The distribution of iron in tissue is shown in Figure 1. Adult men normally have 35 to 45 mg of iron per kilogram of body weight.¹ Premenopausal women have lower iron stores as a result of their recurrent blood loss through menstruation. More than two thirds of the body's iron content is incorporated into hemoglobin in developing erythroid precursors and mature red cells. Uptake of erythroid iron is highly dependent on receptor-mediated endocytosis of diferric transferrin bound to transferrin receptors (the transferrin cycle, Figure 2). Each erythrocyte contains a billion atoms of iron; at normal rates of turnover, this concentration corresponds to the incorporation of 2 × 10²⁰ atoms of iron per day.⁴ Consequently, anemia is the cardinal sign of iron deficiency.
铁在组织中的分布如图 1 所示。成年男性每公斤体重通常含有 35 至 45 毫克铁。 ¹ 绝经前妇女的铁储存量较低，这是因为她们经常因月经失血。人体中三分之二以上的铁都被发育中的红细胞前体和成熟的红细胞结合到血红蛋白中。红细胞对铁的吸收高度依赖于与转铁蛋白受体结合的二价转铁蛋白受体介导的内吞（转铁蛋白循环，图 2）。每个红细胞含有 10 亿个铁原子；在正常周转率下，这一浓度相当于每天结合 2 × 10 ²⁰ 个铁原子。 ⁴ 因此，贫血是缺铁的主要标志。

Most of the remaining body iron is found in hepatocytes and reticuloendothelial macrophages, which serve as storage depots. The liver has first-pass access to dietary nutrients and can readily take up an amount of circulating iron that exceeds the binding capacity of plasma transferrin. Reticuloendothelial macrophages ingest senescent red cells, catabolize hemoglobin to scavenge iron, and load the iron onto transferrin for reuse. This process is indispensable; the erythron alone has a daily requirement of about 20 mg of iron,⁵ but only 1 to 2 mg of iron normally enters the body each day through the intestine.
体内剩余的铁大部分存在于肝细胞和网状内皮巨噬细胞中，它们是铁的储存库。肝脏可第一时间获取膳食营养，并可随时吸收超过血浆转铁蛋白结合能力的循环铁。网状内皮巨噬细胞摄取衰老的红细胞，分解血红蛋白以清除铁，并将铁加载到转铁蛋白上重新使用。这一过程不可或缺；仅红细胞每天就需要约 20 毫克的铁， ⁵ ，但通常每天只有 1 到 2 毫克的铁通过肠道进入人体。

Although the amount of iron extracted from the diet is small, the regulation of the intestinal absorption of iron is critical because humans have no physiologic pathway for excretion. Duodenal crypt cells sense the iron requirements of the body and are programmed by that information as they mature into absorptive enterocytes. Enterocytes lining the absorptive villi close to the gastroduodenal junction are responsible for all iron absorption. Iron must pass from the gut lumen through the apical and basolateral membranes of the enterocyte to reach the plasma (Figure 3). Iron obtained from food is not bound to transferrin, and there is no role for transferrin within the lumen of the intestine. Instead, the low pH of gastric effluent helps dissolve ingested iron and provides a proton-rich milieu. This facilitates enzymatic reduction of ferric iron to its ferrous form by a brush-border ferrireductase.⁶ Divalent metal transporter 1 (DMT1; formerly called Nramp2 or DCT1) is a protein that transfers iron across the apical membrane and into the cell through a proton-coupled process.^7,8 DMT1 is not specific to iron; it can transport a wide variety of divalent metal ions, including manganese, cobalt, copper, zinc, cadmium, and lead.⁸
虽然从饮食中提取的铁量很少，但由于人类没有排泄的生理途径，因此调节肠道对铁的吸收至关重要。十二指肠隐窝细胞能感知人体对铁的需求，并在成熟为吸收性肠细胞时根据这些信息进行编程。靠近胃十二指肠交界处的吸收性绒毛内的肠细胞负责所有铁的吸收。铁必须从肠道腔通过肠细胞的顶端膜和基底膜才能到达血浆（图 3）。从食物中获取的铁不与转铁蛋白结合，转铁蛋白在肠腔内也不起作用。相反，胃液的低 pH 值有助于溶解摄入的铁，并提供一个富含质子的环境。这有利于刷状缘铁还原酶将铁还原成亚铁形式。 ⁶ 二价金属转运体 1（DMT1；以前称为 Nramp2 或 DCT1）是一种蛋白质，它通过质子耦合过程将铁穿过顶端膜转运到细胞内。 ^7,8 DMT1 对铁没有特异性；它可以转运多种二价金属离子，包括锰、钴、铜、锌、镉和铅。 ⁸

Heme iron is taken up by a separate process that is not well characterized. Inside the absorptive enterocyte, iron has two possible fates: it may be stored as ferritin, or it may be transferred across the basolateral membrane to reach the plasma. These are not mutually exclusive, and the determining factor is probably an iron absorption “set point” that was established when the enterocyte developed from a crypt cell. Iron that remains in the form of ferritin as the enterocyte completes its limited life cycle will be sloughed with the senescent cell and will leave the body through the gastrointestinal tract. This process represents an important mechanism of iron loss.
血红素铁是通过一个单独的过程被吸收的，这个过程的特征还不十分明确。在吸收性肠细胞内，铁有两种可能的命运：可能以铁蛋白的形式储存，也可能穿过基底膜到达血浆。这两种情况并不相互排斥，决定因素可能是肠细胞从隐窝细胞发育而来时建立的铁吸收 "设定点"。当肠细胞完成其有限的生命周期时，以铁蛋白形式存在的铁将随衰老细胞脱落，并通过胃肠道排出体外。这一过程是铁流失的重要机制。

The basolateral enterocyte iron transporter has not been definitively identified, but a recently described protein, Ireg1, is a likely candidate.⁹ Genetic studies in mice have shown that the basolateral transporter requires an accessory protein, a multicopper protein called hephaestin.¹⁰ Hephaestin is similar to plasma ceruloplasmin and is presumed to function as a ferroxidase. As will be discussed below, ceruloplasmin also has an important role in iron metabolism.
肠细胞基外侧铁转运体尚未明确确定，但最近描述的一种蛋白质 Ireg1 可能是候选者。 ⁹ 对小鼠的遗传研究表明，基底侧转运体需要一种辅助蛋白，即一种名为 Hephaestin 的多铜蛋白。 ¹⁰ Hephaestin 类似于血浆中的脑磷脂蛋白，据推测具有铁氧化酶的功能。下文将讨论脑磷脂蛋白在铁代谢中的重要作用。

