接上文Part.2

Interactions of Cu and Zn with micronutrients/铜和锌与微量营养素的相互作用

Fortification of foods with iron in iron-deficiency anemia does not significantly affect zinc absorption. But large amounts of supplemental iron, greater than 25 mg, might decrease zinc absorption [86,87]. Taking iron supplements between meals helps decrease its effect on zinc absorption [87]. Several laboratory and human studies have found that high levels of supplemental zinc taken over extended periods of time may result in decreased copper absorption in the intestine, and copper deficiency with associated anemia [88]. But some studies in humans suggest that high dietary Zn may not interfere with the actual tissue or plasma concentrations of Cu [7]. Some experts believe that elevated copper levels, especially when zinc levels are also low, may be a contributing factor in many medical conditions including schizophrenia, hypertension, autism, fatigue, muscle and joint pain, headaches, childhood hyperactivity, depression, insomnia, senility, and premenstrual syndrome [1]. Adults taking copper supplements should also take zinc supplements (8 - 15 mg of zinc for every 1 mg of copper), because of an imbalance of these two minerals [89,90]. Copper is known to react with a variety of nutrients, including iron, zinc, molybdenum, sulfur, selenium and vitamin C [5]. There’s also some evidence, not conclusive, that high supplemental doses of vitamin C in a range approaching 1 gram or more-may decrease Cu availability [91]. There is also some evidence that in the formula feeding of infants, too much iron in a formula can lower absorption of copper from that formula [45,92].

在缺铁性贫血中强化含铁食物不会显著影响锌的吸收。但大量补充铁（超过25毫克）可能会降低锌的吸收 [86,87]。在两餐之间服用铁补充剂有助于降低其对锌吸收的影响 [87]。几项实验室和人体研究发现，长时间补充高水平的锌可能会导致肠道对铜的吸收减少，以及与相关贫血相关的铜缺乏 [88]。但一些人体研究表明，高膳食锌可能不会干扰实际组织或血浆中的铜浓度 [7]。一些专家认为，铜含量升高，特别是当锌含量也很低时，可能是许多疾病的促成因素，包括精神分裂症、高血压、自闭症、疲劳、肌肉和关节疼痛、头痛、儿童多动、抑郁、失眠、衰老和经前期综合征 [1]。服用铜补充剂的成年人还应服用锌补充剂（每1毫克铜含8-15毫克锌），因为这两种矿物质不平衡 [89,90]。众所周知，铜会与多种营养物质发生反应，包括铁、锌、钼、硫、硒和维生素C [5]。还有一些证据表明，在接近1克或更多的范围内补充高剂量的维生素C 可能会降低铜的可用性 [91]。还有一些证据表明，在婴儿配方奶喂养中，配方奶中过多的铁会降低配方奶中铜的吸收[45,92]。

 

Zinc deficiency/锌缺乏

Nearly two billion people in the developing world are deficient in zinc [93]. Zinc deficiency is characterized by growth retardation, loss of appetite, and impaired immune function [94,95,96]. In more severe cases, zinc deficiency causes hair loss, diarrhea, delayed sexual maturation, impotence, hypogonadism in males, and eye and skin lesions. Weight loss and impaired appetite, delayed healing of wounds, taste abnormalities, and altered cognition can also occur [13,17,94,97- 99]. When zinc deficiency does occur, it is usually due to inadequate zinc intake or absorption, increased losses of zinc from the body, or increased requirements for zinc [94,98]. It can be associated with malabsorption, acrodermatitis enteropathica, chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses [97-102]. In children it causes an increase in infection and diarrhea, contributing to the death of about 800,000 children worldwide per year [94,101]. The WHO advocates zinc supplementation for severe malnutrition and diarrhea [103].

