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发表于 2020-4-1 10:17:52 | 显示全部楼层 |阅读模式
Vitamin Toxicities and Therapeutic Monitoring 维生素药理剂量治疗的毒性监测
Joseph E. Pizzorno, ND
CHAPTER CONTENTS Introduction, 1128
Vitamin Toxicity, 1128 维生素毒性
Lipid-Soluble Vitamins, 1128 脂溶性维生素
Water-Soluble Vitamins, 1131 水溶性维生素
Laboratory Tests for Vitamin Toxicity, 1132 维生素毒性的实验室试验
When nutrients such as vitamins are being used at high doses for pharmacologic effects, the physician must be vigilant for possible toxicity or side effects. In general, vitamin therapy is virtually nontoxicand the small risk of developing any toxicity can be further reduced by careful monitoring of the patient. The physician should also be aware of toxicity resulting from self-administered vitamins. The primary signs and symptoms of vitamin toxicity are listed in Tables 137-1 and 137-2, which are complemented by a more detailed discussion of toxicity and guidelines for mon-itoring select vitamins
当维生素等维生素以高剂量用于药理作用时,医生必须警惕可能的毒性或副作用。 一般来说,维生素治疗实际上是“无毒的”,通过仔细监测患者可以进一步降低发生任何毒性的小风险。 医生还应该意识到维生素治疗导致的毒性。 137-1137-2列出了维生素毒性的主要症状和体征,并通过更详细的毒性讨论和监测精
Lipid-Soluble Vitamins 脂溶性维生素
Vitamin A
Although vitamin A deficiency is a much greater problem than vitamin A toxicity, particularly in developing nations, both clinical and subclinical toxicities have been associated with excessive intakes of preformed vitamin A. Many cases of hypervita-minosis A involve ingestion of a large quantity at one time by young children, who, along with the elderly, are more susceptible to toxicity.1,2 Acute toxicity is thought to occur when, within a short period of time, adults ingest more than 100 times the recommended daily allowance (RDA) and children ingest more than 20 times the RDA. However, in addition to acute toxicity, chronic intakes of high-dose vitamin A have also been associated with harm.3 The most recognized among these is an adverse effect on bone, with observational studies suggesting an increased risk of osteoporosis and fracture. Unfortunately, assessment of vitamin A toxicity is limited by the lack of sensitive laboratory markers.
虽然维生素A缺乏症比维生素A毒性更严重,特别是在发展中国家,临床和亚临床毒性都与过量摄入预先形成的维生素A有关。许多维生素A摄入过多的病例一次摄入大量维生素A幼儿与老年人一起更容易发生毒性。1,2一般认为,成年人摄入建议每日摄入量(RDA)100倍以上,和儿童摄入每日摄入量RDA20倍以上,会产生急性毒性。 然而,除了急性毒性之外,长期摄入大剂量维生素A也与伤害有关。3 其中最受认可的是对骨骼的不良影响,观察性研究表明骨质疏松症和骨折的风险增加。 不幸的是,由于缺乏敏感的实验室标记,维生素A毒性的评估受到限制。
Adverse reactions to acute toxicity in children can occur with intakes as low as 1500 international units per kilogram daily (IU/kg/day),4 and they are usually tran-sient. Symptoms of acute hypervitaminosis A in children given 100,000 to 300,000 IU include diarrhea, headache (possibly resulting from elevated intracranial pres-sure), nausea, vomiting, occasional dizziness, and fever as well as a transient bulging of the fontanelle in infants. In adults, symptoms of toxicity may also include blurred vision and lack of muscular coordination.5 Chronic vitamin A excesses can precipi-tate alopecia, arthralgias, anemia, erythema, skin peeling, thickened epithelium, and fatty liver as well as heart, kidney, and testicular defects and hypercholesterol-emia. Other less commonly reported symptoms include dysphagia due to vertebral hyperostosis, and intrahepatic cholestasis.6 Interestingly, in a small number of case reports of dysphagia, none of the patients reported vitamin A supplementation despite high serum retinol levels, suggesting an impairment of vitamin A metabo-lism rather than excessive intake.7 Usually most of the untoward effects of excess vitamin A intake are resolved with cessation of its use.
儿童急性毒性的不良反应可能发生在每日每公斤摄入量低至1500国际单位(IU / kg /天)的情况下4并且通常是短暂的。 急性维生素A摄入过多的症状是,在给予100,000300,000 IU情况下,儿童症状包括腹泻,头痛(可能由颅内压升高引起),恶心,呕吐,偶尔出现头晕,发烧以及婴儿囟门短暂隆起。 在成人中,毒性症状还可能包括视力模糊和缺乏肌肉协调。5慢性维生素A过量可导致脱发,关节痛,贫血,红斑,皮 肤脱落,上皮增厚,脂肪肝以及心脏,肾脏,和睾丸缺陷和高胆固醇血症。 其他不太常见的症状包括由椎体骨肥厚引起的吞咽困难和肝内胆汁淤积。6有趣的是, 在少数病例报告的吞咽困难中,尽管血清视黄醇水平高,但没有患者报告补充维生素A,这表明这是由于维生素A新陈代谢受损而非摄入过量,通常情况下,过量摄入维生素A的不良影响会在停止使用后得到解决。
Of all the reported adverse effects, bone abnormalities have received the most attention, with excessive intake of vitamin A suggested to have a lasting detrimental effect on bone by inducing osteoporosis.8,9 However, the data are mixed and may be confounded by other variables, particularly vitamin D status.