The absorption of intestinal iron is regulated in several ways (Figure 4). First, it can be modulated by the amount of iron recently consumed in the diet, a mechanism referred to as the dietary regulator. For several days after a dietary iron bolus, absorptive enterocytes are resistant to acquiring additional iron. This phenomenon has previously been called “mucosal block.”¹¹ This blocking action probably results from the accumulation of intracellular iron, leading the enterocyte to believe that its set-point requirements have been met. It may occur even in the presence of systemic iron deficiency.
肠道对铁的吸收有几种调节方式（图 4）。首先，肠道铁的吸收可受到最近从饮食中摄入的铁量的调节，这种机制被称为饮食调节器。在摄入铁剂后的几天内，吸收性肠细胞对获得额外的铁具有抵抗力。这种现象以前被称为 "粘膜阻滞"。 ¹¹ 这种阻滞作用可能是由于细胞内铁的积累，导致肠细胞认为其设定点要求已得到满足。即使在全身缺铁的情况下，这种现象也可能发生。

A second regulatory mechanism also senses iron levels but responds to total body iron, rather than dietary iron. This mechanism has been termed the stores regulator.¹² It is capable of changing the amount of iron absorbed to a limited extent: iron absorption is modulated by a factor of only two to three in iron-deficient states as compared with iron-replete states.⁵ Although the molecular details of the stores regulator are not known, it probably acts at the level of crypt-cell programming, in response to the saturation of plasma transferrin with iron. Experiments in animals suggest that the levels of the apical transporter, DMT1, are altered in response to changes in body iron stores.⁸
第二种调节机制也能感知铁的水平，但它对体内总铁而不是食物中的铁做出反应。这种机制被称为储存调节器。 ¹² 它能够在一定程度上改变铁的吸收量：缺铁状态下，铁的吸收量仅比铁充足状态下的吸收量高出 2 到 3 倍。 ⁵ 虽然储存调节器的分子细节尚不清楚，但它可能是在隐窝细胞编程水平上发挥作用，对血浆转铁蛋白的铁饱和度做出反应。动物实验表明，顶端转运体 DMT1 的水平会随着体内铁储存的变化而改变。 ⁸

The third regulatory mechanism, known as the erythropoietic regulator,¹² does not respond to iron levels at all. Rather, it modulates iron absorption in response to the requirements for erythropoiesis. The erythropoietic regulator has a greater capacity to increase iron absorption than the stores regulator.¹² It is logical that the erythron should have some influence on the rate of intestinal iron absorption, since most of the body iron is used for erythropoiesis. Yet how it accomplishes this is unknown. The erythropoietic regulator probably involves a soluble signal that is carried by plasma from the bone marrow to the intestine.
第三种调节机制被称为红细胞生成调节器， ¹² ，它完全不对铁的含量做出反应。相反，它根据红细胞生成的需要调节铁的吸收。与储存调节器相比，红细胞生成调节器增加铁吸收的能力更大。 ¹² 由于体内大部分的铁都用于红细胞生成，因此红细胞生成素理应对肠道铁的吸收率产生一定的影响。然而，它是如何做到这一点的还不得而知。红细胞生成调节器可能涉及一种可溶性信号，这种信号由血浆从骨髓带到肠道。

It is well documented that, in addition to iron-deficiency anemia, several other anemic states may lead to increased absorption of dietary iron. These conditions include the thalassemia syndromes, congenital dyserythropoietic anemias, and sideroblastic anemias. Strikingly, many other forms of anemia that are characterized by similar rates of erythropoiesis do not stimulate intestinal iron absorption. These disorders include hereditary spherocytosis, autoimmune hemolytic anemia, and sickle cell anemia. Thus, hyperproliferative anemias can be divided into two classes: those that stimulate iron absorption and those that do not. The two types can be differentiated in a simple way. The types that stimulate iron absorption have in common the fact that erythroid cells are destroyed near the site of their development within the bone marrow (a situation known as ineffective erythropoiesis). The types that do not stimulate iron absorption involve the destruction of cells in the periphery. The importance of the site of destruction is not well understood. However, cells destroyed before their release from the bone marrow are less mature than circulating erythrocytes, suggesting that the soluble erythropoietic regulator is a molecule derived from precursor forms of erythrocytes, rather than later forms.
有资料表明，除了缺铁性贫血外，其他几种贫血状态也可能导致对膳食铁的吸收增加。这些情况包括地中海贫血综合征、先天性红细胞生成障碍性贫血和红细胞生成障碍性贫血。令人震惊的是，许多其他形式的贫血，其特点是类似的红细胞生成率，但并不刺激肠道对铁的吸收。这些疾病包括遗传性球形红细胞增多症、自身免疫性溶血性贫血和镰状细胞性贫血。因此，高增生性贫血可分为两类：刺激铁吸收的贫血和不刺激铁吸收的贫血。这两种类型的区分方法很简单。能促进铁吸收的类型的共同点是，红细胞在骨髓内的发育部位附近被破坏（这种情况被称为无效红细胞生成）。而不能促进铁吸收的类型则是外周细胞遭到破坏。破坏部位的重要性尚不十分清楚。不过，在从骨髓中释放出来之前被破坏的细胞不如循环中的红细胞成熟，这表明可溶性促红细胞生成调节剂是一种来自红细胞前体而不是后体的分子。

Iron absorption increases in response to acute hypoxia. It is not known whether the hypoxic signal is transduced through one of the regulatory pathways discussed above or through an independent mechanism.
急性缺氧会增加铁的吸收。目前尚不清楚缺氧信号是通过上述调控途径之一还是通过独立机制传递的。