发展中国家近20亿人缺乏锌 [93]。缺锌的特点是生长迟缓、食欲不振和免疫功能受损 [94,95,96]。在更严重的情况下，锌缺乏会导致脱发、腹泻、性成熟延迟、阳痿、男性性腺功能减退以及眼睛和皮肤损伤。体重减轻和食欲不振、伤口愈合延迟、味觉异常和认知改变也可能发生 [13,17,94,97-99]。当确实发生锌缺乏时，通常是由于锌摄入或吸收不足、体内锌流失增加或对锌的需求增加[94,98]。它可能与吸收不良、肠病性肢端皮炎、慢性肝病、慢性肾病、镰状细胞病、糖尿病、恶性肿瘤和其他慢性疾病有关 [97-102]。在儿童中，它会导致感染和腹泻的增加，导致全世界每年约有 800,000 名儿童死亡 [94,101]。WHO提倡对严重营养不良和腹泻进行补锌[103]。

 

Severe Zn deficiency depresses immune function [104], and even mild to moderate degrees of zinc deficiency can impair macrophage and neutrophil functions, natural killer cell activity, and complement activity [105,106]. The body requires zinc to develop and activate T-lymphocytes [107]. Individuals with low zinc levels have shown reduced lymphocyte proliferation response to mitogens and otheradverse alterations in immunity that can be corrected by zinc supplementation [104,108]. These alterations in immune function might explain why low zinc status has been associated with increased susceptibility to pneumonia and other infections in children in developing countries and the elderly [94, 109-111]. However, zinc supplements should not be administered alone, since many in the developing world have several deficiencies, and zinc also interacts with other micronutrients [112].

严重缺锌会抑制免疫功能 [104]，即使是轻度至中度缺锌也会损害巨噬细胞和中性粒细胞功能、自然杀伤细胞活性和补体活性 [105,106]。身体需要锌来发育和激活T淋巴细胞 [107]。锌水平低的个体表现出淋巴细胞对有丝分裂原增殖反应降低，以及其他可以通过正确补锌来改变免疫力 [104,108]。这些免疫功能的改变可以解释为什么低锌状态与发展中国家儿童和老年人肺炎和其他感染的易感性增加有关 [94, 109-111]。但锌补充剂不应单独使用，因为发展中国家的许多补充剂存在多种缺陷，而且锌还与其他微量营养素相互作用 [112]。

 

Groups at risk of Zn inadequacy/存在锌不足风险的群体

Pregnant and lactating women: Pregnant women, particularly those starting their pregnancy with marginal zinc status, are at increased risk of becoming zinc insufficient due, in part, to high fetal requirements for zinc [113]. Lactation can also deplete maternal zinc stores [114]. For these reasons, the RDA for zinc is higher for pregnant and lactating women than for other women [80]. The following study was performed, to analyse the inter-relationship among trace elements: iron, copper and zinc of blood sample in pregnant women. The level of copper was found to be significantly higher in iron deficiency anaemia, when compared to non-iron deficiency anaemia [p<0.05], and it was also higher in non-anaemic pregnant women, compared to non-anaemic non-pregnant women [controls]. The level of zinc was significantly lower in iron deficiency anaemic pregnancy, when compared to the other groups. There is evidence of influence of pregnancy on the level of trace elements in blood. This could be a result of competitive inhibition in the absorption of trace elements in the intestine, or an effect of hormonal changes [insulin, estrogen], during pregnancy [115].

孕妇和哺乳期妇女：孕妇，尤其是那些刚开始怀孕时锌处于边缘状态的妇女，锌不足的风险增加，部分原因是胎儿对锌的高需求[113]。哺乳期也会消耗母体锌的储存 [114]。由于这些原因，孕妇和哺乳期妇女的锌RDA高于其他妇女 [80]。以下研究分析了微量元素之间的相互关系：孕妇血液样本中的铁、铜和锌。与非缺铁性贫血相比，缺铁性贫血中的铜水平显著升高 [p<0.05]，与非贫血非孕妇相比，非贫血孕妇的铜水平也更高 [对照]。与其他组相比，缺铁性贫血妊娠的锌水平显著降低。有证据表明怀孕对血液中的微量元素水平有影响。这可能是由于怀孕期间肠道中微量元素吸收的竞争性抑制，或荷尔蒙变化[胰岛素、雌激素]的影响 [115]。

 

Breast-fed infants: Zinc deficiency in breast-fed infants is a rare disease caused by a low level of zinc in their mother’s milk [116]. Premature infants are more vulnerable to develop zinc deficiency than full-term infants because, despite their high zinc requirements, they have insufficient body stores of zinc and a poor capability to absorb zinc from the gut. Breast milk provides sufficient zinc [2 mg/day] for the first 4–6 months of life but does not provide recommended amounts of zinc for infants aged 7–12 months, who need 3 mg/day. In addition to breast milk, infants aged 7–12 months should consumeage-appropriate foods or formula containing zinc [80,116,117]. Zinc supplementation has improved the growth rate in some children who demonstrate mild-to-moderate growth failure and who have a zinc deficiency [94,117].

