Vitamin K

Vitamin K is a fat-soluble vitamin. The "K" is derived from the German word "koagulation". Coagulation refers to blood clotting, because vitamin K is essential for the functioning of several proteins involved in blood clotting. There are two naturally occurring forms of vitamin K. Plants synthesize phylloquinone, also known as vitamin K1. Bacteria synthesize a range of vitamin K forms, using repeating 5-carbon units in the side chain of the molecule. These forms of vitamin K are designated menaquinone-n (MK-n), where n stands for the number of 5-carbon units. MK-n are collectively referred to as vitamin K2. MK-4 is not produced in significant amounts by bacteria, but appears to be synthesized by animals (including humans) from phylloquinone. MK-4 is found in a number of organs other than the liver at higher concentrations than phylloquinone. This fact, along with the existence of a unique pathway for its synthesis, suggests there is some unique function of MK-4 that is yet to be discovered.

Function

The only known biological role of vitamin K is that of the required coenzyme for a vitamin K-dependent carboxylase that catalyzes the carboxylation of the amino acid, glutamic acid, resulting in its conversion to gamma-carboxyglutamic acid (Gla). Although vitamin K-dependent gamma-carboxylation occurs only on specific glutamic acid residues in a small number of proteins, it is critical to the calcium-binding function of those proteins.

Coagulation (clotting)

The ability to bind calcium ions (Ca2+) is required for the activation of the 7 vitamin K-dependent clotting factors in the coagulation cascade. The term, coagulation cascade, refers to a series of events, each dependent on the other that stops bleeding through clot formation. Vitamin K-dependent gamma-carboxylation of specific glutamic acid residues in those proteins makes it possible for them to bind calcium. Factors II (prothrombin), VII, IX, and X make up the core of the coagulation cascade. Protein Z appears to enhance the action of thrombin (the activated form of prothrombin) by promoting its association with phospholipids in cell membranes. Protein C and protein S are anticoagulant proteins that provide control and balance in the coagulation cascade. Because uncontrolled clotting may be as life threatening as uncontrolled bleeding, control mechanisms are built in to the coagulation cascade. Vitamin K-dependent coagulation factors are synthesized in the liver. Consequently, severe liver disease results in lower blood levels of vitamin K-dependent clotting factors and an increased risk of uncontrolled bleeding (hemorrhage).

Some people are at risk of forming clots, which could block the flow of blood in arteries of the heart, brain, or lungs, resulting in heart attack, stroke, or pulmonary embolism, respectively. Some oral anticoagulants, such as warfarin, inhibit coagulation through antagonism of the action of vitamin K. Although vitamin K is a fat-soluble vitamin, the body stores very little of it, and its stores are rapidly depleted without regular dietary intake. Perhaps, because of its limited ability to store vitamin K, the body recycles it through a process called the vitamin K cycle. The vitamin K cycle allows a small amount of vitamin K to function in the gamma-carboxylation of proteins many times, decreasing the dietary requirement. Warfarin prevents the recycling of vitamin K by inhibiting two important reactions and creating a functional vitamin K deficiency (see diagram). Inadequate gamma-carboxylation of vitamin K-dependent coagulation proteins interferes with the coagulation cascade, and inhibits blood clot formation. Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists, so patients taking these drugs are cautioned against consuming very large or highly variable quantities of vitamin K in their diets (see Drug interactions). Experts now advise a reasonably constant dietary intake of vitamin K that meets current dietary recommendations (60-80 mcg/day) for patients on vitamin K antagonists, like warfarin.

Bone mineralization

Three vitamin-K dependent proteins have been isolated in bone. Osteocalcin is a protein synthesized by osteoblasts (bone forming cells). The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol. The mineral-binding capacity of osteocalcin requires vitamin K-dependent gamma-carboxylation of three glutamic acid residues. The function of osteocalcin is unclear, but is thought to be related to bone mineralization. Matrix Gla protein (MGP) has been found in bone, cartilage, and soft tissue, including blood vessels. The results of animal studies suggest MGP prevents the calcification of soft tissue and cartilage, while facilitating normal bone growth and development. The vitamin K-dependent anticoagulant protein S is also synthesized by osteoblasts, but its role in bone metabolism is unclear. Children with inherited protein S deficiency suffer complications related to increased blood clotting as well as to decreased bone density.

Cell growth

Gas6 is a vitamin K-dependent protein that was identified in 1993. It has been found throughout the nervous system, as well in the heart, lungs, stomach, kidneys, and cartilage. Although the exact mechanism of its action has not been determined, Gas6 appears to be a cellular growth regulation factor with cell signaling activities. It may also play important roles in the developing and aging nervous system.

Deficiency

Overt vitamin K deficiency results in impaired blood clotting, usually demonstrated by laboratory tests that measure clotting time. Symptoms include easy bruising and bleeding that may be manifested as nosebleeds, bleeding gums, blood in the urine, blood in the stool, tarry black stools, or extremely heavy menstrual bleeding. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage).

Adults

Vitamin K deficiency is uncommon in healthy adults for a number of reasons: 1) vitamin K is widespread in foods (see Food sources), 2) the vitamin K cycle conserves vitamin K, and 3) bacteria that normally inhabit the large intestine synthesize menaquinones (vitamin K2), though it is unclear whether a significant amount is absorbed and utilized. Adults at risk of vitamin K deficiency include those taking vitamin K antagonist anticoagulant drugs and individuals with significant liver damage or disease.

Infants

Newborn babies that are exclusively breast-fed are at increased risk of vitamin K deficiency for the following reasons: 1) human milk is relatively low in vitamin K compared to formula, 2) the newborn's intestines are not yet colonized with bacteria that synthesize menaquinones, and 3) the vitamin K cycle may not be fully functional in newborns, especially premature infants. Infants whose mothers are on anticonvulsant medication to prevent seizures are also at risk of vitamin K deficiency. Vitamin K deficiency in newborns may result in a bleeding disorder called vitamin K deficiency bleeding (VKDB) of the newborn. Because VKDB is life threatening and easily prevented, the American Academy of Pediatrics and a number of similar international organizations recommend that an injection of phylloquinone (vitamin K1) be administered to all newborns.

Controversies around vitamin K administration and the newborn

Vitamin K and childhood leukemia: Controversy arose regarding the routine use of vitamin K injections for newborns in the early 1990s when two retrospective studies were published that suggested the possibility of an association between vitamin K injections in newborns and the development of childhood leukemia and other forms of childhood cancer. However, two large retrospective studies in the U.S. and Sweden that reviewed the medical records of 54,000 and 1.3 million children, respectively, found no evidence of a relationship between childhood cancers and vitamin K injections at birth. Moreover, a pooled analysis of 6 case-control studies including 2,431 children diagnosed with childhood cancer and 6,338 cancer-free children found no evidence that vitamin K injections for newborns increased the risk of childhood leukemia. In a policy statement, the American Academy of Pediatrics recommended that routine vitamin K prophylaxis for newborns be continued because VKDB is life threatening and the risks of cancer are unproven and unlikely. Full text of the AAP policy statement on vitamin K and the newborn.

Lower doses of vitamin K1 for premature infants: The results of two studies of vitamin K levels in premature infants suggest that the standard initial dose of vitamin K1 for full term infants (1.0 mg) may be too high for premature infants. These findings have led some experts to suggest the use of an initial vitamin K1 dose of 0.3 mg/kg for infants with birth weights less than 1,000 g (2 lbs, 3 oz), and an initial dose of 0.5 mg for other premature infants.

Disease Prevention

Osteoporosis

The discovery of vitamin K-dependent proteins in bone has led to research on the role of vitamin K in maintaining bone health.

Dietary vitamin K and osteoporotic fracture

Epidemiological studies have demonstrated a relationship between vitamin K and age-related bone loss (osteoporosis). The Nurses Health Study followed more than 72,000 women for 10 years. Investigators found that women whose vitamin K intake was in the lowest quintile (1/5) had a 30% higher risk of hip fracture than women with vitamin K intakes in the highest four quintiles. A study of over 800 elderly men and women followed in the Framingham Heart Study for 7 years found that men and women with dietary vitamin K intakes in the highest quartile (1/4) had only 35% of the risk of hip fracture experienced by those with dietary vitamin K intakes in the lowest quartile (approximately 250 mcg/day vs. 50 mcg/day of vitamin K). However, the investigators found no association between dietary vitamin K intake and bone mineral density (BMD) in the Framingham subjects. Because the primary dietary source of vitamin K is generally green leafy vegetables, high vitamin K intake could just be a marker for a healthy diet that is high in fruits and vegetables. 

Vitamin K-dependent carboxylation of osteocalcin and osteoporotic fracture

Osteocalcin, a bone-related protein that circulates in the blood, has been shown to be a sensitive marker of bone formation. Vitamin K is required for the gamma-carboxylation of osteocalcin. Undercarboxylation of osteocalcin adversely affects its capacity to bind to bone mineral, and the degree of osteocalcin gamma-carboxylation has been found to be a sensitive indicator of vitamin K nutritional status. Circulating levels of undercarboxylated osteocalcin (ucOC) were found to be higher in postmenopausal women than premenopausal women and markedly higher in women over the age of 70. In a study of 195 institutionalized elderly women, the relative risk of hip fracture was six times higher in those who had elevated ucOC levels at the beginning of the study. In a much larger sample of 7500 elderly women living independently, circulating ucOC was also predictive of fracture risk. Although vitamin K deficiency would seem the most likely cause of elevated blood ucOC, investigators have also documented an inverse relationship between measures of vitamin D nutritional status and ucOC levels, as well as a significant lowering of ucOC by vitamin D supplementation. It is also possible that an increased ucOC level is a marker for poor vitamin D or protein nutritional status.

