Prospective Studies Of Phlebotomy Therapy In Hereditary Hemochromatosis

通过基于互联网的信息和给地区医生的信件招募了血色病患者。无论受试者是否符合同种异体捐献标准，均免费提供综合护理和放血治疗。血红蛋白12.5 g/dL，这是美国献血的监管门槛，作为进行静脉切开术的阈值，平均红细胞体积（MCV）和铁蛋白的减少用于指导治疗终点。 截至2007年8月31日，连续入组了324例铁过载受试者。 本研究最常见的转诊途径是自我转诊，由患者在互联网上发起搜索。 74%的受试者为HFE基因C282 Y突变纯合子，75%符合同种异体献血的合格标准，52%为既往献血者。在MCV达到低于基线3%的目标终点之前（此时铁蛋白低于30 mcg/L，转铁蛋白饱和度低于30%），每周或每两周进行一次中位静脉切开术（范围7-99）。在维持治疗期间，将MCV保持在该水平所需的中位放血间隔为10-12周。 血色病献血是安全的：在5,000例献血中没有发生输血传播疾病病原体的血清转化事件。 截至2007年9月，血色素沉着病供体每年贡献800个单位的红细胞，占NIH临床中心收集的同种异体使用单位的11%，另外每年有200个单位可用于研究，这些红细胞来自不符合标准供体资格标准的供体。 通过将护理集中在血液中心，促进了家庭成员筛查和咨询。 在这项研究开展的6年中，研究结果在会议上和医学文献中传播，全国血液中心制定血色素沉着症供体计划的数量从26个增加到76个。 我们的数据表明，血色素沉着症患者可以安全和显着地增加同种异体血液供应。在血液中心提供放血治疗，不受保险报销或捐赠适合性的限制，可以改善获得护理的机会，消除不完全风险披露的激励因素。 迄今为止在该队列中进行的评价表明，血色病受试者中甲状腺异常的发生率高于预期，最常见的是亚临床甲状腺功能减退症。在C282 Y HFE突变纯合性的女性受试者中，30%发现甲状腺功能异常。最近在这些患者中进行的一系列心脏病学研究表明，与正常受试者相比，C282 Y纯合子在心房收缩力和运动相关心律失常方面的轻度亚临床异常的发生率在统计学上增加，这些变化可能与氧化应激的血清标志物升高有关。与对照组相比，C282 Y纯合子的左心室收缩力和应激反应正常。 对这些受试者关节炎的综合分析显示，8%（19/224）的C282 Y纯合子受试者与2.2%（2/91）的非纯合子受试者共接受了24例全髋关节置换术、6例全膝关节置换术和4例全踝关节置换术。全关节置换的频率在C282 Y纯合子中显著高于对照组。到75岁时，全关节置换血色病患者的累积风险为31%。 在C282 Y纯合子中，初始铁蛋白水平大于中位数640 ng/mL的受试者进行全关节置换的风险明显更高。 在每年接受全髋关节置换术的估计23，966名40-79岁的美国白人男性中，数据表明3-4%为C282 Y纯合子。 目前的工作重点是克服社区和红十字血液中心对使用血色素沉着症受试者作为同种异体献血者的抵制，传播本研究中展示的最佳静脉切开术实践，严格检查通过单采术捐献双红细胞在HH受试者管理中的作用，以及评估治疗期间血清非转铁蛋白结合铁水平的变化

Persons with hemochromatosis were recruited via Internet-based information and letters to area physicians. Comprehensive care and phlebotomy therapy were offered free of charge regardless of whether subjects met criteria for allogeneic donation. Hemoglobin of 12.5 g/dL, the regulatory threshold for blood donation in the U.S., was used as the threshold for performing phlebotomy, and decreases in the mean corpuscular volume (MCV) and ferritin were used to guide the endpoints of therapy. 324 subjects with iron overload were consecutively enrolled as of August 31, 2007. The most common route of referral to the study was self-referral, resulting from patient-initiated searches performed on the Internet. 74% of subjects were homozygous for the C282Y mutation in the HFE gene, 75% met eligibility criteria for allogeneic donation, and 52% were previous blood donors. A median of 25 weekly or biweekly phlebotomies (range 7-99) were performed before the MCV reached the targeted endpoint of 3% below baseline, at which time the ferritin was less than 30 mcg/L and the transferrin saturation less than 30%. The median phlebotomy interval necessary to keep the MCV at this level during maintenance therapy was 10-12 weeks. Hemochromatosis donations were safe: no incident seroconversions for agents of transfusion-transmissible disease occurred during 5,000 donations. As of September 2007, hemochromatosis donors were contributing 800 units of red cell yearly, or 11% of the units collected for allogeneic use in the NIH Clinical Center, and another 200 units per year were made available for research use from donors who did not meet standard donor eligibility criteria. Family member screening and counseling were facilitated by concentrating the care within the Blood Center. During the 6 years that this study has been active, and the results disseminated at meetings and in the medical literature, the number of Blood Centers nationwide that have instituted hemochromatosis donor programs has grown from 26 to 76. Our data demonstrate that hemochromatosis subjects can safely and significantly augment the allogeneic blood supply. Provision of phlebotomy therapy in the Blood Center, unrestricted by considerations of insurance reimbursement or suitability for donation, can improve access to care and remove incentives for incomplete risk disclosure. Evaluations performed to date in this cohort indicate that there is a higher than expected incidence of thyroid abnormalities in hemochromatosis subjects, most commonly subclinical hypothyroidism. Thyroid function abnormalities were found in 30% of female subjects with homozygosity for the C282Y HFE mutation. A recent series of cardiology studies in these patients indicate that C282Y homozygotes have a statistically increased incidence of mild, subclinical abnormalities in atrial contractility and exercise-associated arrhythmias when compared to normal subjects, and these changes may be associated with elevated serum markers of oxidative stress. Left ventricular contractility and response to stress were found to be normal in C282Y homozygotes compared with control subjects. A comprehensive analysis of arthritis in these subjects revealed that 8% (19 of 224) C282Y-homozygous versus 2.2% (2 of 91) non-homozygous subjects underwent a total of 24 total hip, 6 total knee, and 4 total ankle replacements. The frequency of total joint replacement was significantly greater in C282Y-homozygotes than in the control group. The cumulative risk of total joint replacement hemochromatosis subjects was 31% by age 75. Among C282Y homozygotes, the risk of total joint replacement was markedly greater in subjects with initial ferritin levels greater than the median value of 640 ng/mL. Among the estimated 23,966 Caucasian U.S. males age 40-79 undergoing total hip replacement each year, the data suggest that 3-4% are C282Y-homozygous. Current efforts are focused on overcoming community and Red Cross Blood Center resistance to use of hemochromatosis subjects as allogeneic blood donors, on dissemination of best phlebotomy practices as exhibited in this study, on critical examination of the role of double red cell donation by apheresis in the management of HH subjects, and on assessing changes in serum non-transferrin bound iron levels during therapy