江苏省人民医院血液内科何广胜

异基因造血干细胞移植受体的铁超负荷：我们立于何处？

摘要 铁超负荷（Iron overload, IO），主要与多次红细胞输注有关，是异基因造血干细胞移植受体相对常见的并发症（allo-hematopoietic stem cell transplant, allo-HSCT）。移植前升高的铁蛋白水平会增加移植后非复发死亡的危险，并可能影响急慢性移植物抗宿主病风险。已有文献报道IO是导致allo-HSCT病死和死亡的重要因素。我们知道，过度的铁沉积能导致组织损伤和器官功能衰竭， (Armand et al., Blood 109:4586–4588, 2007; Kim et al., Acta Haematol 120:182–189, 2008; Kataoka et al., Biol Blood Marrow Transplant 15:195–204, 2009)，。

这主要是因为铁产生氧自由基导致氧化损伤和器官功能障碍，如肝毒性、心脏毒性和内分泌腺功能异常。(Altes et al., Bone Mar- row Transplantation 29: 987–989, 2002; Papanikolaou et al., Toxicol Appl Pharmac 202:199–211, 2005)。近年来，人们努力寻找各类疗法解决allo-HSCT受体铁超负荷的问题，以提高移植的结果。

关键词 铁超负荷 铁蛋白 异基因造血干细胞移植 去铁剂

Keywords Iron overload . Ferritin . AlloHSCT . Iron chelators

引言

由于治疗中经较大量红细胞输注，铁超负荷是行allo-HSCT的血液病患者移植前后常见的一种情况[1, 2]。血清铁蛋白是广泛使用评价全身铁负荷量的指标，移植前血清铁蛋白水平升高与低总生存率[3–7]、高移植相关并发症——慢性肝病[8, 9]、肝静脉窦阻塞综合征[10]、感染[11, 12]和特发性肺炎综合征显著相关[10]。虽然已经有指南推荐在移植后1年随访检测血清铁蛋白[2]，但是尚无特定的标准确定在allo-HSCT受体何时和如何进行铁超负荷的治疗。目前，在行allo-HSCT地贫患者中已经明确铁超负荷是影响患者的生存的[13]。但是在白血病、MDS和淋巴瘤患者中关于铁超负荷对allo-HSCT结果影响的研究仍比较有限。

之前有研究显示移植前的血清铁蛋白水平升高——铁超负荷的替代指标，与恶性血液病患者allo-HSCT的总体生存率（overall survival, OS）降低和死亡率增高有关[14–16]。

铁超负荷治疗方法包括静脉放血（phlebotomy）和去铁药物。静脉放血安全性和有效性好，但是显然不适用于贫血者。

本文主要讨论：

(a) 铁代谢和铁超负荷的病理生理

(b) alloHSCT前后受体铁超负荷的治疗策略

(c) 去铁治疗的日后发展方向

铁代谢和铁超负荷的病理生理

铁是宇宙中最常见的金属，可能也是地球上最重要的金属。在人体内，铁是一种微量元素，是许多蛋白质和酶的必要成分，包括血红蛋白、肌红蛋白、细胞色素、核糖核苷酸还原酶、超氧化物歧化酶、脂氧合酶、脂肪酸去饱和酶、NADH脱氢酶、磷酸酶[17]。

铁是以铁蛋白是形式贮存，以细胞内铁贮存于肝细胞和巨噬细胞系统。

转铁蛋白饱和度下降有助于从循环微生物中夺取铁，但也限制了红系生成的铁获得，这导致了慢性炎症性贫血。在感染和其他炎症的情况下，铁调素（hepcidin）生产增加，导致肠道铁吸收下降和巨噬细胞铁释放。

当铁大量贮存时，因为产生活性氧类物质(Fenton and Haber–Weiss reactions)，铁又是有毒性的。

铁的这样一个双重性质，要求有一个非常严格的调节体内铁浓度的机制。

铁超负荷的评价

今天我们知道，过量的铁能导致组织损伤，使过氧化氢转换为活性氧类物质，引起蛋白质氧化、膜脂质过氧化以及核酸变构 [18]。血清铁蛋白是急性期反应物，所以不是始终能够可靠反映全身铁贮存[19]。移植时明确铁蛋白升高是多次输注红细胞还是炎症所致非常重要。血清铁蛋白和血清转铁蛋白饱和度（serum transferrin saturation, TS）是最容易和有效的确定铁超负荷的方法[20]。TS是确定患者铁超负荷风险的有效试验，升高的TS水平提示存在实质性的铁超负荷[21]。

铁蛋白水平升高可能与肝功能异常，甚至更大水平上与恶性疾病有关联，而不是与allo-HSCT受体有关。目前医生对于评价器官，如肝和心脏的铁超负荷较有经验了[22]。

在临床实践中，肝活检是评价总体铁和肝铁贮存的金方法，许多文章报道了肝活检在确定肝脏铁和总体铁中的作用[23–25]。

Ho 等[26] 评价了121 HSCT (58 异基因, 63自体)伴肝功能异常患者情况，在19例行肝活检患者中肝铁超负荷（hepatic iron overload, HIO） 是最常见的发现。近来，Ali等 [27] 报道HIO在 was com- mon in allo-HSCT受体中很常见，可以经肝活检精确诊断。他们发现HIO和输血数量(r= 0.69319, p 0.001)、血清铁蛋白水平显著相关(r = 0.55, p = 0.004).

