Title: Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D ? 标题：过量补充维生素 D 会在未发展为维生素 D 过多症的情况下产生不良影响吗？
Author: Mohammed S. Razzaque 作者：Mohammed S. Razzaque
Please cite this article as: Mohammed S.Razzaque, Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D?, Journal of Steroid Biochemistry and Molecular Biologyhttp://dx.doi.org/10.1016/j.jsbmb.2017.07.006 请引用本文为：Mohammed S.Razzaque，过量维生素 D 补充是否会在未发展为维生素 D 过多症的情况下产生不良影响？，《类固醇生物化学与分子生物学杂志》http://dx.doi.org/10.1016/j.jsbmb.2017.07.006
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Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D ? 过量补充维生素 D 会在未发展为维生素 D 过多症的情况下产生不良影响吗？
Mohammed S. Razzaque ^("a, b, c, d "){ }^{\text {a, b, c, d }} 穆罕默德·S·拉扎克 ^("a, b, c, d "){ }^{\text {a, b, c, d }}^("a "){ }^{\text {a }} Department of Applied Oral Sciences, Forsyth Institute, Cambridge, MA, USA; ^("a "){ }^{\text {a }} 美国马萨诸塞州剑桥市福赛斯研究所应用口腔科学系;^(b){ }^{\mathrm{b}} Department of Preventive & Community Dentistry, School of Dentistry, University of Rwanda College of Medicine & Health Sciences, Kigali, Rwanda; ^(b){ }^{\mathrm{b}} 卢旺达大学医学院与健康科学学院牙科学院预防与社区牙科系，卢旺达基加利；^(c){ }^{\mathrm{c}} Department of Oral Health Policy & Epidemiology, Harvard School of Dental Medicine, Boston, MA, USA ^(c){ }^{\mathrm{c}} 哈佛牙科学院口腔健康政策与流行病学系，美国马萨诸塞州波士顿^(d){ }^{\mathrm{d}} Department of Pathology, Lake Erie College of Osteopathic Medicine, Lake Erie, PA, USA ^(d){ }^{\mathrm{d}} 美国宾夕法尼亚州伊利湖骨科医学院病理学系
Key words: 关键词：
Vitamin D intoxication, Supplements, Serum 25(OH)D, Heath hazards, Sunlight exposure 维生素 D 中毒，补充剂，血清 25(OH)D，健康危害，阳光照射
Address of correspondence: 通讯地址：
Mohammed S. Razzaque, MBBS, PhD, Department of Applied Oral Sciences, Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. E-mails: mrazzaque@forsyth.org; mrazzaque@hms.harvard.edu 穆罕默德·S·拉扎克，医学学士，博士，应用口腔科学系，福赛斯研究所，美国马萨诸塞州剑桥市第一街 245 号，邮编 02142。电子邮件：mrazzaque@forsyth.org；mrazzaque@hms.harvard.edu
Highlights 亮点
Hypovitaminosis D status usually reflects reduced sunlight exposure 维生素 D 缺乏状态通常反映了阳光照射减少
Vitamin D status is more likely to be a consequence rather than a cause of a disease 维生素 D 状态更可能是疾病的结果，而非原因
Extreme vitamin D supplementation may impair organ function even in hypovitaminosis D 极端的维生素 D 补充即使在维生素 D 缺乏症中也可能损害器官功能
Serum 25(OH)25(\mathrm{OH}) D levels may not be true reflection of total vitamin D status of the body 血清 25(OH)25(\mathrm{OH}) D 水平可能并不是真正反映身体维生素 D 总状态的指标
Supplementation may be useful who are at high-risk of developing vitamin D deficiency 补充剂可能对那些有高风险发展为维生素 D 缺乏的人有用
Abstract 摘要
Vitamin D is a fat-soluble hormone that has endocrine, paracrine and autocrine functions. Consumption of vitamin D-supplemented food & drugs have increased significantly in the last couple of decades due to campaign and awareness programs. Despite such wide use of artificial vitamin D supplements, serum levels of 25 hydroxyvitamin D [25(OH)D] does not always reflect the amount of uptake. In contrast to the safe sunlight exposure, prolonged and disproportionate consumption of vitamin D supplements may lead to vitamin D intoxication, even without developing hypervitaminosis D . One of the reasons why vitamin D supplementation is believed to be safe is, it rarely raises serum vitamin DD levels to the toxic range even after repeated intravenous ingestion of extremely high doses of synthetic vitamin DD analogs. However, prolonged consumption of vitamin D supplementation may induce hypercalcemia, hypercalciuria and hyperphosphatemia, which are considered to be the initial signs of vitamin DD intoxication. It is likely that calcium and phosphorus dysregulation, induced by exogenous vitamin D supplementation, may lead to tissue and organ damages, even without developing hypervitaminosis D . It is needed to be emphasized that, because of tight homeostatic control of calcium and phosphorus, when hypercalcemia and/or hyperphosphatemia is apparent following vitamin D supplementation, the process of tissue and/or organ damage might already have been started. 维生素 D 是一种脂溶性激素，具有内分泌、旁分泌和自分泌功能。由于宣传和意识提升项目，含维生素 D 的食品和药物的消费在过去几十年中显著增加。尽管人工维生素 D 补充剂被广泛使用，血清 25-羟基维生素 D [25(OH)D]水平并不总是反映摄入量。与安全的阳光照射相比，长期和不当摄入维生素 D 补充剂可能导致维生素 D 中毒，即使未发展为维生素 D 过量症。维生素 D 补充剂被认为安全的原因之一是，即使反复静脉注射极高剂量的合成维生素 D 类似物，也很少使血清维生素 DD 水平升高到中毒范围。然而，长期摄入维生素 D 补充剂可能引起高钙血症、高钙尿症和高磷血症，这些被认为是维生素 DD 中毒的初期迹象。 钙和磷的失调，可能由外源性维生素 D 补充引起，即使未发展为维生素 D 过多症，也可能导致组织和器官损伤。需要强调的是，由于钙和磷的严格稳态调控，当维生素 D 补充后出现高钙血症和/或高磷血症时，组织和/或器官损伤的过程可能已经开始。
Vitamin D synthesis 维生素 D 合成
Vitamin D is a fat-soluble circulating hormone. Safe sunlight-exposure, along with diet and vitamin D supplements are the main sources of vitamin D [1, 2]. Vitamin D is added to many fortified foods, including in dairy and whole grain products. The endocrine functions of vitamin DD are mainly involved in regulation of mineral ion metabolism by influencing calcium and phosphate homeostasis, and thereby can influence the mineralization of bone and teeth. The 维生素 D 是一种脂溶性循环激素。安全的阳光照射、饮食和维生素 D 补充剂是维生素 D 的主要来源[1, 2]。维生素 D 被添加到许多强化食品中，包括乳制品和全谷物产品。维生素 DD 的内分泌功能主要通过影响钙和磷的稳态来调节矿物离子代谢，从而影响骨骼和牙齿的矿化。