母乳喂养的婴儿：母乳喂养的婴儿缺锌是一种罕见的疾病，由母乳中锌含量低引起[116]。早产儿比足月儿更容易出现锌缺乏症，因为尽管他们对锌的需求量很高，但他们体内的锌储备不足，而且从肠道吸收锌的能力也很差。母乳为生命的前4-6个月提供足够的锌 [2毫克/天]，但不为需要3毫克/天的7-12个月的婴儿提供推荐量的锌。除母乳外，7-12个月大的婴儿还应食用适合年龄的食物或含锌配方食品 [80,116,117]。补锌提高了一些表现出轻度至中度生长障碍和缺锌的儿童的生长速度 [94,117]。

 

People with gastrointestinal diseases: Gastrointestinal surgery and digestive disorders, such as ulcerative colitis, Crohn’s disease, and short bowel syndrome can decrease zinc absorption and increase endogenous zinc losses primarily from the gastrointestinal tract [100,102,118].

患有胃肠道疾病的人：胃肠道手术和消化系统疾病，如溃疡性结肠炎、克罗恩病和短肠综合征会降低锌的吸收并增加主要来自胃肠道的内源性锌损失 [100,102,118]。

 

Vegetarians: Phytates, which are present in whole-grain breads, cereals, legumes, and other foods, bind Zn and inhibit its absorption. Thus, the bioavailability of zinc from grains and plant foods is lower than that from animal foods, although many grain- and plant-based foods are still good sources of zinc [119-121].

素食者：植酸盐存在于全麦面包、谷物、豆类和其他食物中，可与锌结合并抑制其吸收。因此，谷物和植物性食物中锌的生物利用度低于动物性食物，尽管许多谷物和植物性食物仍然是锌的良好来源 [119-121]。

 

People with sickle cell disease:Results from a large cross-sectional survey suggest that 44% of children with sickle cell disease have a low plasma zinc concentration [122], possibly due to increased nutrient requirements and/or poor nutritional status [123]. Zinc deficiency also affects approximately 60%–70% of adults with sickle cell disease [124]. Zinc supplementation has been shown to improve growth in children with sickle cell disease [123].

镰状细胞病患者：一项大型调查的结果表明，44%的镰状细胞病儿童血浆锌浓度较低 [122]，这可能是由于营养需求增加和/或营养状况不佳 [123]。缺锌也影响大约60%–70%的镰状细胞病成人 [124]。锌补充剂已被证明可以改善镰状细胞病儿童的生长[123]。

 

Diarrhea: Chronic diarrhea also leads to excessive loss of zinc [94]. Pooled analysis of randomized controlled trials show that malnourished children in India, Africa, South America, and Southeast Asia experience shorter and less severe courses of infectious diarrhea after taking zinc supplements [112]. The children in these studies received 4–40 mg of zinc a day in the form of zinc acetate, zinc gluconate, or zinc sulfate [109,112]. Similar findings were reported in a meta-analysis published in 2008 and a 2007 review of zinc supplementation for preventing and treating diarrhea [125,126]. But the effects of zinc suppplementation on diarrhea in children with adequate zinc status, such as most children, are not clear. The WHO and UNICEF now recommend short-term zinc supplementation (20 mg of zinc per day, or 10 mg for infants under 6 months, for 10–14 days) to treat acute childhood diarrhea [103].

腹泻：慢性腹泻也会导致锌过度流失 [94]。随机对照试验的汇总分析表明，印度、非洲、南美洲和东南亚的营养不良儿童在服用锌补充剂后经历的感染性腹泻病程较短且较轻 [112]。这些研究中的儿童每天接受4-40毫克醋酸锌、葡萄糖酸锌或硫酸锌形式的锌 [109,112]。2008年发表的一项荟萃分析和2007年对锌补充剂预防和治疗腹泻的综述报告了类似的发现 [125,126]。但是补锌对锌含量充足儿童（例如大多数儿童）的腹泻影响情况尚不清楚。WHO和UNICEF现在推荐短期补锌（每天20mg 锌，或6个月以下婴儿10 mg，持续10-14天）来治疗急性儿童腹泻 [103]。

 

Alcoholics: Approximately 30%–50% of alcoholics have low zinc status because ethanol consumption decreases intestinal absorption of zinc and increases urinary zinc excretion [127]. In addition, the variety and amount of food consumed by many alcoholics is limited, leading to inadequate zinc intake [128,129].

