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By Susan T. Marcolina, MD
From 1982 to 1992, the prevalence of asthma in the United States increased 42%, primarily in persons younger than age 20.1 It is hypothesized that environmental oxidants and dietary antioxidant deficiencies play roles in this trend.2 Deficiencies of foods containing antioxidants in the American diet and an increased awareness of the role of antioxidants in lung defenses have prompted clinical studies of various antioxidants such as vitamin C.
A water-soluble vitamin, vitamin C or ascorbic acid is an essential micronutrient involved in many biochemical functions. Humans lack the last enzyme in its biosynthetic pathway and thus are unable to synthesize ascorbic acid. Therefore, adequate dietary intake is necessary to provide for bodily needs. Foods rich in vitamin C, primarily fruits and vegetables, are listed in Table 1.
Food sources of vitamin C
|Source (Portion Size)||Vitamin C (mg)|
|Strawberries (1 cup sliced)||95|
|Papaya (1 cup, cubes)||85|
|Kiwi (1 medium)||75|
|Orange (1 medium)||70|
|Broccoli (1/2 cup)||60|
|Cantaloupe (1/4 medium)||60|
|Kale, cooked (1 cup)||55|
|Orange juice (1/2 cup)||50|
|Adapted from: Levine M, et al. Criteria and recommendation for
vitamin C intake. JAMA 1999;281:1415-1423.
Environmental Oxidants, Vitamin C, and Asthma
The frequency of asthma and allergy symptomatology is strongly associated with increases in air pollutants such as ozone and nitrogen dioxide. The nitrogen oxides in mainstream cigarette smoke constitute the largest inhaled oxidant challenge in humans.2 In vitro studies show rapid oxidation of vitamin C upon exposure of cigarette smoke to human blood plasma containing the vitamin.3
Smokers show higher bronchial reactivity to bronchoconstrictor challenge than nonsmokers. Children of parents who smoke have increased airway responsiveness to cold air and histamine provocation.4 Active smokers and their children have higher serum IgE and peripheral eosinophil counts than nonsmokers.5 In a randomized, double-blind, study of 37 male smokers and 38 nonsmokers, Lykkesfeldt et al found that smoking significantly depleted plasma ascorbic acid levels independent of dietary intake.6
Cyclooxygenase products of arachidonic acid metabolism play a role in the pathogenesis of bronchial responsiveness. Vitamin C has been shown to shift this pathway from the synthesis of bronchoconstrictor prostaglandin F2 alpha toward the synthesis of bronchodilator prostaglandin E2.7
The presence of eosinophils in blood and bronchoalveolar lavage fluid is linked closely with airway hyperreactivity. Eosinophils, neutrophils, and alveolar macrophages from asthmatic patients produce more reactive oxygen species than those from normal subjects. These reactive oxygen species cause airway smooth muscle contraction8 and stimulate histamine release from mast cells and mucus secretion.9
Slade et al found that vitamin C appears to be the most abundant antioxidant substance in the respiratory tract lining fluids (RTLF), where it may have an important role in protecting against endogenous and exogenous oxidants.10 Despite links between vitamin C and pulmonary inflammatory mediators, studies of its efficacy in asthma have been conflicting.
Epidemiologic Findings from NHANES I, II, III
Data obtained from the National Health and Nutrition Examination Survey (NHANES) I showed that vitamin C supplementation was associated with increased FEV1 in a random sample of 2,526 adults. The difference, however, between the mean FEV1 for the lowest and the highest tertile of vitamin C intake was 40 ml, an amount not clinically significant.11,12
A cross-sectional study of 9,074 adults aged 30 years or more, NHANES II examined specific dietary factors. Low vitamin C intake correlated significantly with bronchitis and wheezing symptoms after correction for age, race, sex, and smoking status.13
A subsequent study of 19,760 survey participants in NHANES III examined the relationship between vitamin C levels and the use of health care services for respiratory symptoms while controlling for age, race, insurance, income, smoking history, previous diagnosis of asthma, chronic bronchitis, or emphysema. No relationship was found between serum vitamin C levels and the use of health care services.14
Kelley et al studied levels of vitamin C in peripheral blood and in fluids obtained from nasal lavage, bronchial wash, and bronchoalveolar lavage in 20 patients with mild asthma and in 20 healthy controls.15 The asthmatics had significantly decreased levels of ascorbate in bronchial wash and bronchoalveolar lavage fluid (P < 0.00l) compared to controls, despite the fact that the asthmatics’ plasma vitamin C concentrations were not low. This indicates that plasma measurements of ascorbate alone are not a sufficient indicator of airway antioxidant status. At present, the relationship between plasma and RTLF oxidant pools is unknown.
