Prospective Studies Of Phlebotomy Therapy In Hereditary Hemochromatosis

血色沉着症患者是通过基于互联网的信息和致地区医生的信件招募的。无论受试者是否符合异基因捐献的标准，都免费提供全面的护理和静脉采血治疗。血红蛋白12.5g/dL是美国献血的监管阈值，作为进行静脉采血的阈值，平均红细胞体积(MCV)和铁蛋白的减少被用来指导治疗终点。截至2007年8月31日，324名铁超负荷受试者连续入选。转诊到这项研究的最常见的途径是自我转诊，这是由患者在互联网上进行的搜索导致的。74%的受试者HFE基因C282Y突变为纯合子，75%的受试者符合异基因献血标准，52%的受试者以前是献血者。在MCV达到基线以下3%的目标终点之前，平均每周或每两周进行25次静脉采血(范围7-99)，此时铁蛋白<30微克/L，转铁蛋白饱和度<30%。维持治疗期间保持MCV在这个水平所需的中位静脉采血间隔为10-12周。血色沉着症捐献是安全的：在5000例捐献中，没有发生输血传播性疾病试剂的血清转换事件。截至2007年9月，血色素沉着症捐赠者每年捐献800个单位的红细胞，占NIH临床中心收集的供异基因使用的单位的11%，另外每年向不符合标准捐赠者资格标准的捐赠者提供200个单位用于研究。通过将护理集中在血液中心，促进了家庭成员的筛查和咨询。在这项研究开展的6年中，结果在会议和医学文献中传播，全国范围内建立血色素沉着症捐赠者计划的血液中心的数量从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。在血液中心提供静脉采血治疗，不受保险报销或是否适合捐献的考虑，可以改善获得护理的机会，并消除不完全风险披露的诱因。 到目前为止在该队列中进行的评估表明，血色沉着症受试者的甲状腺异常发生率高于预期，最常见的是亚临床甲状腺功能减退症。在C282Y HFE突变纯合子的女性受试者中，有30%的人发现甲状腺功能异常。最近对这些患者进行的一系列心脏病学研究表明，与正常受试者相比，C282Y纯合子在心房收缩功能和运动相关心律失常方面轻度亚临床异常的发生率有统计学意义上的增加，这些变化可能与血清氧化应激标志物的升高有关。与对照组相比，C282Y纯合子受试者的左心室收缩能力和应激反应均正常。对这些受试者的关节炎的综合分析显示，8%(224例)C282Y纯合子受试者接受了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，而91例非纯合型受试者中有2.2%(2例)接受了全髋关节置换术。C282Y纯合子组的全关节置换率显著高于对照组。到75岁时，全关节置换血色沉着症受试者的累积风险为31%。在C282Y纯合子中，初始铁蛋白水平高于中位数640 ng/mL的受试者进行全关节置换术的风险明显更大。据估计，美国每年有23,966名年龄在40-79岁之间的高加索男性接受全髋关节置换术，数据显示，其中3-4%是C282Y纯合子。 目前的努力集中在克服社区和红十字会血液中心将血色素沉着症患者用作异基因献血者的阻力，传播本研究所展示的最佳静脉采血做法，关键检查通过分离的双重红细胞捐献在HH患者管理中的作用，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