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维生素D对健康的影响
维生素D对健康的影响远不止于“帮忙补钙”和“强壮骨骼”，它实际上是人体内一位全能的“健康大管家”，参与调节免疫、保护肾脏、维持生殖系统健康等多个部位的工作；然而，补充维生素D必须讲究“缺了才补、适可而止”，因为全球虽然有超过10亿人缺乏维生素D，但对于体内已经不缺的人来说，盲目吃补充剂并不能带来预防癌症或心脏病等额外的好处，吃多了反而会导致严重的中毒。
下面，我们将把复杂的科学研究翻译成大白话，为您详细拆解维生素D到底在人体内做些什么，以及我们该如何正确对待它。
一、 经典本职工作：骨骼与牙齿的“建筑包工头”
长久以来，人们最熟悉的维生素D的作用就是维持骨骼健康。您可以把人体的骨骼想象成一座大楼，钙和磷就是建楼必需的砖块和水泥。如果没有维生素D这位“包工头”，哪怕您吃下去再多的钙，肠道也无法把它们顺利吸收进血液里，骨骼这座大楼就会因为缺乏材料而变得摇摇欲坠。
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预防儿童与成人的骨骼灾难 在儿童时期，如果严重缺乏维生素D，会导致一种叫做“佝偻病”的疾病，孩子们的骨骼会变软、变形，无法正常生长。 而对于成年人和老年人来说，缺乏维生素D会加速骨骼流失，导致骨质疏松（骨头变得像多孔的马蜂窝一样脆），轻轻一摔就容易发生骨折。 研究表明，每天补充400国际单位（IU）的维生素D可以预防佝偻病；而对于住在养老院或缺乏维生素D的老年人，每天补充800 IU的维生素D并配合适当的钙，能有效降低骨折的风险。
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保护口腔与牙齿 除了大骨头，我们的牙齿也归维生素D管。在儿童的成长过程中，严重缺乏维生素D会导致牙齿矿化不良（也就是牙齿外层的坚硬保护壳没有发育好），这会大大增加长蛀牙（龋齿）的风险。 在成年人中，缺乏维生素D还与牙周炎（一种会导致牙龈红肿、牙齿松动的严重口腔炎症）的高发密切相关。如果能在治疗牙周炎时纠正维生素D的缺乏，治疗效果会更好；相反，如果患者体内缺乏维生素D，牙槽骨（固定牙齿的骨头）的修复手术就更容易失败。
二、 隐藏的全能超人：骨骼之外的“跨界神操作”
随着科学的发展，科学家们惊讶地发现，维生素D不仅在骨骼里发光发热，它的“联络天线”——也就是医学上说的维生素D受体（VDR），几乎存在于人体的每一个角落。您可以把VDR想象成细胞表面的特殊锁孔，当维生素D这把钥匙插进去时，就能启动细胞内部的许多隐藏功能。
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保护肾脏的“微小过滤网” 我们的肾脏就像是人体的净水器，里面有无数个微小的过滤网。在肾脏里，有一种长得像章鱼一样的细胞叫作足细胞（Podocytes），它们是过滤网的重要组成部分。在患有肾小球肾炎（一种常见的肾脏过滤系统生病的疾病）的患者中，过滤网破损，导致体内宝贵的营养物质（蛋白质）从尿液中漏走，形成蛋白尿。研究发现，补充维生素D可以保护这些足细胞的结构完整，减少蛋白质的漏出，同时还能抑制肾脏里的炎症，从而延缓肾脏疾病的恶化。
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调节免疫系统与对抗炎症 维生素D在免疫系统中也扮演着“维和部队”的角色。它不仅能帮助人体对抗外来的感染（比如减少儿童呼吸道感染的风险），还能安抚那些过度兴奋、容易“自己打自己人”的免疫细胞，从而可能对一些自身免疫性疾病（如多发性硬化症）起到调节作用。 此外，对于患有慢性肝病（无论是病毒性肝炎、酒精肝还是脂肪肝）的人来说，体内普遍存在维生素D缺乏的现象，而这种缺乏与肝脏纤维化（肝脏因为反复发炎而长疤痕、变硬的过程）的恶化有关。 肝脏还会制造一种叫做维生素D结合蛋白（VDBP）的“运输船”，专门负责在血液中运送维生素D，这种运输船同时也参与身体受损后的炎症反应处理。
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护航生命孕育与生殖健康 维生素D对母亲和宝宝都至关重要。研究发现，孕妇如果缺乏维生素D，更容易遭遇妊娠期高血压（先兆子痫）、妊娠期糖尿病，并且早产和剖腹产的概率也会上升。 而在婴儿身上，母亲缺维生素D可能导致新生儿出生体重过低，甚至可能与孩子未来患上哮喘、1型糖尿病、自闭症等疾病有关。 此外，维生素D还与男女的生育能力有关，它的缺乏被认为是导致不孕症、多囊卵巢综合征以及子宫内膜异位症（一种让女性非常痛苦的妇科疾病）的风险因素之一。 对于处于更年期的女性，体内激素的剧烈变化本身就会带来各种不适，而缺乏维生素D更会“雪上加霜”，加重更年期相关的健康风险。