paracrine and autocrine effects of vitamin D mostly influence cellular homeostasis by affecting cell proliferation, differentiation, and survival, and therefore, its dysregulation might in turn contribute to the genesis of such pathology as cancer and accelerated ageing [3-5]. In addition to above-mentioned functions, vitamin D is also reported to exert extraskeletal functions on skeletal muscle, immune regulation, cardiovascular health, and metabolic activities. 维生素 D 的旁分泌和自分泌效应主要通过影响细胞增殖、分化和存活来调节细胞稳态，因此，其失调可能反过来促成癌症和加速衰老等病理的发生[3-5]。除了上述功能外，维生素 D 还被报道对骨骼肌、免疫调节、心血管健康和代谢活动具有骨骼外功能。
The sunlight exposure mediated vitamin D synthesis begins in the skin, and continues further in the liver and kidneys to produce biologically active 1,25 dihydroxyvitamin D3 [1,25(OH)2D3][1,25(\mathrm{OH}) 2 \mathrm{D} 3] (Figure 1). The biologically active metabolite, 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3, is generated by two sequential hydroxylations. First by the enzyme 25 hydroxylase (CYP27A1) in the liver to produce 25 hydroxyvitamin D[25(OH)D\mathrm{D}[25(\mathrm{OH}) \mathrm{D}; an inactive circulating storage form of vitamin D]] and is further hydroxylated in the kidneys by the enzyme 1alpha1 \alpha-hydroxylase [ 1alpha1 \alpha (OH)ase; CYP27B1] to produce 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3. The bioactive metabolite, 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 exerts its functions by interacting with the high-affinity vitamin D receptor (VDR) [6]. Of relevance, VDR is a member of the nuclear receptor superfamily that forms a heterodimer with the retinoid receptor to regulate gene transcription by binding the vitamin D responsive elements (VDREs) in the promoter region of target genes. 阳光照射介导的维生素 D 合成始于皮肤，随后在肝脏和肾脏中继续进行，生成具有生物活性的 1,25-二羟基维生素 D3 [1,25(OH)2D3][1,25(\mathrm{OH}) 2 \mathrm{D} 3] （图 1）。这种具有生物活性的代谢物 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 是通过两步连续的羟基化反应生成的。首先在肝脏中由酶 25-羟化酶（CYP27A1）将其转化为 25-羟基维生素 D[25(OH)D\mathrm{D}[25(\mathrm{OH}) \mathrm{D} ；这是一种维生素 D 的非活性循环储存形式 ]] ，随后在肾脏中由酶 1alpha1 \alpha -羟化酶[ 1alpha1 \alpha (OH)ase；CYP27B1]进一步羟基化，生成 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 。这种具有生物活性的代谢物 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 通过与高亲和力的维生素 D 受体（VDR）[6]相互作用发挥其功能。值得注意的是，VDR 是核受体超家族的成员，与视黄醇受体形成异二聚体，通过结合靶基因启动子区域的维生素 D 响应元件（VDREs）调控基因转录。
The cutaneous biosynthesis of vitamin D3 is tightly regulated by a feedback loop to ensure that overproduction of vitamin D and subsequent toxicity do not occur following solar ultraviolet B (UBV) exposure. When the optimal amount of vitamin D is ensured through the sunlight exposure, the unnecessary amount is removed by photodegradation [7] through converting previtamin D to the inactive lumisterol and tachysterol. Serum concentrations of vitamin D usually reaches its peak level within 24 to 48 hours of following exposure to UVB [811]. Furthermore, when adequate amount of 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 is produced, 25(OH)D25(\mathrm{OH}) \mathrm{D} is also catabolized by the enzyme 24-hydroxylase (CYP24) to 24,25(OH)2D24,25(\mathrm{OH}) 2 \mathrm{D} in the kidneys; and similar catabolism process can also take place in the liver. It is needed to be emphasized that the 皮肤中维生素 D3 的生物合成受到反馈回路的严格调控，以确保在太阳紫外线 B（UVB）照射后不会发生维生素 D 的过度生成及随之而来的毒性。当通过阳光照射确保了维生素 D 的最佳量时，多余的部分会通过光降解[7]被去除，将前维生素 D 转化为无活性的鲁米斯特醇和塔奇斯特醇。维生素 D 的血清浓度通常在 UVB 照射后 24 至 48 小时内达到峰值[8-11]。此外，当产生了足够量的 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 时， 25(OH)D25(\mathrm{OH}) \mathrm{D} 也会被肾脏中的 24-羟化酶（CYP24）分解为 24,25(OH)2D24,25(\mathrm{OH}) 2 \mathrm{D} ；类似的分解过程也可以在肝脏中进行。需要强调的是，
supplementation-associated hypercalcemia and hyperphosphatemia can be evident even without developing hypervitaminosis DD state [12]. However, when hypervitaminosis DD is apparent in rare occasions, the irreversible organ damage, usually due to excessive calcium and phosphorus levels, has already started. Though exogenous vitamin D2 (ergocalciferol from yeast or fungi sources) is considered to be less bioavailable than vitamin D3 (cholecalciferol from animal sources) [13], both forms of the vitamin DD (ergocalciferol and cholecalciferol) undergo 25 -hydroxylation in the liver to produce 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 and 25(OH)D325(\mathrm{OH}) \mathrm{D} 3, and may contribute to vitamin D intoxication, when excessive amounts are consumed for prolonged period. 补充相关的高钙血症和高磷血症即使在未发展为维生素 DD 过量状态时也可能明显[12]。然而，当罕见情况下明显出现维生素 DD 过量时，通常由于过量的钙和磷水平，已经开始了不可逆的器官损伤。尽管外源性维生素 D2（来自酵母或真菌的麦角钙化醇）被认为生物利用度低于维生素 D3（来自动物的胆钙化醇）[13]，这两种维生素 DD （麦角钙化醇和胆钙化醇）都在肝脏中经过 25-羟化生成 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 和 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 ，并且在长期摄入过量时可能导致维生素 D 中毒。
Is serum vitamin DD level true reflection of its activities? 血清维生素 DD 水平是否能真实反映其活性？