Vitamin K antagonists and osteoporotic fracture

Certain oral anticoagulants, like warfarin, are known to be antagonists of vitamin K. Two recent studies examined the chronic use of warfarin and the risk of fracture in older women. One study reported no association between long-term warfarin treatment and fracture risk, while the other found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers. A meta-analysis of the results of 11 published studies found that oral anticoagulation therapy was associated with a very modest reduction in bone density at the wrist, and no change in bone density at the hip or spine.

Vitamin K supplementation studies and osteoporosis

Vitamin K supplementation of 1,000 mcg/day of phylloquinone (Vitamin K1) for 2 weeks (more than 10 times the AI for vitamin K) resulted in a decrease of ucOC levels in postmenopausal women, as well as increases in several biochemical markers of bone formation. In Japan, intervention trials in hemodialysis patients and osteoporotic women using very high pharmacologic doses (45 mg/day) of menatetrenone (MK-4) have reported significant reductions in the rate of bone loss. MK-4 is not found in significant amounts in the diet, but can be synthesized in small amounts by humans from phylloquinone. The dose used in the Japanese studies is about 50 times higher than the AI for vitamin K. Experts are not sure whether the effects of such high doses of MK-4 represent a true vitamin K effect.

In the absence of long-term intervention studies using nutritionally optimal doses of vitamin K, evidence of a relationship between vitamin K nutritional status and bone health in adults is considered weak. Further investigation is required to determine the physiological function of vitamin K-dependent proteins in bone and the mechanisms by which vitamin K affects bone health and osteoporotic fracture risk.

Vascular calcification and cardiovascular disease

One of the hallmarks of cardiovascular disease is the formation of atherosclerotic plaques in arterial walls. Calcification of atherosclerotic plaques occurs as the condition progresses, resulting in decreased elasticity of the affected vessels and increased risk of clot formation, the usual cause of a heart attack or stroke. One study of postmenopausal women found low dietary vitamin K intake to be associated with increased risk of aortic calcification, as visualized by chest x-ray. Additionally, laboratory tests examining the vitamin K-dependent gamma-carboxylation of osteocalcin indicated that elevated blood levels of undercarboxylated osteocalcin (ucOC) were also associated with increased aortic calcification. The mechanism by which vitamin K may promote mineralization of bone, while inhibiting mineralization (calcification) of vessels is not entirely clear. One hypothesis is based on the function of two different bone proteins, osteocalcin and matrix Gla protein (MGP). MGP has been found to inhibit the calcification of cartilage and bone during early embryonic development. Osteocalcin appears later during bone development and appears to promote bone mineralization. Some investigators have hypothesized that high levels of MGP found in calcified vessels may represent a defense against vessel calcification, but that inadequate vitamin K nutritional status results in inadequate carboxylation, and presumably inactive MGP. Thus, insufficient dietary vitamin K may increase the risk of vascular calcification. However, it should be noted that this line of reasoning is based on animal research and only one epidemiological study in humans. Further investigations are necessary to establish the nature of the role of bone proteins in human atherosclerotic plaque calcification.

Safety

Toxicity

Although allergic reaction is possible, there is no known toxicity associated with high doses of phylloquinone (vitamin K1), or menaquinone (vitamin K2) forms of vitamin K. The same is not true for menadione (vitamin K3) and its derivatives. Menadione can interfere with the function of glutathione, one of the body's natural antioxidants, resulting in oxidative damage to cell membranes. Menadione given by injection has induced liver toxicity, jaundice, and hemolytic anemia (due to the rupture of red blood cells) in infants, and is no longer used for treatment of vitamin K deficiency. No tolerable upper level (UL) of intake has been established for vitamin K.

Drug interactions

The anticoagulant effect of vitamin K antagonists (e.g., warfarin) may be inhibited by very high dietary or supplemental vitamin K intake. It is generally recommended that individuals using warfarin try to consume the AI for vitamin K (90-120 mcg), while avoiding large fluctuations in vitamin K intake that might interfere with the adjustment of their anticoagulant dose. Large doses of vitamin A and vitamin E have been found to antagonize vitamin K. Excess vitamin A appears to interfere with vitamin K absorption, while a form of vitamin E (tocopherol quinone) may inhibit vitamin K-dependent carboxylase enzymes. Bleeding was reported in a man taking 5 mg of warfarin and 1,200 IU of vitamin E daily. When given to pregnant women, warfarin, anticonvulsants, rifampin, and isoniazid can interfere with fetal vitamin K synthesis and place the newborn at increased risk of vitamin K deficiency. Prolonged use of broad spectrum antibiotics may decrease vitamin K synthesis by intestinal bacteria. Cephalosporins and salicylates may decrease vitamin K recycling by inhibiting vitamin K epoxide reductase (diagram). Cholestyramine, cholestipol, orlistat, mineral oil, and the fat substitute olestra may decrease vitamin K absorption.

Linus Pauling Institute Recommendation

Although the AI for vitamin K was recently increased, it is not clear if it will be enough to opitmize the gamma-carboxylation of vitamin K-dependent proteins in bone (see Osteoporosis). Multivitamins generally contain 10 to 25 mcg of vitamin K while vitamin K or "bone" supplements may contain 100 to 120 mcg of vitamin K. To consume the amount of vitamin K associated with a decreased risk of hip fracture in the Framingham Heart Study (about 250 mcg/day), an individual would need to eat a little more than 1/2 cup of chopped broccoli or a large salad of mixed greens every day. Though the dietary intake of vitamin K required for optimal function of all vitamin K dependent proteins is not yet known, the Linus Pauling Institute recommends taking a multivitamin/mineral supplement and eating at least 1 cup of dark green leafy vegetables daily. Replacing dietary saturated fats like butter and cheese with monounsaturated fats found in olive oil and canola oil will also increase dietary vitamin K intake, and may also decrease the risk of cardiovascular diseases.

Older adults (65 years and older)

Because older adults are at increased risk of osteoporosis and hip fracture, the above recommendation for a multivitamin/mineral supplement and at least 1 cup of dark green leafy vegetables/day is especially relevant.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/

Vitamin E

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols (also alpha-, beta-, gamma- and delta-). Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue. Because alpha-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the latest Recommended Dietary Allowance (RDA) for vitamin E.

Function

Alpha-tocopherol

The main function of alpha-tocopherol in humans appears to be that of an antioxidant.  Free radicals are formed primarily in the body during normal metabolism and also upon exposure to environmental factors such as cigarette smoke or pollutants. Fats, which are an integral part of all cell membranes, are vulnerable to destruction through oxidation by free radicals.  The fat-soluble vitamin, alpha-tocopherol, is uniquely suited to intercepting free radicals and preventing a chain reaction of lipid destruction.  Aside from maintaining the integrity of cell membranes throughout the body, alpha-tocopherol also protects the fats in low density lipoproteins (LDLs) from oxidation.  Lipoproteins are particles composed of lipids and proteins, which are able to transport fats through the blood stream.  LDL transport cholesterol from the liver to the tissues of the body.  Oxidized LDLs have been implicated in the development of cardiovascular diseases (See Disease Prevention).  When a molecule of alpha-tocopherol neutralizes a free radical, it is altered in such a way that its antioxidant capacity is lost.  However, other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of alpha-tocopherol.

Several other functions of alpha-tocopherol have been identified, which likely are not related to its antioxidant capacity. Alpha-tocopherol is known to inhibit the actvity of protein kinase C, an important cell signaling molecule, as well as to affect the expression and activity of immune and inflammatory cells. Additionally, alpha-tocopherol has been shown to inhibit platelet aggregation and to enhance vasodilation.

Gamma-tocopherol

The function of gamma-tocopherol in humans is presently unclear. Although the most common form of vitamin E in the American diet is gamma-tocopherol (see Food Sources), blood levels of gamma-tocopherol are generally ten times lower than those of alpha-tocopherol.  This phenomenon appears due to the action of the alpha-tocopherol transfer protein (a-TTP) in the liver, which preferentially incorporates alpha-tocopherol into lipoproteins that are circulated in the blood and ultimately deliver alpha-tocopherol to different tissues in the body. See the Linus Pauling Institute Newsletter for more information about a-TTP and vitamin E adequacy. Because gamma-tocopherol is initially absorbed in the same manner as alpha-tocopherol, small amounts are detectable in blood and tissue.  Products of the metabolism of tocopherols, known as metabolites, can be detected in the urine. More gamma-tocopherol metabolites are excreted in the urine than alpha-tocopherol metabolites, suggesting less gamma-tocopherol is needed for use by the body. Limited research in the test tube and in animals indicates that gamma-tocopherol or its metabolites may play a role in the protection of the body from damage by free radicals, but these effects have not been convincingly demonstrated in humans. Recently, concern has been raised regarding the fact that taking alpha-tocopherol supplements lowers gamma-tocopherol levels in the blood.  However, no adverse effects of moderate alpha-tocopherol supplementation have been demonstrated, while many benefits have been documented (see Disease Prevention and Disease Treatment). In one recent prospective study, increased plasma gamma-tocopherol levels were associated with a significantly reduced risk of developing prostate cancer, while significant protective associations for increased levels of plasma alpha-tocopherol and toenail selenium were found only when gamma-tocopherol levels were also high. These limited findings, in addition to the fact that taking alpha-tocopherol supplements lower gamma-tocopherol levels in the blood, have led some scientists to call for additional research on the effects of dietary and supplemental gamma-tocopherol on health. For more information see the article, Which Form of Vitamin E, Alpha- or Gamma-Tocopherol, is Better? in the Linus Pauling Institute Research Report.