三、 全球超10亿人的大流行：为什么我们这么缺？
既然维生素D这么重要，为什么现在全球会有超过10亿的儿童和成年人缺乏它呢？
这主要是因为，人类获取维生素D最自然、最主要的方式是晒太阳。当皮肤暴露在阳光中的紫外线B（UVB）下时，人体就能自己合成维生素D。 然而，现代人的生活方式发生了巨大改变：我们大部分时间待在室内，出门裹得严严实实，还要涂抹防晒霜；加上有些人居住在纬度较高（离赤道远）的地方，阳光照射角度太斜，这些都极大地阻挡了皮肤制造维生素D的机会。
既然晒太阳不够，能不能靠吃来补呢？很难。因为自然界中天然含有丰富维生素D的食物简直是凤毛麟角。 我们来看一些具体的数据： 如果想要维持健康，欧洲食品安全局设定的目标是每天摄入15微克（μg）的维生素D。 但是看看我们常吃的食物里含多少：
- 鱼类：每100克通常含有5到25微克，算是比较丰富的了。
- 蘑菇：每100克含有21.1到58.7微克。
- 奶酪、牛肝和鸡蛋：每100克仅仅含有1.3到2.9微克。
- 黑巧克力：每100克仅含4微克。
- 极其丰富的特例：驯鹿地衣（87微克/100克）和鱼肝油（高达250微克/100克），但这些根本不是普通人每天会大量吃的食物。
正因为光靠一日三餐很难达标，所以对于无法保证充足日照的人群来说，服用维生素D补充剂成为了防范缺乏的重要手段。
四、 科学的冷水：不缺的人多吃无益
看到这里，您可能觉得：“既然维生素D这么神奇，那我平时多吃点补充剂，是不是就能包治百病、延年益寿了？” 科学家的回答是：绝对不是。
医学界为了弄清楚给普通人补充维生素D到底有没有额外的好处，开展了代号为VITAL、ViDA和D2d等超大型的随机对照试验，总共拉来了超过3万名志愿者参与。 这3万多人被分成了两组，一组吃真实的维生素D，另一组吃没有作用的安慰剂，进行了长期的观察。
结果非常明确：对于血液中维生素D浓度已经达到正常健康水平（即血液里的25-羟基维生素D浓度大于50 nmol/L）的成年人来说，额外再吃维生素D补充剂，并不能预防癌症、不能预防心血管疾病（如心脏病发作）、不能减少老年人跌倒的次数，也不能阻止身体发展成2型糖尿病。 此外，科学家们还查阅了60多项孟德尔随机化研究（这是一种利用人类天生基因差异来进行的超级公平的“抽奖式”研究方法，能最大程度排除其他生活习惯的干扰），结果绝大多数也显示，天生维生素D水平高低与许多非骨骼疾病的发病率并没有因果关系。
这就像是给汽车加油：如果油箱空了（严重缺乏，血液浓度小于30 nmol/L），汽车会熄火抛锚（得病），这时候您必须把油加满；但如果油箱已经是满的（浓度大于50 nmol/L），您再往里面拼命灌油，汽车也不会因此飞起来变成飞机。因此，科学界的共识是：严重缺乏必须纠正，但对于已经不缺的人，补充维生素D并不会带来可证明的额外健康益处。
五、 极度危险的警示：吃多了会中毒！
不仅“多吃无益”，更可怕的是“多吃有害”。维生素D属于脂溶性维生素。水溶性维生素（比如维生素C）吃多了，多余的部分会顺着尿液排走；但脂溶性维生素一旦吃多，就会像囤积狂在仓库里堆东西一样，堆积在人体的脂肪组织里，很难快速排泄出去（它在人体内的半衰期长达大约2个月，也就是说，两个月后体内还有一半没消化完）。
如果长期过量服用市面上的非处方维生素D补充剂，或者误服了含有极高剂量维生素D的药物，就会导致维生素D中毒（VDT）。 当血液中的25-羟基维生素D浓度飙升到150 ng/ml（相当于375 nmol/l）以上时，就是典型的服药过量中毒标志。
中毒会带来什么后果呢？最核心的病理灾难叫做高钙血症。 我们在第一部分说过，维生素D能疯狂促进肠道吸收钙。当体内维生素D多到爆炸时，大量的钙被强行塞进血液里。血液里的钙浓度一旦超标，就会引发全身大乱：
- 轻度超标（总钙量小于12 mg/dL）：人可能会感到莫名其妙的极度疲惫、乏力，或者严重的便秘。
- 严重超标（总钙量达到或超过14 mg/dL，或者发展非常迅速）：这会引起恶心、反复呕吐、肚子痛。 因为身体想把多余的钙排出去，就会拼命制造尿液，导致多尿（频繁上厕所），进而引发极度口渴和严重脱水。 更可怕的是，过高的钙会像短路一样干扰大脑神经，导致患者出现意识混乱、神情淡漠、嗜睡，最终甚至会陷入昏迷，如果不及时抢救，会有生命危险。
治疗这种严重的高钙血症，医生通常需要给患者紧急大量输液以补充流失的水分，并使用特殊的药物（如静脉注射双膦酸盐）来把血液里的钙赶回骨头里或者排泄掉。
总结建议