One 9.5-year study involving almost 35,000 postmenopausal women with hip and other fractures found little evidence of an increased risk of fracture with higher intakes of vitamin A or retinol. There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements. Furthermore, the results showed no association between vitamin A ingestion from food and supplements or food only and the risk of fractures of any kind.10 Similar results were published in the American Jour-nal of Clinical Nutrition in 2009. This was a large observational study that included over 75,000 participants from the Womens Health Initiative. Retinol and vitamin A intake were not signifi-cantly associated with either hip or total fracture incidence among postmenopausal women. However, women in the highest quintile of retinol and vitamin A intake who also had a low intake of vita-min D did have a modest (15%-20%) increased total fracture risk.11 A smaller study that enrolled Spanish postmenopausal women did find an independent risk for osteoporosis among those with the highest intake, but this risk was magnified when com-bined with low vitamin D levels.12 The interaction between high vitamin A and low vitamin D levels appears biologically plausible, as vitamin A may antagonize some of vitamin Ds actions,including calcium absorption.13 This may be relevant not only to bone health but possibly to susceptibility to respiratory infection as well.14 A 2007 review of the bone effects of vitamin A con-cluded that the poor sensitivity of laboratory markers and assess-ment of dietary intake may contribute to the conflicting findings; it suggested that future studies incorporate superior analytic techniques, specifically stable-isotope-dilution methodology.15 Although serum retinol is often employed to screen for vitamin A toxicity, it is thought to have poor sensitivity because it is subject to homeostatic control over a wide range of intakes as well as hepatic concentrations, and thus does not necessarily represent liver stores.16 Additionally, many clinical factors interfere with its accuracy. One alternative is the measurement of fasting retinyl ester concentrations. When more than 5% to 10% of circulating vitamin A is in the form of retinyl esters, it may indicate either hepatic storage capacity or the capacity of the retinol-binding pro-tein has been exceeded. Unfortunately, elevated retinyl esters do not necessarily indicate impaired liver function and are not sensi-tive to subclinical toxicity.15,17
一项长达9.5年的研究涉及近35000名绝经后女性髋部骨折和其他骨折患者,但几乎没有证据表明维生素A或视黄醇的摄入增加了骨折的风险。 也没有证据表明髋部骨折风险与补充剂中维生素A或视黄醇含量的增加存在剂量-反应关系。 此外,结果显示维生素A摄入食物和补充剂或仅食物与任何类型的骨折风险之间没有关联。10类似的结果发表在2009年美国临床营养学杂志上。这是一项大型观察性研究。 其中包括来自妇女健康倡议的75,000多名参与者。 绝经后妇女的视网膜和维生素A摄入量与髋部或全部骨折发生率无显着相关性。 然而,摄入视黄醇和维生素A摄入量最高的女性,维生素D摄入量较低,确实有较低的总体骨折风险(15-20%)。 11一项针对西班牙绝经后妇女的研究较少在摄入量最高的人群中发现骨质疏松症的独立风险,但与低维生素D水平相结合时,这种风险被放大。12高维生素A和低维生素D水平之间的相互作用在 生物学上似乎是合理的,因为维生素A可能会对抗一些维生素D的 作用,包括钙的吸收。13这可能不仅与骨骼健康有关,也可能与呼吸道感染的易感性有关。142007年对维生素A骨效应的综述得出结论,实验室标志物的敏感性差,评估为膳食摄入可能导 致相互矛盾的发现; 它表明未来的研究结合了优越的分析技术,特别是稳定同位素稀释方法。15虽然血清视黄醇通常用 于筛查维生素A毒性,但它被认为具有较差的敏感性,因为 它受到稳态控制。广泛的摄入量和肝脏浓度,因此不一定代 表肝脏储存。16此外,许多临床因素会影响其准确性。 一种 替代方案是测量空腹视黄酯的浓度。 当超过5%至10%的循 环维生素A为视黄酯时,可能表明肝储存能力或视黄醇结合 蛋白的容量已被超过。 不幸的是,升高的视黄酯不一定表 明肝功能受损,对亚临床毒性不敏感。15,17
TABLE 137-1 Toxic Dosages and Side Effects of Lipid-Soluble Vitamins
Long-term: none
No apparent toxicity, even at large doses (250 mg/day); synthetic form poses a risk for heavy smokers or asbestos-exposed persons not taking other antioxidants.
Vitamin A
Infants: 75,000-300,000 IU
Adults: 2-5 million IU
Anorexia, bulging fontanelle, hyperirritability, vomiting.Headache, drowsiness, nausea, vomiting.
Infants: 18,000-60,000/day
Adults: 100,000 IU/day
Premature epiphyseal bone closing, long bone growth retardation.Anorexia, headache, blurred vision, loss of hair, bleeding lips, cracking and peeling skin, muscular stiffness and pain, severe hepatic damage and enlargement, anemia, teratogenesis.
Vitamin D
Short-term: 1000-3000 IU/kg
Anorexia, nausea, vomiting, diarrhea, headache, polyuria,polydipsia.
Long-term: >40,000 IU/day
Hypercalcemia (unlikely).高钙血症(不可能)
Vitamin E
Long-term: >800 IU/ day
Severe weakness, fatigue, exacerbation of hypertension,potentiation of anticoagulants. α-tocopherol used alone may increase disease risk.
Vitamin K
Long-term: none
Phylloquinone (K1), unlike menadione (K3), is not associated with side effects when given orally. Caution is in order with anticoagulant medications.
TABLE 137-2 Toxic Dosages and Side Effects of Water-Soluble Vitamins
Ascorbic acid抗坏血酸维生素C
Short-term: usually >10g
Nausea, diarrhea, flatulence.恶心、腹泻、胀气。
Long-term: >3 g/day
Increased urinary oxalate and uric acid levels in rare cases, impaired carotene utilization, chelation and resultant loss of minerals.
Long-term: >10 mg/ day
No reported side effects from oral administration at therapeutic doses.
Folic acid
Long-term: 15 mg/ day
Abdominal distention, anorexia, nausea, sleep disturbances
May pose increased cancer risk (see text).