Deficiency

Vitamin E deficiency has been observed in individuals with severe malnutrition, genetic defects affecting the alpha-tocopherol transfer protein, and fat malabsorption syndromes.  For example, children with cystic fibrosis or cholestatic liver disease, who have an impaired capacity to absorb dietary fat and therefore fat-soluble vitamins, may develop symptomatic vitamin E deficiency.  Severe vitamin E deficiency results mainly in neurological symptoms, including impaired balance and coordination (ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and damage to the retina of the eye (pigmented retinopathy). For this reason, people who develop peripheral neuropathy, ataxia or retinitis pigmentosa should be screened for vitamin E deficiency.  The developing nervous system appears to be especially vulnerable to vitamin E deficiency because children with severe vitamin E deficiency from birth, who are not treated with vitamin E, develop neurological symptoms rapidly. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for 10-20 years.  It should be noted that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported.

Although true vitamin E deficiency is rare, suboptimal intake of vitamin E is relatively common in the U.S. The National Health and Nutrition Examination Survey III (NHANES III) examined the dietary intake and blood levels of alpha-tocopherol in 16,295 multi-ethnic adults over the age of 18. Twenty seven % of white participants, 41% of African Americans, 28% of Mexican Americans and 32% of the other participants were found to have blood levels of alpha-tocopherol less than 20 micromoles/liter, a value chosen because the literature suggests an increased risk for cardiovascular disease below this level.

Disease Prevention

Cardiovascular disease

The results of at least five large observational studies suggest that increased vitamin E consumption is associated with decreased risk of myocardial infarction (heart attack) or death from heart disease in both men and women.  Each study was a prospective study which measured vitamin E consumption in presumably healthy people and followed them for a number of years to determine how many of them were diagnosed with, or died as a result of heart disease.  In two of the studies, those individuals who consumed more than 7 mg of alpha-tocopherol in food were only approximately 35% as likely to die from heart disease as those who consumed less than 3-5 mg of alpha-tocopherol.  Two other large studies found a significant reduction in the risk of heart disease only in those women and men who consumed alpha-tocopherol supplements of at least 100 IU (67 mg of RRR-alpha-tocopherol) daily. More recently, several studies have observed plasma or red blood cell levels of alpha-tocopherol to be inversely associated with the presence or severity of carotid atherosclerosis detected using ultrasonography. In contrast, intervention studies with vitamin E supplements in patients with heart disease have not shown vitamin E to be effective in preventing heart attacks or death (see Disease Treatment).

Cataracts

Cataracts appear to be formed by the oxidation of proteins in the lens of the eye, which may be prevented by antioxidants such as alpha-tocopherol.  To date, ten observational studies have examined the association between vitamin E consumption and the incidence and severity of cataracts. Of these studies, five found increased vitamin E intake to be associated with protection from cataracts, while five reported no association. A recent intervention trial of a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene in 4,629 men and women found that the antioxidant supplement was no different than a placebo in its effects on the development and progression of age-related cataracts over a 7-year period. Another intervention trial found that a daily supplement of 50 mg of synthetic alpha-tocopherol daily (equivalent to 25 mg of RRR- alpha-tocopherol) did not alter the incidence of cataract surgery in male smokers. Presently, the relationship between vitamin E intake and the development of cataracts requires further clarification before specific recommendations can be made.

Immune Function

Alpha-tocopherol has been shown to enhance specific aspects of the immune response that appear to decline as people age.  For example, 200 mg of synthetic alpha-tocopherol (equivalent to 100 mg of RRR-alpha-tocopherol) daily for several months increased the formation of antibodies in response to hepatitis B vaccine and tetanus vaccine in elderly adults. Whether alpha-tocopherol associated enhancements in the immune response actually translate to increased resistance to infections such as the flu (influenza virus) in older adults remains to be determined.

Cancer

Many types of cancer are thought to result from oxidative damage to DNA caused by free radicals.  The ability of alpha-tocopherol to neutralize free radicals has made it the subject of a number of cancer prevention studies.  However, several large prospective studies have failed to find significant associations between alpha-tocopherol intake and the incidence of lung cancer or breast cancer.  A placebo-controlled intervention study designed to look at the effect of alpha-tocopherol supplementation on lung cancer in smokers found a 34% reduction in the incidence of prostate cancer in smokers given supplements of 50 mg of synthetic alpha-tocopherol (equivalent to 25 mg of RRR-alpha-tocopherol) daily.  Because of these findings a large randomized, placebo-controlled intervention study is currently being conducted to examine the effect of alpha-tocopherol supplementation on prostate cancer risk.

Disease Treatment

Cardiovascular disease

Observational studies have suggested that supplemental alpha-tocopherol might have value in the treatment of cardiovascular disease.  For example, a small observational study of men who had previously undergone a coronary artery bypass surgery found a reduction in the progression of coronary artery atherosclerosis by angiography in those men who took at least 100 IU of alpha-tocopherol (67 mg of RRR-alpha-tocopherol) daily.  A randomized, placebo-controlled intervention trial in Great Britain (the CHAOS study) found that supplementing heart diseasepatients with either 400 or 800 IU  of synthetic alpha-tocopherol (equivalent to 268 or 536 mg of RRR-alpha-tocopherol) for an average of 18 months resulted in a dramatic 77% reduction in nonfatal heart attacks.  However, total deaths from heart disease were not significantly reduced. Chronic renal dialysis patients are at much greater risk of dying from cardiovascular disease than the general population, and there is evidence that they are also under increased oxidative stress. Supplementation of renal dialysis patients with 800 IU of natural alpha-tocopherol (536 mg of RRR-alpha-tocopherol) for an average of 1.4 years resulted in a significantly reduced risk of heart attack compared to placebo. In contrast, three other intervention trials failed to find significant risk reductions with alpha-tocopherol supplementation.  One study, which was designed mainly to examine cancer prevention, found that 50 mg of synthetic alpha-tocopherol daily (equivalent to 25 mg of RRR-alpha-tocopherol) resulted in a non-significant decrease in nonfatal heart attacks in those participants who had had previous heart attacks. However, two other large trials found that daily supplements of 400 IU of natural alpha-tocopherol (equivalent to 268 mg RRR-alpha-tocopherol) and 300 mg of synthetic alpha-tocopherol (equivalent to 150 mg of RRR-alpha-tocopherol) in individuals with evidence of cardiovascular disease (previous heart attack, stroke, or evidence of vascular disease) did not significantly change the risk of a subsequent heart attack or stroke. The results of several other large intervention trials, which are presently in progress may clarify the role of alpha-tocopherol supplementation in the treatment of cardiovascular disease.

A more thorough discussion of the complex issues involved in analyzing the results of recent trials of vitamin E in heart disease can be found in the Fall/Winter 1999 issue of the Linus Pauling Institute Newsletter: Fish Oil, Vitamin E, Genes, Diet, and CHAOS. For a discussion of some of the limitations of the HOPE study see the article, Vitamin E: Hope or Hopeless, in the Spring/Summer 2000 issue of the Linus Pauling Institute Newsletter.

Diabetes mellitus

Alpha-tocopherol supplementation of individuals with diabetes has been proposed because diabetes appears to increase oxidative stress and because cardiovascular complications (heart attack and stroke) are among the leading causes of death in diabetics.  A recent study found a biochemical marker of oxidative stress to be elevated in diabetic individuals.  Supplementation with 600 mg of synthetic alpha-tocopherol daily (equivalent to 300 mg of RRR-alpha-tocopherol) for 14 days resulted in a reduction in the oxidative stress marker.  Studies of the effect of alpha-tocopherol supplementation on blood glucose control have been contradictory.  One study reported improved control of blood glucose levels with supplementation of only 100 IU of synthetic alpha-tocopherol daily (equivalent to 45 mg RRR-alpha-tocopherol), while studies using 900 to 1,600 IU of synthetic alpha-tocopherol daily (equivalent to 405 to 720 mg RRR-alpha-tocopherol) found either minimal or no improvement, respectively. Although there is reason to suspect that alpha-tocopherol supplementation may be beneficial for individuals with diabetes, evidence from well-controlled clinical trials is lacking.

Dementia (impaired cognitive function)

The brain is particularly vulnerable to oxidative stress, which is thought to play a role in the pathology of neurodegenerative diseases, such as Alzheimer's disease. In a large placebo-controlled intervention trial, supplementation of individuals who had moderate neurological impairment with 2,000 IU of synthetic alpha-tocopherol daily for two years (equivalent to 900 mg/day of RRR-alpha-tocopherol) resulted in a significant slowing of the progression of Alzheimer's dementia. After Alzheimer's disease, vascular dementia (dementia resulting from strokes) is the most common cause of dementia in the U.S. A case-control study examining risk factors for vascular dementia in elderly Japanese-American men found that supplemental vitamin E and vitamin C intake was associated with a significantly decreased risk of vascular and other types of dementia, but not Alzheimer's dementia. Among those without dementia, vitamin E supplement use was associated with better scores on cognitive tests. Although these findings are promising, further studies are required to determine the role of alpha-tocopherol supplementation in the treatment of Alzheimer's disease and other types of dementia.

