Vitamin C adalah mikronutrien esensial yang tidak dapat disintesis oleh manusia. Vitamin C dibutuhkan untuk biosintesis kolagen yang dibutuhkan untuk membentuk jaringan konektif/penghubung dan meningkatkan absorpsi zat besi (Fe). Selain itu, ia adalah antioksidan dan banyak studi yang dilakukan terus-menerus untuk mempelajari manfaat vitamin C. Vitamin C sering dipromosikan sebagai pencegah dan penanganan flu. Vitamin C defisiensi berakibat sariawan, suatu penyakit dengan konsekuensi parah yang bila dibiarkan tak tertangani dapat menyebabkan kematian.
Beruntung, banyak orang di negara maju memenuhi asupan harianvitamin C yang dipersyaratkan karenatersedianya diet sumber vitamin C. Kriteria dan rekomendasi vitamin C direvisi pada tahun 2000 dikarenakan beberapa studi yang terbit setelah ditetapkannya Recommended Dietary Allowance (RDA) atau Rekomendasi Asupan.
-berikutnya tertulis dalam bahasa Inggris mengingat sempitnya waktu penerjemah 🙂
VITAMIN C: THE METABOLIC PROCESS
Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that cannot be synthesized by humans because we lack the enzyme gulonolactone oxidase.1 Ascorbic acid acts as a reducing agent by being an electron donor to 8 human enzymes, including those enzymes that assist in synthesizing collagen, carnitine, norepinephrine, peptide hormone, and tyrosine metabolism.2 Additionally, ascorbic acid is a chemical reducing agent, also known as an antioxidant, and thereby decreases oxidative DNA and/or protein damage, low-density lipoprotein (LDL) oxidation, lipid peroxidation, oxidants and nitrosamines in gastric juice, and extracelluar oxidants from neutrophils. It also increases endothelium-dependent vasodilation.
There are a few examples of how vitamin C may provide protection benefits by acting as an antioxidant. By decreasing low-density lipoprotein (LDL) oxidation, vitamin C interferes with LDL’s structural modification, which leads to atherogenesis in vitro; unfortunately, in vivo effects are not as consistent.2 Therefore, although vitamin C does have a correlation with impacting LDL at the molecular level, there is not any consistent evidence to suggest that it can be used as a lipid-lowering agent. Additionally, epidemiologic studies have observed a link between high vitamin C dietary intakes and decreased gastric cancer; however, there is no firm evidence that can ascertain which component of the food that contains vitamin C is linked to the protection. Ascorbic acid is also a chemical reductant that may increase iron absorption in the gastrointestinal tract by 1.5- to 10-fold. Meals that include 25 to 50 mcg of ascorbate may double iron absorption.2
The body stores approximately 1.5 g of ascorbic acid; the highest levels are found in the brain, pituitary and adrenal glands, leukocytes, and eye tissues. The pharmacokinetics of vitamin C is dependent upon its route of administration. It is available orally, both in foods and as an oral supplement, as well as by intramuscular, subcutaneous, and intravenous injection.
The bioavailability of vitamin C in foods is approximately 70% to 90%; the range is due to the degradation that occurs secondary to cooking or the interaction with preservatives such as sodium bicarbonate. Higher plasma concentrations are possible with the intravenous routes due to the lack of tolerability of oral vitamin C at higher doses. Additionally, in doses more than 1 g/day or in patients with gastrointestinal disease, absorption decreases to less than 50%. Ascorbic acid is reversibly oxidized to dehydroascorbic acid or excreted in the urine, either (1) after being metabolized to inactive metabolites or (2) unchanged with higher intake.3
HOW ARE REFERENCE VALUES DETERMINED?