Short-term: >100 mg
Transient flushing, headache, cramps, nausea, vomiting.
Long-term: 3-7 g/day
Anorexia, abnormal glucose tolerance, increased plasma
uric acid levels, gastric ulceration, liver enzyme elevations.
Niacin-amide 烟酸酰胺
Long-term: >2000 mg/day
Same as for niacin.和烟酸一样。
Pantothenic acid 泛酸
Occasional diarrhea.偶尔腹泻。
Pyridoxine 维生素B6
No acute effects have been noted at therapeutic dose.没有发现治疗剂量的急性作用。
Long-term: 300 mg/ day
Sensory and motor neuropathies.感觉和运动神经疾病。
Riboflavin 核黄素
No toxic effects have been noted. 没有注意到任何毒性效应。
No toxic effects noted for humans
after oral administration. 口服对人类没有毒性作用
Vitamin B12
No side effects from oral 口服无副作用
administration have been reported.
Although expensive and not widely available, stable isotope dilution techniques appear to correlate well with values deter-mined by liver biopsy and may emerge as the best marker of total vitamin A stores in both deficiency and toxicity. Indeed, varia-tions of this method may be used to determine the intake needed to maintain target body storage levels. In animal models they have shown 100% sensitivity for the diagnosis of hypervitamin-osis A.18,19 Although the deuterated retinol dilution method has been validated in both children and adults to give a quantitative estimate of internal stores, it needs further verification among diverse populations and greater accessibility.20 When large doses of vitamin A are being given, careful monitoring is necessary. Rather than sudden ingestion of large doses, a gradual stepwise increase in dosage is indicated, with an evaluation of symptoms made before the dosage is increased. Usually, the first symptom of hypervitaminosis to be recognized is frontal headache. If signs or symptoms appear, supplementation should be discontinued until they disappear. Levels of liver enzymes should be determined periodically to check for hepatic damage. Typically, levels of aspartate transaminase are the first to be affected.1,2,21,22 Patients whose liver function is compromised by viral hepatitis, protein-energy malnutrition, cirrhosis, or hemodialysis seem to be the most vulnerable to vitamin A toxicity and to require close moni-toring.4 Vitamin A levels during pregnancy must be carefully assessed because both deficiency and excess can bring about undesirable results. Supplementation above the RDA is not war-ranted in pregnant or potentially pregnant women. According to one large observational study published in the New England Jour-nal of Medicine, women consuming greater than 10,000 IU of vitamin A during pregnancy (specifically during the first 7 weeks after conception) had a 1 in 57 risk for having a child born with a birth defect.22a
尽管价格昂贵且无法广泛获得,但稳定同位素稀释技术似乎与通过肝活检确定的值很好地相关,并且可能在缺乏和毒性中作为总维生素A储存的最佳标记出现。 实际上,该方法的变化可用于确定维持目标体储存水平所需的摄入量。 在动物模型中,他们对超维生素A的诊断显示出100%的敏感性。18,19虽然氘代视黄醇稀释方法已在儿童和成人中得到验证,以对内部储存进行定量估计,但需要在不同人群和更大的可及性。20当给予大剂量的维生素A时,需要仔细监测。 不是突然摄入大剂量,而是指示逐渐逐步增加剂量,并在剂量增加之前评估症状。 通常,要识别的维生素过多症的第一个症状是额部头痛。 如果出现体征或症状, 应停止补充,直至消失。 应定期测定肝酶水平以检查肝脏损伤。
通常,天冬氨酸转氨酶水平首先受到影响。1,2,21,22肝功能受病毒性肝炎,蛋白质 - 能量营养不良,肝硬化或血液透析影响的患者似乎最容易受到维生素A毒性的影响,需要密切监测4必须仔细评估怀孕期间的维生素A水平,因为缺乏和过量都会导致不良后果。 在怀孕或可能怀孕的妇女中,不保证RDA以上的补充。 根据发表在“新英格兰医学杂志”上的一项大型观察性研究,在怀孕期间(特别是在受孕后的前7周内)消耗超过10,000 IU维生 素A的女性患有出生婴儿的风险为1/57缺陷。22a
It is the opinion of this author that much if not most of the problem of vitamin A toxicity, except at very high dosages, is likely due to the high prevalence of vitamin D deficiency.
Carotenoids 类胡萝卜素
Carotenoids appear to be without toxic effects at the therapeutic doses customarily used. The only effect of large dosages is an apparently benign yellowing of the skin. Although carotenoid tox-icity is limited, there is concern that some individuals have diffi-culty converting carotenoids to vitamin A and may be more prone to vitamin A deficiency.23-25
Several large, widely publicized therapeutic trials with syn-thetic beta-carotene have found that it appears to raise the risk of lung cancer in heavy smokers. It may also pose an increased risk for gastric cancer, particularly among smokers and those exposed to asbestos.26 However, several factors complicate the interpretation of these results. The significance of these trials is fully discussed in Chapter 69.