酗酒者：大约30%–50%的酗酒者处于低锌状态，因为饮酒会降低肠道对锌的吸收并增加尿中锌的排泄 [127]。此外，许多酗酒者食用的食物种类和数量有限，导致锌摄入不足 [128,129]。

 

Acrodermatitis enteropathica：Zinc supplementation is an effective treatment for acrodermatitis enteropathica, an inborn error of zinc metabolism that is inherited as an autosomal recessive disorder. The lack of zinc presents, characteristically, as: pustular dermatitis, diarrhea, and nail dystrophy. Irritability and emotional disturbances are due to atrophy of the brain cortex. The severity of the disease is proportional to the zinc level. Before zinc supplementations acrodermatitis enteropathica was fatal to babies born with it [97,98].

肠病性肢端皮炎：补锌是治疗肠病性肢端皮炎的有效治疗方法，这是一种先天性锌代谢障碍，是一种常染色体隐性遗传病。缺锌的典型表现是：脓疱性皮炎、腹泻和指甲营养不良。易怒和情绪障碍是由于大脑皮层萎缩所致。疾病的严重程度与锌水平成正比。在补锌之前，肠病性肢端皮炎对出生时携带它的婴儿是致命的 [97,98]。

 

Cooper deficiency/铜缺乏

Because copper is involved in many functions of the body, copper deficiency can produce an extensive range of symptoms [130]. Deficiencies of copper can result in hernias, aneurysms, blood vessel breakage manifesting as bruising or nosebleeds [5], iron deficiency anemia [45], osteoporosis and joint problems [131], brain disturbances [54], abnormalities in glucose and cholesterol metabolism [132], increased susceptibility to infections due to poor immune function [neutropenia] [133], loss of pigment, weakness, fatigue, skin sores, poor thyroid function [5], irregular heart beat [134] and low body temperature [46]. If copper is important in cellular membrane structure, then a copper deficiency could seriously alter the movemenof nutrients through cell walls [5].

由于铜涉及身体的许多功能，铜缺乏会产生广泛的症状 [130]。铜的缺乏会导致疝气、动脉瘤、血管破裂，表现为瘀伤或流鼻血 [5]、缺铁性贫血 [45]、骨质疏松症和关节问题 [131]、脑部紊乱 [54]、葡萄糖和胆固醇代谢异常 [5] 132]、由于免疫功能差 [中性粒细胞减少症] [133]、色素减退、虚弱、疲劳、皮肤溃疡、甲状腺功能差 [5]、心律不齐 [134] 和体温低 [46] 导致感染易感性增加.如果铜在细胞膜结构中很重要，那么铜缺乏会严重改变营养物质通过细胞壁的运动 [5]。

 

Groups at risk of Cu inadequacy/存在铜不足风险的群体

Despite the fact that most people consume less than recommended amounts of copper in their diet, these symptoms of copper deficiency are relatively rare [5]. However, certain medical conditions including chronic diarrhea, celiac sprue, Crohn’s disease and GIT surgery result in decreased absorption of copper and may increase the risk of developing a copper deficiency. Inflammatory bowel disease (IBD) may be related to oxidation or damage caused by free radicals. In fact, copper levels may be low in the inflamed tissue of those with IBD, particularly Crohn’s disease. When treating IBD, clinicians often recommend multivitamin containing essential minerals [135]. In addition, copper requires sufficient stomach acid for absorption, so people who consume antacids regularly may increase the risk of developing a copper deficiency [7]. Inadequate copper status is also observed in children with low protein intake and in infants fed only cow’s milk without supplemental copper (they might have poor feeding habits and lack of proper gowth) [5,45].

