Walsh Alissa, Dixon Jeannette L, Ramm Grant A, Hewett David G, Lincoln Douglas J, Anderson Gregory J, Subramaniam V Nathan, Dodemaide Julian, Cavanaugh Juleen A, Bassett Mark L, Powell Lawrie W
The Department of Gastroenterology & Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Australia.
Clin Gastroenterol Hepatol. 2006 Nov;4(11):1403-10. doi: 10.1016/j.cgh.2006.07.009. Epub 2006 Sep 18.
BACKGROUND & AIMS: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes.
Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated.
C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes.
C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.
血色素沉着症基因（HFE）内定义了两种主要突变。尽管C282Y替代的影响已得到充分表征，但C282Y/H63D状态的临床意义仍不明确。本研究评估了C282Y/H63D受试者与C282Y纯合子相比的表型表达。
数据来自91名C282Y/H63D先证者、158名通过家族筛查确定的C282Y/H63D受试者以及483名C282Y纯合子。受试者接受了临床评估、基因分型、生化评估，并在临床指征明确时进行了肝活检检查。
C282Y/H63D先证者的临床和生化表达明显低于C282Y纯合子。C282Y/H63D先证者的生化表达高于通过家族筛查确定的C282Y/H63D受试者（P <.001）。在血清铁蛋白水平大于1000μg/L的C282Y/H63D受试者中，所有受试者都有已知的合并因素，这些因素可能导致铁蛋白水平升高。在接受肝活检检查的51名C282Y/H63D受试者中，9名受试者的铁储存显著增加，13名受试者存在肝纤维化。13名受试者中有12名有肝脂肪变性、过量饮酒或糖尿病的证据。C282Y纯合子男性的可动员铁水平显著高于复合杂合子男性（P <.001）。对C282Y/H63D一级亲属的基因筛查检测到5名C282Y纯合子。
接受评估的C282Y/H63D受试者铁指标升高的患病率较高，但在没有脂肪变性、糖尿病或过量饮酒等合并因素的情况下，不会发展为进行性临床疾病。当出现纤维化时，几乎总是存在1种或更多合并因素。因此，放血疗法是必要的，并且应该对亲属进行级联筛查，因为可能会检测到表达C282Y纯合子的个体。