类胡萝卜素似乎在通常使用的治疗剂量下没有毒性作用。 大剂量的唯一影响是皮肤明显的良性泛黄。 虽然类胡萝卜素的毒性有限,但有人担心某些人难以将类胡萝卜素转化为维生素A,并且可能更容易出现维生素A缺乏症。23-25
几项大规模,广泛宣传的合成β-胡萝卜素治疗试验发现,它似乎会增加重度吸烟者患肺癌的风险。 它也可能增加胃癌的风险,特别是吸烟者和接触石棉的人群。26然而,有几个因素使这些结果的解释复杂化。 第69章充分讨论了这些试验的重要性。
Vitamin D 维生素D
Significant advances have been made in understanding the role and importance of vitamin D in human health. Deficiency is now known to be widespread, with suboptimal levels much more preva-lent than toxicity. The use of 25-OH vitamin D is widely accepted as a reliable biomarker, with most indicators suggesting that a level of 75 to 110 nmol/L is sufficient, although some studies indicate that even higher levels may be optimal.27,28 The upper limits of 25-OH vitamin D are not clearly established, although levels less than 250 nmol/L are considered safe.29 Therapeutic strategies should target 25-OH vitamin D levels rather than a specific supple-mental dose, as the effect of supplementation on serum levels varies
在了解维生素D在人类健康中的作用和重要性方面取得了重大进展。 现在已知缺乏是普遍存在的,其次优水平比毒性更普遍。  25-OH维生素D的使用被广泛接受作为可靠的生物标志物,大多数指标表明75 110 nmol / L的水平就足够了,尽管一些研究表明更高的水平可能是最佳的。27,2825-OH维生素D的上限没有明确规定,尽管低于250 nmol/L的水平被认为是安全的。29治疗策略应针对25-OH维生素D水平而非特定补充剂量,作为补充剂的作用。血清水平各不相同
considerably between individuals. Doses between 2000 IU and 4000 IU will bring the majority of individuals within the range of 75 to 110 nmol/L.27 Nevertheless, some will require higher dosing, and this is also a consideration for individuals with less functional vitamin D receptor polymorphisms. Doses as high as 40,000 IU per day have not been associated with toxicity.28 However, very high single doses (500,000 IU in a single annual dose) have been associated with an increased risk for fracture and falls in a temporal pattern, with the highest risk in the period after administration.30 Thus, lower doses given more frequently (i.e., more physiologically) are preferred. Despite ongoing controversy, vitamin D3 appears to be more potent and to produce greater storage than D2.31
在个人之间。  2000 IU4000 IU之间的剂量将使大多数个体在 75110 nmol / L范围内。27然而,一些人需要更高的剂量,这也是维生素D受体多态性较低的个体的考虑因素. . 每天高达 40,000 IU的剂量与毒性无关。28然而,非常高的单剂量(单次年剂量500,000 IU)与骨折风险增加和颞下降有关,给药后期间的最高风险30因此,优选更频繁地给予较低剂量(比如,生理上)。 尽管存在争议,维生素D3似乎更有效,并且比D2产生更多的储存。31
Granulomatous diseases, such as sarcoidosis, warrant special concern because these individuals are more susceptible to hyper-calcemia. Although many have low levels of 25-OH vitamin D (which appears to increase the risk for sarcoidosis), they also have elevated levels of 1,25 dihydroxyvitamin D and thus require care-ful management.32 Apparently there is overconversion of 25-OH vitamin D3 to 1,25(OH)2-vitamin D3 by macrophages in granu-lomatous disease.33
肉芽肿等肉芽肿病需要特别关注,因为这些人更容易患高钙血症。 尽管许多人的25-OH维生素D水平较低(似乎会增加结节病的风险),但他们的1,25二羟基维生素D水平也会升高,因此需 要仔细管理。32显然有25-OH的过度转化巨噬细胞在肉芽肿病中 维生素D31,25OH2 - 维生素D333
Vitamin E 维生素E.
Although for many years observational studies found vitamin E supplementation to be safe, several controlled trials have been published suggesting harm with supplementation. For example, in a large meta-analysis of randomized placebo-controlled trials in which participants were given between 50 and 800 IU natural or synthetic vitamin E per day, supplementation was found to reduce the risk of ischemic stroke by 10% but to increase the risk of hem-orrhagic stroke by 22%.34 Similarly, a meta-analysis published in the Annals of Internal Medicine found that supplementation with more than 400 IU vitamin E increased all-cause mortality.35
尽管多年来观察性研究发现维生素E补充剂是安全的,但已发表了几项对照试验,表明补充剂有害。 例如,在随机安慰剂对照试验的大型荟萃分析中,参与者每天给予50800 IU天然或合成维生素E,补充剂被发现可将缺血性卒中风险降低10%但增加出血性卒中风险增加22%。34类似地,“内科医学年鉴”发表的一 项荟萃分析发现补充超过400 IU的维生素E可增加全因死亡率。35
Although the use of synthetic versus natural vitamin E may explain some of the increase in adverse effects, the natural form of vitamin D (d-alpha tocopherol) used in many clinical trials is not without risk. For example, supplementation with natural vitamin E at 400 IU per day was associated with an increased risk of heart failure among patients with diabetes or vascular disease.36
尽管合成与天然维生素E的使用可以解释一些不良反应的增 加,但许多临床试验中使用的维生素Dd-α生育酚)的天然 形式并非没有风险。 例如,每天400 IU补充天然维生素E与 糖尿病或血管疾病患者心力衰竭的风险增加有关。36
An explanation that appears more plausible is that despite the physiologic benefits of alpha-tocopherol, high-dose supplementa-tion depletes other forms of naturally occurring vitamin E, such as beta- or gamma-tocopherol, which have greater physiologic sig-nificance. For example, in an observational study of elderly patients, higher plasma levels of beta-tocopherol were associated with a reduced risk of developing Alzheimers disease, whereas other forms of vitamin E were only marginally significant.37 The use of both gamma- and alpha-tocopherol in patients with the metabolic syndrome was shown to be superior to either used alone. Moreover, in vitro and in vivo evidence indicates that alpha-tocopherol not only failed to demonstrate anticancer properties but also blocked the anticancer effects of gamma-tocopherol.38,39 Gamma-tocopherol is actually more prevalent than the alpha form in the U.S. diet as well as in many plant seeds, although the vast majority of trials and available products use alpha-tocopherol.40 Thus, it may not be vitamin Ethat has the harmful effects men-tioned above but rather the isolated use of alpha-tocopherol. Additional factors are likely to have an influence as well, such as age and vitamin C intake.41 Genetics are also likely to play a role, as diabetic patients with the haptoglobin 2-2 genotype are more likely to receive benefit from supplementation.42 Unfortunately, most laboratory evaluations of vitamin Es toxicity are based on alpha-tocopherol plasma or serum levels and thus may not be helpful in determining toxicity.