The levels of vitamin D are clinically estimated from measuring the circulating levels of 25(OH)D25(\mathrm{OH}) \mathrm{D}, which include circulating forms of both 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 and 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 of the vitamin; yet not all the immunoassays used to measure 25(OH)D25(\mathrm{OH}) \mathrm{D} in clinical practice can detect 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 [14]. Such technical limitation might be related to a stronger affinity of the vitamin D binding protein (DBP) for 25(OH)D2 [15]. The biochemical assays have wide variability and sensitivities depending on the method used to detect the level of 25(OH)D25(\mathrm{OH}) \mathrm{D}. Studies have shown that total serum vitamin D[25(OH)D2+25(OH)D3]D[25(\mathrm{OH}) D 2+25(\mathrm{OH}) D 3] levels, as measured by liquid chromatographytandem mass spectrometry (LC-MS/MS), were lower than the total levels obtained by chemiluminescence assays [16]. It is likely that the cross-reactivity of various vitamin DD metabolites such as 24,25(OH)2D324,25(\mathrm{OH}) 2 \mathrm{D} 3 and 25,26(OH)2D325,26(\mathrm{OH}) 2 \mathrm{D} 3 may influence the values obtained by the chemiluminescence assays [17]. 维生素 D 的水平通过测量循环中的 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平进行临床估计，这包括维生素的 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 和 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 两种循环形式；然而，并非所有用于临床测量 25(OH)D25(\mathrm{OH}) \mathrm{D} 的免疫测定法都能检测到 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 [14]。这种技术限制可能与维生素 D 结合蛋白（DBP）对 25(OH)D2 的较强亲和力有关[15]。生化测定法的变异性和灵敏度因检测 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平所用的方法不同而差异较大。研究表明，通过液相色谱-串联质谱法（LC-MS/MS）测得的血清总维生素 D[25(OH)D2+25(OH)D3]D[25(\mathrm{OH}) D 2+25(\mathrm{OH}) D 3] 水平低于化学发光测定法获得的总水平[16]。各种维生素 DD 代谢物如 24,25(OH)2D324,25(\mathrm{OH}) 2 \mathrm{D} 3 和 25,26(OH)2D325,26(\mathrm{OH}) 2 \mathrm{D} 3 的交叉反应性可能影响化学发光测定法获得的数值[17]。
The circulating levels of vitamin D may not always reflect its true values and activities, as there are tissues beyond kidneys that possess an enzymatically active 1alpha(OH)1 \alpha(\mathrm{OH}) ase [18], and are able to generate biologically active 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 locally. For example, VDRs are present in most of the human tissues, including in vascular smooth muscle cells [19, 20]. Of relevance, vascular smooth muscle cells also have 1alpha(OH)1 \alpha(\mathrm{OH}) ase enzyme to be able to produce bioactive 循环中的维生素 D 水平可能并不总是反映其真实的数值和活性，因为除了肾脏之外，还有组织具有酶活性的 1alpha(OH)1 \alpha(\mathrm{OH}) 酶[18]，能够局部生成生物活性的 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 。例如，VDRs 存在于大多数人体组织中，包括血管平滑肌细胞[19, 20]。相关的是，血管平滑肌细胞也具有 1alpha(OH)1 \alpha(\mathrm{OH}) 酶，能够产生生物活性物质。
metabolite, 1,25(OH)1,25(\mathrm{OH}) 2D3 [18], and thereby can establish a locally active vitamin D circuit that might not be evident from the circulating levels of vitamin DD. Similar locally active vitamin DD acting ligand-receptor circuit is also detected in other tissues, including in macrophages, monocytes and activated T cells. It is becoming increasingly apparent that all the autocrine, paracrine, and endocrine functions of vitamin D are not always reflected from its serum levels. 代谢物， 1,25(OH)1,25(\mathrm{OH}) 2D3 [18]，从而可以建立一个局部活性的维生素 D 回路，这在循环维生素 DD 水平中可能并不明显。类似的局部活性维生素 DD 作用的配体-受体回路也在其他组织中被检测到，包括巨噬细胞、单核细胞和活化的 T 细胞。越来越明显的是，维生素 D 的所有自分泌、旁分泌和内分泌功能并不总是能从其血清水平反映出来。
In an accidental vitamin D intoxication following high dose of supplement consumption (60,000 IU daily for 4 months) by a 42-year-old woman resulted in serum 25(OH)D levels of 746 ng/mL. Despite such extremely high vitamin D level, her serum calcium level was within normal range, and the investigators did not provide any data on serum phosphorus levels [16]. In other words, normal range of serum calcium and phosphorus levels following supplement consumption does not necessarily make supplements safe. Thus, emphasis should be made on best use of safe sunlight exposure as a valid option to acquire daily requirement of vitamin D , when available. Of clinical importance, inadequate sunlight exposure was believed to be associated with a total of 566,400 cancer-related death in the USA from 1970 through 1994 [21]. In a separate study, insufficient sunlight exposure that leads to vitamin DD deficiency was linked to 50,000 to 63,000 premature deaths per year in the USA [22]. 一名 42 岁女性因意外摄入高剂量维生素 D 补充剂（每日 60,000 IU，持续 4 个月）导致血清 25(OH)D 水平达到 746 ng/mL。尽管维生素 D 水平极高，她的血清钙水平仍在正常范围内，且研究人员未提供血清磷水平的数据[16]。换言之，补充剂摄入后血清钙和磷水平在正常范围内并不一定意味着补充剂是安全的。因此，应强调在条件允许时，合理利用安全的阳光照射作为获取每日维生素 D 需求的有效途径。临床上重要的是，不足的阳光照射被认为与 1970 年至 1994 年间美国共计 566,400 例癌症相关死亡有关[21]。另一项研究显示，阳光照射不足导致的维生素 D 缺乏与美国每年 50,000 至 63,000 例过早死亡相关[22]。
It is relevant to mention that measuring the circulating level of 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 is not a suitable option, perhaps because of its relatively shorter half-life ( 4 to15 hours vs. couple of weeks) and lower concentrations (picomole vs. nanomole), compared to 25(OH)D25(\mathrm{OH}) \mathrm{D}. In fact 1,25(OH)2D3 levels could even be misleading, as studies have found either normal or elevated levels of 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 in mild to moderate osteomalacia, possibly due to secondary hyperparathyroidism [23]. Moreover, even a very low level of 25(OH)D can be converted to 1,25(OH)2D3, thus may present a false scenario of vitamin D sufficiency [24]. 值得一提的是，测量循环中的 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 水平并不是一个合适的选择，可能是因为其半衰期相对较短（4 到 15 小时对比几周）且浓度较低（皮摩尔对比纳摩尔），与 25(OH)D25(\mathrm{OH}) \mathrm{D} 相比。事实上，1,25(OH)2D3 的水平甚至可能具有误导性，因为研究发现轻度到中度软骨病中 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 的水平可能正常或升高，这可能是由于继发性甲状旁腺功能亢进[23]。此外，即使 25(OH)D 的水平非常低，也可以转化为 1,25(OH)2D3，因此可能呈现维生素 D 充足的假象[24]。