- 明确自己是否需要补：如果您是长时间待在室内、很少晒太阳的办公族，或者是防晒极其严格的人，又或者是不爱吃鱼虾蘑菇的人群，您很有可能存在维生素D不足。最好的办法是在体检时抽血查一下“25-羟基维生素D”的水平。
- 适量为王，绝不贪多：如果确诊缺乏，一般建议普通成人每天补充800-1000国际单位（IU）来维持健康水平即可，千万不要为了追求所谓的“抗癌”或“预防心脏病”去自行购买超大剂量的药丸当糖吃。
- 阳光与饮食并重：在阳光温和的时候（避开暴晒以防皮肤癌），适度露出手臂和小腿晒一小会儿太阳，并在日常饮食中适当增加鱼类（如三文鱼、沙丁鱼）、蘑菇和鸡蛋的摄入，是获得这位“健康大管家”最安全、最自然的方式。
References
1The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention.PubMed
Michael F Holick
Rev Endocr Metab Disord. 2017 Jun;18(2):153-165. doi: 10.1007/s11154-017-9424-1.
Vitamin D deficiency and insufficiency is a global health issue that afflicts more than one billion children and adults worldwide. The consequences of vitamin D deficiency cannot be under estimated. There has been an association of vitamin D deficiency with a myriad of acute and chronic illnesses including preeclampsia, childhood dental caries, periodontitis, autoimmune disorders, infectious diseases, cardiovascular disease, deadly cancers, type 2 diabetes and neurological disorders. This review is to put into perspective the controversy surrounding the definition for vitamin D deficiency and insufficiency as well as providing guidance for how to treat and prevent vitamin D deficiency.
2Hypercalcemia: A Review.PubMed
Marcella Donovan Walker, Elizabeth Shane
JAMA. 2022 Oct 25;328(16):1624-1636. doi: 10.1001/jama.2022.18331.
IMPORTANCE: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. OBSERVATIONS: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. CONCLUSIONS AND RELEVANCE: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.
3Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.PubMed
Sylvia Christakos, Puneet Dhawan, Annemieke Verstuyf, et al.
Physiol Rev. 2016 Jan;96(1):365-408. doi: 10.1152/physrev.00014.2015.
1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.
4Vitamin D: Before, during and after Pregnancy: Effect on Neonates and Children.PubMed
José Luis Mansur, Beatriz Oliveri, Evangelina Giacoia, et al.
Nutrients. 2022 May 1;14(9):1900. doi: 10.3390/nu14091900.
