ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants,Clinical Gastroenterology and Hepatology

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ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants
Clinical Gastroenterology and Hepatology ( IF 11.6 ) Pub Date : 2022-09-09 , DOI: 10.1016/j.cgh.2022.08.041
Jeremy S Nayagam ₁ , Rebecca Jeyaraj ₂ , Pierre Foskett ₂ , Anil Dhawan ₃ , Aftab Ala ₄ , Deepak Joshi ₂ , Adrian Bomford ₂ , Richard J Thompson ₅

Affiliation

Background and Aims

Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants.

Methods

This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators.

Results

Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7–17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7–18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03).

Conclusions

Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.

中文翻译：

Wilson 病的 ATP7B 基因型和慢性肝病治疗结果：功能丧失变异的生存更差

背景和目标

尽管尚未在威尔逊病 (WD) 中建立良好的基因型-表型相关性，但具有功能丧失 (LOF) ATP7B变异的患者表现出不同的临床和生化特征。我们旨在描述慢性肝病 (CLD) 表型的长期治疗结果，并评估与 LOF 变异的关联。

方法

这是对至少有 1 个ATP7B变异的 WD 患者的单中心回顾性研究。获得了人口统计学、生化、遗传和临床参数。肝移植或死亡的复合临床终点用于在螯合剂上具有 CLD 表型的先证者。

结果

117例肝性WD患者中：71例为CLD，27例为暴发性肝功能衰竭需要紧急肝移植，19例经家系筛查确诊。诊断时的中位年龄为 13.1（四分位间距，9.7–17.6）岁。在研究人群中总共鉴定出 91 个ATP7B变体。60 名 (51.3%) 患者中至少存在 1 个 LOF 变体。在 10.7 年（四分位数间距，6.7–18.9）年的中位随访期间，10 名 (14.1%) 患有 CLD 的先证者达到了复合终点。至少有 1 种 LOF 变异的患者接受螯合治疗后，无移植生存期更差 ( P = .03)。