目的 研究肝豆状核变性(WD)不同基因型患者的肝病表型及临床特征.方法 选取2008年8月—2023年6月在解放军总医院第五医学中心确诊并进行基因检测的163例WD患者,收集临床表现、实验室检查、病理学检查、影像学检查和ATP7B基因检测结果.根据ATP7B基因突变情况将患者分为R778L突变组和非R778L突变组;P992L突变组和非P992L突变组;截断突变组和非截断突变组.分析ATP7B基因c.2333G>T/p.R778L突变(R778L突变)、c.2975C>T/p.P992L突变(P992L突变)以及截断突变患者的肝病表型和临床特征.计量资料组间比较采用Mann-Whitney U检验或Kruskal-Wallis H检验.计数资料组间比较采用χ2检验或Fisher确切概率法.结果 163例WD患者均表现为不同严重程度的肝病表型,121例(74.23%)被临床诊断为慢性肝病,36例(22.09%)为失代偿期肝硬化,6例(3.68%)为暴发性WD;此外,有5例(2例慢性肝病,3例失代偿期肝硬化)合并神经系统异常.163例WD患者最常见的ATP7B基因突变为R778L突变(等位基因频率为28.2%),其次为P992L突变(等位基因频率为12.6%),截断突变的等位基因频率为11.0%.3种突变在不同肝病表型之间的分布差异均无统计学意义(P值均>0.05).R778L突变组的铜蓝蛋白水平显著低于非R778L突变组[0.04(0.02～0.08)g/L vs 0.08(0.03～0.13)g/L,Z=-2.889,P=0.004].P992L组的ALT[135.0(80.5～237.0)U/L vs 80.5(36.0～173.3)U/L,Z=2.684,P=0.007]和AST[121.4(77.0～195.0)U/L vs 84.0(39.0～123.3)U/L,Z=3.388,P<0.001]均显著高于非P992L突变组.截断突变组的铜蓝蛋白[0.03(0.02～0.08)g/L vs 0.06(0.03～0.11)g/L,Z=-3.136,P=0.002]和血清铜[3.20(2.15～5.00)mg/L vs 4.20(2.60～7.50)mg/L,Z=-2.296,P=0.025]水平均显著低于非截断突变组.结论 R778L突变、P992L突变和截断突变均与WD患者的肝病表型无关;但R778L突变与较低的铜蓝蛋白水平相关,P992L突变与较高的ALT和AST水平相关,截断突变与较低的铜蓝蛋白和血清铜水平相关.
Liver disease phenotypes and clinical features of patients with different genotypes of Wilson's disease
Objective To investigate the liver disease phenotypes and clinical features of patients with different genotypes of Wilson's disease(WD).Methods A retrospective analysis was performed for 163 patients with WD who were diagnosed and underwent genetic testing in The Fifth Medical Center of Chinese PLA General Hospital from August 2008 to June 2023,and clinical manifestations,laboratory examination,pathological examination,imaging examination,and ATP7B genetic testing results were collected.According to ATP7B gene mutation,the patients were divided into groups as follows:R778L mutation group and non-R778L mutation group;P992L mutation group and non-P992L mutation group;truncation mutation group and non-truncation mutation group.Liver disease phenotypes and clinical features were analyzed for the patients with c.2333G>T/p.R778L mutation(R778L mutation),c.2975C>T/p.P992L mutation(P992L mutation),and truncation mutation of the ATP7B gene.The Mann-Whitney U test or the Kruskal-Wallis H test was used for comparison of continuous data between groups,and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups.Results The 163 patients with WD had varying severities of liver disease phenotypes,among whom 121(74.23%)were diagnosed with chronic liver disease,36(22.09%)were diagnosed with decompensated cirrhosis,and 6(3.68%)were diagnosed with fulminant WD,and in addition,there were 5 patients(2 with chronic liver disease and 3 with decompensated cirrhosis)with neurological abnormalities.For the 163 patients with WD,R778L mutation(with an allele frequency of 28.2%)was the most common mutation in the ATP7B gene,followed by P992L mutation(with an allele frequency of 12.6%),and truncation mutation showed an allele frequency of 11.0%.There was no significant difference in the distribution of the three mutations across different liver disease phenotypes(P>0.05).The R778L mutation group had a significantly lower level of ceruloplasmin(CP)than the non-R778L mutation group[0.04(0.02-0.08)g/L vs 0.08(0.03-0.13)g/L,Z=-2.889,P=0.004].Compared with the non-P992L mutation group,the P992L mutation group had significantly higher levels of alanine aminotransferase[135.0(80.5-237.0)U/L vs 80.5(36.0-173.3)U/L,Z=2.684,P=0.007]and aspartate aminotransferase[121.4(77.0-195.0)U/L vs 84.0(39.0-123.3)U/L,Z=3.388,P<0.001].Compared with the non-truncation mutation group,the truncation mutation group had significantly lower levels of CP[0.03(0.02-0.08)g/L vs 0.06(0.03-0.11)g/L,Z=-3.136,P=0.002]and serum copper[3.20(2.15-5.00)mg/L vs 4.20(2.60-7.50)mg/L,Z=-2.296,P=0.025].Conclusion R778L mutation,P992L mutation and truncation mutation are not associated with liver disease phenotype in WD patients;however,R778L mutation is associated with a lower level of CP,P992L mutation is associated with higher levels of ALT and AST,and truncation mutation is associated with lower levels of CP and serum copper.
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