The human body prioritizes the use of iron in several ways. During development, the fetus draws iron away from its mother for itself. After birth, the erythron has relative priority as compared with other tissues. Red-cell production is unperturbed until iron stores are depleted, as reflected by low serum ferritin levels. When the stores have been used up, the iron saturation of transferrin decreases and patients begin to show evidence of iron-deficient erythropoiesis. The first biochemical clues of iron deficiency are increased levels of free protoporphyrin and zinc protoporphyrin in erythrocytes. The levels of soluble transferrin receptor, a protein-cleavage product that is present in plasma, increase when the lack of iron limits the production of new red cells. Frank anemia with microcytosis is detected later. A decreased reticulocyte hemoglobin level is a useful early indicator of iron-deficient erythropoiesis and may be superior to other laboratory measures in this respect.¹⁵
人体通过多种方式优先使用铁。在发育过程中，胎儿会从母体汲取铁元素。出生后，与其他组织相比，红细胞具有相对优先权。红细胞的生成不受影响，直到储存的铁消耗殆尽，血清铁蛋白水平低就反映了这一点。当储存的铁耗尽时，转铁蛋白的铁饱和度会降低，患者开始出现缺铁性红细胞生成的迹象。缺铁的第一个生化线索是红细胞中游离原卟啉和锌原卟啉水平的升高。可溶性转铁蛋白受体是一种存在于血浆中的蛋白裂解产物，当缺铁限制了新红细胞的生成时，可溶性转铁蛋白受体的水平就会升高。伴有小红细胞增多症的法兰克贫血在后期才被发现。网织红细胞血红蛋白水平的降低是铁缺乏性红细胞生成的一个有用的早期指标，在这方面可能优于其他实验室指标。 ¹⁵

The symptoms and signs of iron deficiency are partially explained by the presence of anemia. They include pallor, fatigue, poor exercise tolerance, and decreased work performance. However, there also appears to be a direct effect of iron deficiency on the central nervous system. In young children, measurable cognitive abnormalities may develop.¹⁶ In both children and adults, pica — a bizarre behavioral symptom that is highly characteristic of severe iron deficiency — can develop.¹⁷ Pica is characterized by the inappropriate consumption of nonnutritive substances; it disappears with iron treatment. Severe, long-standing iron deficiency may also be associated with koilonychia and the Plummer–Vinson syndrome, but these conditions are very rare in clinical practice in the United States.
缺铁的症状和体征部分是由贫血引起的。这些症状和体征包括面色苍白、疲劳、运动耐力差和工作能力下降。不过，缺铁似乎也会直接影响中枢神经系统。幼儿可能会出现明显的认知异常。 ¹⁶ 在儿童和成人中，都可能会出现 "偏食"（pica）--一种严重缺铁的特征性怪异行为症状。 ¹⁷ 偏食的特点是不适当地进食非营养物质；在接受铁剂治疗后，偏食症状会消失。严重、长期的缺铁还可能伴有疳积和普拉默-文森综合症，但这些症状在美国的临床实践中非常罕见。

Causes of iron deficiency are easy to understand when one accepts the fact that there is no physiologic pathway for iron excretion. Iron deficiency will result from any condition in which dietary iron intake does not meet the body's demands. For this reason, rapidly growing children and premenopausal women are at highest risk. Worldwide, dietary insufficiency as a cause of iron deficiency is usually secondary to intestinal blood loss resulting from parasitosis. In such cases, dietary intake is unable to keep up with chronic losses. A comprehensive list of the causes of iron deficiency is shown in Table 1.
只要接受一个事实，即人体没有排泄铁的生理途径，那么缺铁的原因就不难理解了。如果膳食中铁的摄入量不能满足身体的需求，就会导致缺铁。因此，生长发育迅速的儿童和绝经前妇女的风险最高。在世界范围内，膳食不足导致的缺铁通常继发于寄生虫病引起的肠道失血。在这种情况下，膳食摄入量无法跟上长期流失的铁。表 1 全面列出了缺铁的原因。

Congenital and acquired abnormalities of the intestinal epithelium can also result in iron deficiency. Congenital defects in iron metabolism are fascinating but are poorly understood on a molecular level. Hypotransferrinemia, also called atransferrinemia, is a condition in which little or no plasma transferrin is produced. This rare disorder leads to severe iron-deficiency anemia accompanied by parenchymal iron overload.^18–21
先天性和后天性肠上皮细胞异常也会导致缺铁。先天性铁代谢缺陷令人着迷，但对其分子水平却知之甚少。低转铁蛋白血症，又称无转铁蛋白血症，是一种血浆转铁蛋白生成很少或根本不生成转铁蛋白的疾病。这种罕见的疾病会导致严重的缺铁性贫血，并伴有实质铁超载。 ^18–21

A distinct group of patients with normal plasma transferrin levels have iron-deficiency anemia that is unresponsive to oral iron therapy and incompletely responsive to parenteral iron therapy.^22,23 Bannerman²⁴ made note of the similarity between patients with this condition and mutant mice that are now known to have an abnormality in the iron transporter DMT1.⁷ However, no mutations in the gene encoding DMT1 have been found in humans thus far.²⁵ It is possible that such patients have defects in other iron-transport steps.
有一类血浆转铁蛋白水平正常的患者患有缺铁性贫血，对口服铁剂治疗无反应，对肠道外铁剂治疗反应不完全。 ^22,23 Bannerman ²⁴ 指出，这种情况的患者与突变小鼠有相似之处，现在已知突变小鼠的铁转运体 DMT1 存在异常。 ⁷ 但迄今为止，人类尚未发现编码 DMT1 的基因发生突变。 ²⁵ 这类患者有可能在其他铁转运步骤上存在缺陷。

Several forms of iron salt are used to treat iron deficiency. Remarkably, however, the treatment used by the 19th-century French physician Blaud²⁶ (ferous sulfate) is still as effective as any other oral therapy. Perseverance is the cornerstone of successful treatment; it takes several months of replacement therapy to replenish body iron stores. Some patients have difficulty tolerating iron salts, because these substances tend to cause gastrointestinal distress. Liquid iron-salt preparations, given to young children, may cause permanent staining of the teeth. These problems can be circumvented by the use of an oral iron–polysaccharide complex. Both iron salts and the iron–polysaccharide preparation are inexpensive.
有几种铁盐可用于治疗缺铁症。但值得注意的是，19 世纪法国医生布劳（Blaud ²⁶ ）使用的治疗方法（硫酸亚铁）仍然与其他口服疗法一样有效。持之以恒是成功治疗的基石；需要几个月的替代疗法才能补充体内的铁储存。有些患者难以耐受铁盐，因为这些物质容易引起肠胃不适。给幼儿服用液体铁盐制剂可能会导致牙齿永久染色。使用口服铁多糖复合物可以避免这些问题。铁盐和铁多糖制剂都很便宜。