A worldwide high prevalence of vitamin D (VD) deficiency has become of growing concern because of potential adverse effects on human health, including pregnant women and their offsprings. Beyond its classical function as a regulator of calcium and phosphate metabolism, together with its fundamental role in bone health in every stage of life, its deficiency has been associated to multiple adverse health effects. The classic effects of VD deficiency in pregnancy and neonates have been late hypocalcemia and nutritional rickets. Nevertheless, recent studies have linked VD to fertility and 25(OH)D with several clinical conditions in pregnancy: preeclampsia, gestational diabetes, higher incidence of cesarean section and preterm birth, while in infants, the clinical conditions are low birth weight, lower bone mass and possible relationship with the development of such diseases as bronchiolitis, asthma, type 1 diabetes, multiple sclerosis and autism included as VD non-classical actions. The supplementation with Vitamin D and achievement of optimal levels reduce maternal-fetal and newborn complications. Supplementation in children with VD deficiency reduces the risk of respiratory infections and possibly autoimmune diseases and autism. This review emphasizes the roles of Vitamin D deficiency and the consequences of intervention from preconception to infancy.
5Vitamin D Toxicity-A Clinical Perspective.PubMed
Ewa Marcinowska-Suchowierska, Małgorzata Kupisz-Urbańska, Jacek Łukaszkiewicz, et al.
Front Endocrinol (Lausanne). 2018 Sep 20;9:550. doi: 10.3389/fendo.2018.00550. eCollection 2018.
Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite - 1,25(OH)D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)D in congenital disorders, such as Williams-Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D-related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase.
6Vitamin D Deficiency and Oral Health: A Comprehensive Review.PubMed
João Botelho, Vanessa Machado, Luís Proença, et al.
Nutrients. 2020 May 19;12(5):1471. doi: 10.3390/nu12051471.
Vitamin D (VD) levels have been gaining growing attention in Oral Health. During growth and adulthood, VD deficiency (VDD) is associated with a wide variety of oral health disorders, and impaired VD synthesis may expedite some of these conditions. In children, severe VDD can induce defective tooth mineralization, resulting in dentin and enamel defects. As a consequence, these defects may increase the risk of the onset and progression of dental caries. Further, VDD has been associated with higher prevalence of periodontitis and gingival inflammation, and several recent preclinical and clinical studies have unveiled potential pathways through which Vitamin D may interact with the periodontium. VDD correction through supplementation may contribute to a successful treatment of periodontitis; however, alveolar bone regeneration procedures performed in baseline VDD patients seem more prone to failure. Vitamin D may also be linked with some oral pathology entities such as certain oral cancers and events of osteonecrosis of the jaw. This review aims to provide comprehensive evidence of how VD levels should be considered to promote good oral health, and to summarize how VDD may hamper oral development and its role in certain oral conditions.
8Vitamin D: sources, physiological role, biokinetics, deficiency, therapeutic use, toxicity, and overview of analytical methods for detection of vitamin D and its metabolites.PubMed
Jiří Janoušek, Veronika Pilařová, Kateřina Macáková, et al.
Crit Rev Clin Lab Sci. 2022 Dec;59(8):517-554. doi: 10.1080/10408363.2022.2070595. Epub 2022 May 16.
Vitamin D has a well-known role in the calcium homeostasis associated with the maintenance of healthy bones. It increases the efficiency of the intestinal absorption of dietary calcium, reduces calcium losses in urine, and mobilizes calcium stored in the skeleton. However, vitamin D receptors are present ubiquitously in the human body and indeed, vitamin D has a plethora of non-calcemic functions. In contrast to most vitamins, sufficient vitamin D can be synthesized in human skin. However, its production can be markedly decreased due to factors such as clothing, sunscreens, intentional avoidance of the direct sunlight, or the high latitude of the residence. Indeed, more than one billion people worldwide are vitamin D deficient, and the deficiency is frequently undiagnosed. The chronic deficiency is not only associated with rickets/osteomalacia/osteoporosis but it is also linked to a higher risk of hypertension, type 1 diabetes, multiple sclerosis, or cancer. Supplementation of vitamin D may be hence beneficial, but the intake of vitamin D should be under the supervision of health professionals because overdosing leads to intoxication with severe health consequences. For monitoring vitamin D, several analytical methods are employed, and their advantages and disadvantages are discussed in detail in this review.