In addition, circulating 25(OH)D25(\mathrm{OH}) \mathrm{D} levels are also influenced by season, weather condition, latitude, clothing patterns, and dietary habits (Table1). Of relevance, the amount of hepatic conversion of 25(OH)D25(\mathrm{OH}) \mathrm{D} depends on availability of ergocalciferol and cholecalciferol, and 此外，循环中的 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平还受季节、天气状况、纬度、服装样式和饮食习惯的影响（表 1）。相关的是，肝脏对 25(OH)D25(\mathrm{OH}) \mathrm{D} 的转化量取决于麦角钙化醇和胆钙化醇的供应情况，且
therefore is a major rate-limiting step in vitamin D synthesis that might be reflected from the seasonal variations in 25(OH)D25(\mathrm{OH}) \mathrm{D} levels [25]. In addition, race, pigmentation and age can influence the plasma levels of 25(OH)D25(\mathrm{OH}) \mathrm{D}. As mentioned, most of the peripheral tissues are able to process circulating 25(OH)D25(\mathrm{OH}) \mathrm{D} to the biologically active metabolite 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 to cover their local needs and might not be reflected from its serum levels [18]. Furthermore, because of lipid solubility, supplement-derived vitamin D2 or D3 can be stored in the liver, muscles and fat tissues which would not reflect on serum levels. A major problem in evaluating the earlier studies on the effects of vitamin D status on various organ system is impaired by the wide variability of the results obtained from laboratories that adopt different methods to detect circulating 25(OH)D25(\mathrm{OH}) \mathrm{D} levels [26,27]. Fortunately, this problem is partly minimized in recent years by the availability of certified standard reference materials for 25(OH)D25(\mathrm{OH}) \mathrm{D}; the National Institute of Standards and Technology (NIST) has developed a standard reference material (SRM 972) in order to minimize the variations of measurements in various laboratories [28]. Despite certain limitations, circulatory level of 25(OH)D (half-life is approximately 2 to 3 weeks) is currently used to assess the vitamin DD status to diagnose vitamin DD deficiency or insufficiency (hypovitaminosis D) or toxicity in human. 因此，这是维生素 D 合成中的一个主要限速步骤，可能反映在 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平的季节性变化中[25]。此外，种族、肤色和年龄也会影响血浆中 25(OH)D25(\mathrm{OH}) \mathrm{D} 的水平。如前所述，大多数外周组织能够将循环中的 25(OH)D25(\mathrm{OH}) \mathrm{D} 转化为生物活性代谢物 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 以满足其局部需求，这可能不会反映在其血清水平中[18]。此外，由于脂溶性，补充的维生素 D2 或 D3 可以储存在肝脏、肌肉和脂肪组织中，这不会反映在血清水平上。评估早期关于维生素 D 状态对各种器官系统影响的研究的一个主要问题是，由于采用不同方法检测循环中 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平的实验室结果差异很大，导致结果的广泛变异[26,27]。幸运的是，近年来通过提供认证的标准参考材料来检测 25(OH)D25(\mathrm{OH}) \mathrm{D} ，这一问题得到了部分缓解；美国国家标准与技术研究院（NIST）开发了标准参考材料（SRM 972），以尽量减少各实验室测量的差异[28]。 尽管存在某些限制，循环中的 25(OH)D 水平（半衰期约为 2 到 3 周）目前用于评估维生素 DD 状态，以诊断人体维生素 DD 缺乏或不足（维生素 D 缺乏症）或中毒。
Can vitamin D intoxication occur without developing hypervitaminosis D? 维生素 D 中毒是否可能在未发展为维生素 D 过多症的情况下发生？
Optimal level of vitamin D is required for physiologic regulations of mineral ion metabolism. It is also involved in modulation of inflammation, cell proliferation and cell differentiation. Vitamin D can induce the expression of various genes [29], thorough interacting with its ubiquitously distributed receptors (VDRs). Numerous studies have shown that serum calcium and phosphate levels increased after intake of high doses of vitamin D supplementation, even when circulating vitamin D level remained low [12]. Such low level of circulating vitamin D is usually used as an evidence of safety by the advocates of vitamin DD supplementation. In fact, individuals consuming high doses of vitamin D2 supplements could be at risk of vitamin D 维生素 D 的最佳水平对于矿物离子代谢的生理调节是必需的。它还参与炎症、细胞增殖和细胞分化的调节。维生素 D 可以通过与其广泛分布的受体（VDRs）相互作用，诱导多种基因的表达[29]。大量研究表明，即使循环维生素 D 水平较低，摄入高剂量维生素 D 补充剂后，血清钙和磷酸盐水平也会升高[12]。这种低水平的循环维生素 D 通常被维生素 DD 补充倡导者用作安全性的证据。事实上，服用高剂量维生素 D2 补充剂的个体可能面临维生素 D 的风险。
intoxication, as some of the commonly used assays are unable to detect 25(OH)D225(\mathrm{OH}) \mathrm{D} 2, and thereby might continue to show insufficient and/or false circulating 25(OH)25(\mathrm{OH}) D status based on the amount of 25(OH)D325(\mathrm{OH}) \mathrm{D} 3. As mentioned above, the ideal assay system would be a measuring method that could detect circulating forms of both 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 and 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 of vitamin D [24, 30]. Of relevance, accidental consumption of 600,000 IU vitamin D2 per day for 21 days resulted in nausea, vomiting, and weight loss, thirst, polyuria, and poor mental concentration in an elderly man [31]. 中毒，因为一些常用的检测方法无法检测 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 ，因此可能会基于 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 的量继续显示不足和/或错误的循环 25(OH)25(\mathrm{OH}) D 状态。如上所述，理想的检测系统应是一种能够检测维生素 D 的循环形式 25(OH)D225(\mathrm{OH}) \mathrm{D} 2 和 25(OH)D325(\mathrm{OH}) \mathrm{D} 3 的测量方法[24, 30]。相关的是，一位老年男子意外摄入每天 600,000 IU 维生素 D2，持续 21 天，导致恶心、呕吐、体重减轻、口渴、多尿和注意力不集中[31]。