Infants and toddlers need relatively more iron than adults to support their rapid growth. Normal, full-term infants have a generous iron endowment at birth, totaling about 75 mg per kilogram.²⁷ Premature infants, infants of mothers with diabetes mellitus, and infants who are small for gestational age have substantially smaller iron stores than normal, full-term infants.²⁸ Stores are rapidly depleted, however, even in normal children, and there is little margin in iron balance. For that reason, iron-fortified infant formulas have been widely used since the early 1970s. There are no known contraindications to feeding with iron-fortified formulas and no apparent side effects.²⁸ Although a small proportion of infants have a genetic predisposition to iron overload later in life (see below), the amount of iron given in infant feedings should be inconsequential. All formula consumed by infants in the first year of life should contain 4 to 12 mg of iron per liter; “low iron” formulas containing less than 4 mg of iron per liter should not be given. Breast-fed infants receive adequate iron in a highly bioavailable form, and breast-feeding is recommended by the Committee on Nutrition of the American Academy of Pediatrics.²⁸
婴幼儿需要比成人相对更多的铁来支持他们的快速生长。正常足月婴儿出生时就拥有丰富的铁禀赋，每公斤约 75 毫克。 ²⁷ 与正常足月婴儿相比，早产儿、母亲患有糖尿病的婴儿和胎龄小的婴儿体内的铁储量要少得多。 ²⁸ 不过，即使是正常婴儿，体内储存的铁也会迅速耗尽，铁平衡的余量很小。因此，自 20 世纪 70 年代初以来，强化铁的婴儿配方奶粉已被广泛使用。使用铁强化配方奶粉喂养没有已知的禁忌症，也没有明显的副作用。 ²⁸ 虽然有一小部分婴儿有日后铁过量的遗传倾向（见下文），但婴儿喂养中的铁量应该无关紧要。婴儿出生后第一年食用的所有配方奶粉每升都应含有 4 到 12 毫克的铁；不应喂食每升含铁量低于 4 毫克的 "低铁 "配方奶粉。母乳喂养的婴儿能以高生物利用率的形式获得充足的铁，美国儿科学会营养委员会推荐母乳喂养。 ²⁸

Patients who cannot tolerate or absorb oral iron, those with severe iron deficiency who are not compliant with oral treatment, and those with profound iron deficits may benefit from parenteral iron therapy. Iron dextran is given intravenously, because intramuscular administration frequently leads to complications. Although there are rare cases of anaphylaxis, this treatment is generally safe and effective, particularly if the patient tolerates a test dose given before the replacement dose. Although the manufacturer recommends administering a maximum of 2 ml (100 mg) per day, most clinicians find that there is no problem in giving an entire replacement dose at one time.²⁹ Regimens for intravenously administered iron differ from those for orally administered iron. The correct dose can easily be determined with the use of a calculator provided by the manufacturer on the Internet (at http://www.infed.com/calcltor.htm). Intravenous iron dextran is taken up rapidly by reticuloendothelial macrophages, where it can be processed and loaded onto transferrin without toxic effects.
无法耐受或吸收口服铁剂的患者、无法坚持口服治疗的严重缺铁患者以及严重缺铁的患者可能会从肠外铁剂治疗中获益。右旋糖酐铁需要静脉注射，因为肌肉注射经常会导致并发症。虽然出现过敏性休克的病例极少，但这种治疗方法通常是安全有效的，尤其是如果患者能够耐受替代剂量前的试验剂量。虽然生产商建议每天最多给药 2 毫升（100 毫克），但大多数临床医生发现，一次性给药整个替代剂量并无问题。 ²⁹ 静脉注射铁剂的疗程与口服铁剂不同。使用制造商在互联网上提供的计算器（网址：http://www.infed.com/calcltor.htm），可以轻松确定正确的剂量。静脉注射的右旋糖酐铁能迅速被网状内皮巨噬细胞吸收，并在巨噬细胞中被处理和加载到转铁蛋白上，而不会产生毒性作用。

Anemia of chronic inflammation, also known as anemia of chronic disease, has some features in common with iron-deficiency anemia. Iron-deficient erythropoiesis results from a defect in iron recycling. As a result, reticuloendothelial iron is plentiful in bone marrow macrophages, but this iron is not available to erythroid precursors. In patients with anemia of chronic inflammation, there appears to be a defect in the freeing of iron from macrophages, the loading of iron onto plasma transferrin, or both. Characteristic laboratory findings include low serum iron levels, low serum iron-binding capacity, increased serum ferritin, and normocytic or slightly microcytic erythrocytes. In contrast to patients with iron-deficiency anemia, those with anemia of chronic inflammation do not have elevated levels of serum transferrin receptor.³⁰ The pathophysiology of anemia of chronic inflammation is not understood, but the condition probably evolved as a cytokine-mediated defense against microbial pathogens. It effectively leads to the withholding of iron from microbes as well as from erythroid precursors.³¹ Mild anemia may be a relatively small price to pay for the attenuation of infection. The only effective treatment for anemia of chronic inflammation is correction of the underlying disorder.
慢性炎症性贫血又称慢性疾病性贫血，与缺铁性贫血有一些共同之处。缺铁性红细胞生成是由铁回收缺陷造成的。因此，骨髓巨噬细胞中的网状内皮铁含量丰富，但红细胞前体无法获得这些铁。在慢性炎症性贫血患者中，巨噬细胞中的铁释放、血浆转铁蛋白中的铁负载或两者似乎都存在缺陷。典型的实验室检查结果包括血清铁含量低、血清铁结合能力低、血清铁蛋白升高以及正常红细胞或轻微小红细胞。与缺铁性贫血患者不同，慢性炎症性贫血患者的血清转铁蛋白受体水平不会升高。 ³⁰ 慢性炎症性贫血的病理生理学尚不清楚，但这种情况很可能是作为细胞因子介导的抵御微生物病原体的一种防御手段演变而来的。它能有效地阻止微生物和红细胞前体吸收铁元素。 ³¹ 轻度贫血可能是为减轻感染而付出的相对较小的代价。治疗慢性炎症性贫血的唯一有效方法是纠正潜在的疾病。