Cancer

Cancer cells proliferate rapidly and are resistant to death by apoptosis (programmed cell death). Cell culture studies indicate that the vitamin E ester, alpha-tocopheryl succinate, can inhibit proliferation and induce apoptosis in a number of cancer cell lines. The ester form, alpha-tocopheryl succinate, not alpha-tocopherol, is required to effectively inhibit proliferation or induce cancer cell death. Although the mechanisms for the effects of alpha-tocohpheryl succinate on cancer cells are not yet clear, the fact that the ester form has no antioxidant activity argues against an antioxidant mechanism. Limited data from animal models of cancer indicate that alpha-tocopheryl succinate administered by injection may inhibit tumor growth, but much more research is required to determine whether alpha-tocopheryl succinate will be a useful adjunct to cancer therapy in humans. Certainly, administration by injection will be necessary for any benefit, because alpha-tocopheryl succinate is cleaved to form alpha-tocopherol in the intestine when taken orally. There is currently no evidence in humans that taking oral alpha-tocopheryl succinate supplements delivers alpha-tocopheryl succinate to tissues.

Safety

Toxicity

Few side effects have been noted in adults taking supplements of less than 2,000 mg of alpha-tocopherol daily (RRR- or all-rac-alpha-tocopherol).  However, most studies of toxicity or side effects of alpha-tocopherol supplementation have lasted only a few weeks to a few months, and side effects occurring as a result of long-term alpha-tocopherol supplementation have not been adequately studied.  The most worrisome possibility is that of impaired blood clotting resulting in an increased likelihood of hemorrhage in some individuals. The Food and Nutrition Board of the Institute of Medicine established a tolerable upper intake level (UL) for alpha-tocopherol supplements, based on the prevention of hemorrhage (see table below).  The Board felt that 1,000 mg/day of alpha-tocopherol of any form (equivalent to 1,500 IU/day of RRR-alpha-tocopherol or 1,100 IU/day of all-rac-alpha-tocopherol) would be the highest dose unlikely to result in hemorrhage in almost all adults.  Although only certain isomers of alpha-tocopherol are retained in the circulation, all forms are absorbed, and the liver must break them down and eliminate them. The rationale that any form of alpha-tocopherol (natural or synthetic) that can be absorbed could potentially have adverse effects is the basis for a UL that refers to all forms of alpha-tocopherol.

Some physicians recommend that high-dose vitamin E supplementation be discontinued one month before elective surgery to decrease the risk of hemorrhage. Premature infants appear to be especially vulnerable to adverse effects of alpha-tocopherol supplementation, which should be used only under controlled supervision by a pediatrician. Supplementation with 400 IU/day of vitamin E has been found to accelerate the progression of retinitis pigmentosa that is not associated with vitamin E deficiency.

Vitamin E Supplementation and All-Cause Mortality

A recent meta-analysis that combined the results of 19 clinical trials of vitamin E supplementation for various diseases, including heart disease, end-stage renal failure and Alzheimer's disease, reported that adults who took supplements of 400 IU/day or more were 6% more likely to die from any cause than those who did not take vitamin E supplements. However, further breakdown of the risk by vitamin E dose and adjustment for other vitamin and mineral supplements revealed that the increased risk of death was statistically significant only at a dose of 2,000 IU/day, which is higher than the UL for adults. Furthermore, three other meta-analyses that combined the results of randomized controlled trials designed to evaluate the efficacy of vitamin E supplementation for the prevention or treatment of cardiovascular disease found no evidence that vitamin E supplementation up to 800 IU/day significantly increased or decreased cardiovascular disease mortality or all-cause mortality. At present, there is no convincing evidence that vitamin E supplementation up to 800 IU/day increases the risk of death from cardiovascular disease or other causes.

Drug interactions

Individuals on anticoagulant therapy (blood thinners) or individuals who are vitamin K deficient should not take alpha-tocopherol supplements without close medical supervision because of the increased risk of hemorrhage. A number of medications may decrease the absorption of vitamin E, including cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, and the fat substitute, olestra. Anticonvulsant drugs such as phenobarbitol, phenytoin, or carbamazepine may decrease plasma levels of vitamin E.

Antioxidants and HMG-CoA reductase inhibitors (statins)

A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke. Surprisingly, when an antioxidant combination (1000 mg vitamin C, 800 IU alpha-tocopherol, 100 mcg of selenium, and 25 mg beta-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. However, in a much larger randomized controlled trial of simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) in more than 20,000 men and women with coronary artery disease or diabetes, the antioxidant combination did not adversely affect the cardioprotective effects of simvastatin therapy over a 5-year period. These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplementation and cholesterol-lowering agents, such as HMG-CoA reductase inhibitors (statins).

Linus Pauling Institute Recommendation

Scientists at the Linus Pauling Institute feel there exists credible evidence that taking a supplement of 200 IU of natural source d-alpha-tocopherol (RRR-alpha-tocopherol) daily with a meal may help protect adults from chronic diseases like heart disease, stroke, neurodegenerative diseases, and some types of cancer. The amount of alpha-tocopherol required for such beneficial effects appears to be much greater than that which could be achieved through diet alone (see Sources). Since supplements containing 200 IU of d-alpha-tocopherol are often as expensive as supplements containing 400 IU of d-alpha-tocopherol, a less expensive alternative may be to take 400 IU of d-alpha-tocopherol every other day. Alpha-tocopherol supplements are unlikely to be absorbed unless taken with food.

Older adults (65 years and older)

The Linus Pauling Institute's recommendation of a supplement providing 200 IU of natural source d-alpha-tocopherol daily (or 400 IU of d-alpha-tocopherol every other day) with a meal is also appropriate for generally healthy older adults.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminE/

Vitamin D

Vitamin D is a fat-soluble vitamin that is essential for maintaining normal calcium metabolism. Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize vitamin D2 (ergocalciferol), which also has vitamin D activity in humans. When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D3 in the skin, adequate intake of vitamin D from the diet is essential for health.

Function

Activation of Vitamin D

Vitamin D itself is biologically inactive, and it must be metabolized to its biologically active forms. After it is consumed in the diet or synthesized in the skin, vitamin D enters the circulation and is transported to the liver. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. Increased exposure to sunlight or increased intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful indicator of vitamin D nutritional status. In the kidney and other tissues, the 25(OH)D3-1-hydroxylase enzyme catalyzes a second hydroxylation of 25(OH)D, resulting in the formation of 1alpha,25-dihydroxyvitamin D [1,25(OH)2D]—the most potent form of vitamin D. Most of the physiological effects of vitamin D in the body are related to the activity of 1,25(OH)2D.

Mechanisms of Action

Many of the biological effects of 1,25(OH)2D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR). Upon entering the nucleus of a cell, 1,25(OH)2D associates with the VDR and promotes its association with the retinoic acid X receptor (RXR). In the presence of 1,25(OH)2D the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs), and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by 1,25(OH)2D. Some physiological responses to 1,25(OH)2D occur too rapidly to be acting through gene transcription, suggesting that their may be also be a receptor for 1,25(OH)2D on the outer membrane of cells.

Calcium Balance

Maintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth, and maintenance of bone density. Vitamin D is essential for the efficient utilization of calcium by the body. The parathyroid glands sense serum calcium levels, and secrete parathyroid hormone (PTH) if calcium levels drop too low (diagram). Elevations in PTH increase the activity of 25(OH)D3-1-hydroxylase enzyme in the kidney, resulting in increased production of 1,25(OH)2D. Increasing 1,25(OH)2D production results in changes in gene expression that normalize serum calcium by 1) increasing the intestinal absorption of dietary calcium, 2) increasing the reabsorption of calcium filtered by the kidneys and 3) mobilizing calcium from bone when there is insufficient dietary calcium to maintain normal serum calcium levels. Parathyroid hormone and 1,25(OH)2D are required for the latter two effects.

Cell Differentiation

Cells that are dividing rapidly are said to be proliferating. Differentiation results in the specialization of cells for specific functions. In general, differentiation of cells leads to a decrease in proliferation. While cellular proliferation is essential for growth and wound healing, uncontrolled proliferation of cells with certain mutations may lead to diseases like cancer. The active form of vitamin D, 1,25(OH)2D, inhibits proliferation and stimulates the differentiation of cells.

Immunity

Vitamin D in the form of 1,25(OH)2D is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages. Macrophages also produce the 25(OH)D3-1-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D. There is considerable scientific evidence that 1,25(OH)2D has a variety of effects on immune system function that may enhance innate immunity and inhibit the development of autoimmunity.

Insulin Secretion

The VDR is expressed by insulin secreting cells of the pancreas, and the results of animal studies suggest that 1,25(OH)2D plays a role in insulin secretion under conditions of increased insulin demand. Limited data in humans suggests that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (noninsulin-dependent diabetes mellitus; NIDDM).

Blood Pressure Regulation

The renin-angiotensin system plays an important role in the regulation of blood pressure. Renin is an enzyme that catalyzes the cleavage (splitting) of a small peptide (Angiotensin I) from a larger protein (angiotensinogen) produced in the liver. Angiotensin converting enzyme (ACE) catalyzes the cleavage of angiotensin I to form angiotensin II, a peptide that can increase blood pressure by inducing the constriction of small arteries and increasing sodium and water retention. The rate of angiotensin II synthesis is dependent on renin. Recent research in mice lacking the gene encoding the VDR, indicates that 1,25(OH)2D decreases the expression of the gene encoding renin through its interaction with the VDR. Since inappropriate activation of the renin-angiotensin system is thought to play a role in some forms of human hypertension, adequate vitamin D levels may be important for decreasing the risk of high blood pressure.

Deficiency

In vitamin D deficiency, calcium absorption cannot be increased enough to satisfy the body’s calcium needs. Consequently, PTH production by the parathyroid glands is increased and calcium is mobilized from the skeleton to maintain normal serum calcium levels—a condition known as secondary hyperparathyroidism. Although it has long been known that severe vitamin D deficiency has serious consequences for bone health, recent research suggests that less obvious states of vitamin D deficiency are common and increase the risk of osteoporosis and other health problems.