The National Academy of Sciences created the Institute of Medicine (IOM) to serve as an advisor to the federal government and to identify pertinent issues, including disease prevention, in medical care, research, and education. The Food and Nutrition Board (FNB) is a multidisciplinary group of experts, established in 1940, to provide recommendations and guidelines for adequate nutrition. It is a unit of the IOM and it focuses on nutritional deficiencies as well as excesses or imbalances in food components to improve public health.4
The FNB in conjunction with other experts determines the Dietary Reference Intakes (DRIs). The DRIs, reference values for estimated proper nutrient intake in healthy people, includes the following values: RDA, Adequate Intake (AI), the Tolerable Upper Intake Level (UL), and the Estimated Average Requirement (EAR). The RDA is defined as the reference value that meets most (97%-98%) of healthy individuals’ sufficient dietary intake level and is specified by gender and age. The AI is used when the RDA cannot be determined and is defined as an approximate reference value of adequate dietary intake determined by observation or experimentation. The highest value at which most individuals do not experience an adverse effect is the UL; risks of adverse effects increase with intake above this level. The EAR is the average amount of nutrient required in a certain age group so that 50% of that group will have their dietary needs met.1
The reference values were last determined in 2000; prior to that, recommendations were issued in 1989. The reason for the evaluation of prior recommendations was the availability of new clinical, epidemiologic, molecular, and biochemical data. The RDA for vitamin C differs among gender, age, and smoking status, as noted in Table 1. In regard to gender, studies have found that the serum ascorbate level is higher in women of the same population, which may be in part because of the larger body and muscle mass of men as well as hormonal or metabolic differences among men and women. Therefore, adult men require a higher dietary intake of vitamin C versus adult women.1
The RDA for infants is determined by the AI, defined as the average vitamin C intake of infants fed primarily with breast milk from the age of 0 to 6 months and the average intake of vitamin C from breast milk and solid foods for infants 7 to 12 months. For children and adolescents, the RDA is estimated by relative body weight. Evaluative studies were completed to determine if there should be a difference in the RDA for adults aged 19 to 30 years, 31 to 50 years, and older than 51 years.
Because the absorption or metabolism of ascorbic acid did not change in these various age groups, the RDA recommendations are the same for adults older than 18 years; RDAs are adjusted based on gender, smoking status, and pregnancy, however. Hemodilution and active transport to the fetus decreases the plasma vitamin C level during pregnancy and, therefore, the RDA is higher at this time. Additionally, if a woman continues to abuse drugs or smoke cigarettes during pregnancy, she should be advised to further increase her vitamin C intake.
Similarly, any adult who smokes has a higher RDA, because smokers have a higher vitamin C turnover in their plasma, possibly because of substances found in the cigarette that cause increased oxidative stress. Although the RDA has not been adjusted for people who are exposed to secondhand smoke, because of the exposures to the dangerous substances in cigarettes that secondhand smokers experience, it is recommended that they fully meet the RDA.1
BENEFITS OF VITAMIN C
Inverse relationships between dietary vitamin C and certain cancers, as well as lower levels of vitamin C in patients with cancer, have been noted in case control studies. Considering vitamin C’s antioxidant properties, it has also been studied prospectively to evaluate its effectiveness. Most studies have found that there is little evidence to support that the incidence of cancer is decreased with additional vitamin C supplementation at modest doses.
Additionally, research has been conducted to see the effect of both oral and intravenous vitamin C on cancer mortality. One study concluded that oral vitamin C did not show a difference in patients when compared with placebo; however, newer data suggest that because intravenous vitamin C can produce higher plasma levels than oral vitamin C due to saturation issues, it is possible that dosage form may play a role. Patients need to discuss vitamin C supplementation, especially at higher doses, with their oncologists, due to potential interactions with chemotherapy and radiation.1,5
Cardiovascular Benefits? The use of vitamin C supplementation (and/or vitamin E) at 500 mg daily to decrease cardiovascular events in 14,641 male physicians 50 years or older was evaluated in the Physician’s Health Study II Randomized Control Trial (PHS II). The study found no statistically significant difference between the study and placebo groups in preventing cardiovascular or adverse events. PHS II authors concluded that although this study did not show beneficial effects of vitamin C on cardiovascular events, consideration should be made to study vitamin C at varying doses among other populations.6
Prevention of Preeclampsia? Antioxidants such as vitamin C inhibit perioxidation reactions so cellular integrity is maintained during pregnancy, and there is evidence that shows women who have preeclampsia have lower levels of vitamin C. In one study that gave vitamin C to 283 women at risk of preeclampsia, a 17% versus 8% decrease in preeclampsia was noted. In another study of 109 women, no difference was noted. Finally, a multicenter study of 1877 women, the Australian Collaborative Trial of Supplements, evaluated the effect of the supplementation of vitamin C 1000 mg (and vitamin E 400 IU) in women pregnant with their first child. Of note, the dietary intake was higher than the RDA in most of the women enrolled in the study. The authors concluded that daily supplementation did not decrease the risk of preeclampsia.7
Protection Against Cataracts? An 8-year, multicenter prospective study was conducted in 1980 evaluating the relationship between vitamins C and E, carotene, and riboflavin and cataract extraction. This study included 50,828 registered female nurses aged 45 to 67 years. The conclusion in regard to vitamin C was that supplementation with vitamin C for at least 10 years may decrease the risk of severe cataracts requiring extraction. There is a high concentration of vitamin C found in the ocular tissues, suggesting a connection between the oxidative destruction to the eye and the use of vitamin C.8 Even though the aforementioned study did show a benefit, however, there is no strong recommendation about the use of vitamin C supplementation in preventing extractions due to cataracts.1
CASE: “THIS 1000-MG VITAMIN C TABLET’S GOING TO KEEP ANY COLD AWAY!”