Clinical Trials in Asthma
Cohen et al conducted a randomized, double-blind, placebo-controlled study.16 Twenty patients with exercise-induced asthma (EIA) were randomly assigned to receive either 2 g of ascorbic acid or placebo one hour before a seven-minute treadmill exercise session. Pulmonary function testing was performed after an eight-minute rest. The procedure was repeated one week later with each patient receiving the alternative medication. This dose prevented the development of EIA in nine of the 20 patients and reduced airway responsiveness to exercise in two other patients. Four responders who continued receiving oral ascorbic acid, 500 mg/d for two more weeks experienced a protective effect, documented by results of repeated post-exercise spirometry. However, since neither plasma nor RTLF vitamin C levels were checked for each subject, it is impossible to know whether the responders were in fact vitamin C-deficient and whether this affected the results.
Schacter and Schlesinger performed a randomized, double-blind, controlled prospective study in 12 asthmatics.17 After ingestion of 500 mg of vitamin C, the immediate post-exercise peak expiratory flow rate was significantly improved. Five minutes after exercise, however, only forced vital capacity showed significant improvement compared to placebo.
In a double-blind, randomized, placebo-controlled trial of 16 nonsmoking adults with asthma, Malo et al showed that ingestion of 2 g/d of vitamin C for three days had no effect on histamine-induced bronchoconstriction.18
Recommended Daily Dosage
In 1998, after review of pharmacologic data published by the National Institutes of Health on vitamin C kinetics, the Food and Nutrition Board of the National Academy of Sciences derived new classifications for nutrient intake estimates termed Dietary Reference Intakes (DRI). One of four these reference values is the Adequate Intake or AI—the level just above the better known DRI. This current revised recommendation is 200 mg/d vitamin C from five servings of fruit and vegetables.19 The AI also can be attained with vitamin supplements.
Levine et al at the NIH performed human pharmacokinetic studies with a wide range of vitamin C daily doses administered to fasting subjects as two divided doses.19 They found that the active transport mechanism that mediates intracellular accumulation of vitamin C saturated at a plasma concentration of 66 mmol/L, which was achieved with a 200 mg/d oral dosage. Bioavailability at this dose was nearly complete. There was a substantial decrease in bioavailability with an increase in urinary excretion when doses greater than 500 mg/d were studied.
Levine found the half-life of vitamin C to be between two to four hours.20 In view of its short half-life and the saturability of intracellular transport mechanisms, vitamin C is best administered in divided doses.
Certain clinical circumstances, including smoking, infectious disease states, aging, and post-surgical status, may increase ascorbate requirements.21
Vitamin C is a labile, water-soluble micronutrient with the amount in food varying with season, shelf-time, and cooking practices.19 As a supplement, it is available in powder and tablet form in a wide range of dosages. The presence of the United States Pharmacopoeia (USP) insignia on the product label should ensure consumers of consistency and quality of vitamin content.
Adverse effects are related to dose. The most common symptoms of diarrhea and abdominal bloating occur when several grams are taken at once. Since oxalate is a product of vitamin C catabolism, daily doses greater than 1 g can predispose to oxalate renal stone formation in susceptible patients.19 Intravenous vitamin C should not be given to patients with glucose-6-phosphate dehydrogenase deficiency. Oral doses exceeding 6 g/d can precipitate hemolysis in such patients.22
High-dose vitamin C can interfere with the efficacy of anticoagulants, including warfarin and heparin.23 It increases absorption of dietary ferric iron.19 Vitamin C supplements should not be used in persons with hemochromatosis or sickle cell anemia and other conditions that predispose to iron overload. Use of oral contraceptives can lower plasma ascorbate concentrations.21
Although the studies of vitamin C for asthma prevention are short, involve small numbers of patients, and have conflicting results, the studies do suggest that it may benefit some asthmatics, particularly those under repetitive oxidant stress such as smokers or those with exercise-induced symptoms. The efficacy of vitamin C for prevention of asthma, however, cannot be predicted.
Physicians should be cognizant of the revised recommendations for adequate vitamin C intake of 200 mg/d, especially for smokers. Patients should try to obtain their vitamin C through consumption of five daily servings of fruit and vegetables or the use of 200 mg of supplemental vitamin C taken in two divided doses. Vitamin C doses in excess of 1 g/d should be avoided since adverse consequences may occur and its efficacy for asthma is controversial. However, since the studies suggest a benefit for some patients with EIA, a one-month trial of 500 mg of vitamin C administered as a twice daily divided dose may be warranted as adjunctive therapy.
Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA.
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20. Levine M, et al. Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended daily allowance. Proc Natl Acad Sci USA 1996;93:3706.
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23. Owen CA, et al. Heparin-ascorbic acid antagonism. Mayo Clin Proc 1970;45:140-145.