9Vitamin D and Menopause.PubMed
Megha Sharma, Sanjay Kalra
J Pak Med Assoc. 2024 Apr;74(4):815-817. doi: 10.47391/JPMA.24-27.
Menopause is the transition period in female life cycle. Resultant hormonal changes lead to adverse health effects. Women may seek treatment due to significant impairment in quality of life. Vitamin D deficiency is a globally prevalent problem. Vitamin D deficiency in menopausal women may aggravate the adverse health risks associated with menopause. In this article, the authors discuss endocrinology and clinical features of menopause, Vitamin D and its links with menopause, and the potential role of Vitamin D supplementation to combat detrimental multi-organ system effects of menopause.
10Sources of vitamin D for humans.PubMed
Evgen Benedik
Int J Vitam Nutr Res. 2022 Mar;92(2):118-125. doi: 10.1024/0300-9831/a000733. Epub 2021 Oct 18.
Both vitamin D insufficiency and deficiency are now well-documented worldwide in relation to human health, and this has raised interest in vitamin D research. The aim of this article is therefore to review the literature on sources of vitamin D. It can be endogenously synthesised under ultraviolet B radiation in the skin, or ingested through dietary supplements and dietary sources, which include food of animal and plant origin, as well as fortified foods. Vitamin D is mainly found in two forms, D (cholecalciferol) and D (ergocalciferol). In addition to the D and D forms of vitamin D, 25-hydroxy vitamin D also contributes significantly to dietary vitamin D intake. It is found in many animal-derived products. Fortified food can contain D or D forms or vitamin D metabolite 25-hydroxy vitamin D. Not many foods are a rich source (> 4 μg/100 g) of vitamin D (D represents D and/or D), e.g., many but not all fish (5-25 μg/100 g), mushrooms (21.1-58.7 μg/100 g), Reindeer lichen (87 μg/100 g) and fish liver oils (250 μg/100 g). Other dietary sources are cheese, beef liver and eggs (1.3-2.9 μg/100 g), dark chocolate (4 μg/100 g), as well as fortified foods (milk, yoghurt, fat spreads, orange juice, breakfast grains, plant-based beverages). Since an adequate intake of vitamin D (15 μg/day set by the European Food Safety Authority) is hard to achieve through diet alone, dietary supplements of vitamin D are usually recommended. This review summarizes current knowledge about different sources of vitamin D for humans.
11The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases.PubMed
Tudor Lucian Pop, Claudia Sîrbe, Gabriel Benţa, et al.
Int J Mol Sci. 2022 Sep 14;23(18):10705. doi: 10.3390/ijms231810705.
Vitamin D (calciferol) is a fat-soluble vitamin that has a significant role in phospho-calcium metabolism, maintaining normal calcium levels and bone health development. The most important compounds of vitamin D are cholecalciferol (vitamin D3, or VD3) and ergocalciferol (vitamin D2, or VD2). Besides its major role in maintaining an adequate level of calcium and phosphate concentrations, vitamin D is involved in cell growth and differentiation and immune function. Recently, the association between vitamin D deficiency and the progression of fibrosis in chronic liver disease (CLD) was confirmed, given the hepatic activation process and high prevalence of vitamin D deficiency in these diseases. There are reports of vitamin D deficiency in CLD regardless of the etiology (chronic viral hepatitis, alcoholic cirrhosis, non-alcoholic fatty liver disease, primary biliary cirrhosis, or autoimmune hepatitis). Vitamin D binding protein (VDBP) is synthesized by the liver and has the role of binding and transporting vitamin D and its metabolites to the target organs. VDBP also plays an important role in inflammatory response secondary to tissue damage, being involved in the degradation of actin. As intense research during the last decades revealed the possible role of vitamin D in liver diseases, a deeper understanding of the vitamin D, vitamin D receptors (VDRs), and VDBP involvement in liver inflammation and fibrogenesis could represent the basis for the development of new strategies for diagnosis, prognosis, and treatment of liver diseases. This narrative review presents an overview of the evidence of the role of vitamin D and VDBP in CLD, both at the experimental and clinical levels.
12The health effects of vitamin D supplementation: evidence from human studies.PubMed
Roger Bouillon, Despoina Manousaki, Cliff Rosen, et al.