Classic hereditary hemochromatosis is the most prevalent monoallelic genetic disease in whites. It was first described in 1865 as a clinical triad of glycosuria, cirrhosis, and hyperpigmentation of the skin.³² Von Recklinghausen later established that these clinical features were due to iron deposition and coined the term hemochromatosis.³³ In 1976, Simon et al. discovered that the genetic predisposition for hemochromatosis cosegregated with the HLA-A3 allele, indicating that the defective gene was closely linked to the human major histocompatibility complex.³⁴ This critical finding paved the way for positional cloning of the hemochromatosis gene 20 years later.³⁵
典型遗传性血色病是白人中最常见的单偶性遗传病。1865 年，该病首次被描述为糖尿、肝硬化和皮肤色素沉着的临床三联征。 ³² 后来，Von Recklinghausen 确定这些临床特征是由铁沉积引起的，并创造了血色沉着病一词。 ³³ 1976 年，西蒙等人发现，血色病的遗传倾向与 HLA-A3 等位基因共存，表明缺陷基因与人类主要组织相容性复合体密切相关。 ³⁴ 这一重要发现为 20 年后血色病基因的定位克隆铺平了道路。 ³⁵

The majority of patients with hereditary hemochromatosis are descended from a common Celtic ancestor who lived 60 to 70 generations ago.³⁶ They carry a unique missense mutation (C282Y) that alters a major-histocompatibility-complex class I–like protein designated HFE.³⁵ On the basis of data from blood donors, it is estimated that as many as 1 in 10 white Americans carries at least one allele with this mutation.³⁷ Clinically significant iron overload usually develops in patients who are homozygous for this mutation. A subgroup of heterozygous persons is also affected. Several other polymorphisms have been found in the gene encoding the HFE protein, but their clinical significance is unclear.^33,38–40 At least one of these mutations, H63D, is probably deleterious when it is present as the second allele in persons who are heterozygous for C282Y.^41,42
大多数遗传性血色沉着病患者的祖先是凯尔特人，他们的共同祖先生活在 60 到 70 代之前。 ³⁶ 他们携带一种独特的错义突变（C282Y），这种突变改变了一种名为 HFE 的主要组织相容性复合物 I 类蛋白。 ³⁵ 根据献血者的数据，估计每 10 个美国白人中就有 1 人携带至少一个具有这种突变的等位基因。 ³⁷ 这种基因突变的同型患者通常会出现明显的临床铁负荷过重。杂合子亚群患者也会受到影响。在编码 HFE 蛋白的基因中还发现了其他几种多态性，但其临床意义尚不清楚。 ^33,38–40 其中至少有一种突变，即 H63D，如果作为第二等位基因出现在 C282Y 杂合子患者中，很可能是有害的。 ^41,42

HFE forms a heterodimer with beta₂-microglobulin. This heterodimer is expressed on the surface of many cells, including duodenal crypt cells and macrophages. The C282Y mutation alters the conformation of the HFE protein and interferes with its function. In the three years since this finding was first reported, the crystal structure of HFE has been identified, and it has been shown to form a high-affinity complex with the transferrin receptor.^43–48 Nonetheless, it remains unclear how HFE regulates iron absorption. Insight may come from mouse strains that have been engineered to carry mutated Hfe genes, serving as models in which to study the pathophysiology of iron loading in hemochromatosis.^49,50
HFE 与 beta ₂ -微球蛋白形成异二聚体。这种异源二聚体在许多细胞表面表达，包括十二指肠隐窝细胞和巨噬细胞。C282Y 突变会改变 HFE 蛋白的构象并干扰其功能。自这一发现首次被报道以来的三年中，HFE 的晶体结构已被确定，并被证明能与转铁蛋白受体形成高亲和力复合物。 ^43–48 然而，HFE 如何调节铁的吸收仍不清楚。小鼠品系经改造后携带突变的 Hfe 基因，可作为研究血色沉着病铁负荷病理生理学的模型，这可能会给我们带来启示。 ^49,50

Although there is no doubt that the C282Y mutation causes hemochromatosis, there is a broad spectrum of clinical presentations in both persons homozygous for C282Y and those who are heterozygous. A small proportion of C282Y homozygotes have no clinical or biochemical evidence of iron overload. This finding indicates that other genetic and environmental factors must affect the phenotypic expression of the mutation.⁴²
尽管 C282Y 基因突变导致血色沉着病这一点毋庸置疑，但无论是 C282Y 基因同型还是异型患者，其临床表现都有很大差异。有一小部分 C282Y 基因同卵者没有铁超载的临床或生化证据。这一发现表明，其他遗传和环境因素一定会影响该突变的表型表达。 ⁴²

Patients with hemochromatosis regularly absorb two to three times as much dietary iron as normal persons. Most do not have symptoms until adulthood, although the saturation of serum transferrin is usually increased by adolescence. Hemochromatosis should be suspected when the serum transferrin saturation exceeds 50 percent in premenopausal women and 60 percent in men and postmenopausal women. Excess iron is deposited in parenchymal cells of the liver, heart, pancreas, pituitary gland, and parathyroid gland. Early symptoms are nonspecific; they include fatigue, arthralgia, erectile dysfunction, and increased skin pigmentation. As the disease progresses, tender hepatomegaly develops and leads to liver fibrosis and cirrhosis. There is an increased incidence of hepatocellular carcinoma after substantial damage to the liver has occurred. Iron deposition in the heart causes cardiomyopathy that is usually congestive but may be restrictive or associated with pericarditis and arrhythmias. Associated types of endocrinopathy include diabetes mellitus, hypopituitarism, hypogonadism, and hypoparathyroidism. Patients with hemochromatosis are more susceptible than others to infection, particularly with Vibrio vulnificus, Listeria monocytogenes, Yersinia enterocolitica, Salmonella enteritidis serotype typhimurium, Klebsiella pneumoniae, Escherichia coli, Rhizopus arrhizus, and mucor species.
血色沉着病患者经常吸收的饮食铁是正常人的两到三倍。虽然血清转铁蛋白饱和度通常在青春期时就会升高，但大多数患者直到成年后才会出现症状。当绝经前女性的血清转铁蛋白饱和度超过 50%，男性和绝经后女性的血清转铁蛋白饱和度超过 60% 时，就应怀疑血色沉着病。过量的铁沉积在肝脏、心脏、胰腺、垂体和甲状旁腺的实质细胞中。早期症状无特异性，包括疲劳、关节痛、勃起功能障碍和皮肤色素沉着。随着病情的发展，会出现触痛性肝肿大，并导致肝纤维化和肝硬化。肝脏受到严重损害后，肝细胞癌的发病率会增加。铁沉积在心脏会导致心肌病，通常是充血性的，但也可能是局限性的，或伴有心包炎和心律失常。伴发的内分泌病包括糖尿病、垂体功能减退、性腺功能减退和甲状旁腺功能减退。血色素沉着症患者比其他人更容易受到感染，尤其是弧菌、单核细胞增生李斯特菌、小肠结肠炎耶尔森菌、肠炎沙门氏菌血清型伤寒杆菌、肺炎克雷伯氏菌、大肠埃希氏菌、根霉菌和粘菌。

