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It has been more than a century since an Englishman, William Fletcher in 1905 while researching the cause of the disease Beriberi, discovered that it could be prevented by eating unpolished rice. He concluded that the husk of rice must have special nutrients, which we know today as vitamins. The term vitamin originated from “vitamine,” a word first used in 1911 by the Polish scientist Casimir Funk to designate a group of compounds considered vital for life; each was thought to have a nitrogen-containing component known as an amine. The final “e” of vitamine was dropped when it was discovered that not all of the vitamins contain nitrogen and, therefore not all are amines.
The thirteen essential vitamins are either fat soluble (A,D,E,K) or water soluble vitamins viz. C, B1 (thiamine), B2 (riboflavin), B3 (niacin), B6, B12, pantothenic acid, biotin and folate (folic acid). Fat soluble vitamins are stored in the body for prolonged periods and as a class deal with the regulation of protein synthesis. Vitamin C and B-complex vitamins are stored to a limited extent (except B12) and frequent consumption is necessary.
B-complex vitamins generally form coenzymes and catalyse the oxidation of small molecules in the production of energy. Vitamin C is an anti-oxidant and plays a specific role in the hydroxylation of specific compounds [1, 2]. A well balanced Indian diet is able to provide most vitamins and micronutrients except B12 in strict vegetarians (Table 1).
Vitamins in therapeutic amounts (normally 5-10 times, the recommended daily allowance) are indicated for the treatment of deficiency states or pathologic conditions in which absorption and utilisation of vitamins is reduced or when requirements are increased . In addition, they are also recommended for the treatment of nonnutritional disease in which a large dose has a unique effect independent of nutritive activity e.g. alcoholic neuritis and Wernicke's syndrome (thiamine), hyperlipoproteinaemias (niacin), to prevent neuropathy in those on isoniazid (pyridoxine), sideroblastic anemia (pyridoxine), infantile seborrhea (biotin) and acute promyelocytic leukaemia (all-trans-retinoic acid) [4, 5, 6, 7].
The term multivitamin came into vogue sixty years ago when Miles Laboratory, United States marketed a combination of Vit A, Vit D, β-carotene, B-vitamins and micronutrients (iron, calcium etc). Since then a number of combinations have been marketed as multivitamins . The National Health and Nutrition Examination Survey (NHANES) USA, defines multivitamin as a formulation containing three or more vitamins with or without minerals . These may be marketed as specialised products such as multivitamin for men, senior women, menopausal women, persons with diabetes, for energy, for hair growth and so on. The content of each multivitamin is determined by the manufacturer, e.g. a brand of multivitamin available in the Armed Forces contains 26 vitamins and micro nutrients (Table 2). The bioavailability of the individual vitamin or micronutrient in a multivitamin depends on the homeostatic mechanism which regulates absorption and excretion depending on level of nutrient in the host. It also depends on the dose of each vitamin/micronutrient in a preparation of multivitamin and the interaction of the various components, for instance vitamin C increases the bioavailability of iron.
Both observational studies and randomised controlled trials (RCT's) have been conducted for studying effect of single nutrient supplementation or multivitamins in healthy individuals. Antioxidants scavenge free radicals and other reactive oxygen species that damage cellular membranes, organelles and macromolecules. There has been an interest in assessing the role of antioxidants (vitamin C, vitamin E and β carotenes found in vitamin A preparation) in cardiovascular disease and cancer. Several studies have shown that vitamin E in doses higher than recommended daily allowance had cardio protective effect. Low density lipoprotein concentration decreased significantly in blood taken from subjects receiving >200 IU a day but not in those on < 200 IU a day. A double blind placebo controlled trial showed a significant decrease in non-fatal myocardial infarction in high risk subjects consuming either 400 or 800 IU vitamin E/day as supplement. Vitamin E was also shown to be effective in prevention of cancer . However, Lee et al , in a randomised controlled trial (Women's Health Study) using vitamin E 600 IU on alternate days in women >45 years, found no overall benefit for prevention of major cardiovascular diseases or cancer. The strength of the study lies in the fact that it involved a large population (39,876) studied over a long duration (10.1 years) of time.
In vitro observation and epidemiologic studies have shown that people with high intake of β carotene or high blood concentration of this nutrient have reduced risk of various diseases including cancer and heart disease. The effect has been attributed to antioxidant properties of β carotene. However when a RCT used β carotene and α tocopherol in Finnish smokers to test this hypothesis, there was an increase rather than decrease in the incidence of lung cancer in the β carotene group .
Higher intake of folate has been inversely associated with coronary heart disease (CHD), possibly due to decrease in homocysteine levels. The Nurses Health Study, a prospective cohort study of 1,21,700 nurses in the United States suggested that intake of folate and vitamin B6 above the recommended dietary allowance may be beneficial for primary prevention of CHD among women. The primary sources of folate in this study were multivitamin and diet . However a recent RCT has come up with contradictory evidence. A combination pill of folic acid (2.5mg), Vit B6 (50 mg) and Vit B12 failed to reduce cardiovascular events among high risk women despite reduction in homocysteine levels .
Selenium in doses of 200 μg (thrice the recommended daily intake) was used in a multi centre double blind, placebo controlled trial to determine whether it decreased the incidence of cancer. After a follow up of 6.4 years, there was no decrease in the incidence of squamous or basal cell carcinoma (primary end point). However there was a significant reduction in cancer mortality, incidence of carcinoma of lung, prostate and colorectal carcinoma (secondary end point) . This is a solitary trial and needs confirmation.
