Sham R L, Ou C Y, Cappuccio J, Braggins C, Dunnigan K, Phatak P D
Department of Medicine, Rochester General Hospital and the Mary M. Gooley Hemophilia Center Inc., Rochester, New York 14621, USA.
Blood Cells Mol Dis. 1997 Aug;23(2):314-20. doi: 10.1006/bcmd.1997.0148.
This report assesses the degree of iron overload in a cohort of patients in relationship to the presence or absence of the recently described 845 G-->A (C282Y) and 187 C-->G (H63D) mutations in the HFE (HLA-H) gene. Sixty-one patients with hereditary hemochromatosis diagnosed either with liver biopsy or on clinical grounds were included in this analysis. Forty-one patients were homozygous for C282Y, the genotype considered to be characteristic of hereditary hemochromatosis. At the time of this analysis, 37 of these 41 patients had achieved a state of iron depletion and mobilizable iron was calculated: 19 had less than 4 grams. Twenty-five of these 41 patients had liver biopsies; 4 of these patients had a hepatic iron index less than 1.9. Of the 4 patients with a normal hepatic iron index, 3 had a quantitative hepatic iron of greater than 50 micromol/g dry weight, and one had an inadequate biopsy sample. These findings support our suspicion that individuals may have hereditary hemochromatosis and homozygous C282Y despite relatively low body iron stores. Five patients were compound heterozygotes for C282Y and H63D. Four of these patients underwent liver biopsy; two had a hepatic iron index greater than 1.9. a third patient had a hepatic iron index of 1.3 but a quantitative hepatic iron of 90.6 micromol/g dry weight. All patients were phlebotomized to a state of iron depletion and only one of these patients had a mobilizable iron greater than 4 grams. Three patients were homozygous for H63D; these patients had either a hepatic iron index >1.9 or greater than 4 grams of mobilizable iron. Patients with homozygous H63D and significant iron overload are not well described. Seven patients were heterozygous for either C282Y or H63D; 4 had significant iron overload but three did not. Five patients had no HFE mutations; one of these patients unequivocally has iron overload with a hepatic iron index of 4.4 We conclude that: (1) Identification of HFE mutations will be clinically useful in identifying patients with hereditary hemochromatosis, (2) Patient genotyping will help confirm a diagnosis of hereditary hemochromatosis in some patients with relatively low body iron stores, (3) Significant iron loading can occur in the absence of homozygous C282Y, adding to the evidence that genes other than HFE may be involved in iron loading, and (4) Homozygous H63D can be associated with significant iron overload.
本报告评估了一组患者的铁过载程度，以及其与HFE（HLA-H）基因中最近发现的845G→A（C282Y）和187C→G（H63D）突变的有无之间的关系。本分析纳入了61例经肝活检或基于临床诊断为遗传性血色素沉着症的患者。41例患者为C282Y纯合子，该基因型被认为是遗传性血色素沉着症的特征性基因型。在进行本分析时，这41例患者中有37例已达到铁耗竭状态，并计算了可动员铁：其中19例的可动员铁少于4克。这41例患者中有25例行肝活检；其中4例患者的肝铁指数低于1.9。在肝铁指数正常的4例患者中，3例的肝脏定量铁大于50微摩尔/克干重，1例的活检样本不充分。这些发现支持了我们的怀疑，即尽管体内铁储存相对较低，但个体仍可能患有遗传性血色素沉着症且为C282Y纯合子。5例患者为C282Y和H63D的复合杂合子。其中4例患者接受了肝活检；2例患者的肝铁指数大于1.9。第3例患者的肝铁指数为1.3，但肝脏定量铁为90.6微摩尔/克干重。所有患者均接受静脉放血直至达到铁耗竭状态，这些患者中只有1例的可动员铁大于4克。3例患者为H63D纯合子；这些患者要么肝铁指数>1.9，要么可动员铁大于4克。关于H63D纯合子且有明显铁过载的患者，目前尚无充分描述。7例患者为C282Y或H63D杂合子；4例有明显铁过载，但3例没有。5例患者无HFE突变；其中1例患者肝铁指数为4.4，明确存在铁过载。我们得出以下结论：（1）鉴定HFE突变在临床上有助于识别遗传性血色素沉着症患者；（2）患者基因分型将有助于在一些体内铁储存相对较低的患者中确诊遗传性血色素沉着症；（3）在没有C282Y纯合子的情况下也可能发生明显的铁负荷增加，这进一步证明除HFE外的其他基因可能参与铁负荷过程；（4）H63D纯合子可能与明显的铁过载有关。