Furthermore, some of the commercially available measuring systems are not able to differentiate among various vitamin DD metabolites and can present inaccurate levels. For instance, in some antibody-based detecting system, 24,25(OH)2D24,25(\mathrm{OH}) 2 \mathrm{D}, which may represent up to 10-15%10-15 \% of the total quantity of 25(OH)D25(\mathrm{OH}) \mathrm{D}; in physiological conditions, about 83%83 \% of total 25(OH)D25(\mathrm{OH}) \mathrm{D} in the circulation is bound to DBP (the main serum carrier of vitamin D metabolites) [32, 33]. Of biological importance, DBP plays an important role in the bioavailability, activation, and end-organ responsiveness of vitamin D [34]. A recent study has shown an association between bone mineral density (BMD) and levels of free 25(OH)D25(\mathrm{OH}) \mathrm{D}; no such association was found between BMD and total circulating values of the vitamin [35]. Of clinical importance, the active 25(OH)25(\mathrm{OH}) D fraction (the free fraction) can be elevated even when total 25(OH)D25(\mathrm{OH}) \mathrm{D} values may be reduced and vice versa. 此外，一些市售的测量系统无法区分各种维生素 DD 代谢物，可能会显示不准确的水平。例如，在某些基于抗体的检测系统中， 24,25(OH)2D24,25(\mathrm{OH}) 2 \mathrm{D} ，其可能占 25(OH)D25(\mathrm{OH}) \mathrm{D} 总量的 10-15%10-15 \% ；在生理条件下，约有 83%83 \% 的循环中总 25(OH)D25(\mathrm{OH}) \mathrm{D} 与 DBP（维生素 D 代谢物的主要血清载体）结合[32, 33]。在生物学上，DBP 在维生素 D 的生物利用度、活化和靶器官反应性中起重要作用[34]。一项最新研究显示骨密度（BMD）与游离 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平相关；而 BMD 与维生素总循环值之间未发现此类关联[35]。在临床上，活性 25(OH)25(\mathrm{OH}) D 部分（游离部分）即使在总 25(OH)D25(\mathrm{OH}) \mathrm{D} 值降低时也可能升高，反之亦然。
It is important to note that vitamin D intoxication following intense UVB exposure is unlikely, as the dermal synthesis of vitamin D is self-regulated process. The dietary consumption of vitamin D usually provides about 10 to 20%20 \% of required amount, and therefore vitamin DD intoxication by dietary intake is practically not conceivable. Consequently, vitamin DD intoxication may only be induced by excessive ingestion of vitamin D supplements [36, 37]. The need and effects of vitamin DD supplementation on health are not easy to determine, as circulating levels of 25(OH)25(\mathrm{OH}) D could be influenced by the sunlight exposure and consumption of fortified food. Furthermore, lack of uniform standard makes it harder to compare the published 需要注意的是，强烈的 UVB 照射后维生素 D 中毒是不太可能的，因为皮肤合成维生素 D 是一个自我调节的过程。膳食摄入的维生素 D 通常只提供所需量的约 10%到 20%20 \% ，因此通过膳食摄入维生素 DD 中毒实际上是不可想象的。因此，维生素 DD 中毒只能由过量摄入维生素 D 补充剂引起[36, 37]。维生素 DD 补充对健康的需求和效果不易确定，因为循环中的 25(OH)25(\mathrm{OH}) D 水平可能受到阳光照射和强化食品摄入的影响。此外，缺乏统一标准使得比较已发表的研究更加困难。
results of the studies that used different 25(OH)D25(\mathrm{OH}) \mathrm{D} assays [38, 39]. Though, the mean lethal dose (LD50) of vitamin D in humans has been estimated as 21mg//kg21 \mathrm{mg} / \mathrm{kg} ( 840,000IU//kg840,000 \mathrm{IU} / \mathrm{kg} ) [40], in reality, extreme high doses of supplement consumption would rarely raise the vitamin D level that is deemed toxic, and is used as evidence by the advocates of vitamin D supplementation to convince the consumers of taking higher doses supplement for prolonged periods. It is important to mention that, because of lipid solubility, supplement-derived vitamin D2 or D3 can be stored in the liver, muscles and fat tissues and serum vitamin D[25(OH)D]D[25(\mathrm{OH}) D] levels would not reflect such storage amount. The features of vitamin D intoxication, including hypercalcemia and/or hypercalciuria, therefor, may persist for months despite the removal of the exogenous source of vitamin D due its lipophilic properties and storage in fat tissues. An enhanced bone resorption, as demonstrated by increased fasting urinary calcium excretion, is noted in the patients with vitamin DD intoxication; of importance, even after clinically normalizing the plasma calcium levels, the abnormally elevated fasting urinary calcium excretion and high serum 25(OH)D concentrations persisted [41]. 使用不同 25(OH)D25(\mathrm{OH}) \mathrm{D} 测定方法的研究结果[38, 39]。尽管人体维生素 D 的平均致死剂量（LD50）估计为 21mg//kg21 \mathrm{mg} / \mathrm{kg} （ 840,000IU//kg840,000 \mathrm{IU} / \mathrm{kg} ）[40]，但实际上，极高剂量的补充剂摄入很少会使维生素 D 水平达到被认为有毒的程度，这也被维生素 D 补充剂的支持者用来作为证据，劝说消费者长期服用更高剂量的补充剂。需要指出的是，由于脂溶性，补充剂来源的维生素 D2 或 D3 可以储存在肝脏、肌肉和脂肪组织中，血清维生素 D[25(OH)D]D[25(\mathrm{OH}) D] 水平无法反映这种储存量。维生素 D 中毒的特征，包括高钙血症和/或高钙尿症，因此，尽管去除了外源性维生素 D 来源，但由于其脂溶性和在脂肪组织中的储存，这些症状可能持续数月。 维生素 DD 中毒患者表现出骨吸收增强，表现为空腹尿钙排泄增加；重要的是，即使临床上血浆钙水平恢复正常，异常升高的空腹尿钙排泄和高血清 25(OH)D 浓度仍然持续存在[41]。