Severe Vitamin D Deficiency

Rickets

In infants and children, severe vitamin D deficiency results in the failure of bone to mineralize. Rapidly growing bones are most severely affected by rickets. The growth plates of bones continue to enlarge, but in the absence of adequate mineralization, weight-bearing limbs (arms and legs) become bowed. In infants, rickets may result in delayed closure of the fontanels (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. In severe cases, low serum calcium levels (hypocalcemia) may cause seizures. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported in cities throughout the world.

Osteomalacia

Although adult bones are no longer growing, they are in a constant state of turnover. In adults with severe vitamin D deficiency, the collagenous bone matrix is preserved but bone mineral is progressively lost, resulting in bone pain and osteomalacia (soft bones).

Muscle Weakness and Pain

Vitamin D deficiency causes muscle weakness and pain in children and adults. Muscle pain and weakness was a prominent symptom of vitamin D deficiency in a study of Arab and Danish Moslem women living in Denmark. In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, nonspecific musculoskeletal pain, 93% had serum 25(OH)D levels indicative of vitamin D deficiency. A randomized controlled trial found that supplementation of elderly women with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three months increased muscle strength and decreased the risk of falling by almost 50% compared to supplementation with calcium alone.

Risk Factors for Vitamin D Deficiency

Exclusively breast fed infants: Infants who are exclusively breast fed and do not receive vitamin D supplementation are at high risk of vitamin D deficiency, particularly if they have dark skin and/or receive little sun exposure. Human milk generally provides 25 IU of vitamin D per liter, which is not enough for an infant if it is the sole source of vitamin D. Older infants and toddlers exclusively fed milk substitutes and weaning foods that are not vitamin D fortified are also at risk of vitamin D deficiency. The American Academy of Pediatrics recommends that all infants that are not consuming at least 500 ml (16 ounces) of vitamin D fortified formula or milk be given a vitamin D supplement of 200 IU/day.

Dark skin: People with dark skin synthesize less vitamin D on exposure to sunlight than those with light skin. The risk of vitamin D deficiency is particularly high in dark-skinned people who live far from the equator. In the U.S., 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of White women.

Aging: The elderly have reduced capacity to synthesize vitamin D in the skin when exposed to UVB radiation, and are more likely to stay indoors or use sunscreen. Institutionalized adults are at extremely high risk of vitamin D deficiency without supplementation.

Covering all exposed skin or using sunscreen whenever outside: Osteomalacia has been documented in women who cover all of their skin whenever they are outside for religious or cultural reasons. The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95%.

Fat malabsorption syndromes: Cystic fibrosis and cholestatic liver disease impair the absorption of dietary vitamin D.

Inflammatory bowel disease: People with inflammatory bowel disease like Crohn’s disease appear to be at increased risk of vitamin D deficiency, especially those who have had small bowel resections.

Obesity: Obesity increases the risk of vitamin D deficiency. Once vitamin D is synthesized in the skin or ingested, it is deposited in body fat stores, making it less bioavailable to people with large stores of body fat.

Assessing Vitamin D Nutritional Status

Growing awareness that vitamin D insufficiency has serious health consequences beyond rickets and osteomalacia highlights the need for accurate assessment of vitamin D nutritional status. Although there is general agreement that the serum 25(OH)D level is the best indicator of vitamin D deficiency and sufficiency, the cutoff values have not been clearly defined. While laboratory reference ranges for serum 25(OH)D levels are often based on average values from populations of healthy individuals, recent research suggests that health-based cutoff values aimed at preventing secondary hyperparathyroidism and bone loss should be considerably higher. In general, serum 25(OH)D values less than 20-25 nmol/L indicate severe deficiency associated with rickets and osteomalacia. Although 50 nmol/L has been suggested as the low end of the normal range, more recent research suggests that PTH levels and calcium absorption are not optimized until serum 25(OH)D levels reach approximately 80 nmol/L . Thus, at least one vitamin D expert has argued that serum 25(OH)D values less than 80 nmol/L should be considered deficient, while another suggests that a healthy serum 25(OH)D value is between 75 nmol/L and 125 nmol/L. Data from supplementation studies indicates that vitamin D intakes of at least 800-1,000 IU/day are required by adults living in temperate latitudes to achieve serum 25(OH)D levels of at least 80 nmol/L.

Disease Prevention

Osteoporosis

Although osteoporosis is a multifactorial disease, vitamin D insufficiency can be an important contributing factor. Without sufficient vitamin D, calcium absorption cannot be maximized and the resulting elevation in PTH secretion by the parathyroid glands results in increased bone resorption, which may lead to osteoporotic fracture. A prospective cohort study that followed more than 72,000 postmenopausal women in the U.S. for 18 years found that those who consumed at least 600 IU/day of vitamin D from diet and supplements had a risk of osteoporotic hip fracture that was 37% lower than women who consumed less than 140 IU/day. The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women who are unlikely to be getting enough vitamin D.

Supplementation of postmenopausal women in the U.S. with 500 mg/day of calcium and either 100 IU/day or 700 IU/day of vitamin D for two years slowed bone density losses at the hip only in the group taking 700 IU/day. Daily supplementation of elderly men and women with 500 mg/day of calcium and 700 IU/day of vitamin D for three years reduced bone density losses at the hip and spine and reduced the frequency of nonvertebral fractures. When the calcium and vitamin D supplements were discontinued, the bone density benefits were lost within 2 years. In Denmark, supplementation of elderly women with 400 IU/day of vitamin D for two years increased bone density at the hip.

An annual injection of 150,000-300,000 IU of vitamin D2 (ergocalciferol) for four years decreased the incidence of fracture in elderly Finnish women, and oral supplementation with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three years decreased the incidence of hip fracture in elderly French women. Oral supplementation of elderly adults in the UK with 100,000 IU of vitamin D once every four months (equivalent to about 800 IU/day) for five years reduced the risk of osteoporotic fracture by 33% compared to placebo. However, oral supplementation with 400 IU/day of vitamin D for more than 3 years did not affect the incidence of fracture in a study of elderly Dutch men and women. Overall, the evidence to date suggests that vitamin D supplements of about 800 IU/day may be helpful in reducing bone loss and fracture rates in the elderly. In order for vitamin D supplementation to be effective in preserving bone health, adequate calcium (1,000 to 1,200 mg/day) should also be consumed.

Cancer

Two characteristics of cancer cells are their lack of differentiation (specialization) and their rapid growth or proliferation. Many malignant tumors have been found to contain vitamin D receptors (VDR), including breast, lung, skin (melanoma), colon, and bone. Biologically active forms of vitamin D, such as 1,25(OH)2D and its analogs, have been found to induce cell differentiation and/or inhibit proliferation of a number of cancerous and noncancerous cell types maintained in cell culture.

Colorectal Cancer

The geographic distribution of colon cancer is similar to the historic geographic distribution of rickets, providing circumstantial evidence that decreased sunlight exposure and diminished vitamin D nutritional status may be related to an increased risk of colon cancer. However, prospective cohort studies have not generally found total vitamin D intake to be associated with significant reductions in colorectal cancer when other risk factors are taken into account. One five-year study of more than 120,000 people found that men with the highest vitamin D intakes had a risk of colorectal cancer that was 29% lower than men with the lowest vitamin D intakes. Vitamin D intake was not significantly associated with colorectal cancer risk in women. Serum 25(OH)D level, which reflects vitamin D intake and vitamin D synthesis, was inversely associated with the risk of potentially precancerous colorectal polyps and indices of colonic epithelial cell proliferation, which are considered biomarkers for colon cancer risk.

Breast Cancer

Although breast cancer mortality follows a similar geographic distribution to that of colon cancer, direct evidence of an association between vitamin D nutritional status and breast cancer risk is limited. A prospective study of women who participated in the first National Health and Nutrition Examination Survey (NHANES I) found that several measures of sunlight exposure and dietary vitamin D intake were associated with a reduced risk of breast cancer 20 years later. More recently, a 16-year study of more than 88,000 women found that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women.

Prostate Cancer

Epidemiological studies show correlations between risk factors for prostate cancer and conditions that can result in decreased vitamin D levels. Increased age is associated with an increased risk of prostate cancer, as well as with decreased sun exposure and decreased capacity to synthesize vitamin D. The incidence of prostate cancer is higher in African American men than in White American men, and the high melanin content of dark skin is known to reduce the efficiency of vitamin D synthesis. Geographically, mortality from prostate cancer is inversely associated with the availability of sunlight. Recent findings that prostate cells in culture can synthesize the 25(OH)D3-1-hydroxylase enzyme and that, unlike the renal enzyme, its synthesis is not influenced by PTH or calcium levels also provide support for the idea that increasing 25(OH)D levels may be useful in preventing prostate cancer. In contrast, prospective studies have not generally found significant relationships between serum 25(OH)D levels and subsequent risk of developing prostate cancer. Although a prospective study of Finnish men found that low serum 25(OH)D levels were associated with earlier and more aggressive prostate cancer development, another prospective study of men from Finland, Norway and Sweden found a U-shaped relationship between serum 25(OH)D levels and prostate cancer risk. In that study serum 25(OH)D concentrations of 19 nmol/L or lower and 80 nmol/L or higher were associated with higher prostate cancer risk. Further research is needed to determine the nature of the relationship between vitamin D nutritional status and prostate cancer risk.