Nat Rev Endocrinol. 2022 Feb;18(2):96-110. doi: 10.1038/s41574-021-00593-z. Epub 2021 Nov 23.
Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.
13Pharmacokinetics of vitamin D toxicity.PubMed
Glenville Jones
Am J Clin Nutr. 2008 Aug;88(2):582S-586S. doi: 10.1093/ajcn/88.2.582S.
Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin.
14Vitamin D deficiency: a worldwide problem with health consequences.PubMed
Michael F Holick, Tai C Chen
Am J Clin Nutr. 2008 Apr;87(4):1080S-6S. doi: 10.1093/ajcn/87.4.1080S.
Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800-1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
15Vitamin D and reproductive disorders: a comprehensive review with a focus on endometriosis.PubMed
Pooya Farhangnia, Morvarid Noormohammadi, Ali-Akbar Delbandi
Reprod Health. 2024 May 2;21(1):61. doi: 10.1186/s12978-024-01797-y.
Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis.
16Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions.PubMed
Roger Bouillon, Claudio Marcocci, Geert Carmeliet, et al.
Endocr Rev. 2019 Aug 1;40(4):1109-1151. doi: 10.1210/er.2018-00126.
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
17A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.PubMed
Carolina Rodrigues Tonon, Taline Alisson Artemis Lazzarin Silva, Filipe Welson Leal Pereira, et al.
Med Sci Monit. 2022 Feb 26;28:e935821. doi: 10.12659/MSM.935821.
Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.
18Vitamin D and Glomerulonephritis.PubMed
Guido Gembillo, Rossella Siligato, Michela Amatruda, et al.
Medicina (Kaunas). 2021 Feb 22;57(2):186. doi: 10.3390/medicina57020186.
Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin-Angiotensin-Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin-megalin-amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.
19Vitamin D Deficiency: Defining, Prevalence, Causes, and Strategies of Addressing.PubMed
Kevin D Cashman
Calcif Tissue Int. 2020 Jan;106(1):14-29. doi: 10.1007/s00223-019-00559-4. Epub 2019 May 8.
There are variable definitions of vitamin D deficiency, based on different thresholds of serum 25-hydroxyvitamin D (25(OH)D); this has a major bearing on the prevalence estimates of vitamin D deficiency and consequently on the magnitude of the public health issue of low vitamin D status. Despite this, there is widespread acknowledgement of the presence of vitamin D deficiency, even using the most conservative serum 25(OH)D threshold of < 25/30 nmol/L, in both low- and high-income country setting and the pressing need to address this deficiency. While ultraviolet B-rich sunlight stimulates synthesis of vitamin D in skin, there are environmental factors and personal characteristics which prevent or impede such dermal synthesis. There are several complexities and concerns in advocating sun exposure as a public health approach for increasing vitamin D status. This places increased emphasis on addressing vitamin D deficiency through dietary means. However, naturally rich sources of vitamin D are few and infrequently consumed, and nutrition surveillance data from various countries have indicated that habitual vitamin D intakes in the population are much lower than the recommendations. There are a number of strategies that can be considered for the control of micronutrient malnutrition, these include (i) increasing the diversity of foods consumed, (ii) food fortification, and (iii) supplementation. The present narrative review will consider these strategies for addressing low dietary vitamin D intake and consequently lowering the risk of vitamin D deficiency.
20Vitamin D ToxicityPubMed
Anum Asif, Nauman Farooq
Vitamin D is a fat-soluble vitamin found in various animal products and fortified foods and is also made endogenously in the human body. Vitamin D is also available as both a prescription and over-the-counter supplement. Vitamin D is important for bone health, and deficiency can lead to the development of rickets and osteopenia. More recently, it has been determined that vitamin D also plays an important role in various metabolic processes. It also has been linked to autoimmune disease, cancer, cardiovascular disease, depression, dementia, infectious diseases, and musculoskeletal decline. Vitamin D deficiency has become less of a problem with the availability of supplements and fortified foods. Hypervitaminosis D is rare and usually caused by excessive doses of vitamin D due to misuse of over-the-counter supplements or erroneous prescriptions. Less commonly, poisoning from exposure to rodenticides containing cholecalciferol can also lead to vitamin D toxicity. Toxicity leads to hypercalcemia and an imbalance in the regulation of bone metabolism with resultant hypercalcemia and its associated signs and symptoms.