In 27 reported cases of vitamin D intoxication, the average serum calcium level was 12.1+-2.8mg//dL12.1 \pm 2.8 \mathrm{mg} / \mathrm{dL} and serum phosphate level was 6.1+-1.2mg//dL6.1 \pm 1.2 \mathrm{mg} / \mathrm{dL} [42]; both serum calcium and phosphate levels were significantly higher than the accepted normal ranges. Of particular clinical importance, the mineral ion dysregulation, induced by vitamin DD supplement consumption could exert harmful effects, even when serum vitamin DD levels show hypovitaminosis D state. A single dose (600,000IU) of intramuscular injection of vitamin D2 resulted in an increased serum levels of phosphate beyond normal range by 4 weeks and persisted till the follow up period of 8 weeks, even when serum 25(OH)D25(\mathrm{OH}) \mathrm{D} level was below the normal range [12]. Prolonged and excessive consumption of vitamin D supplementation can cause hypercalcemia and/or hyperphosphatemia [43], leading to ectopic soft tissue mineralization [44]. For instance, supplement-mediated increase in serum calcium and phosphate levels and subsequent generation of supra saturating calcium-phosphate product 在 27 例维生素 D 中毒的报告病例中，平均血清钙水平为 12.1+-2.8mg//dL12.1 \pm 2.8 \mathrm{mg} / \mathrm{dL} ，血清磷水平为 6.1+-1.2mg//dL6.1 \pm 1.2 \mathrm{mg} / \mathrm{dL} [42]；血清钙和磷水平均显著高于公认的正常范围。临床上特别重要的是，由维生素 DD 补充剂引起的矿物离子失调可能产生有害影响，即使血清维生素 DD 水平显示维生素 D 缺乏状态。单次肌肉注射 600,000IU 维生素 D2 导致血清磷水平在 4 周内超过正常范围，并持续到 8 周的随访期，即使血清 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平低于正常范围[12]。长期和过量服用维生素 D 补充剂可引起高钙血症和/或高磷血症[43]，导致异位软组织矿化[44]。例如，补充剂介导的血清钙和磷水平升高及随后产生的过饱和钙磷产物
can be deposited in various organs, including in the kidneys (nephrocalcinosis) and in the blood vessels (vascular calcification). When such vascular calcification superposed with atherosclerotic plaques involves the coronary arteries, the resultant effects could be fatal. In a study of 27 vitamin D intoxicated patients, more than 25%25 \% patients showed features of nephrocalcinosis during the follow-up period [45] 可以沉积在各种器官中，包括肾脏（肾钙质沉着症）和血管（血管钙化）。当这种血管钙化叠加在动脉粥样硬化斑块上并涉及冠状动脉时，结果可能是致命的。在一项对 27 名维生素 D 中毒患者的研究中，随访期间超过 25%25 \% 名患者表现出肾钙质沉着的特征[45]。
Effects of vitamin D supplementation 维生素 D 补充的效果
The adverse effects of severe hypercalcemia and hyperphosphatemia induced by exogenous vitamin DD supplementation can be detected on most of the organ systems, including the gastrointestinal system, renal system, central nervous system, cardiovascular system, and musculoskeletal system (Table 2). Analysis of 27 clinically validated patients with vitamin D intoxication, 86%86 \% complained of vomiting, 57%57 \% with loss of appetite, 48%48 \% with weight loss, 43%43 \% with thirst, 38%38 \% with excessive water intake with polyuria, and 33%33 \% with constipation [45]; most of these complains were likely to be related to vitamin D-induced abnormal mineral ion metabolism (increased serum calcium and phosphate levels). In a retrospective study of 41 children with acute lymphoblastic leukemia, the longitudinal effects with vitamin D and phosphate showed a trend toward increasing phosphate concentrations in patients who received vitamin D supplements; phosphate concentrations increased by 0.035mg//dL0.035 \mathrm{mg} / \mathrm{dL} per day in the patients who received vitamin D supplementation compared with an increase of 0.010 mg//dL\mathrm{mg} / \mathrm{dL} per day in the non-vitamin D group [46]. Of clinical importance, the cellular phosphorus burden induced by excessive vitamin DD supplementation might contribute to the cellular pathology, even when serum vitamin D levels show hypovitaminosis D status. A wide range of cellular pathology is attributed to cellular phosphorus burden, including necrosis, apoptosis and senescence [47-53]. Available evidences suggest that phosphorus toxicity is a stealth biochemical stress factor that needs greater recognition by researchers and nutrition boards [54]. Of biological significance, vitamin D can induce the expression of fibroblast growth factor 由外源性维生素 DD 补充引起的严重高钙血症和高磷血症的不良影响可在大多数器官系统中检测到，包括胃肠系统、肾脏系统、中枢神经系统、心血管系统和肌肉骨骼系统（表 2）。对 27 例临床确诊的维生素 D 中毒患者的分析显示， 86%86 \% 抱怨呕吐， 57%57 \% 食欲减退， 48%48 \% 体重减轻， 43%43 \% 口渴， 38%38 \% 多饮多尿， 33%33 \% 便秘[45]；这些症状大多可能与维生素 D 引起的异常矿物离子代谢（血清钙和磷水平升高）有关。在一项对 41 名急性淋巴细胞白血病儿童的回顾性研究中，维生素 D 和磷的纵向效应显示，接受维生素 D 补充的患者磷浓度有增加的趋势；接受维生素 D 补充的患者磷浓度每天增加 0.035mg//dL0.035 \mathrm{mg} / \mathrm{dL} ，而非维生素 D 组每天仅增加 0.010 mg//dL\mathrm{mg} / \mathrm{dL} [46]。 临床上重要的是，过量维生素 D 补充引起的细胞磷负荷可能导致细胞病理，即使血清维生素 D 水平显示维生素 D 缺乏状态。细胞磷负荷被归因于多种细胞病理，包括坏死、凋亡和衰老[47-53]。现有证据表明，磷毒性是一种隐秘的生化应激因素，需要研究人员和营养委员会给予更多关注[54]。具有生物学意义的是，维生素 D 可以诱导成纤维细胞生长因子的表达
23 (FGF23), a master regulator of phosphate homeostasis, while FGF23 can suppress renal expression of 1alpha(OH)1 \alpha(\mathrm{OH}) ase to reduce 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 activities [51, 52, 55-59]. 23（FGF23），磷酸盐稳态的主要调节因子，而 FGF23 可以抑制肾脏中 1alpha(OH)1 \alpha(\mathrm{OH}) 酶的表达以减少 1,25(OH)2D31,25(\mathrm{OH}) 2 \mathrm{D} 3 活性[51, 52, 55-59]。
Although there is an ongoing debate on the optimal levels of vitamin D , the Institute of Medicine (IOM) estimated that 25(OH)D levels of at least 50nmol//L50 \mathrm{nmol} / \mathrm{L} would meet the vitamin D requirements of majority of the population [60]. Of relevance, a European survey result showed that around 40%40 \% of the studied population have serum 25(OH)25(\mathrm{OH}) D levels below 50nmol//L[61]50 \mathrm{nmol} / \mathrm{L}[61]. Since the purpose of this article is to discuss the supplement-associated adverse effects, deliberating the longstanding debate of IOM recommendation is beyond the scope of this article, and interested readers are referred to the earlier publications [38, 62-64]. In a recently published randomized trial in women of childbearing age in Germany, supplementing 800 IU vitamin D3 per day resulted in desired serum 25(OH)25(\mathrm{OH}) D levels of at least 50nmol//L50 \mathrm{nmol} / \mathrm{L} in most of the study participants within 8 weeks [65]. In a separate study conducted during the winter time showed that a vitamin D intake of 800 IU per day was sufficient to achieve a 25(OH)D25(\mathrm{OH}) \mathrm{D} level of around 50 nmol//L\mathrm{nmol} / \mathrm{L} in about 90-95%90-95 \% of the Irish population [66]; of clinical importance, the 25(OH)D levels are significantly lower during winter period compared to summer time, mostly because the UV-B radiation is thought to be too weak during the winter months to be able to generate sufficient vitamin D in the skin [67]. 