然而，肝活检是 侵入操作，对于alloHSCT受体有血小板减少或凝血问题时会引发创伤。而且，由于肝铁分布的异质性，需要多点活检以取得可靠结果[28]。

超导量子干涉器件（superconducting quantum interference device, SQUID）测定肝脏铁的顺磁性评价肝脏贮存铁[29]。活检已证实该方法与肝脏铁 含量（liver iron content, LIC）有很好的相关性。 但是，世界范围只有较少的中心有 SQUID，极大限制了该技术的应用。

双能量CT（Dual-energy CT, DECT）技术于1976实施，但临床应用亦部广泛 [30]。DECT可以测定心脏铁，对于因幽闭恐惧症和禁忌症不能使用磁共振者，可以替代之（magnetic resonance imaging, MRI） 31]。DECT 也被用于测定肝脏铁和脂肪[32]，但是尚待活检确认该技术。

MRI 最早于1980测定组织铁，但成为实用性技术是近10年的事。LIC 值低于 5 mg/g 时利于去铁胺和地拉罗司清楚心脏铁[33]。但是没有什么的肝脏铁对于心脏和内分泌腺是“安全”的，以MRI技术透视和监测肝外的铁是必须的。鉴于MRI的非侵入性特性和与肝活检的良好相关性，该技术被广泛用于心脏和肝铁负荷的测定，见表1。

Allo-HSCT受体中铁超负荷及并发症

allo-HSCT受体移植前频繁输血和高血清铁蛋白与早期的非复发死亡风险增加相关[16]。输血相关的IO是HSCT并发症之一，近来有共识推荐所有的移植后生存者筛查铁超负荷。[34]。但是移植后晚期的铁超负荷及其临床意义目前尚不清楚。

近来研究显示IO与移植后早期的毒性、感染并发症紧密相关，如黏膜炎、菌血症和发热[35]。一些研究显示伴IO患者急性移植物抗宿主病（graft versus host disease, GVHD）[36]或 肝静脉闭塞综合征 [37, 38] 发生率升高。

Pullarkat 等 [39] 认为升高的血清铁蛋白水平(defined as 1,000 ng/ml) 对allo-HSCT后的总生存率、急性GVHD和血流感染负性影响。 GVHD是alloHSCT的主要病死和死亡原因，一些研究显示 HSCT 前血清铁蛋白升高与急性GVHD相关[7]，当然也有发现没有特别关联[40]。

Gaziev 等 [42]发现地中海贫血患者移植后铁贮存依然很高，65例患者移植后规律的静脉放血疗法成功的使得铁贮存正常。作者认为，移植后及时的进行除铁治疗，能够阻止铁超负荷对各器官的毒性作用损害。

IO使得细菌和真菌获得铁——必须的营养素变得容易，而且铁也损害了宿主的防御[43]。游离铁能抑制细胞的趋化作用和噬菌作用，并损害细胞免疫。

近来对357例MDS患者输血史和铁超负荷对移植后结果的影响进行了分析[44]。数据显示，输血依赖是影响移植后生存率下降 (hazard ratio=1.48, P= 0.017)和非复发死亡率(hazard ratio= 1.68, p = 0.024)升高的独立因素。输注次数与移植后总生存呈反相关(P=0.022)。输注次数超过20次者结果差得更厉害。需要指出的，输血依赖的影响只是出现在清髓性移植的患者中(overallsurvival: hazard ratio = 1.76, p = 0.003; non-relapse mortality: hazard ratio = 1.70, p = 0.02)。

一些研究确定了铁贮存增加与感染的阳性关系，如：假单胞菌、小肠结肠炎耶尔森菌、李斯特氏菌、霉菌、金黄色葡萄球菌[11, 44–48]。 Maertens研究发现 [11]，IO 与 allo-HSCT中侵袭性真菌感染有关。 Table 2列出了近年来关于allo-HSCT中铁超负荷研究的情况。