似乎更合理的解释是,尽管α-生育酚具有生理学益处,但高剂量补充剂会消耗其他形式的天然存在的维生素E,例如β-或γ-生育酚,其具有更大的生理意义。 例如,在一项针对老年患者 的观察性研究中,血浆中β-生育酚水平升高与患阿尔茨海默病 的风险降低有关,而其他形式的维生素E仅略微显着。37使用γ-和代谢综合征患者的α-生育酚显示优于单独使用。 此外,体外 和体内证据表明,α-生育酚不仅未能显示出抗癌特性,而且还 阻断了γ-生育酚的抗癌作用。38,39γ-生育酚实际上比美国饮食 中的α形式更普遍,以及在许多植物种子中,尽管绝大多数试验 和现有产品都使用α-生育酚。40因此,它可能不是具有上述有 害作用的“维生素E”,而是α-生育酚的分离使用。 其他因素 也可能会产生影响,如年龄和维生素C摄入量。41遗传也可能发 挥作用,因为触珠蛋白2-2基因型的糖尿病患者更有可能从补充 剂中获益。 42不幸的是,大多数维生素E毒性的实验室评估是基 于α-生育酚血浆或血清水平,因此可能无助于确定毒性。
Vitamin K 维生素K
Large doses of the synthetic water-soluble vitamin K3 (menadi-one) administered to infants may cause hemolytic anemia, hyper-bilirubinemia, hepatomegaly, and possibly death. Adults with glucose-6-phosphate dehydrogenase deficiency may show hemo-lytic reactions.43 The natural vitamin K1 (phylloquinone) and the menaquinones (MK-4, MK-7) do not appear to cause toxicity when given orally unless huge doses (e.g., 200 mg) are given.44 Dr. Bruce Ames, professor of biochemistry and molecular biology, has provided compelling evidence for the triage theory; that given a suboptimal intake, vitamin K is shunted to basic functions nec-essary for survival at the expense of less essential functions, which are likely to be associated with aging and chronic disease. Given that many individuals have suboptimal vitamin K intake, supple-mentation with menaquinones has the potential to reduce the incidence of chronic disease.45
给婴儿施用大剂量的合成水溶性维生素K3(甲萘醌)可引起溶血性贫血,高胆红素血症,肝肿大,并可能导致死亡。 葡萄糖-6-磷酸脱氢酶缺乏症患者可能出现溶血反应。43天然维生素K1(叶 绿醌)和甲基萘醌类(MK-4MK-7)口服时似乎不会引起毒性, 除非巨大给予剂量(例如,200毫克)。44生物化学和分子生物 学教授Bruce Ames博士为分类理论提供了令人信服的证据; 如果 摄入量不理想,维生素K会被分流到生存所必需的基本功能,而 这些基本功能会以不太重要的功能为代价,这些功能可能与衰老 和慢性疾病有关。 鉴于许多人的维生素K摄入量不理想,补充甲基萘醌有可能降低慢性病的发病率。45
All forms of vitamin K can interfere with some anticoagulant medications, such as warfarin (Coumadin) and should be used with caution. Given that the menaquinones may have greater potency than vitamin K1, an upper limit of 50 mcg/day (MK-7) has been proposed for those patients on anticoagulant therapy.46 However, the longer half-life of MK-7 (compared with other forms of vitamin K) may help to maintain a more stable interna-tional normalized ratio while also protecting these patients from the arterial calcification and osteoporosis for which they are at increased risk.47
所有形式的维生素K都会干扰某些抗凝药物,如华法林(香豆 素),应谨慎使用。 鉴于甲基萘醌可能具有比维生素K1更大的 效力,已经提出对抗凝治疗患者的上限为50 mcg /天(MK-7)。 46然而,MK-7的半衰期更长(与其他形式的维生素K相比,可以帮助维持更稳定的国际标准化比率,同时保护这些患者免受动脉 钙化和骨质疏松症的危害。47
Water-Soluble Vitamins 水溶性维生素
Ascorbic Acid 抗坏血酸
Vitamin C has been reported to have perhaps the lowest toxicity of all vitamins. Diarrhea and intestinal distention or gas are the most common complaints when it is consumed at higher dosages. It has been shown that high doses of vitamin C
据报道,维生素C可能是所有维生素中毒性最低的。 当以较高剂 、量食用时,腹泻和肠道扩张或气体是最常见的主诉。 已经证明高剂量的维生素C.
Increase the urinary excretion of calcium, iron, and manganese
Increase the absorption of iron
Raise urinary oxalate or uric acid levels, but only in a small sub-
group of the population (This may vary with the form of vita-min C, as ester-C has been shown to reduce oxalate levels in a crossover study.48)
Alter many routine laboratory parameters (e.g., serum vitamin B12, aminotransferases, bilirubin, glucose, stool occult blood)
Cause nausea, edema, and dry mouth or skin when used intra-venously, all considered minor49
• 增加钙,铁和锰的尿排泄
• 增加铁的吸收
• 提高尿草酸盐或尿酸水平,但仅限于人群的一小部分(这可能因维生素C的形式而异,因为在交叉研究中酯-C已被证明可降低草酸盐水平。48
• 改变许多常规实验室参数(例如血清维生素B12,氨基转移酶, 胆红素,葡萄糖,粪便隐血)
• 静脉注射时会引起恶心,水肿,口干或皮肤干燥,均为轻微49
The clinician must take these effects into consideration when supplementing with megadoses of vitamin C. Also, the ability of oral vitamin C to increase plasma levels is limited, with intravenous administration of vitamin C having been shown to raise levels 70-fold higher.50 Even at the high plasma levels documented with intravenous therapy, toxicity does not appear to be a significant concern.