尽管关于维生素 D 的最佳水平仍存在争议，但美国医学研究院（IOM）估计，25(OH)D 水平至少达到 50nmol//L50 \mathrm{nmol} / \mathrm{L} 即可满足大多数人群的维生素 D 需求[60]。相关的是，一项欧洲调查结果显示，约有 40%40 \% 的研究人群血清 25(OH)25(\mathrm{OH}) D 水平低于 50nmol//L[61]50 \mathrm{nmol} / \mathrm{L}[61] 。由于本文的目的是讨论补充剂相关的不良反应，深入讨论 IOM 建议的长期争议超出了本文的范围，有兴趣的读者可参考早期的文献[38, 62-64]。在德国一项最近发表的针对育龄妇女的随机试验中，每天补充 800 IU 维生素 D3 使大多数研究参与者在 8 周内达到期望的血清 25(OH)25(\mathrm{OH}) D 水平至少为 50nmol//L50 \mathrm{nmol} / \mathrm{L} [65]。 在另一项冬季进行的独立研究中显示，每天摄入 800 IU 的维生素 D 足以使约 90-95%90-95 \% 的爱尔兰人群达到约 50 nmol//L\mathrm{nmol} / \mathrm{L} 的 25(OH)D25(\mathrm{OH}) \mathrm{D} 水平[66]；临床上重要的是，25(OH)D 水平在冬季明显低于夏季，主要原因是冬季的 UV-B 辐射被认为过于微弱，无法在皮肤中生成足够的维生素 D[67]。
In addition to the inconsistency of the various vitamin DD assays, a lack of consensus on optimal vitamin D levels making it harder to determine the dose and necessity of exogenous supplements in clinical practice. For instance, an intervention study done on 2,256 communitydwelling Australian women by Sanders et al. [68] found that consumption of vitamin D supplements (single dose of 12,500 mug12,500 \mu \mathrm{~g} vitamin D3 or placebo annually) for 3 to 5 years increased the risk of falls and fractures in supplement treated group. In a separate study conducted on 247,574 patients showed an increased risk for all-cause mortality above the range of 50-60nmol//L50-60 \mathrm{nmol} / \mathrm{L} of 25(OH)D25(\mathrm{OH}) \mathrm{D} [69]; these authors concluded that 20-24ng//mL20-24 \mathrm{ng} / \mathrm{mL} is an optimal level, along the line of Institute of Medicine (IOM) recommendations [70]. Another trial reported that 除了各种维生素 DD 检测方法的不一致外，关于最佳维生素 D 水平缺乏共识，使得在临床实践中更难确定外源性补充剂的剂量和必要性。例如，Sanders 等人[68]对 2256 名居住在社区的澳大利亚女性进行的一项干预研究发现，服用维生素 D 补充剂（每年一次单剂量 12,500 mug12,500 \mu \mathrm{~g} 维生素 D3 或安慰剂）3 至 5 年后，补充剂组的跌倒和骨折风险增加。在另一项对 247,574 名患者进行的研究中，显示当维生素 D 水平超过 25(OH)D25(\mathrm{OH}) \mathrm{D} 的 50-60nmol//L50-60 \mathrm{nmol} / \mathrm{L} 范围时，全因死亡率风险增加[69]；这些作者得出结论， 20-24ng//mL20-24 \mathrm{ng} / \mathrm{mL} 是一个最佳水平，与美国医学研究院（IOM）的建议一致[70]。另一项试验报告称
300,000 IU ergocalciferol given intramuscularly for 3 years to elderly people during fall season resulted in increased risk of bone fractures [71]. A 2.5-fold increased incidence of atrial fibrillation was reported in patients with high levels of vitamin D( > 100ng//dL)\mathrm{D}(>100 \mathrm{ng} / \mathrm{dL}) that are difficult to reach without consuming a high dose of vitamin D supplements [72]. An increased risk of allcause mortality and acute coronary syndrome were noted in a cohort of 420,000 patients, when 25(OH)D levels exceeded 36ng/mL [73]. Although, some of these studies are limited by the fact that the investigators did not take an account of participants with high 25(OH)D levels, who were given vitamin D supplement [74]. However, meta-analyses and subsequent subanalyses of vitamin D supplement treatment did not reliably show a decrease in skeletal fracture risk, when compared with a non-treated control (placebo) group [64, 75, 76]. In fact, the US Preventive Services Task Force found that the currently available evidences do not justify the recommendation of > 400IU//>400 \mathrm{IU} / day of vitamin D supplement and > 1000mg//>1000 \mathrm{mg} / day calcium, and lower doses are not recommended at all [77]. Similarly, despite some studies that have suggested a possible association between hypovitaminosis D and evolvements of metabolic syndrome and all-cause mortality rate [78], a recent randomized controlled trial on Chinese population found that the correction of hypovitaminosis D did not improve the metabolic syndrome risk profile [79]. Summarizing the above cited evidences, it is clear that consuming higher doses of vitamin D supplements for a prolonged period does not always yield better health outcome. 在秋季对老年人肌肉注射 30 万国际单位的麦角钙化醇，持续 3 年，导致骨折风险增加[71]。在维生素 D( > 100ng//dL)\mathrm{D}(>100 \mathrm{ng} / \mathrm{dL}) 水平较高的患者中，房颤发生率增加了 2.5 倍，而这种水平难以通过不服用高剂量维生素 D 补充剂达到[72]。在一项包含 42 万名患者的队列研究中，当 25(OH)D 水平超过 36ng/mL 时，观察到全因死亡率和急性冠状动脉综合征的风险增加[73]。尽管这些研究中有些存在局限性，调查者未考虑那些 25(OH)D 水平较高且服用维生素 D 补充剂的参与者[74]。然而，维生素 D 补充治疗的荟萃分析及后续亚分析并未可靠显示与未治疗对照（安慰剂）组相比，骨折风险有下降[64, 75, 76]。事实上，美国预防服务工作组发现，目前可用的证据不足以支持推荐每日 > 400IU//>400 \mathrm{IU} / 剂量的维生素 D 补充剂和每日 > 1000mg//>1000 \mathrm{mg} / 剂量的钙补充剂，且不推荐使用更低剂量[77]。 同样，尽管有些研究表明维生素 D 缺乏可能与代谢综合征的发展及全因死亡率有关[78]，但最近一项针对中国人群的随机对照试验发现，纠正维生素 D 缺乏并未改善代谢综合征的风险状况[79]。综上所述，以上证据表明，长期服用较高剂量的维生素 D 补充剂并不总能带来更好的健康结果。
Conclusion 结论