As part of Women's Health Initiative (WHI), healthy post menopausal women received Vit D3(400 IU) and calcium carbonate (containing elemental calcium 1000 mg), with an aim to prevent hip and other fractures. At the end of study period there was a small but significant increase in bone mineral density (BMD), without any reduction in the incidence of hip fractures .
In a questionnaire study on apparently healthy individuals, 58% of respondents took multivitamins for prevention against chronic diseases and 32% took them for “feeling better” . Single nutrient studies discussed above do not provide concrete evidence of benefit. The dose of these nutrients in multivitamin formulations is much less and it seems illogical to prescribe multivitamins to prevent chronic disease. Few trials have been conducted to study the effect of multivitamin supplementation in healthy individuals for prevention of chronic diseases. In Cancer Prevention Study II, a cohort of 10,63,023 adult Americans were examined prospectively to determine the relation between multivitamin use and mortality from heart disease, cerebrovascular accidents and cancers. Users of multivitamin had similar mortality due to cardiovascular disease and cancers as compared to non-users. There was a concern raised regarding increased mortality among male smokers . Similarly Physicians Health Study observed a cohort of 83,639 US male physicians and found that use of vitamin E, vitamin C and multivitamin was not associated with any change in cardiovascular mortality .
Multivitamins are commonly used in residents of old age homes and in those who do not take adequate diet. Poor exposure to sunlight leads to lower 25 hydroxylated vitamin D levels and potentially increases the risk of fractures. Supplementation of calcium carbonate containing 1000 mg of elemental calcium and vitamin D has shown increased BMD, without decreasing the risk of fractures. The incidence of Alzheimer's disease (AD) is increasing as a result of longer life span. Cross sectional and prospective studies have shown use of antioxidants in the form of Vit E and Vit C to reduce the severity and incidence of AD. Cache County Study, a cross sectional and prospective study has reported reduced risk of AD in users of vitamin E and multivitamins containing vitamin C .
The purpose of micronutrient supplementation in pregnancy is to improve pregnancy outcome and breast milk quality. For those who are well nourished and adhere to a balanced diet there is little need for multivitamin supplementation. The use of folate supplement in pre-conceptional stage is important to reduce the number of births with neural tube defects and in later part of pregnancy along with iron to prevent dimorphic anemia. There is some evidence that supplementation of calcium may decrease the incidence of pregnancy associated hypertension, pre-eclampsia and depression in population with low calcium intake .
The misuse of vitamins is not without its safety concerns. The amount of vitamins or nutrients in multivitamins generally does not exceed the recommended daily allowance. For vitamins to cause side effects the intake should exceed recommended daily allowance several fold (Table 3). Excess intake may occur if single vitamins are taken in addition to multivitamins . The vitamins and micronutrients for which excess intake has been reported are vitamin A, vitamin C, niacin, iron and zinc . The common interactions with other drugs are those involving vitamin E and aspirin leading to increased antithrombotic effect and that between vitamin E and warfarin leading to increased likelihood of bleeding.
From the above it is apparent that vitamins are indicated in therapeutic doses only in deficiency states and for certain nonnutritional diseases. They have role as prophylaxis in pregnancy and possibly in elderly. However when used to prevent disease not much is to be gained if a person is eating a healthy, balanced diet and has no absorptive defect. Yet the multivitamin industry is thriving. One reason is the easy availability of these preparations over the counter or as one author put it from “brick and mortar shops”. In a questionnaire study, the Hawaii Los Angeles Multi Ethnic trial (MEC); of the 1,00,196 respondents, 48% of men and 56% of women reported using multivitamin at least once weekly for the preceding year . In another study multivitamins were more likely to be used by women, individuals from older age group, with higher educational level and low BMI. These were the individuals who would be health conscious and be involved in health promoting activities .
The question arises regarding our position in the Armed Forces: Do we use or abuse multivitamins? The authors conducted a survey of 2000 prescriptions containing multivitamins prescribed over a span of two months from a tertiary level Armed Forces hospital. The findings are as shown in Table 4. Multivitamins had been prescribed for all possible ailments encountered in practice. There appeared to be no scientific rationale for prescriptions of multivitamins and they seem to be prescribed like a placebo. The common brands of vitamins prescribed were Polybion, Zevit, Becosule and Rivonia. We did a rough costing of the multivitamins. The cost of each tablet of multivitamin preparation ranged from Rupees (Rs) 1 to 5. The cost of the multivitamin preparation in Table 2 was Rs 4.50 per tablet. If the vitamins were prescribed for a month, the average expenditure incurred over one year would be approximately Rupees Thirty two lacs and forty thousand. If one were to extrapolate this figure to other major hospitals, there would be a staggering expenditure of approximately Rupees Two crores. The drawback of the above calculation is that we have used the most expensive brand, while the number of prescriptions and the duration of therapy is an approximation. In addition, the procurement price may be different from the retail price. However the discussion shows that we are spending significant amount of money on a medicine, which has no significant benefit in most patients.
It would not be incorrect to conclude that the current data does not support the nonspecific use of multivitamin, in the absence of deficiency states and that specific vitamin/mineral supplements rather than multivitamins should be used where indicated.
We acknowledge the contribution of Col UK Sharma, Senior Advisor (Medicine), INHS Asvini in compiling the data on multivitamin usage.