Autoimmune Diseases

Insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and rheumatoid arthritis (RA) are each examples of autoimmune disease. Autoimmune diseases occur when the body mounts an immune response to its own tissue, rather than a foreign pathogen. In IDDM, insulin producing beta-cells of the pancreas are the target of the inappropriate immune response. In MS, the targets are the myelin producing cells of the central nervous system, and in RA, the targets are the collagen producing cells of the joints. Autoimmune responses are mediated by immune cells called T cells. The biologically active form of vitamin D, 1,25(OH)2D, has been found to modulate T cell responses, such that the autoimmune responses are diminished. Treatment with 1,25(OH)2D has beneficial effects in animal models of IDDM , MS, and RA. epidemiological studies have found that the prevalence of IDDM, MS, and RA increases as latitude increases, suggesting that lower exposure to UVB radiation and associated decreases in vitamin D synthesis may play a role in the pathology of these diseases. The results of several prospective cohort studies also suggest that adequate vitamin D intake may decrease the risk of autoimmune diseases. A prospective cohort study of children born in Finland during the year 1966 and followed for thirty years found that those who received vitamin D supplementation in the first year of life had a significantly lower risk of developing IDDM, while children suspected of developing rickets (severe vitamin D deficiency) during the first year of life had a significantly higher risk of developing IDDM. Vitamin D supplement use was associated with a significant reduction in the risk of developing MS in two large cohorts of women followed for at least ten years. Similarly, postmenopausal women with the highest total vitamin D intakes were at significantly lower risk of developing RA after eleven years of follow up than those with the lowest intakes. Evidence from animal models and epidemiological studies suggests that maintaining sufficient vitamin D levels may help decrease the risk of several autoimmune diseases.

Hypertension (High Blood Pressure)

The results of epidemiological and clinical studies suggest an inverse relationship between serum 1,25(OH)2D levels and blood pressure, which may be explained by recent findings that 1,25(OH)2D decreases the expression of the gene encoding renin (see Function). Data from epidemiological studies suggest that conditions that decrease vitamin D synthesis in the skin, such as having dark skin and living in temperate latitudes, are associated with increased prevalence of hypertension. A controlled clinical trial in 18 hypertensive men and women living in the Netherlands found that exposure to UVB radiation three times weekly for six weeks during the winter increased serum 25(OH)D levels and significantly decreased 24-hour ambulatory systolic and diastolic blood pressure measurements by an average of 6 mm Hg. In randomized controlled trials of vitamin D supplementation, a combination of 1,600 IU/day of vitamin D and 800 mg/day of calcium for eight weeks significantly decreased systolic blood pressure in elderly women by 9% compared to calcium alone, but supplementation with 400 IU/day or a single dose of 100,000 IU of vitamin D did not significantly lower blood pressure in elderly men and women over the next two months. At present, data from controlled clinical trials are too limited to determine whether vitamin D supplementation will be effective in lowering blood pressure or preventing hypertension.

Sources

Sunlight

Sunlight exposure provides most people with their entire vitamin D requirement. Children and young adults who spend a short time outside two or three times a week will generally synthesize all the vitamin D they need. The elderly have diminished capacity to synthesize vitamin D from sunlight exposure and frequently use sunscreen or protective clothing in order to prevent skin cancer and sun damage. The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95%. In latitudes around 40 degrees north or 40 degrees south (Boston is 42 degrees north), there is insufficient UVB radiation available for vitamin D synthesis from November to early March. Ten degrees farther north or south (Edmonton, Canada) this “vitamin D winter” extends from mid October to mid March. According to Dr. Michael Holick, as little as 5-10 minutes of sun exposure on arms and legs or face and arms three times weekly between 11:00 am and 2:00 pm during the spring, summer, and fall at 42 degrees latitude should provide a light-skinned individual with adequate vitamin D and allow for storage of any excess for use during the winter with minimal risk of skin damage.

Safety

Toxicity

Vitamin D toxicity (hypervitaminosis D) induces abnormally high serum calcium levels (hypercalcemia), which could result in bone loss, kidney stones, and calcification of organs like the heart and kidneys if untreated over a long period of time. When the Food and Nutrition Board of the Institute of Medicine established the tolerable upper intake level (UL) for vitamin D, published studies that adequately documented the lowest intake levels of vitamin D that induced hypercalcemia were very limited. Because the consequences of hypercalcemia are severe, the Food and Nutrition Board established a very conservative UL of 2,000 IU/day (50 mcg/day) for children and adults. Research published since 1997 suggests that the UL for adults is likely overly conservative and that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day. Vitamin D toxicity has not been observed to result from sun exposure. Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma. People with these conditions may develop hypercalcemia in response to any increase in vitamin D nutrition and should consult a qualified health care provider regarding any increase in vitamin D intake.

Drug interactions

The following medications increase the metabolism of vitamin D and may decrease serum 25(OH)D levels: phenytoin (Dilantin), fosphenytoin (Cerebyx), phenobarbital (Luminal), carbamazepine (Tegretol), and rifampin (Rimactane). The following medications should not be taken at the same time as vitamin D because they can decrease the intestinal absorption of vitamin D: cholestyramine (Questran), colestipol (Colestid), orlistat (Xenical), mineral oil, and the fat substitute Olestra. The oral anti-fungal medication, ketoconazole, inhibits the 25(OH)D3-1-hydroxylase enzyme and has been found to reduce serum levels of 1,25(OH)D in healthy men . The induction of hypercalcemia by toxic levels of vitamin D may precipitate cardiac arrhythmia in patients on digitalis (Digoxin).

Linus Pauling Institute Recommendation

The Linus Pauling Institute recommends that generally healthy adults take a multivitamin supplement that supplies 400 IU (10 mcg) of vitamin D daily. Additionally, at least 10-15 minutes of sun exposure on the arms and legs or face and arms at least three times weekly between 11:00 am and 2:00 pm during the spring, summer, and fall may help residents of temperate latitudes (much of the U.S.) avoid vitamin D deficiency at the end of winter.

Older adults (65 years and older) and people with minimal sun exposure

In addition to the 400 IU (10 mcg) of vitamin D provided by a multivitamin supplement, people over the age of 65 and people who get minimal sun exposure throughout the year should take an additional vitamin D supplement of 400 IU/day (10 mcg/day) to provide a total of 800 IU/day (20 mcg/day).

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/

Vitamin C

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin. Unlike most mammals, humans do not have the ability to make their own vitamin C. Therefore, we must obtain vitamin C through our diet.

Function

Vitamin C is required for the synthesis of collagen, an important structural component of blood vessels, tendons, ligaments, and bone. Vitamin C also plays an important role in the synthesis of the neurotransmitter, norepinephrine. Neurotransmitters are critical to brain function and are known to affect mood. In addition, vitamin C is required for the synthesis of carnitine, a small molecule that is essential for the transport of fat to cellular organelles called mitochondria, for conversion to energy.  Recent research also suggests that vitamin C is involved in the metabolism of cholesterol to bile acids, which may have implications for blood cholesterol levels and the incidence of gallstones.

Vitamin C is also a highly effective antioxidant. Even in small amounts vitamin C can protect indispensable molecules in the body, such as proteins, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA) from damage by free radicals and reactive oxygen species that can be generated during normal metabolism as well as through exposure to toxins and pollutants (e.g. smoking). Vitamin C may also be able to regenerate other antioxidants such as vitamin E.

Deficiency

Scurvy

Severe vitamin C deficiency has been known for many centuries as the potentially fatal disease, scurvy. By the late 1700's the British navy was aware that scurvy could be cured by eating oranges or lemons, even though vitamin C would not be isolated until the early 1930's. Symptoms of scurvy include bleeding and bruising easily, hair and tooth loss, joint pain and swelling. Such symptoms appear to be related to the weakening of blood vessels, connective tissue, and bone, which contain collagen. Early symptoms of scurvy such as fatigue may result from diminished levels of carnitine, needed to derive energy from fat, or decreased synthesis of the neurotransmitter norepinephrine (see Function). Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily. However, recent cases have occurred in children and the elderly on very restricted diets.

Disease Prevention

The amount of vitamin C required to prevent chronic disease appears to be more than that required for prevention of scurvy. Much of the information regarding vitamin C and the prevention of chronic disease is based on prospective studies, in which vitamin C intake is assessed in large numbers of people who are followed over time to determine whether they develop specific chronic diseases.

Cardiovascular Disease

Coronary Heart Disease

Until recently, the results of most prospective studies indicated that low or deficient intakes of vitamin C were associated with an increased risk of cardiovascular diseases and that modest dietary intakes of about 100 mg/day were sufficient for maximum reduction of cardiovascular disease risk among nonsmoking men and women. In addition, several studies had failed to find significant reductions in the risk of coronary heart disease (CHD) among vitamin C supplement users in well-nourished populations. One notable exception was the First National Health and Nutrition Examination Study (NHANES I) Epidemiologic Follow-up Study. This study found that the risk of death from cardiovascular diseases was 42% lower in men and 25% lower in women who consumed more than 50 mg/day of dietary vitamin C and who regularly took vitamin C supplements, corresponding to a total vitamin C intake of about 300 mg/day. Results from the Nurses’ Health Study, based on the follow-up of more than 85,000 women over 16 years, also suggest that higher vitamin C intakes may be cardioprotective. In this study, vitamin C intakes of more than 359 mg/day from diet plus supplements or supplement use itself were associated with a 27-28% reduction in CHD risk. However, in those women who did not take vitamin C supplements, dietary vitamin C intake was not significantly associated with CHD risk. More recently, a pooled analysis of 9 prospective cohort studies, including more than 290,000 adults who were free of CHD at baseline and followed for an average of 10 years, found that those who took more than 700 mg/day of supplemental vitamin C had a 25% lower risk of CHD than those who did not take vitamin C supplements. Data from the National Institutes of Health (NIH) indicate that plasma and circulating cells in healthy, young subjects became fully saturated with vitamin C at a dose of about 400 mg/day. The results of the pooled analysis of prospective cohort studies suggest that maximum reduction of CHD risk may require vitamin C intakes high enough to saturate plasma and circulating cells, and thus the vitamin C body pool.

