Shaheen N J, Bacon B R, Grimm I S
Division of Digestive Diseases and Nutrition, University of North Carolina, Chapel Hill 27599-7080, USA.
Hepatology. 1998 Aug;28(2):526-9. doi: 10.1002/hep.510280233.
Approximately 85% of patients with typical hereditary hemochromatosis (HH) are homozygous for the C282Y mutation (C282Y/C282Y) in the recently identified candidate gene for HH. However, some HH patients are instead homozygous for the wild-type allele (wt/wt) at this locus. These wt/wt patients may represent a phenotypically similar, but genotypically different, heritable trait, or may be unrecognized cases of secondary iron overload. The purpose of this study is to provide an in-depth analysis of the wt/wt HH patients identified in the original description of the HH gene, and to compare them with 62 patients from the same analysis who were homozygous for the C282Y mutation. Eighteen of the 21 wt/wt HH patients from the original study were assessed for 14 historical and laboratory variables, including previously unrecognized causes of secondary iron overload, the heritability of iron overload and liver disease, and other clinical characteristics. Ten of these 18 wt/wt HH patients (55.6%) were found to have previously unrecognized causes for secondary iron overload compared with 3 of 62 (4.8%) of the C282Y/C282Y patients (P < .001). The remaining 8 wt/wt patients had no recognizable etiology of secondary iron overload. None of the 18 wt/wt patients had a family history of iron overload or liver disease, compared with 58% of the C282Y/C282Y patients (P < .001). When compared with C282Y homozygotes, the 8 wt/wt patients without secondary iron overload had a higher presenting hepatic iron index (HII) (9.5 vs. 4.7; P = .01). We conclude that, in this series of patients, over half of the wt/wt HH patients possessed previously unrecognized causes of secondary iron overload, and therefore, may have been misdiagnoses. If these cases are excluded, the number of false-negative tests is decreased, and the sensitivity of the mutational analysis is increased. However, there is a subgroup of wt/wt patients who have typical hemochromatosis without an identifiable cause of secondary iron overload. These patients may have more severe iron loading than C282Y homozygotes.
在最近确定的遗传性血色素沉着症（HH）候选基因中，约85%典型遗传性血色素沉着症患者为C282Y突变纯合子（C282Y/C282Y）。然而，一些HH患者在该位点却是野生型等位基因纯合子（wt/wt）。这些wt/wt患者可能代表一种表型相似但基因型不同的可遗传性状，也可能是未被识别的继发性铁过载病例。本研究的目的是对在HH基因最初描述中确定的wt/wt HH患者进行深入分析，并将他们与同一分析中的62例C282Y突变纯合子患者进行比较。对原研究中21例wt/wt HH患者中的18例进行了14项病史和实验室变量评估，包括先前未被识别的继发性铁过载原因、铁过载和肝病的遗传性以及其他临床特征。这18例wt/wt HH患者中有10例（55.6%）被发现有先前未被识别的继发性铁过载原因，而62例C282Y/C282Y患者中有3例（4.8%）有此情况（P <.001）。其余8例wt/wt患者没有可识别的继发性铁过载病因。18例wt/wt患者中无一例有铁过载或肝病家族史，而C282Y/C282Y患者中有58%有此情况（P <.001）。与C282Y纯合子相比，8例无继发性铁过载的wt/wt患者的初始肝铁指数（HII）更高（9.5对4.7；P = 0.01）。我们得出结论，在这一系列患者中，超过一半的wt/wt HH患者有先前未被识别的继发性铁过载原因，因此可能被误诊。如果排除这些病例，假阴性检测数量会减少，突变分析的敏感性会增加。然而，有一小部分wt/wt患者患有典型的血色素沉着症，却没有可识别的继发性铁过载原因。这些患者的铁负荷可能比C282Y纯合子更严重。
