues. There is no gold standard for the diagnosis of Wilson's disease, which is often delayed due to the non-specific clinical features and the need for a combination of clinical and laboratory tests for diagnosis. This delay may in turn affect clinical outcome and has implications for other family members in terms of diagnosis. The Leipzig criteria were established to help standardise diagnosis and management. However, it should be emphasised that these criteria date from 2003, and many of these have not been formally evaluated; this review examines the evidence behind biochemical testing for Wilson's disease.
To determine the diagnostic accuracy of three biochemical tests at specified cut-off levels for Wilson's disease. The index tests covered by this Cochrane Review are caeruloplasmin, 24-hour urinary copper and hepatic copper content. These tests were evaluated in those with suspected Wilson's disease and appropriate controls (either healthy or those with chronic liver disease other than Wilson's). In the absence of a gold standard for diagnosing Wilson's disease, we have used the Leipzig criteria as a clinical reference standard. To investigate whether index tests should be performed in all individuals who have been recommended for testing for Wilson's disease, or whether these tests should be limited to subgroups of individuals.
We identified studies by extensive searching of, e.g. the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the Web of Science and clinical trial registries (29 May 2019). Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Inborn Errors of Metabolism Register: 29 May 2019.
We included prospective and retrospective cohort studies that assessed the diagnostic accuracy of an index test using the Leipzig criteria as a clinical reference standard for the diagnosis of Wilson's disease.
Two review authors independently reviewed and extracted data and assessed the methodological quality of each included study using the QUADAS-2 tool. We had planned to undertake meta-analyses of the sensitivity, specificity at relevant cut-offs for each of the biochemical tests for Wilson's, however, due to differences in the methods used for each biochemical index test, it was not possible to combine the results in meta-analyses and hence these are described narratively.
Eight studies, involving 5699 participants (which included 1009 diagnosed with Wilson's disease) were eligible for inclusion in the review. Three studies involved children only, one adults only and the four remaining studies involved both children and adults. Two evaluated participants with hepatic signs and six with a combination of hepatic and neurological signs and symptoms of Wilson's disease, as well as pre-symptomatic individuals. The studies were of variable methodological quality; with high risk if bias for participant selection and the reference standard used being of greatest methodological concern. Key differences between studies include differences in assay methodology, different cut-off values for diagnostic thresholds, different age and ethnicity groups. Concerns around study design imply that diagnostic accuracy figures may not transfer to populations outside of the relevant study.
caeruloplasmin Five studies evaluated various thresholds of caeruloplasmin (4281 participants, of which 541 had WD). For caeruloplasmin a cut-off of 0.2 g/L as in the Leipzig criteria achieved a sensitivity of 77.1% to 99%, with variable specificity of 55.9% to 82.8%. Using the cut-off of 0.1 g/L of the Leipzig criteria seemed to lower the sensitivity overall, 65% to 78.9%, while increasing the specificity to 96.6% to 100%.
hepatic copper Four studies evaluated various thresholds of hepatic copper (1150 participants, of which 367 had WD). The hepatic copper cut-off of 4 μmol/g used in the Leipzig criteria achieved a sensitivity of 65.7% to 94.4%, with a variable specificity of 52.2% to 98.6%.
24-hour urinary copper Three studies evaluated various thresholds of 24-hour urinary copper (268 participants, of which 101 had WD). For 24-hour urinary copper, a cut-off of 0.64 to 1.6 μmol/24 hours used in the Leipzig criteria achieved a variable sensitivity of 50.0% to 80.0%, with a specificity of 75.6% to 98.3%.
AUTHORS' CONCLUSIONS: The cut-offs used for caeruloplasmin, 24-hour urinary copper and hepatic copper for diagnosing Wilson's disease are method-dependent and require validation in the population in which such index tests are going to be used. Binary cut-offs and use of single-test strategies to rule Wilson's disease in or out is not supported by the evidence in this review. There is insufficient evidence to inform testing in specific subgroups, defined by age, ethnicity or clinical subgroups.