Stroke

With respect to vitamin C and cerebrovascular disease, a prospective study that followed more than 2,000 residents of a rural Japanese community for 20 years found that the risk of stroke in those with the highest serum levels of vitamin C was 29% lower than in those with the lowest serum levels of vitamin C. Additionally, the risk of stroke in those who consumed vegetables 6-7 days of the week was 54% lower than in those who consumed vegetables 0-2 days of the week. In this population, serum levels of vitamin C were highly correlated with fruit and vegetable intakes. Therefore, as in many studies of vitamin C intake and cardiovascular disease risk, it is difficult to separate the effects of vitamin C on stroke risk from the effects of other components of fruits and vegetables, emphasizing the benefits of a diet rich in fruits and vegetables.

Cancer

A large number of studies have shown that increased consumption of fresh fruits and vegetables is associated with a reduced risk for most types of cancer. Such studies are the basis for dietary guidelines endorsed by the U.S. Department of Agriculture and the National Cancer Institute, which recommend at least 5 servings of fruits and vegetables per day. A number of case-control studies have investigated the role of vitamin C in cancer prevention.  Most have shown that higher intakes of vitamin C are associated with decreased incidence of cancers of the mouth, throat and vocal chords, esophagus, stomach, colon-rectum, and lung. Because the possibility of bias is greater in case-control studies, prospective studies are generally given more weight in the evaluation of the effect of nutrient intake on disease.  In general, prospective studies in which the lowest intake group consumed more than 86 mg of vitamin C daily have not found differences in cancer risk, while studies finding significant cancer risk reductions found them in people consuming at least 80 to 110 mg of vitamin C daily.

A prospective study of 870 men over a period of 25 years found that those who consumed more than 83 mg of vitamin C daily had a striking 64% reduction in lung cancer compared with those who consumed less than 63 mg per day. Although most large prospective studies found no association between breast cancer and vitamin C intake, two recent studies found dietary vitamin C intake to be inversely associated with breast cancer risk in certain subgroups. In the Nurses' Health Study, premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of vitamin C from foods had a 63% lower risk of breast cancer than those who consumed an average of 70 mg/day. In the Swedish Mammography Cohort, women who were overweight and consumed an average of 110 mg/day of vitamin C had a 39% lower risk of breast cancer compared to overweight women who consumed an average of 31 mg/day. A number of observational studies have found increased dietary vitamin C intake to be associated with decreased risk of stomach cancer, and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic compounds in the stomach. Infection with the bacteria, helicobacter pylori (H. pylori) is known to increase the risk of stomach cancer and also appears to lower the vitamin C content of stomach secretions. Although two intervention studies did not find a decrease in the occurrence of stomach cancer with vitamin C supplementation, more recent research suggests that vitamin C supplementation may be a useful addition to standard H. pylori eradication therapy in reducing the risk of gastric cancer.

Cataracts

Cataracts are a leading cause of visual impairment throughout the world. In the U.S., cataract-related expenditure is estimated to exceed 3 billion dollars annually. Cataracts occur more frequently and become more severe as people age. Decreased vitamin C levels in the lens of the eye have been associated with increased severity of cataracts in humans. Some, but not all, studies have observed increased dietary vitamin C intake and increased blood levels of vitamin C to be associated with decreased risk of cataracts. Those studies that have found a relationship suggest that vitamin C intake may have to be higher than 300 mg/day for a number of years before a protective effect can be detected. Recently, a 7-year controlled intervention trial of a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene in 4,629 men and women found no difference between the antioxidant combination and a placebo on the development and progression of age-related cataracts. Therefore, the relationship between vitamin C intake and the development of cataracts requires further clarification before specific recommendations can be made.

Lead toxicity

Although the use of lead paint and leaded gasoline has been discontinued in the U.S., lead toxicity continues to be a significant health problem, especially in children living in urban areas. Abnormal growth and development has been observed in infants of women exposed to lead during pregnancy, while children who are chronically exposed to lead are more likely to develop learning disabilities, behavioral problems, and to have low IQs. In adults, lead toxicity may result in kidney damage and high blood pressure. In a study of 747 older men, blood lead levels were significantly higher in those who reported total dietary vitamin C intakes averaging less than 109 mg/day compared to men who reported higher vitamin C intakes. A much larger study of 19,578 people, including 4,214 children from 6 to 16 years of age, found higher serum vitamin C levels to be associated with significantly lower blood lead level (26). An intervention trial that examined the effects of vitamin C supplementation on blood lead levels in 75 adult male smokers found that 1,000 mg/day of vitamin C resulted in significantly lower blood lead levels over a 4-week treatment period compared to placebo. A lower dose of 200 mg/day did not significantly affect blood lead levels, despite the finding that serum vitamin C levels were not different than those of the group that took 1,000 mg/day. The mechanism for the relationship between vitamin C intake and blood lead levels is not known, although it has been postulated that vitamin C may inhibit intestinal absorption or enhance urinary excretion of lead.

Disease Treatment

Cardiovascular Disease

Vasodilation

The ability of blood vessels to relax or dilate is compromised in individuals with atherosclerosis.  The damage to the heart muscle caused by a heart attack and damage to the brain caused by a stroke is related, in part, to the inability of blood vessels to dilate enough to allow blood flow to the affected areas.  The pain of angina pectoris is also related to insufficient dilation of the coronary arteries.  Treatment with vitamin C has consistently resulted in improved dilation of blood vessels in individuals with atherosclerosis as well as those with angina pectoris, congestive heart failure, high cholesterol, and high blood pressure.  Improved blood vessel dilation has been demonstrated at a dose of 500 mg of vitamin C daily.

Hypertension

Individuals with high blood pressure (hypertension) are at increased risk of developing cardiovascular diseases.  Several studies have demonstrated a blood pressure lowering effect of vitamin C supplementation. One recent study of individuals with high blood pressure found that a daily supplement of 500 mg of vitamin C resulted in an average drop in systolic blood pressure of 9% after 4 weeks. It should be noted that those participants who were taking antihypertensive medication continued taking it throughout the 4-week study. Because the findings regarding vitamin C and high blood pressure have not yet been replicated in larger studies it is important for individuals with significantly high blood pressure to continue current therapy (medication, lifestyle changes, etc.) in consultation with their health care provider.

Cancer

Studies in the 1970's and 1980's conducted by Linus Pauling and colleagues suggested that very large doses of vitamin C (10 grams/day intravenously for 10 days followed by at least 10 grams/day orally indefinitely) were helpful in increasing the survival time and improving the quality of life of terminal cancer patients. However, two randomized placebo-controlled studies conducted at the Mayo clinic found no differences in outcome between terminal cancer patients receiving 10 grams of vitamin C/day orally or placebo There were significant methodological differences between the Mayo Clinic and Pauling's studies, and recently, two researchers from the NIH suggested that the route of administration (intravenous versus oral) may have been the key to the discrepant results. Intravenous (IV) administration can result in much higher blood levels of vitamin C than oral administration, and levels that are toxic to certain types of cancer cells in culture can be achieved with intravenous but not oral administration of vitamin C. Thus, it appears reasonable to reevaluate the use of high-dose vitamin C as cancer therapy.

Currently, there are no results from controlled clinical trials indicating that vitamin C would adversely affect the survival of cancer patients. However, vitamin C should not be used in place of  therapy that has been demonstrated effective in the treatment of a particular type of cancer, for example, chemotherapy or radiation therapy.  If an individual with cancer chooses to take vitamin supplements, it is important that the clinician coordinating his or her treatment is aware of the type and dose of each supplement. While research is underway to determine whether combinations of antioxidant vitamins might be beneficial as an adjunct to conventional cancer therapy, definitive conclusions are not yet possible.

In a presentation at a meeting of the American Cancer Society, a scientist suggested that supplemental vitamin C might enhance the growth of cancer cells or protect them from cell-killing free radicals produced by radiation and some forms of chemotherapy.  An article published in the Spring/Summer 2000 issue of the Linus Pauling Institute newsletter, Is vitamin C harmful for cancer patients?, provides additional insight on this topic.

Diabetes Mellitus

Cardiovascular diseases (heart disease and stroke) are the leading cause of death in individuals with diabetes. Evidence that diabetes is a condition of increased oxidative stress led to the hypothesis that higher intakes of antioxidant nutrients could help decrease cardiovascular disease risk in diabetic individuals. In support of this hypothesis, a 16-year study of 85,000 women, 2% of whom were diabetic, found that vitamin C supplement use (400 mg/day or more) was associated with significant reductions in the risk of fatal and nonfatal coronary heart disease in the entire cohort as well as those with diabetes. In contrast, a 15-year study of postmenopausal women found that diabetic women who reported taking at least 300 mg/day of vitamin C from supplements when the study began were at significantly higher risk of death from coronary heart disease and stroke than those who did not take vitamin C supplements. Vitamin C supplement use was not associated with a significant increase in cardiovascular disease mortality in the cohort as a whole. Although a number of observational studies have found that higher dietary intakes of vitamin C are associated with lower cardiovascular disease risk, randomized controlled trials have not found antioxidant supplementation that included vitamin C to reduce the risk of cardiovascular disease in diabetic or other high-risk individuals.