One concern with high dosages of vitamin C often cited in the medical literature is the development of calcium oxalate kidney stones. As mentioned above, various forms of ascorbic acid may negate this effect, as demonstrated with ester-C versus ascorbic acid. Additionally, in  vitro oxidation of ascorbic acid to oxalic acid during storage or analysis is thought to be a common con-founder in these studies. Nonetheless, 500 mg/day may be a rea-sonable limit for those prone to stone formation.51 With regard to intravenous administration of vitamin C, less than 0.5% of a 100-g dose was converted to oxalic acid in individuals with nor-mal renal function, much less than might be expected from such a large dose.52
医学文献中经常引用的高剂量维生素C的一个问题是草酸钙肾结石的发展。 如上所述,各种形式的抗坏血酸可以抵消这种作用,如酯-C与抗坏血酸所证明的。 另外,在储存或分析期间将抗坏血酸体外氧化成草酸被认为是这些研究中常见的混淆因素。 尽管如此,对于那些容易结石形成的人来说,500毫克/天可能是 一个合理的限制。51关于静脉注射维生素C,在正常肾脏的个体 中,少于0.5%的100克剂量被转化为草酸。功能,远远低于如此大剂量的预期功能。52
A second, more theoretical concern about vitamin C relates to its excess use in progressive inflammatory diseases such as rheuma-toid arthritis and Crohns disease. It is theorized that available sur-plus vitamin C may interact with metal ions, eliciting a prooxidant consequence.53 Alternatively, more recent data suggest that vita-min C may chelate metal ions, actually reducing their ability to generate reactive oxygen species, and animal models suggest that megadosing may reduce inflammation.54,55 Although no clinical information is available to clarify this concern, it may be prudent to consider limiting the megadosing of vitamin C in patients with unresponsive or worsening chronic inflammatory conditions and to be cautious about giving large doses of vitamin C to patients with known conditions of iron or copper excess. This may also be relevant to the dietary intake of iron. For example, high dietary heme intake among women taking more than 500 mg vitamin C per day was found to increase the risk of lung cancer, whereas high zinc intake reduced the risk.56
关于维生素C的第二个更理论上的关注涉及其过量用于进行性 炎性疾病,例如类风湿性关节炎和克罗恩病。 理论上认为,可 用的过剩维生素C可能与金属离子相互作用,引起促氧化后果。 53另外,最近的数据表明维生素C可能螯合金属离子,实际上降低了它们产生活性氧的能力,动物模型表明大剂量可以减轻炎症。 54,55尽管没有临床信息可用于澄清这种担忧,但考虑限制慢性炎症状态无反应或恶化的患者的维生素C的大剂量可能是谨慎的, 并且对于给予大剂量的剂量要谨慎。维生素C给已知铁或铜过量 的患者。 这也可能与铁的膳食摄入量有关。 例如,发现每天服 用超过500毫克维生素C的女性摄入高血糖会增加患肺癌的风险, 而高锌摄入可降低患病风险。56
There have been reports that abrupt cessation of high-dose vitamin C intake leads to rebound scurvy, which has also been reported to occur after birth in the babies of pregnant women who have been taking high doses. However, other studies do not support the existence of rebound scurvy under these conditions. Although some experts question the existence of rebound scurvy, it is better to err on the side of caution. At this time a safe rec-ommendation to pregnant women would be a daily dosage of 500 mg vitamin C.
有报道称,大剂量维生素C摄入量的突然停止会导致“坏血 病反弹”,据报道,在服用高剂量孕妇的婴儿出生后也会出现 这种情况。 然而,其他研究并不支持在这些条件下存在反跳 坏血病。 虽然有些专家质疑反跳坏血病的存在,但最好还是 谨慎行事。 此时,对孕妇的安全建议是每日服用500毫克维生素C.
Folic Acid 叶酸
Although generally considered safe, caution should be exercised in supplementing with folic acid in the presence of a vitamin B12 deficiency. Although folic acid will correct a macrocytosis, it will not correct the underlying neurologic degeneration caused by vitamin B12 deficiency. Additionally, high folic acid levels appear to accentuate the toxicity of low vitamin B12.57,58
尽管通常认为是安全的,但在维生素B12缺乏的情况下,应该谨慎补充叶酸。 虽然叶酸可以纠正大红细胞症,但它不能纠正由维生素B12 缺乏引起的潜在神经变性。 此外,高叶酸水平似乎加重了低维生素B12的毒性
High-dose folic acid (15 mg/day) has been used without adverse effects in several studies. For example, when given as 5-methyltet-rahydrofolate to postmenopausal women, it significantly reduced their blood pressure and homocysteine levels and improved their insulin sensitivity.59 Folic acid given at 5 mg/day with vitamins B12 and B6 was found to reduce subclinical atherosclerosis among individuals with a fasting homocysteine level greater than 9.0 μmol/L when given over 3 years. This was a randomized placebo-controlled trial with over 500 participants, and no difference in adverse effects between groups was cited.60 A meta-analysis also found that folic acid supplementation reduced the risk of stroke in primary prevention, especially when continued for a longer period of time.61
在一些研究中使用了高剂量的叶酸(15毫克/天)而没有副作用。 例如,当给予绝经后妇女5-甲基四氢叶酸时,它显着降低了他们的 血压和同型半胱氨酸水平,并提高了他们的胰岛素敏感性。59维生素 B12B65毫克/天给予叶酸结果发现,当给予3年以上禁食同型半胱 氨酸水平大于9.0μmol/ L的个体时,可减少亚临床动脉粥样硬化。 这是一项随机的安慰剂对照试验,参与人数超过500人,并且引用组 间不良反应没有差异。60荟萃分析还发现补充叶酸可降低一级预防中风的风险,特别是持续时间较长时一段时间。61
A very important placebo-controlled randomized trial, pub-lished in 2008, found that folic acid given at 5 mg/day over 3 years reduced the recurrence of colorectal adenomas; the recurrence rate in the placebo group was twice as high as in the folic acid group. Additionally, none of the patients who received folate was found to have histologically aggressive adenomas or carcinoma at their final endoscopy.62 This study is particularly relevant because con-cerns have been raised that both low and high folate levels may increase the risk of cancer.63,64 For example, in two previous trials, folic acid given at 1 mg/day was associated with more advanced colorectal lesions as well as an increased risk of prostate cancer.65,66 It is possible that the high folic acid content of fortified foods can be a confounding variable when a low dose of 1 mg/day is used. Additionally, there is most likely a difference between synthetic folic acid and the more natural reduced and methylated forms, primarily 5-methyl tetrahydrofolate.
