Vitamin Toxicities and Therapeutic Monitoring

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Chapter 137 Vitamin Toxicities and Therapeutic Monitoring

image 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.

image 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

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.

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

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