JJ, a 52-year-old man, wants to buy vitamin C 1000 mg because he saw an advertisement in the paper stating these megadoses will keep him from getting a cold this year. His past medical history includes hypertension. What would you advise him?
Answer: Although there is marketing for a vast number of products containing megadoses of vitamin C, there is no strong evidence that it does truly prevent colds, and so it is generally not recommended to take high doses. Recommend that JJ practice good hand washing hygiene as much as possible and avoid close contact with individuals who have a cold. Also, remind him that exercise has been shown to provide beneficial effects on the immune system. Additionally, because the common cold and influenza virus share some of the same symptoms, encourage him to get a flu shot this year.
Explanation: Vitamin C is an essential vitamin that people need to obtain either through dietary means or supplements, and data have shown that it may improve immune function. Various studies have concluded opposing results, however; some studies show a decrease in infections as well as an impact on the common cold from vitamin C supplementation, whereas others show no difference. The studies conducted in respect to the common cold have shown that megadoses of vitamin may decrease the severity and duration of illness in some groups of people; however, other studies concluded that there is no significant treatment effect of high-dose vitamin C. Therefore, there is no strong evidence that supports using vitamin C as a prevention or treatment for infections and the common cold.1
In 2007, the Cochrane Database of Systematic Reviews published a review of 30 trials involving 11,350 participants evaluating the literature about the role of vitamin C in the prevention and treatment of the common cold. Only studies that involved oral daily doses of at least 0.2 g and had a placebo group were included in this review. There was a difference found in people who were exposed short-term, intense exercise or a cold environment, however. The authors concluded that there were no significant differences when compared with placebo in cold prevention, severity, and duration in the “normal” population, and therefore preventive megadoses of vitamin C should not be recommended to the general population.9
INDICATIONS OF VITAMIN C
Considering that vitamin C is a nutraceutical and that these agents do not always have strong scientific data to support various indications, there are only 2 FDA-approved indications for vitamin C: the treatment of scurvy and nutritional supplementation. Vitamin C is also used in patients for the treatment of burns, furunculosis, iron toxicity, and methemoglobinemia, as well as for urinary acidification (Table 2).3
VITAMIN C DEFICIENCY AND INADEQUACY
Vitamin C deficiency, defined as an intake of less than 10 mg/day, leads to scurvy, a disease that was found in sailors who were on long voyages during the 15th to 18th centuries. Scurvy is rare in developed countries due to the availability of foods that are enriched with vitamins.5 However, despite the availability of vitamin C–containing foods and vitamin supplements, the National Health and Nutrition Examination Study reported that 10% to 14% of adults in the United States are deficient in vitamin C. Taking this into consideration, a differential diagnosis of scurvy should be taken into account in patients who present with symptoms consistent with scurvy and who report a dietary history with nutritional deficiencies.10
Scurvy, which can lead to syncope and sudden death, may occur over time and is dependent on the amount of vitamin C stored in one’s body. Initial signs and symptoms, including fatigue and malaise, usually appear within 1 month of vitamin C deficiency with body stores less than 300 mg. Cutaneous findings, such as petechiae, ecchymoses, purpura, poor wound healing, hyperkeratosis, and corkscrew hairs (bent or coiled body hairs) occur due to decreased collagen synthesis and weak connective tissues. Additionally, joint pain and back pain may be present.11 If an individual has teeth, inflammation and bleeding in the gums may occur as well as the loosening/loss of teeth. Also, hematologic blood work may show iron deficiency anemia and leukopenia.10,11
Vitamin C inadequacy, defined as an intake more than 10 mg/day but below the RDA, is more common than vitamin C deficiency in developed countries. The following populations are at greatest risk of vitamin C inadequacy: smokers/ passive smokers, infants fed with evaporated/ boiled milk, individuals with limited food variety and those with malabsorption, cachexia, or cancer disorders.5,12 Additionally, individuals that are attempting to lose weight by following diets that limit eating carbohydrates, fruits, and vegetables may also be at risk of vitamin C deficiency.
