重新评估铁指标在遗传性血色素沉着症基因分型中的效用：一项回顾性研究。

Re-evaluating the utility of iron indices in hereditary hemochromatosis genotyping: A retrospective study.

作者信息

Lou Amy, Elnenaei Manal O, Zhu Julie, Peltekian Kevork, Liu Eric, Jamieson Jennifer A, Said Hammam, Nassar Bassam A

机构信息

Division of Clinical Chemistry, Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

出版信息

Clin Biochem. 2025 Jan;135:110860. doi: 10.1016/j.clinbiochem.2024.110860. Epub 2024 Nov 29.

DOI:10.1016/j.clinbiochem.2024.110860

PMID:39617311

Abstract

INTRODUCTION

Hereditary hemochromatosis (HH), associated with C282Y or H63D mutations in the HFE gene, is the commonest genetic disorder in Canada. The majority of HH cases are attributable to C282Y homozygosity which can precipitate iron overload and organ damage, but with low penetrance. Elevated transferrin saturation (TSat) and ferritin levels are key biochemical indicators of iron overload in C282Y homozygotes. This retrospective study examined TSat and ferritin levels as predictors of C282Y homozygosity in genotyped patients.

METHODS

This study included 23,432 individuals from Maritime provinces who underwent HFE genotyping from 2009 to 2022. Those with available biomarkers (TSat, ferritin, ALT) were included in the study sample. C282Y and H63D variants were identified based on HFE genotying. Median values for each biomarker were compared across genotypes and their diagnostic performance in predicting C282Y homozygosity evaluated using ROC analysis.

RESULTS

1241 individuals (5.3 %) showed C282Y homozygosity, marking the largest North American study cohort. C282Y homozygotes showed significantly higher median TSat and ferritin levels than wildtypes. TSat showed the best diagnostic performance in detecting C282Y homozygosity (AUC = 0.82, 95 % CI: 0.78-0.85), outperforming ferritin (AUC = 0.54, 95 % CI: 0.50-0.58) and ALT (AUC = 0.59, 95 % CI: 0.56-0.63). TSat thresholds of 32 % (females) and 35 % (males) had a 90 % sensitivity for C282Y homozygosity. Using thresholds of TSat ≤46 % and ferritin ≤370 µg/L (females), and TSat ≤49 % and ferritin ≤703 µg/L (males) reduced the need for genotyping by up to 50 % without missing significant biochemical iron overload cases. Implementing this strategy across 23,432 tests could save $1,701,163 and potentially reduce unnecessary downstream management.

CONCLUSION

Our study suggests significant efficiency savings by implementing an algorithm to reduce unnecessary HFE genotyping and alleviate unwarranted genetic testing anxiety.

摘要

引言

遗传性血色素沉着症（HH）与HFE基因中的C282Y或H63D突变相关，是加拿大最常见的遗传性疾病。大多数HH病例归因于C282Y纯合子，其可导致铁过载和器官损伤，但外显率较低。转铁蛋白饱和度（TSat）和铁蛋白水平升高是C282Y纯合子中铁过载的关键生化指标。这项回顾性研究将TSat和铁蛋白水平作为基因分型患者中C282Y纯合子的预测指标进行了研究。

方法

本研究纳入了2009年至2022年在海洋省份接受HFE基因分型的23432名个体。有可用生物标志物（TSat、铁蛋白、ALT）的个体被纳入研究样本。基于HFE基因分型鉴定C282Y和H63D变异。比较各生物标志物在不同基因型中的中位数，并通过ROC分析评估其预测C282Y纯合子的诊断性能。

结果

1241名个体（5.3%）表现为C282Y纯合子，这是北美最大的研究队列。C282Y纯合子的TSat和铁蛋白中位数水平显著高于野生型。TSat在检测C282Y纯合子方面表现出最佳的诊断性能（AUC = 0.82，95%CI：0.78 - 0.85），优于铁蛋白（AUC = 0.54，95%CI：0.50 - 0.58）和ALT（AUC = 0.59，95%CI：0.56 - 0.63）。TSat阈值为32%（女性）和35%（男性）时，对C282Y纯合子的敏感性为90%。使用TSat≤46%和铁蛋白≤370μg/L（女性）以及TSat≤49%和铁蛋白≤703μg/L（男性）的阈值，可将基因分型需求减少多达50%，且不会遗漏显著的生化铁过载病例。在23432次检测中实施该策略可节省1701163美元，并可能减少不必要的下游管理。