肝豆状核变性发病机制、临床表型-基因型关系及药物治疗研究进展

玛力帕提·艾尔肯江; 凯迪日亚·库尔班; 徐玲; 孙晓风

doi:10.3969/j.issn.1001-5256.2023.06.037

肝豆状核变性发病机制、临床表型-基因型关系及药物治疗研究进展

DOI: 10.3969/j.issn.1001-5256.2023.06.037

新疆医科大学第一附属医院感染科，乌鲁木齐 830000

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：玛力帕提·艾尔肯江负责查阅文献及撰写论文；凯迪日亚·库尔班、徐玲负责修改文章；孙晓风负责拟定写作思路，指导撰写文章并最后定稿。

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通信作者:
孙晓风，xjwlsxf@163.com (ORCID：0000-0002-2596-3669)

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出版历程
- 收稿日期: 2022-11-02
- 录用日期: 2022-12-19
- 出版日期: 2023-06-20

Research advances in the pathogenesis, phenotype-genotype relationship, and pharmacotherapy of hepatolenticular degeneration

Department of Infectious Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, China

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Corresponding author: SUN Xiaofeng, xjwlsxf@163.com (ORCID: 0000-0002-2596-3669)

摘要

摘要: 肝豆状核变性又称Wilson病(WD)，WD中铜与铜蓝蛋白结合受损，导致游离铜主要在肝脏、大脑和其他器官中沉积。WD的患病率为1/30 000。在临床上，大多数WD患者都是年轻人，其特征是锥体外系症状、肝硬化、角膜K-F环、血清低铜蓝蛋白水平(＜50 mg/L)和24 h高尿铜排泄(＞100 mg/L)。目前WD主要的治疗措施为药物治疗。在一些终末期肝病或急性肝衰竭的病例中，肝移植是提高生存率的一种选择。本综述结合国内外对WD发病机制、临床表型与基因型的关系及药物治疗进展的研究作出了概述。
- 肝豆状核变性 /
- 基因型 /
- 药物疗法
Abstract: In hepatolenticular degeneration, also known as Wilson's disease (WD), the binding of copper to ceruloplasmin is impaired, resulting in the deposition of free copper mainly in the liver, brain, and other organs. The prevalence rate of WD was 1/30 000. In clinical practice, most WD patients are young adults and are characterized by extrapyramidal symptoms, liver cirrhosis, Kayser-Fleischer ring of the cornea, low serum ceruloplasmin level (< 50 mg/L), and high 24-hour urinary copper excretion (> 100 mg/L). At present, pharmacotherapy is the main treatment method for WD, and in some cases of end-stage liver disease or acute liver failure, liver transplantation is an option to improve survival rate. This article reviews the research advances in the pathogenesis of hepatolenticular degeneration, phenotype-genotype relationship, and pharmacotherapy in China and globally.
- Hepatolenticular Degeneration /
- Genotype /
- Drug Therapy

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图 1 人体Cu代谢机制

注：CCS，超氧化物歧化酶铜伴侣; SCO1、SCO2，细胞色素C氧化酶蛋白1、2。

Figure 1. Mechanism of copper metabolism in human body

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表 1 ATP7B基因突变类型与临床表型关系

Table 1. Relationship between ATP7B gene mutation type and clinical phenotype

作者(年份)	样本量(例)	主要突变类型	研究结局
Das等(2022)^[16]	≥80	纯合p.His1069Gln p.Arg778Leu	p.Arg778Leu患者发病年龄早，CP水平低，大多表现为肝脏症状；p.His1069Gln患者主要表现为迟发性神经系统症状
张天鹤等(2022)^[17]	70	p.Arg778Leu	p.Arg778Leu突变患者表现出较低的CP水平及肝脏症状
周霄颖等(2020)^[18]	55	p.Arg778Leu	p.Arg778Leu突变发病年龄早，肝脏损害较重
Zhang等(2022)^[20]	1 366	p.Arg778Leu、p.Pro992Leu、p.Ala874Val	p.Arg778Leu、p.Pro992Leu发病年龄早，p.Ala874Val发病年龄较晚并与构音障碍有关
Nagral等(2022)^[21]	58	p.Cys271Ter	未发现基因变异与临床表现关联
刘攀等(2022)^[22]	75	p.Arg778Leu、p.Ala874Val、p.Pro992Leu	基因型-表型无明显相关性

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表 2 WD与其他Cu代谢指标异常遗传性疾病的鉴别

Table 2. Differential diagnosis of WD and other genetic diseases with abnormal copper metabolism indexes

疾病类型	病因	实验室特征	临床特征
Menkes综合征^[23]	ATP7A基因突变	血清Cu、CP及肝Cu减少	严重的神经退行性病变、毛发异常、癫痫发作、体温过低、结缔组织紊乱
MEDNIK综合征^[24]	AP1S1基因突变	血清Cu减少，血清CP减少和肝Cu升高	智力迟钝，肠病，耳聋，神经病变，皮肤表现(鱼鳞病和角化皮病)
遗传性铜蓝蛋白缺乏症	CP基因突变	血清CP无法检测或明显降低，血清Cu、尿Cu及肝Cu水平正常	神经系统疾病、糖尿病和贫血，这些都与全身铁的过度积累有关
Huppke-Brendel综合征^[6]	编码乙酰辅酶A转运体1的SLC33A1基因突变	血清Cu和CP水平低	先天性白内障、听力丧失和严重发育迟缓，也可见明显的小脑发育不全和骨髓鞘减少
WD	ATP7B基因突变	血清Cu和CP降低，尿Cu排泄增加，肝Cu水平增加	肝脏疾病、神经系统疾病和精神表现、角膜K-F环

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