During the NHANES II study, it was found that smokers had decreased vitamin C intake overall and that the lowest intake was in people who smoked 20 cigarettes or more per day. Another study then took into account the decreased preference for dietary vitamin C intake in smokers, and discovered that even when the dietary intake was adjusted, smokers still had lower vitamin C serum levels. Based in part on the findings of these studies, the RDA for smokers is 35 mg more than other adults. Additionally, people exposed to secondhand smoke may also have vitamin C inadequacy; however, there is no adjustment in RDA specified for this group.5
In developed countries, the practice of boiling milk for infants is not as common as feeding them breast milk or formula. Boiling cow’s milk is not recommended, because heat may destroy the little vitamin C that is present. Additionally, most people are able to obtain the RDA for vitamin C through fruits, vegetables, and other foods; however, there are some people who have limited resources. At highest risk of vitamin C inadequacy are the elderly, indigent, alcohol- or drug-abusing, and mentally ill populations. Vitamin C inadequacy may also occur due to pathologic conditions, such as intestinal malabsorption, end-stage renal disease, or cancer. These conditions may hinder the body’s ability to absorb vitamin C.5
VITAMIN C: ADVERSE EFFECTS AND TOXICITY
The UL of vitamin C is 2000 mg, and the most common adverse effects above the UL are gastrointestinal disturbances, including diarrhea, nausea, and abdominal cramps. Generally, adverse effects are mild; however, people should keep their intake below the UL.
There are some data that link higher vitamin C doses with increased oxalate excretion and kidney stone formation, including a study that included 51,529 male health professionals aged 40 to 75 years who provided full dietary information every 4 years, unless a kidney stone occurred. This study did show an association between high vitamin C dietary intake and the increased risk of kidney stones; however, because much of the food with high vitamin C also had high potassium levels, they concluded that there is no strong data that support decreasing dietary vitamin C for the prevention of stones.13
Additionally, increased iron absorption leading to iron overload is a possibility with high levels of vitamin C intake; however, data suggest that although this could be an issue in people with blood disorders, it does not increase iron stores in healthy individuals. Therefore, because the studies did not show conclusive evidence of adverse effects of vitamin C in the aforementioned areas, the UL was based on the occurrence of diarrhea and gastrointestinal disturbances.1
VITAMIN C SOURCES
Vitamin C is naturally found in foods, the best sources being fruits and vegetables (Table 3). Other foods, such as cereals, may be fortified with vitamin C. Additionally, dietary supplements also contain vitamin C and the bioavailability is equivalent to that of the naturally occurring kind. For infants and toddlers, vitamin C is also found in breast milk.
Foods that contain the most vitamin C are generally raw fruits and vegetables, with peppers and citrus fruits having the highest amounts. Heat generally destroys ascorbic acid, because it is water-soluble, and therefore cooking, boiling, or prolonged storage lessens the vitamin C content. Although consuming the foods raw keeps it most intact, steaming or microwaving does preserve more vitamin C than other methods of cooking.
VITAMIN C SUPPLEMENTS
As mentioned before, there is no difference in bioavailability with oral vitamin C intake, whether from natural sources or from supplements. There are many vitamin C supplements readily available, and this section will discuss some important considerations when making recommendations to your patients.
Because vitamin C supplements fall under the dietary supplement category, manufacturers do not need FDA approval prior to manufacture, and are therefore responsible for the safety and efficacy of their products.14 Additionally, makers of supplements are not allowed to make disease state claims; however, they are allowed to make structure/function claims. Oftentimes, claims are made that may lead patients to think something that is not completely true. Considering the various amount of dietary supplements that are available and the numerous manufacturers that make each supplement, it is vital that the pharmacist be able to counsel the patient appropriately, both in terms of the necessity of the supplement and product selection.
According to Natural Medicines Comprehensive Database, there are 12,437 products containing ascorbic acid and 219 of them are United States Pharmacopeia (USP)–verified.15 Because dietary supplements do not have regulatory standards, the USP developed a quality program to assist patients in choosing supplements that meet the highest standards for integrity, purity, and potency. Looking for the USP-verified symbol may be an advantageous way to choose among the thousands of supplements that are available to assure that certain standards have been met.