虽然在HSCT中关于铁超负荷造成损害已有较多经验，但是治疗IO的数据仍很有限。一项回顾性的研究显示[49]：口服地拉罗司治疗allo-HSCT的IO是安全和有效的。患者是移植后口服地拉罗司治疗，中位3个月血清铁蛋白降至1,000 ng/ml 以下。不良反应与MDS、地中海贫血和其他疾病去铁时类似，包括：皮疹，恶心，呕吐。

allo－HSCT的IO治疗策略

所有 allo-HSCT者应该在移植前评价 IO和输血史。

在围移植期和随访中应进行去铁治疗，以把IO的并发症降到最小，如：感染、心脏疾病和内分泌功能失调。

特别是MDS，目前数据和指南推荐治疗的早期即行除铁治疗[61, 62]。 意大利 GITMO研究结果推荐进行除铁治疗以降低全身铁负荷，并且不要因此延误移植的时机[63]。

去铁胺

去铁胺在40年前开发出来，做为除铁剂去铁胺能够有效除铁，提高生活质量和生存率 [67]。但是去铁胺的患者依从性差，因为去铁胺的口服生物利用度差和半衰期段，需要持续皮下或者静脉输注，比如通宵的应用[68]

去铁胺应该每周给予5到7次每周，特别是对儿童患者有莫大限制。 Gaziev等分析了地贫患者移植前和移植中使用去铁胺的情况[43], BMT后6个月去铁胺治疗的患者血清铁蛋白显著下降(2,081 versus 4,187; p, 0.007)。

去铁胺与铁紧密结合，铁－去铁胺复合物经尿和粪便排出。虽然有较多副作用，但是在地贫患者中，使用去铁胺确实能改善患者的生存率 [69]。近来发现去铁胺能影响一些胞内信号转到系统而起到抗肿瘤细胞作用 [70, 71]。这是使用去铁胺的优点之一，但是尚待进一步和大系列的临床研究确认。

GITMO推荐使用静脉去铁胺治疗移植前IO的剂量为 40 mg/kg/day, 24小时持续静脉输注。

地拉罗司

地拉罗司是新开发出来的去铁剂，每日只需服药一次。

地拉罗司在地贫、MDS、镰状细胞贫血、再障和Diamond–Blackfan 贫血等贫血类疾病中去铁的安全性和有效性已获得确认[75, 76]。

对于大多数患者，推荐地拉罗司 20 mg/kg/day起，实际剂量依铁的摄入量定。

如果有必要，根据铁蛋白水平，每3－6个月调整地拉罗司剂量5－10mg/kg/day。 非移植情况下，地拉罗司引发的是中度胃肠道功能紊乱，包括：腹泻和便秘，恶心，呕吐和腹痛[77]。

另外，地拉罗司与环孢菌素、他克莫司联用时引发肾毒性的问题尚待进一步临床研究以获得进一步可靠结果。

Ibrahim等[78] 发现地拉罗司在体外有杀灭毛霉菌的活性，与脂质体二性霉素B有协同作用。小鼠试验显示能提高生存率和降低组织毛霉菌感染负荷。

若地拉罗司与食物同服，其生物利用度受食物类型影响，如高热量和脂肪含量食物。

最大的地拉罗司治疗输血依赖IO的前瞻性多中心，开放式临床试验纳入了 1,700患者，包括341 MDS患者，约50 % 患者之前接受了去铁治疗，血清铁蛋白较基线显著下降( 264 ng/ml; P 0.0001)，该实验同时确证了地拉罗司治疗需要兼顾剂量调整和铁摄入情况。

讨论

移植前后应该常规检测血清铁蛋白。移植后血清铁蛋白超过1,000 ng/ml可能即是移植后的并发症之一。

对于血清铁蛋白 4,000 ng/ml者，为迅速降低机体铁建议使用静脉去铁胺24小时持续静滴，推荐剂量在25 - 40 mg/kg/day。 无禁忌症时 ( 肝肾功能不全)， 地拉罗司起始剂量 20– 25 mg/kg 每日。

治疗应该持续至血清铁蛋白达500 ng/ml以下。

FBS0701 是个新开发出来的口服去铁药物， I 期临床试验显示其肾毒性甚小 [80] ，有效成分是 desferrithiocin。 2分子desferrithiocin 结合1分子铁， FBS0701 对于输血依赖贫血治疗显示，在 3, 8, 16, and 32 mg/kg效果都不错，主要不良反应是尿色异常，头痛和消化道症状。 FBS0701 去铁效果的有效性的II期临床试验正在开展。

结论

移植前后理想的评价铁超负荷和降低铁负荷的策略尚待明确。迄今为止，我们关注于移植的成功率和结果，可能忽视了移值前铁超负荷对移植结果的负性影响。

现在我们已经知道移值前的铁超负荷与移植后的高血清铁蛋白血症需要治疗，在正常血清铁蛋白水平下移植可能降低感染和GVHD的发生， 改善死亡率，从而提高生存率。

同时，allo-HSCT移植前化疗过程中监测血清铁蛋白水平，并在移植前去铁治疗能改善移植的结果。
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