Liver biopsy is the gold standard for quantifying iron. The hepatic iron concentration typically exceeds 80 μmol per gram of liver, dry weight, resulting in a hepatic iron index of more than 1.9 mmol per kilogram per year (the hepatic iron index is the ratio of the hepatic iron concentration to the age of the patient in years). Iron overload may also be assessed by quantitative phlebotomy to the point of iron depletion. The diagnosis can be confirmed by direct mutation analysis of the HFE gene. Homozygosity for the C282Y mutation plus biochemical evidence of iron overload makes the diagnosis of hemochromatosis indisputable.
肝脏活检是量化铁的黄金标准。肝铁浓度通常超过每克肝干重 80 μmol，导致肝铁指数超过每年每公斤 1.9 mmol（肝铁指数是肝铁浓度与患者年龄（岁）的比值）。铁超载也可通过定量抽血法评估铁耗尽程度。可通过对 HFE 基因的直接突变分析来确诊。C282Y基因突变的同型性加上铁超载的生化证据使血色沉着病的诊断无可争议。

The availability of a genetic test for hemochromatosis has fueled controversy about the benefits of screening for the disease. The test is simple, and the disease is highly prevalent and treatable. However, important disadvantages must also be considered. There is concern, particularly in the United States, that persons known to be homozygous for the C282Y mutation would face discrimination from health and life insurers. Furthermore, the test is not always predictive; some persons who are homozygous for C282Y never have adverse effects resulting from iron overload,⁴² and some patients with genetic iron overload do not have mutations in the HFE gene.⁵¹
血色沉着病基因检测的问世，引发了关于筛查该疾病的益处的争议。这种检测方法很简单，而且这种疾病的发病率很高，可以治疗。然而，重要的缺点也必须考虑在内。有人担心，特别是在美国，已知为 C282Y 基因同源突变的人会受到医疗和人寿保险公司的歧视。此外，该检测并不总是具有预测性；一些 C282Y 基因同源的人从未因铁超载而出现不良反应， ⁴² ，而一些遗传性铁超载患者并没有 HFE 基因突变。 ⁵¹

The treatment of hemochromatosis has not changed substantially since 1950.⁵² Therapeutic phlebotomy is safe, effective, and inexpensive. Each 450 to 500 ml of blood contains 200 to 250 mg of iron. Ideally, therapy is begun before symptoms develop, when the serum ferritin level exceeds 200 μg per liter in nonpregnant, premenopausal women or 300 μg per liter in men and postmenopausal women.⁵³ Typically, phlebotomy is performed at a rate of 1 unit of blood per week until the patient has mild hypoferritinemia. Thereafter, it is continued as needed to keep the serum ferritin level below 50 μg per liter. On average, men require phlebotomy three to four times per year, and women require it one to two times per year.⁵³ When phlebotomy is instituted before end-stage organ damage has occurred, patients can have a normal life expectancy and quality of life. Even if begun later, phlebotomy can improve constitutional symptoms, relieve hepatomegaly and liver tenderness, and protect joints from arthritis. However, endocrine abnormalities and liver fibrosis, once they have developed, usually do not resolve.⁵³
自 1950 年以来，血色素沉着病的治疗方法没有发生重大变化。 ⁵² 治疗性抽血安全、有效且成本低廉。每 450 至 500 毫升血液中含有 200 至 250 毫克铁。理想情况下，在出现症状之前就开始治疗，即非怀孕、绝经前妇女的血清铁蛋白水平超过每升 200 微克，或男性和绝经后妇女的血清铁蛋白水平超过每升 300 微克。 ⁵³ 通常情况下，每周抽血 1 单位，直到患者出现轻度低铁蛋白血症。此后，根据需要继续抽血，以保持血清铁蛋白水平低于每升 50 微克。男性平均每年需要抽血三到四次，女性每年需要一到两次。 ⁵³ 如果在终末期器官损伤发生之前就进行抽血，患者可以获得正常的预期寿命和生活质量。即使较晚开始，抽血疗法也能改善体质症状，缓解肝肿大和肝触痛，保护关节免受关节炎的影响。然而，内分泌异常和肝纤维化一旦发生，通常不会缓解。 ⁵³

In addition to performing phlebotomy, it is prudent to advise patients with hemochromatosis to modify their diets. They should avoid iron supplementation and restrict their intake of vitamin C, since vitamin C facilitates the absorption of iron. In addition, they should limit their consumption of red meat (a rich source of heme iron) and alcohol. It is wise for such patients to avoid raw shellfish, because several cases of fatal infection with V. vulnificus have been reported in patients with hemochromatosis.⁵³
除了进行抽血检查外，建议血色沉着病患者调整饮食也是谨慎之举。他们应避免补充铁剂，并限制维生素 C 的摄入量，因为维生素 C 有助于铁的吸收。此外，他们还应限制食用红肉（血红素铁的丰富来源）和酒精。血色素沉着病患者最好不要吃生的贝类，因为有几例血色素沉着病患者感染弧菌致死的报道。 ⁵³

A subgroup of patients with hereditary hemochromatosis, indistinguishable from those described above, do not have mutations in HFE, and their disease does not appear to be linked to the HLA complex.⁵¹ The genetic basis for their condition has not yet been determined.
遗传性血色素沉着症患者中有一个亚群，与上述患者没有区别，但没有 HFE 基因突变，他们的疾病似乎与 HLA 复合物无关。 ⁵¹ 他们的遗传基础尚未确定。

