Chapter 137 Vitamin Toxicities and Therapeutic Monitoring
Introduction
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 “nontoxic” and 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 monitoring select vitamins.
TABLE 137-1 Toxic Dosages and Side Effects of Lipid-Soluble Vitamins
| VITAMIN | TOXIC DOSAGE | TOXIC SIGNS AND SYMPTOMS |
|---|---|---|
| Carotenoids | 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 | Short-term: | |
| Infants: 75,000-300,000 IU | Anorexia, bulging fontanelle, hyperirritability, vomiting. | |
| Adults: 2-5 million IU | Headache, drowsiness, nausea, vomiting. | |
| Long-term: | ||
| Infants: 18,000-60,000/day | Premature epiphyseal bone closing, long bone growth retardation. | |
| Adults: 100,000 IU/day | 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). | |
| 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
| VITAMIN | TOXIC DOSAGE | TOXIC SIGNS AND SYMPTOMS |
|---|---|---|
| Ascorbic acid | Short-term: usually >10g | Nausea, diarrhea, flatulence. |
| Long-term: >3 g/day | Increased urinary oxalate and uric acid levels in rare cases, impaired carotene utilization, chelation and resultant loss of minerals. | |
| Biotin | 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). |
| Niacin | 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. | |
| Niacinamide | Long-term: >2000 mg/day | Same as for niacin. |
| Pantothenic acid | Long-term | Occasional diarrhea. |
| Pyridoxine | Short-term | No acute effects have been noted at therapeutic dose. |
| Long-term: 300 mg/day | Sensory and motor neuropathies. | |
| Riboflavin | Long-term | No toxic effects have been noted. |
| Thiamine | Long-term | No toxic effects noted for humans after oral administration. |
| Vitamin B12 | Long-term | No side effects from oral administration have been reported. |
Vitamin Toxicity
Lipid-Soluble Vitamins
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 hypervitaminosis 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.
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 transient. Symptoms of acute hypervitaminosis A in children given 100,000 to 300,000 IU include diarrhea, headache (possibly resulting from elevated intracranial pressure), 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 precipitate alopecia, arthralgias, anemia, erythema, skin peeling, thickened epithelium, and fatty liver as well as heart, kidney, and testicular defects and hypercholesterolemia. 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 metabolism rather than excessive intake.7 Usually most of the untoward effects of excess vitamin A intake are resolved with cessation of its use.
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 Journal of Clinical Nutrition in 2009. This was a large observational study that included over 75,000 participants from the Women’s Health Initiative. Retinol and vitamin A intake were not significantly 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 vitamin 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 combined 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 D’s 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 concluded that the poor sensitivity of laboratory markers and assessment 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 protein has been exceeded. Unfortunately, elevated retinyl esters do not necessarily indicate impaired liver function and are not sensitive to subclinical toxicity.15,17
Although expensive and not widely available, stable isotope dilution techniques appear to correlate well with values determined by liver biopsy and may emerge as the best marker of total vitamin A stores in both deficiency and toxicity. Indeed, variations 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 hypervitaminosis 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 monitoring.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 warranted in pregnant or potentially pregnant women. According to one large observational study published in the New England Journal 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
Carotenoids
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 toxicity is limited, there is concern that some individuals have difficulty converting carotenoids to vitamin A and may be more prone to vitamin A deficiency.23–25
Several large, widely publicized therapeutic trials with synthetic 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.
Vitamin 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 prevalent 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 supplemental dose, as the effect of supplementation on serum levels varies 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
Granulomatous diseases, such as sarcoidosis, warrant special concern because these individuals are more susceptible to hypercalcemia. 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 careful management.32 Apparently there is overconversion of 25-OH vitamin D3 to 1,25(OH)2-vitamin D3 by macrophages in granulomatous disease.33
Vitamin 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 hemorrhagic 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
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
An explanation that appears more plausible is that despite the physiologic benefits of alpha-tocopherol, high-dose supplementation depletes other forms of naturally occurring vitamin E, such as beta- or gamma-tocopherol, which have greater physiologic significance. For example, in an observational study of elderly patients, higher plasma levels of beta-tocopherol were associated with a reduced risk of developing Alzheimer’s 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 E” that has the harmful effects mentioned 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 E’s toxicity are based on alpha-tocopherol plasma or serum levels and thus may not be helpful in determining toxicity.
Vitamin K
Large doses of the synthetic water-soluble vitamin K3 (menadione) administered to infants may cause hemolytic anemia, hyperbilirubinemia, hepatomegaly, and possibly death. Adults with glucose-6-phosphate dehydrogenase deficiency may show hemolytic 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 necessary 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, supplementation with menaquinones has the potential to reduce the incidence of chronic disease.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 international normalized ratio while also protecting these patients from the arterial calcification and osteoporosis for which they are at increased risk.47
Water-Soluble Vitamins
Ascorbic Acid
• 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 subgroup of the population (This may vary with the form of vitamin 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 intravenously, all considered minor49
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 confounder in these studies. Nonetheless, 500 mg/day may be a reasonable 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 normal renal function, much less than might be expected from such a large dose.52
A second, more theoretical concern about vitamin C relates to its excess use in progressive inflammatory diseases such as rheumatoid arthritis and Crohn’s disease. It is theorized that available surplus vitamin C may interact with metal ions, eliciting a prooxidant consequence.53 Alternatively, more recent data suggest that vitamin 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
Folic Acid
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
High-dose folic acid (15 mg/day) has been used without adverse effects in several studies. For example, when given as 5-methyltetrahydrofolate 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
A very important placebo-controlled randomized trial, published 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 concerns 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.
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
Niacin
The acute side effects of niacin (nicotinic acid) are well known. The most common and bothersome is the skin flushing that typically 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-release” niacin 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 percentage (78%) of patient withdrawals from the study because of side effects; 52% of the patients taking the sustained-release niacin 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 niacin are rare and that elevations leading to severe hepatotoxicity occur rarely, if at all.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 diabetic 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
Side effects can occur with any form of niacin, including niacinamide. Although niacinamide does not cause the acute flushing of the skin, it can also cause liver damage and has not demonstrated 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
Pyridoxine
Doses greater than 1000 mg/day can produce symptoms of nerve toxicity (tingling sensations in the feet, loss of muscle coordination, and degeneration of nerve tissue) in some individuals, with ataxia being the clinical hallmark of vitamin B6 hypervitaminosis.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 neuropathy.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.
Laboratory Tests for Vitamin Toxicity
Only a limited number of routine laboratory tests are available for detecting vitamin toxicity. These are presented in Table 137-3.
| VITAMIN | LABORATORY MEASUREMENT |
|---|---|
| Vitamin A | AST, serum retinol, serum free retinyl esters, stable isotope dilution (preferred) |
| Vitamin D | Serum calcium, 25(OH) vitamin D |
| Niacin | AST, ALT |
| Vitamin C | Urinary oxalate and uric acid |
ALT, Alanine transaminase; AST, aspartate aminotransferase.
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