尽管大多数人在饮食中摄入的铜低于推荐量，但这些铜缺乏症状相对罕见 [5]。然而，某些疾病，包括慢性腹泻、乳糜泻、克罗恩病和胃肠道手术，会导致铜的吸收减少，并可能增加患铜缺乏症的风险。炎症性肠病(IBD)可能与自由基引起的氧化或损伤有关。事实上，IBD患者，尤其是克罗恩病患者的炎症组织中的铜含量可能较低。在治疗IBD时，临床医生通常建议使用含有必需矿物质的复合维生素 [135]。此外，铜需要足够的胃酸才能吸收，因此经常服用抗酸剂的人可能会增加患铜缺乏症的风险[7]。在蛋白质摄入量低的儿童和仅喂食牛奶而没有补充铜的婴儿中也观察到铜状态不足（他们可能有不良的喂养习惯和缺乏适当的生长发育）[5,45]。

 

Menke's disease：Menkes disease is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copperdependent enzymes. A diversity of mutations in the gene encoding of the copper-transporting ATPase, ATP7A (located on chromosome Xq12-q13), underlies Menkes disease [68]. Signs and symptoms of this disorder include weak muscle tone, sagging facial features, seizures, mental retardation, developmental delay and kinky, colorless hair. There can be an extensive neurodegeneration in the gray matter of the brain. Arteries in the brain can also be twisted with split inner walls. This can lead to rupture or blockage of the arteries. Osteoporosis may result in fractures. Most patients die in early childhood, although mild forms have also been described [53,54].

Menke's病：Menke's病是一种X连锁隐性疾病，其特征是铜缺乏导致铜依赖性酶的功能减弱。铜转运ATP酶ATP7A（位于染色体Xq12-q13上）的编码基因中的多种突变是Menke's病的基础 [68]。这种疾病的体征和症状包括肌张力弱、面部特征下垂、癫痫发作、智力迟钝、发育迟缓和卷曲、无色的头发。大脑的灰质可能存在广泛的神经退行性变。大脑中的动脉也可以通过分裂的内壁扭曲。这可能导致动脉破裂或阻塞。骨质疏松症可能导致骨折。大多数患者在儿童早期死亡，尽管也有轻度患者的描述 [53,54]。

 

Diagnosis of Copper and Zinc Deficiency/铜和锌缺乏症的诊断

The diagnosis of Cu and Zn deficiency is based on four main criteria, namely anamnesis, symptomatology, belonging to well-defined risk groups and the determination of biomarkers [5,7,8]. The optimal plasma or serum ratio between these two elements is 0.70 - 1.00 [1]. Diagnosing zinc deficiency is a persistent challenge. Zinc nutritional status is difficult to measure adequately using laboratory tests due to its distribution throughout the body as a component ofvarious proteins and nucleic acids [18,136]. Plasma or serum zinc levels are the most commonly used indices for evaluating zinc deficiency, but plasma zinc, has poor sensitivity and specificity - these levels do not necessarily reflect cellular zinc status due to tight homeostatic control mechanisms. So clinical effects of zinc deficiency can be present in the absence of abnormal laboratory indices [17,25,47]. Severe Cu deficiency can be found by testing for low plasma or serum copper levels, low ceruloplasmin, and low red blood cell superoxide dismutase levels; but these are not sensitive at a state of marginal copper status [46,137]. The cytochrome c oxidase activity of leucocytes and platelets has been stated as another factor in deficiency, but in the studies this hypotesis has not been confirmed yet [138].

铜和锌缺乏症的诊断基于四个主要标准，即病史、症状、属于明确定义的风险组和生物标志物的确定 [5,7,8]。这两种元素之间的最佳血浆或血清比例为0.70-1.00 [1]。诊断锌缺乏症是一项持久的挑战。锌的营养状况难以通过实验室测试充分测量，因为它作为各种蛋白质和核酸的组成部分分布在全身各处 [18,136]。血浆或血清锌水平是评估锌缺乏最常用的指标，但血浆锌的敏感性和特异性较差——由于严格的稳态控制机制，这些水平不一定反映细胞锌的状态。因此，在没有异常实验室指标的情况下，可能会出现缺锌的临床影响 [17,25,47]。通过检测低血浆或血清铜水平、低铜蓝蛋白和低红细胞超氧化物歧化酶水平可以发现严重的铜缺乏症；但这些在处于边缘铜状态的状态下并不敏感 [46,137]。白细胞和血小板的细胞色素c氧化酶活性已被认为是缺乏的另一个因素，但在研究中，这种假设尚未得到证实 [138]。

 

接Part.4