Iron overload is not limited to persons of European descent. A distinct iron-loading disorder is prevalent in Africa, affecting up to 10 percent of some rural populations.⁵⁴ Formerly termed Bantu siderosis, African iron overload results from a predisposition to iron loading that is exacerbated by excessive intake of dietary iron.⁵⁵ It is particularly problematic among Africans who drink a traditional beer brewed in nongalvanized steel drums. Although the disorder was once attributed to dietary excess, serious iron overload does not develop in all beer drinkers, and not all patients with iron overload consume excessive amounts of the beer. Investigators have concluded that heterozygosity for an unidentified iron-loading gene confers susceptibility; homozygous persons may be more severely affected.⁵⁶ African iron overload is not due to mutations in the HFE gene and is not linked to the HLA locus.^55,57
铁超载不仅限于欧洲后裔。非洲普遍存在一种独特的铁负荷过重症，在一些农村人口中发病率高达 10%。 ⁵⁴ 非洲铁负荷过重症以前被称为班图铁病，是由于铁负荷过重的易感性导致的，而饮食中铁的过量摄入又会加重这种易感性。 ⁵⁵ 这种疾病在饮用用非镀锌钢桶酿造的传统啤酒的非洲人中尤为严重。虽然这种疾病曾被归因于饮食过量，但并非所有喝啤酒的人都会出现严重的铁超载，而且并非所有铁超载患者都摄入过量的啤酒。研究人员得出结论，一种未确定的铁负荷基因的杂合子会导致易感性；同种基因的人可能会受到更严重的影响。 ⁵⁶ 非洲铁过载不是由于 HFE 基因突变造成的，也与 HLA 基因座无关。 ^55,57

The pattern of iron deposition among persons with African iron overload differs from that among those with hereditary hemochromatosis.⁵⁸ Among the former, there is marked iron loading of Kupffer's cells as well as hepatocytes, resembling the pattern seen in patients with transfusional siderosis and suggesting a defect in erythroid iron recycling. Cirrhosis, occasionally complicated by hepatocellular carcinoma, is the predominant organ manifestation. Cardiomyopathy and diabetes are less common. Although serum ferritin levels are elevated, the transferrin saturation does not always reflect the true extent of iron overload in these patients. Patients with African iron overload are probably more susceptible than others to infection, and they have an increased incidence of tuberculosis.^59,60
非洲铁超载患者的铁沉积模式与遗传性血色病患者不同。 ⁵⁸ 在前者中，Kupffer 细胞和肝细胞都有明显的铁负荷，与输血性巩膜沉着症患者的模式相似，表明红细胞铁回收功能有缺陷。肝硬化是主要的器官表现，偶尔会并发肝细胞癌。心肌病和糖尿病较少见。虽然血清铁蛋白水平升高，但转铁蛋白饱和度并不总能反映这些患者铁超载的真实程度。非洲铁超载患者可能比其他人更容易受到感染，他们的结核病发病率也会增加。 ^59,60

Clinically significant iron overload may also occur in Americans of African descent,^61–63 although such persons rarely have mutations in the HFE gene.⁶⁴ It has been suggested that the mutation associated with African iron overload was brought to the United States primarily through the slave trade.⁶¹ The true incidence of siderosis among African Americans is not yet known. The results of epidemiologic studies may be confounded by the fact that the defective gene has not yet been identified and by the presence of coexisting conditions, such as various types of hemoglobinopathy, viral hepatitis, or alcoholism. If black Americans have the same disorder as patients with African iron overload, the transferrin saturation may not be elevated and it may be less useful as a screening tool for these patients than for patients with hemochromatosis.⁶⁵ Nonetheless, it seems prudent to consider a diagnosis of iron overload in black patients and to measure serum ferritin in those with pertinent clinical findings.
非裔美国人也可能出现临床上严重的铁超载， ^61–63 ，尽管这些人很少有 HFE 基因突变。 ⁶⁴ 有人认为，与非洲人铁超载有关的基因突变主要是通过奴隶贸易传到美国的。 ⁶¹ 目前尚不清楚非裔美国人中巩膜沉着症的真实发病率。流行病学研究的结果可能会受到以下因素的影响：有缺陷的基因尚未确定，以及存在并存病症，如各种类型的血红蛋白病、病毒性肝炎或酗酒。如果美国黑人与非裔铁过载患者患有相同的疾病，转铁蛋白饱和度可能不会升高，因此作为筛查工具，转铁蛋白饱和度对这些患者的作用可能不如血色病患者。 ⁶⁵ 尽管如此，考虑对黑人患者进行铁超载诊断，并对有相关临床表现的患者测量血清铁蛋白，似乎仍是谨慎之举。

In rare instances, iron overload develops in a pattern resembling that of hereditary hemochromatosis but at a greatly accelerated rate. Several Italian families with multiple affected members have been particularly well characterized.⁶⁶ Their disorder has been termed juvenile hemochromatosis. Perhaps because of the young age of these patients, or perhaps because of the rate of iron loading, they are more likely to present with cardiomyopathy and endocrinopathy than with severe liver disease. Patients with this disorder typically die of heart failure before their 30th birthdays. The genetic basis of juvenile hemochromatosis is unknown. The HFE gene has been ruled out as a possible locus, and juvenile hemochromatosis maps to human chromosome 1q.^67,68 It is reasonable to speculate that the product of the juvenile hemochromatosis gene participates in the same regulatory pathway as the HFE gene.
在极少数情况下，铁超载的发展模式与遗传性血色病相似，但速度大大加快。有几个意大利家族的多个成员都患有这种病，他们的病症特征尤为明显。 ⁶⁶ 他们的疾病被称为青少年血色病。也许是因为这些患者年龄小，也许是因为铁负荷的速度快，他们更容易出现心肌病和内分泌病，而不是严重的肝病。这种疾病的患者通常在 30 岁前死于心力衰竭。幼年血色病的遗传基础尚不清楚。HFE 基因已被排除为可能的基因位点，而幼年血色病的基因图谱位于人类 1q 染色体上。 ^67,68 我们有理由推测，幼年血色病基因的产物与 HFE 基因参与了相同的调控途径。