2008年发表的一项非常重要的安慰剂对照随机试验发现,3年 内以5 mg /天给予叶酸可减少结直肠腺瘤的复发; 安慰剂组的复 发率是叶酸组的两倍。 此外,在最终内镜检查中,没有发现接 受过叶酸的患者有组织学侵袭性腺瘤或癌。62这项研究特别相关,因为人们担心低和高叶酸水平都可能增加患癌症的风险。 63,64 例如,在之前的两项试验中,1毫克/天给予的叶酸与更晚期的结 肠直肠病变以及前列腺癌的风险增加有关。65,66有可能强化高叶 酸含量当使用1mg /天的低剂量时,食物可能是一个混杂的变量。此外,合成叶酸与更天然的还原和甲基化形式(主要是5-甲基四 氢叶酸)之间很可能存在差异。
Finally, a serum folate level greater than 45.3 nmol/L is often used to define elevated levels, but it is arbitrarily chosen because of technical difficulties in analysis rather than a functional toxicity.67
最后,通常使用大于45.3 nmol / L的血清叶酸水平来定义 升高的水平,但由于分析中的技术困难而不是功能毒性,它 是任意选择的。67
Niacin 烟酸
The acute side effects of niacin (nicotinic acid) are well known. The most common and bothersome is the skin flushing that typ-ically occurs 20 to 30 minutes after the niacin is taken. Long-term consequences of niacin therapy include gastric irritation, nausea, and liver damage. In an attempt to combat the acute reaction of skin flushing, several manufacturers began marketing sustained-release,” “timed-release,and slow-releaseniacin products. These formulations allow the niacin to be absorbed gradually, thereby reducing the flushing reaction. However, although these forms of niacin reduce skin flushing, they have actually proved to be more toxic to the liver, particularly the slow-release products. One study strongly recommended that the use of slow-release niacin be restricted because of the high per-centage (78%) of patient withdrawals from the study because of side effects; 52% of the patients taking the sustained-release nia-cin had liver damage compared with none of the patients taking immediate-release niacin.68 Extended-release (ER)niacin (Niaspan) appears to have similar toxicity as immediate-release niacin, with a 2008 review documenting that significant increases in liver enzymes with either extended- or immediate-release nia-cin are rare and that elevations leading to severe hepatotoxicity occur rarely, if at all.69
烟酸(烟酸)的急性副作用是众所周知的。 最常见和令人烦 恼的是皮肤潮红,通常在服用烟酸2030分钟后发生。 烟酸 治疗的长期后果包括胃刺激,恶心和肝损伤。 为了对抗皮肤 潮红的急性反应,一些制造商开始销售“持续释放”,“定时释 放”和“缓释”烟酸产品。 这些配方使烟酸逐渐被吸收,从而 减少潮红反应。 然而,尽管这些形式的烟酸可以减少皮肤潮 红,但事实证明它们对肝脏的毒性更大,尤其是缓释产品。 一项研究强烈建议限制使用缓释烟酸,因为由于副作用,患 者退出研究的比例很高(78%); 与不立即释放烟酸的患者 相比,服用持续释放烟酸的患者中有52%患有肝损伤。68 “延 长释放(ER)“烟酸(Niaspan)似乎具有与立即释放烟酸类 似的毒性2008年的一篇综述记录显示,延长或立即释放烟酸 的肝酶显着增加是罕见的,并且导致严重肝毒性的升高很少 发生(如果有的话)。69
Niacin has also been shown to cause a 4% to 5% increase in fasting glucose and a 20% to 28% reduction in insulin sensitivity. For this reason it should be used with caution in diabetic patients and those at risk for diabetes. However, its cardiovascular benefit often significantly outweighs the risk, even in these patients. In a recent meta-analysis published in Atherosclerosis, nicotinic acid given alone or in combination was associated with a reduction in the risk of coronary events and stroke (approximately by 75%) as well as positive effects on the evolution of atherosclerosis when used at 1 to 3 g/day. The authors of this analysis also point out that it reduces low-density-lipoprotein cholesterol to a similar degree as statin medications, and is the only effective therapy for reducing lipoprotein (a).70 When extended-release niacin was given to dia-betic patients at 1000 to 1500 mg/day, it was associated with only a 0.3% increase in hemoglobin A1c compared with placebo, with a dose-dependent improvement in levels of triglycerides and high-density-lipoprotein cholesterol. However, increases in diabetes medications may have prevented a larger increase in hemoglobin A1c.71 Given that improving high-density-lipoprotein cholesterol is a primary goal in diabetes, the use of nicotinic acid is often indicated for these patients.72
烟酸也显示空腹血糖增加4%至5%,胰岛素敏感性降低20% 至28%。 因此,糖尿病患者和有糖尿病风险的人应谨慎使用。 然而,即使在这些患者中,其心血管益处通常也远远超过风险。 在最近发表于动脉粥样硬化的荟萃分析中,单独或联合 使用的烟酸与冠状动脉事件和中风的风险降低(约75%)以 及在1时使用时对动脉粥样硬化进展的积极影响有关。至3/ 天。 该分析的作者还指出,它将低密度脂蛋白胆固醇降低至 与他汀类药物相似的程度,并且是减少脂蛋白的唯一有效疗 法(a)。70当给予糖尿病延长释放烟酸时与安慰剂相比, 10001500毫克/天的患者血红蛋白A1c仅增加0.3%,甘油三 酯和高密度脂蛋白胆固醇水平呈剂量依赖性改善。 然而,糖 尿病药物的增加可能阻止了血红蛋白A1c的更大增加。71鉴于 改善高密度脂蛋白胆固醇是糖尿病的主要目标,通常需要使 用烟酸。72