威尔逊病由塞缪尔·威尔逊于1912年首次描述，是一种常染色体隐性代谢紊乱疾病，由ATP7B基因突变引起。该疾病是由于铜在受影响组织中蓄积而发展形成的。威尔逊病的诊断没有金标准，由于临床特征不具特异性，且诊断需要结合临床和实验室检查，其诊断往往会延迟。这种延迟反过来可能会影响临床结果，并对其他家庭成员的诊断产生影响。莱比锡标准的制定是为了帮助规范诊断和管理。然而，应该强调的是，这些标准可追溯到2003年，其中许多尚未经过正式评估；本综述探讨了威尔逊病生化检测背后的证据。
确定三种生化检测在特定临界值水平下对威尔逊病的诊断准确性。本Cochrane系统评价涵盖的指标检测为血浆铜蓝蛋白、24小时尿铜和肝铜含量。在疑似威尔逊病患者及适当对照（健康者或患有除威尔逊病外的慢性肝病者）中对这些检测进行评估。由于缺乏诊断威尔逊病的金标准，我们将莱比锡标准用作临床参考标准。调查指标检测是否应在所有被推荐进行威尔逊病检测的个体中进行，还是应仅限于个体亚组。
我们通过广泛检索，如Cochrane对照试验中心注册库（CENTRAL）、PubMed、Embase、科学引文索引和临床试验注册库（2019年5月29日）来识别研究。对Cochrane囊性纤维化和遗传性疾病先天性代谢缺陷注册库的最新检索日期为2019年5月29日。
我们纳入了前瞻性和回顾性队列研究，这些研究使用莱比锡标准作为威尔逊病诊断的临床参考标准，评估了指标检测的诊断准确性。
两位综述作者独立审查并提取数据，并使用QUADAS-2工具评估每项纳入研究的方法学质量。我们原计划对威尔逊病各生化检测在相关临界值下的敏感性、特异性进行Meta分析，然而，由于各生化指标检测所采用的方法存在差异，无法在Meta分析中合并结果，因此将以叙述方式进行描述。
八项研究，涉及5699名参与者（其中1009名被诊断为威尔逊病）符合纳入本综述的条件。三项研究仅涉及儿童，一项仅涉及成人，其余四项研究涉及儿童和成人。两项研究评估了有肝脏体征的参与者，六项研究评估了有威尔逊病肝脏和神经体征及症状的参与者以及症状前个体。这些研究的方法学质量各不相同；参与者选择和所使用的参考标准存在偏倚的风险最高，是方法学方面最值得关注的问题。研究之间的主要差异包括检测方法的差异、诊断阈值的不同临界值、不同的年龄和种族群体。对研究设计的担忧意味着诊断准确性数据可能不适用于相关研究之外的人群。
血浆铜蓝蛋白 五项研究评估了血浆铜蓝蛋白的各种临界值（4281名参与者，其中541名患有威尔逊病）。对于血浆铜蓝蛋白，如莱比锡标准中0.2g/L的临界值，敏感性为77.1%至99%，特异性在55.9%至82.8%之间变化。使用莱比锡标准中0.1g/L的临界值似乎总体上降低了敏感性，为65%至78.9%，同时将特异性提高到96.6%至100%。
肝铜 四项研究评估了肝铜的各种临界值（1150名参与者，其中367名患有威尔逊病）。莱比锡标准中使用的肝铜临界值4μmol/g，敏感性为65.7%至94.4%，特异性在52.2%至98.6%之间变化。
24小时尿铜 三项研究评估了24小时尿铜的各种临界值（268名参与者，其中101名患有威尔逊病）。对于24小时尿铜，莱比锡标准中0.64至1.6μmol/24小时的临界值，敏感性在50.0%至80.0%之间变化，特异性为75.6%至98.3%。
用于诊断威尔逊病的血浆铜蓝蛋白、24小时尿铜和肝铜的临界值取决于检测方法，需要在将使用此类指标检测的人群中进行验证。本综述中的证据不支持使用二元临界值和单检测策略来判定威尔逊病的诊断。没有足够的证据为按年龄、种族或临床亚组定义的特定亚组的检测提供依据。