Vitamin C is available in various dosage forms and strengths. It is found in supplements alone or in combination with other ingredients, including herbal formulations. It is usually found in multivitamins, including ones made for children, adults, and prenatal care. Dosage forms include chewable, tablet, capsule, liquid, and topical preparations. It was available in an injectable formulation; however, the FDA warned a manufacturer in early 2011 to discontinue its intravenous form of vitamin C in part because it is considered an unapproved drug.16 Ascorbic acid is typically found in dosages of 500 to 1000 mg, although some formulations may have more or less. Because vitamin C is an ingredient in many supplements, pharmacists should assist patients in reviewing labeling information to avoid taking more than the UL for ascorbic acid.
As with most other drugs and supplements, vitamin C may interact with other drugs, but most of the interactions are considered mild to moderate in severity with an occurrence rating of possible to probable. Chemotherapy may warrant patients avoiding vitamin C use because of the antioxidant effect; however, as mentioned above, vitamin C use is not contraindicated with chemotherapy; rather, it is recommended that patients discuss its use with their oncologist.
Vitamin C supplements may also increase estrogen levels; however, this is mainly seen in patients who are deficient in vitamin C. In addition, the high-density lipoprotein increases caused by statin and nicotinic acid medications may be blunted with the use of combination vitamin C, vitamin E, carotene, and selenium supplementation. It is unclear if vitamin C alone causes this change; therefore, lipid panels should be closely monitored if a patient is taking supplements with either medication.
Certain herbal medications also may interact with vitamin C; many of these interactions are due to the high concentrations of vitamin C in the herbs, causing the patient to reach levels of vitamin C above the UL. Two such herbs are rose hip and acerola. Also, vitamin C can improve the absorption of iron, but if a patient has sufficient vitamin C levels, supplementation may not be necessary. In general, although there are interactions that may occur with vitamin C, most of these interactions allow the use of ascorbic acid with the caveat that the monitoring parameters are closely observed.
Vitamin C is an essential part of everyone’s dietary intake, with deficiencies in vitamin C carrying significant consequences. Fortunately, due to its widespread availability, including naturally in many fruits and vegetables as well as through fortification in foods such as cereals and juices, most people in developed countries do not suffer deficiencies in ascorbic acid.
In conjunction with the FNB, the FDA has developed guidelines stating the RDAs for vitamin C, which depend on an individual’s gender, age, and pregnancy and smoking status. Although most people meet their RDA through dietary intake, there are a number of individuals who may not be meeting their RDA because they are unable to obtain food or have dietary restrictions that limit their choices.
Therefore, it is vital that pharmacists understand the importance of vitamin C and are aware of symptoms that indicate scurvy in the differential diagnosis. Additionally, many patients may fall on the opposite end of the spectrum, where their intake is close to or exceeding the UL because of their diet and supplementation intake.
Pharmacists should be aware of the adverse effects of exceeding the UL as well as the possible interactions of vitamin C and other medications. Pharmacists are a pillar of knowledge in matters of drugs and supplements and they are able to provide excellent recommendations and counseling for patients. The most important points about vitamin C are summarized below.
PHARMACIST’S CORNER-TOP 5 COUNSELING POINTS ABOUT VITAMIN C
Determine your patient’s RDA-don’t forget to ask if your patient is a smoker and/or pregnant. Although most of the population easily meets their daily intake requirement, assess your patient’s diet to assure the RDA is met.
Determine your patient’s reason for wanting a vitamin C supplement. Most indications marketed do not have strong evidence to support the claims. However, there is data that do show positive benefits; therefore, provide a recommendation based on what is important to the patient as well as what the current evidence shows.
Counsel on the possible adverse effects of vitamin C at higher doses. Although in general diarrhea and gastrointestinal disturbances are considered mild toxicities, the possibility of dehydration and/or the impact of the gastrointestinal effects on other drugs (eg, increased risk of hypoglycemia with sulfonylureas/insulin if patient can’t eat, fluctuation of international normalized ratio) can be of significance.
If a vitamin C supplement is appropriate for your patient, help choose the proper supplement, keeping in mind the importance of dose, length of therapy, storage method, and choosing a brand that is USP verified.
If a vitamin C supplement is not appropriate for your patient, discuss dietary sources of vitamin C. Citrus fruits, tomatoes, broccoli, and strawberries have a significant amount of vitamin C and a few servings a day can help achieve an individual’s RDA.