Side effects can occur with any form of niacin, including nia-cinamide. Although niacinamide does not cause the acute flushing of the skin, it can also cause liver damage and has not demon-strated the same benefit to lipid profiles as nicotinamide. Inositol hexaniacinate is an alternative form of niacin that may have very few side effects, but large, well-designed studies to document its benefit are lacking.73
任何形式的烟酸(包括烟酰胺)都可能出现副作用。 尽管 烟酰胺不会引起皮肤的急性潮红,但它也可能导致肝脏损伤,并且与烟酰胺相比,未显示出与脂质特征相同的益处。 肌醇 六亚硝酸盐是烟酸的另一种形式,可能副作用很少,但缺乏 大量,精心设计的研究证明其益处。73
TABLE 137-3 Laboratory Tests for Vitamin Toxicity 维生素毒性的实验室试验
Vitamin A
AST, serum retinol, serum free retinylesters, stable isotope dilution (preferred) AST,血清视黄醇,无血清维甲酸,稳定同位素稀释(首选)
Vitamin D
Serum calcium, 25(OH) vitamin D 血清钙,25(OH)维生素D
Niacin  烟酸
Vitamin C
Urinary oxalate and uric acid 尿草酸和尿酸
ALT, Alanine transaminase 丙氨酸转氨酶; AST, aspartate aminotransferase. 天冬氨酸氨基转移酶。
Regardless of the form of niacin being used, periodic checking (at least every 3 months) of liver function is indicated when high-dose (i.e., 2 to 6 g/day) niacin, inositol hexaniacinate, or niacina-mide therapy is being used. Niacin should be used with caution in patients with preexisting liver disease or elevation in liver enzyme values, gout, or peptic ulcers.
无论使用何种烟酸,当使用高剂量(即26/天)烟酸,肌醇六亚硝酸盐或烟酰胺治疗时,都需要定期检查(至少每3个月一次)肝功能。 对于既往存在肝病或肝酶,痛风或消化性溃疡升高的患者,应谨慎使用烟酸。
Pyridoxine 吡哆醇
Vitamin B6 is one of the few water-soluble vitamins that is associ-ated with toxicity when taken in large doses or in moderate dos-ages for long periods, and it is known to cause a transient sensory neuropathy. Large doses of vitamin B6 are currently being used for a wide variety of conditions.
维生素B6是少量水溶性维生素中的一种,当大剂量或中等剂量长 期服用时会与毒性相关,并且已知会引起短暂的感觉神经病变。 大剂量的维生素B6目前用于各种各样的病症。
Doses greater than 1000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coor-dination, and degeneration of nerve tissue) in some individuals, with ataxia being the clinical hallmark of vitamin B6 hypervita-minosis.74 Long-term intake of dosages greater than 500 mg/day can be toxic if taken daily for several months.75 There are also a few rare reports of toxicity occurring at chronic long-term dosages as low as 150 mg/day.76-78 One animal study reports the increased possibility of nerve toxicity in individuals with renal failure who have uremia, owing to decreased pyridoxine excretion, which induces an increase in susceptibility to pyridoxine-induced neu-ropathy.79 Because patients with renal failure are commonly given long-term pyridoxine therapy, caution is advised, and it is prudent to look for neuropathic signs in pyridoxine-supplemented uremic patients with renal failure.
大于1000毫克/天的剂量可以在一些个体中产生神经毒性症状(脚部刺痛感,肌肉协调性丧失和神经组织退化),共济 失调是维生素B6维生素过多症的临床标志。 TF437)长期摄入大于500毫克/天的剂量,如果每天服用几个月就会有毒。75 在慢性长期剂量低至150毫克/天的情况下,也有一些罕见的毒性报告76-78一项动物研究报告,由于吡哆醇排泄减少导致尿毒症肾功能衰竭患者神经毒性增加,导致吡哆醇诱导的神经病变易感性增加79因为肾衰竭患者是通常给予长期吡哆醇治疗,建议谨慎行事,谨慎寻找补充吡哆醇的尿毒症肾功能 衰竭患者的神经病理征。
Toxicity is thought to occur when supplemental pyridoxine overwhelms the livers ability to add a phosphate group to produce the active form of vitamin B6 (pyridoxal-5-phosphate, or PLP). As a result, it is speculated that pyridoxine is either toxic to the nerve cells or that it actually acts as an antimetabolite by binding to PLP receptors, thereby creating a relative deficiency of vitamin B6. Doses should therefore be limited to 50 mg. If more than 50 mg is desired, then the doses should be spread throughout the day or the active form (PLP) could be used.
Only a limited number of routine laboratory tests are available for detecting vitamin toxicity. These are presented in Table 137-3.
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