Despite our broaden understanding of vitamin DD biology in last couple of years, it is necessary to develop an ideal vitamin assay system to be able to access true vitamin DD status in human. As mentioned, existing vitamin DD assay systems have limitations, both in sensitivity and specificity. Moreover, the needs of vitamin D supplements to otherwise healthy individuals require careful clinical considerations, to avoid undesirable adverse effects of prolonged consumption of supplement. Of relevance, despite lack of concrete evidences of role of vitamin 尽管我们在过去几年中对维生素 DD 生物学的理解有所拓展，但有必要开发一个理想的维生素检测系统，以便能够评估人体内真实的维生素 DD 状态。如前所述，现有的维生素 DD 检测系统在灵敏度和特异性方面均存在局限性。此外，对于健康个体补充维生素 D 的需求需要谨慎的临床考虑，以避免长期服用补充剂带来的不良副作用。相关的是，尽管缺乏维生素作用的确凿证据
D supplements on otherwise healthy individuals, the amount spent on vitamin D supplements had climbed from $40\$ 40 million in 2001 to $600\$ 600 million in 2011 in the USA [80]. Although there is disagreement on optimal vitamin D levels, there are evidences showing increased levels in serum calcium and phosphate after intake of high doses of vitamin DD supplementation, even in hypovitaminosis D state. Humans have an innate ability to produce endogenous vitamin D in response to sunlight exposure [81]. Since lower vitamin D status, without any preexisting disease condition, reflects reduced sunlight contact, the obvious primary source of vitamin D should be safe sunlight exposure, and not exogenous supplements that have the potential to induce harmful effects. Of clinical importance, supplementation might be useful in special groups of individuals those who are at high-risk of developing vitamin D deficiency due to lack of sunlight exposure or preexisting diseases that might impair endogenous vitamin D synthesis [82]. Finally, though rare, diagnosis of symptomatic vitamin D intoxication with hypercalciuria with hypercalcemia and hyperphosphatemia is not clinically difficult. In contrast, the possibility of supplement-mediated vitamin DD intoxication with abnormal mineral ion metabolism in hypovitaminosis D status is not well appreciated in clinical practice; a greater awareness of such clinical scenario would serve better to the affected individuals, as when hypercalcemia and/or hyperphosphatemia is apparent following vitamin DD supplementation, the process of tissue and/or organ damage might already have started. To end, iatrogenic subclinical hypervitaminosis DD is more common clinical observation than acute symptomatic vitamin DD intoxication. 在其他健康个体中，维生素 D 补充剂的支出金额从 2001 年的 $40\$ 40 百万美元增加到 2011 年的 $600\$ 600 百万美元[80]。尽管对最佳维生素 D 水平存在分歧，但有证据表明，即使在维生素 D 缺乏状态下，摄入高剂量维生素 DD 补充剂后血清钙和磷酸盐水平也会升高。人体具有在阳光照射下产生内源性维生素 D 的先天能力[81]。由于较低的维生素 D 状态（无任何既存疾病）反映了阳光接触减少，维生素 D 的明显主要来源应是安全的阳光照射，而非可能引起有害影响的外源性补充剂。在临床上，补充剂可能对那些因缺乏阳光照射或既存疾病导致内源性维生素 D 合成受损而处于维生素 D 缺乏高风险的特殊人群有用[82]。最后，尽管罕见，伴有高钙尿症、高钙血症和高磷血症的症状性维生素 D 中毒的诊断并不困难。 相比之下，在维生素 D 缺乏状态下，补充剂介导的维生素 3 中毒伴随异常矿物离子代谢的可能性在临床实践中并未得到充分重视；对这种临床情况的更高认识将更有利于受影响的个体，因为当维生素 4 补充后出现高钙血症和/或高磷血症时，组织和/或器官损伤的过程可能已经开始。最后，医源性亚临床维生素 5 过多症比急性症状性维生素 6 中毒更为常见的临床观察。
Acknowledgements 致谢
Thanks to Mrs. Rufsa H. Afroze for carefully reading the manuscript and providing useful suggestions. Dr. Razzaque is a Visiting Professor of the Harvard School of Dental Medicine, Boston, USA and a faculty of the Rwanda Human Resources for Health (HRH) Program at the University of Rwanda School of Dentistry in Kigali, Rwanda. 感谢 Rufsa H. Afroze 女士仔细阅读手稿并提供有益的建议。Razzaque 博士是美国波士顿哈佛牙科学院的访问教授，同时也是卢旺达人力资源健康（HRH）项目的教师，任职于卢旺达基加利卢旺达大学牙科学院。
Figure 1 图 1
Simplified diagram of the different source and stages of vitamin D synthesis, modified from earlier publications [83, 84]. For simplicity, only essential steps of vitamin synthesis are included. VDR: vitamin D receptor. 维生素 D 合成的不同来源和阶段的简化图，改编自早期出版物[83, 84]。为简便起见，仅包含维生素合成的关键步骤。VDR：维生素 D 受体。
Table 1 表 1
Factors that influence UVB absorption from the sunlight [85] 影响阳光中 UVB 吸收的因素[85]
Thicker epidermal layer 表皮层较厚
Skin pigmentation 皮肤色素沉着
Lotions and creams 乳液和面霜
Location (e.g., higher latitude geographically) 位置（例如，地理上更高的纬度）
Application of sunscreen 防晒霜的应用
Air quality (e.g., pollution) 空气质量（例如，污染）
Aging 衰老
Table 2 表 2
Partial list of hypercalcemia and /or hyperphosphatemia-associated symptoms due to vitamin D intoxication [42]. 维生素 D 中毒引起的高钙血症和/或高磷血症相关症状的部分列表[42]。
Gastrointestinal system 胃肠系统
Abdominal pain 腹痛
Anorexia 厌食症
Constipation 便秘
Nausea 恶心
Pancreatitis 胰腺炎
Peptic ulcer 消化性溃疡
Vomiting 呕吐
Renal system 肾脏系统
Acute and chronic renal failure 急性和慢性肾功能衰竭
Chronic interstitial nephritis 慢性间质性肾炎
Distal renal tubular acidosis 远端肾小管性酸中毒
Hematuria 血尿
Nephrocalcinosis 肾钙质沉着症
Nephrogenic diabetes insipidus 肾性尿崩症
Nephrolithiasis 肾结石
Polyuria 多尿症
Central nervous system 中枢神经系统
Anxiety 焦虑
Confusion 困惑
Deep tendon reflexes reduction 深腱反射减弱
Depression 抑郁症
Hallucination 幻觉
Headache 头痛
Hypotonia 肌张力低下
Paresthesia 感觉异常
Psychosis 精神病
Seizures 癫痫发作
Cardiovascular system 心血管系统
Arrhythmia 心律失常
Cardiac arrest 心脏骤停
Cardiac calcification 心脏钙化
Cardiomyopathy 心肌病
Hypertension 高血压
Musculoskeletal system 肌肉骨骼系统
Bone pain 骨痛
Long bones metastatic calcification 长骨转移性钙化
Muscle weakness 肌肉无力
Osteopenia/osteoporosis 骨质减少/骨质疏松症
Osteopetrosis 骨质致密症
Eyes 眼睛
Band keratopathy 带状角膜病
Conjunctival calcification 结膜钙化
Skin 皮肤
Itching 瘙痒
Metastatic calcification 转移性钙化
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