Neonatal hemochromatosis is a fulminant dis-ease characterized by massive hepatic iron loading and liver failure in the perinatal period.⁶⁹ Like other iron-overload disorders, neonatal hemochromatosis is characterized by the accumulation of iron in the myocardium and pancreatic acinar cells.^70,71 The pathophysiology of this disorder is poorly understood, and it is not yet known whether iron loading is the primary problem or secondary to some other insult to developing hepatocytes.^72,73 Rare familial cases have been reported, in some of which there was consanguinity, but the inheritance pattern has not been clearly defined.^74,75 Unaffected siblings and parents do not have evidence of iron loading,^70,76 and there is no genetic linkage to the HLA complex.⁷⁵ Liver transplantation is the primary treatment, but it is often unsuccessful.^77–79
新生儿血色病是一种以围产期大量肝铁负荷和肝功能衰竭为特征的暴发性疾病。 ⁶⁹ 与其他铁负荷过重的疾病一样，新生儿血色病的特点是铁在心肌和胰腺棘细胞中的蓄积。 ^70,71 人们对这种疾病的病理生理学了解甚少，尚不清楚铁负荷是主要问题还是继发于发育中的肝细胞受到其他损伤。 ^72,73 罕见的家族性病例已有报道，其中一些病例存在近亲关系，但遗传模式尚未明确。 ^74,75 未受影响的兄弟姐妹和父母没有铁负荷的证据， ^70,76 ，也没有与 HLA 复合体的遗传联系。 ⁷⁵ 肝移植是主要的治疗方法，但往往不成功。 ^77–79

In 1995, two groups described patients with progressive extrapyramidal signs, cerebellar ataxia, dementia, and diabetes mellitus, which were associated with low serum ceruloplasmin levels resulting from mutations in the ceruloplasmin gene.^80,81 This disorder, aceruloplasminemia, is distinct from Wilson's disease, in which low serum ceruloplasmin levels result from a copper-transport defect. Ceruloplasmin has ferroxidase activity, which is involved in the release of iron from cells.⁸² Accordingly, patients with aceruloplasminemia have accumulation of iron in neural and glial cells of the brain (particularly the basal ganglia and dentate nucleus), hepatocytes, and pancreatic islet cells.⁸³ Aggressive chelation with deferoxamine may halt the progression of these complications.⁸⁴ Treatment with plasma or ceruloplasmin concentrate may be helpful. However, the decision about therapy must take into account the difficulty of moving proteins across an intact blood–brain barrier. Phlebotomy is unlikely to be helpful and may exacerbate hypochromic microcytic anemia, which develops in some patients as a result of their inability to recycle iron efficiently through the reticuloendothelial system.
1995 年，两个研究小组描述了患有进行性锥体外系症状、小脑共济失调、痴呆和糖尿病的患者，这些症状与脑磷脂蛋白基因突变导致的血清脑磷脂蛋白水平低有关。 ^80,81 这种疾病，即aceruloplasminemia，与威尔逊氏病不同，后者的血清脑磷脂含量低是由于铜转运缺陷造成的。脑磷脂蛋白具有铁氧化酶活性，可参与铁从细胞中的释放。 ⁸² 因此，aceruloplasminemia 患者的大脑神经和神经胶质细胞（尤其是基底节和齿状核）、肝细胞和胰岛细胞中会有铁积聚。 ⁸³ 使用去铁胺进行积极的螯合治疗可阻止这些并发症的发展。 ⁸⁴ 使用血浆或脑磷脂浓缩物治疗可能会有帮助。但是，在决定治疗方法时必须考虑到蛋白质很难通过完整的血脑屏障。抽血疗法不太可能有帮助，而且可能会加重低色素性小红细胞性贫血，一些患者出现这种贫血是因为他们无法通过网状内皮系统有效地回收铁元素。

In addition to aceruloplasminemia, there are several other iron-loading disorders that lead to degenerative neurologic conditions, including Hallervorden–Spatz disease and Friedreich's ataxia. Descriptions of these disorders are beyond the scope of this review.
除了阿卡波蛋白血症外，还有其他几种导致神经系统退行性病变的铁负荷疾病，包括哈勒沃登-斯帕兹病和弗里德雷希共济失调症。对这些疾病的描述超出了本综述的范围。

Long-term transfusion therapy is now a routine, life-saving treatment for patients with intractable anemia resulting from thalassemia, bone marrow failure, or aggressive treatment of cancer. In many centers, it is also used for patients with serious complications of sickle cell disease. As discussed earlier, there is no mechanism for iron excretion. Repeated transfusion leads to rapid iron loading, because each unit of blood contains 200 to 250 mg of iron and can cause what is known as transfusional siderosis. Since this iron is derived from red cells, reticuloendothelial macrophages become iron-loaded before parenchymal tissue cells. However, in transfusional siderosis iron is ultimately deposited in the same sites as in other iron-overload disorders (hepatocytes, the myocardium, and endocrine tissues). Cardiomyopathy is more prominent in patients with transfusional iron overload than in those with hemochromatosis, probably because of rapid iron loading. The body iron burden is best determined by quantitative liver biopsy or magnetic-susceptibility measurement⁸⁵; measurement of serum ferritin and magnetic resonance imaging are less accurate methods. Phlebotomy is usually not a treatment option for patients with transfusional siderosis, because of their underlying diseases. Iron overload must be treated by chelation therapy. At present, the only option that is widely available is deferoxamine administered by continuous infusion. The goal of chelation is to maintain a hepatic iron burden of less than 15 mg per gram of liver, dry weight.⁸⁶ Oral chelators are under development, but to date none are as effective or safe as deferoxamine.
对于因地中海贫血、骨髓衰竭或积极治疗癌症而导致顽固性贫血的患者来说，长期输血疗法现已成为挽救生命的常规疗法。在许多中心，它还用于镰状细胞病严重并发症患者。如前所述，目前还没有铁排泄的机制。反复输血会导致快速铁负荷，因为每单位血液中含有 200 至 250 毫克铁，会引起所谓的输血性巩膜沉着症。由于这些铁来自红细胞，因此网状内皮巨噬细胞会先于实质组织细胞出现铁负荷。然而，输血性铁质沉着病的铁最终沉积的部位与其他铁负荷过重疾病相同（肝细胞、心肌和内分泌组织）。与血色素沉着症患者相比，输血性铁过载患者的心肌病更为突出，这可能是因为铁负荷过快所致。确定体内铁负荷的最佳方法是进行定量肝活检或磁感应测量 ⁸⁵ ；而测量血清铁蛋白和磁共振成像则是不太准确的方法。由于输血性巩膜沉着症患者患有基础疾病，因此通常不能选择抽血疗法。铁超载必须通过螯合疗法来治疗。目前，唯一广泛使用的方法是持续输注去铁胺。螯合治疗的目标是将肝脏铁负荷维持在每克肝脏干重 15 毫克以下。 ⁸⁶ 口服螯合剂正在开发中，但迄今为止还没有一种能像去铁胺那样有效或安全。