It is possible that genetic differences may influence the effect of vitamin C supplementation on cardiovascular disease. When the results of one randomized controlled trial were reanalyzed based on haptoglobin genotype, antioxidant therapy (1000 mg/d vitamin C + 800 IU/d vitamin E) was associated with improvement of coronary atherosclerosis in diabetic women with two copies of the haptoglobin 1 gene but worsening of coronary atherosclerosis in those with two copies of the haptoglobin 2 gene. The significance of these findings is not entirely clear, but they suggest that there may be a subpopulation of people with diabetes who will benefit from antioxidant therapy while others may not benefit or could actually be harmed. Since randomized controlled trials have not found that supplementation with vitamin C is beneficial in preventing or treating heart disease in individuals with diabetes, individuals with diabetes should avoid consuming more than 250 mg/day from vitamin C supplements until more research is available. Since vitamin C intake from foods was not associated with increased mortality from cardiovascular disease, there is no reason to limit the intake of vitamin C-rich fruits and vegetables.

Common cold

The work of Linus Pauling stimulated public interest in the use of large doses (greater than 1 g/day) of vitamin C to prevent the common cold. In the past 30 years, numerous placebo-controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A meta-analysis of 30 placebo-controlled prevention trials found that vitamin C supplementation in doses up to 2 g/day did not decrease the incidence of colds. However, in a subgroup of marathon runners, skiers and soldiers training in the Arctic, doses ranging from 250 mg/day to 1 g/day decreased the incidence of colds by 50%. Overall, the preventive use of vitamin C supplementation reduced the duration of colds by about 8% in adults and 14% in children. Most of the prevention trials used a dose of 1 g/day. When treatment was started at the onset of symptoms, vitamin C supplementation did not shorten the duration of colds in 7 placebo-controlled trials at doses ranging from 1-4 g/day. For a more detailed discussion on vitamin C and the common cold, see the Linus Pauling Institute's Spring/Summer 2006 Research Newsletter.

Natural vs. synthetic vitamin C

Natural and synthetic L-ascorbic acid are chemically identical and there are no known differences in their biological activities or bioavailability.

Mineral ascorbates

Mineral salts of ascorbic acid are buffered and therefore, less acidic than ascorbic acid. Some people find them less irritating to the gastrointestinal tract than ascorbic acid. Sodium ascorbate and calcium ascorbate are the most common forms, although a number of other mineral ascorbates are available. Sodium ascorbate generally provides 131 mg of sodium per 1,000 mg of ascorbic acid, and pure calcium ascorbate provides 114 mg of calcium per 1,000 mg of ascorbic acid.

Vitamin C with bioflavonoids

Bioflavonoids are a class of water-soluble plant pigments that are often found in vitamin C-rich fruits and vegetables, especially citrus fruits. Although many bioflavonoids are thought to function as antioxidants, there is little evidence that the bioflavonoids in most commercial preparations increase the bioavailability or efficacy of vitamin C.

Ascorbate and vitamin C metabolites

One such supplement (Ester-C®) contains mainly calcium ascorbate, but also contains small amounts of the vitamin C metabolites dehydroascorbate (oxidized ascorbic acid), calcium threonate, and trace levels of xylonate and lyxonate. Although the metabolites are supposed to increase the bioavailability of vitamin C, the only published study in humans found no difference between Ester-C® and commercially available ascorbic acid tablets with respect to the absorption and urinary excretion of vitamin C. Ester-C® should not be confused with ascorbyl palmitate, which is also marketed as "vitamin C ester" (see below).

Ascorbyl palmitate

Ascorbyl palmitate is actually a vitamin C ester (vitamin C that has been esterified to a fatty acid). In this case, vitamin C is esterified to the saturated fatty acid, palmitic acid, resulting in a fat-soluble form of vitamin C. Ascorbyl palmitate has been added to a number of skin creams due to interest in its antioxidant properties as well as the important role of vitamin C in collagen synthesis. Although ascorbyl palmitate is also available as an oral supplement, it is likely that most of it is hydrolyzed (broken apart) to ascorbic acid and palmitic acid in the digestive tract before it is absorbed (44). Ascorbyl palmitate is also marketed as, "vitamin C ester," which should not be confused with Ester-C® (see above).

For a more detailed review of scientific research on the bioavailability of different forms of vitamin C, see The Bioavailability of Different Forms of Vitamin C.

Toxicity

A number of possible problems with very large doses of vitamin C have been suggested, mainly based on in vitro experiments or isolated case reports, including: genetic mutations, birth defects, cancer, atherosclerosis, kidney stones, "rebound scurvy", increased oxidative stress, excess iron absorption, vitamin B-12 deficiency, and erosion of dental enamel. However, none of these adverse health effects have been confirmed, and there is no reliable scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults) are toxic or detrimental to health. With the latest RDA published in 2000, a tolerable upper intake level (UL) for vitamin C was set for the first time. A UL of 2 grams (2,000 milligrams) daily was recommended in order to prevent most adults from experiencing diarrhea and gastrointestinal disturbances. Such symptoms are not generally serious, especially if they resolve with temporary discontinuation or reduction of high-dose vitamin C supplementation. For a more thorough discussion of the Linus Pauling Institute's response to the UL for vitamin C, see the article, The New Recommendations for Dietary Antioxidants: A Response and Position Statement by the Linus Pauling Institute, in the Spring/Summer 2000 newsletter. A more detailed discussion of vitamin C and the risk of kidney stones can be found in the article, What About Vitamin C and Kidney Stones?, in the Fall/Winter 1999 newsletter.

Does vitamin C promote oxidative damage under physiological conditions? Vitamin C is known to function as a highly effective antioxidant in living organisms. However, in test tube experiments, vitamin C can interact with some free metal ions to produce potentially damaging free radicals. Although free metal ions are not generally found under physiological conditions, the idea that high doses of vitamin C might be able to promote oxidative damage in vivo has received a great deal of attention. Widespread publicity has been given to a few studies suggesting a pro-oxidant effect of vitamin C, but these studies turned out to be either flawed or of no physiological relevance. A recent comprehensive review of the literature found no credible scientific evidence that supplemental vitamin C promotes oxidative damage under physiological conditions or in humans. Studies that report a pro-oxidant effect for vitamin C should be evaluated carefully to determine whether the study system was physiologically relevant, and to rule out the possibility of methodological and design flaws.

For example, a study in the June 15, 2001, issue of the journal Science shows that lipid hydroperoxides (rancid fat molecules) can react with vitamin C to form products that could potentially harm DNA, although the reaction of these products with DNA was not demonstrated in the study. To find out why the Linus Pauling Institute considers the study's conclusions unwarranted, see Vitamin C doesn't cause cancer! in the Linus Pauling Institute Newsletter.

Drug Interactions

A number of drugs are known to lower vitamin C levels, requiring an increase in its intake. Estrogen-containing contraceptives (birth control pills) are known to lower vitamin C levels in plasma and white blood cells. Aspirin can lower vitamin C levels if taken frequently.  For example, two aspirin tablets taken every six hours for a week has been reported to lower white blood cell vitamin C by 50%, primarily by increasing urinary excretion of vitamin C.

There is some evidence, though controversial, that vitamin C interacts with anticoagulant medications (blood thinners) such as warfarin (Coumadin).  Large doses of vitamin C may block the action of warfarin, requiring an increase in dose to maintain its effectiveness. Individuals on anticoagulants should limit their vitamin C intake to 1 gram/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy. Because high doses of vitamin C have also been found to interfere with the interpretation of certain laboratory tests (e.g., serum bilirubin, serum creatinine, and the guaiac assay for occult blood) it is important to inform one's health care provider of any recent supplement use.

Antioxidant Supplements and HMG-CoA Reductase Inhibitors (Statins)

A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction (heart attack) and stroke. Surprisingly, when an antioxidant combination (1,000 mg vitamin C, 800 IU alpha-tocopherol, 100 mcg selenium, and 25 mg beta-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of vitamin C cannot be determined. In contrast, a much larger randomized controlled trial of simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) in more than 20,000 men and women with coronary artery disease or diabetes found that the antioxidant combination did not diminish the cardioprotective effects of simvastatin therapy over a 5-year period. These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering agents, such as HMG-CoA reductase inhibitors (statins).

Linus Pauling Institute Recommendations

The Linus Pauling Institute recommends a vitamin C intake of at least 400 mg daily—the amount that has been found to fully saturate plasma and circulating cells with vitamin C in young, healthy nonsmokers. Consuming at least five servings (2½ cups) of fruits and vegetables daily may provide about 200 mg of vitamin C. Most multivitamin supplements provide 60 mg of vitamin C.

Older adults (65 years and older)

Although it is not yet known with certainty whether older adults have higher requirements for vitamin C than younger people, some older populations have been found to have vitamin C intakes considerably below the RDA of 75 and 90 mg/day for women and men, respectively. A vitamin C intake of at least 400 mg daily may be particularly important for older adults who are at higher risk for chronic diseases.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/

Vitamin B12

Vitamin B12 is the largest and most complex of all the vitamins. It is unique among vitamins in that it contains a metal ion, cobalt. For this reason cobalamin is the term used to refer to compounds having B12 activity. Methylcobalamin and 5-deoxyadenosyl cobalamin are the forms of vitamin B12 used in the human body. The form of cobalamin used in most supplements, cyanocobalamin, is readily converted to 5-deoxyadenosyl and methylcobalamin.

Function

Cofactor for methionine synthase

Methylcobalamin is required for the function of the folate-dependent enzyme, methionine synthase. This enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA. Methylation of DNA may be important in cancer prevention. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular diseases (diagram).

Cofactor for L-methylmalonyl-CoA mutase

5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA. This biochemical reaction plays an important role in the production of energy from fats and proteins. Succinyl CoA is also required for the synthesis of hemoglobin, the oxygen carrying pigment in red blood cells.

Deficiency

Vitamin B12 deficiency is estimated to affect 10%-15% of individuals over the age of 60. Absorption of vitamin B12 from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B12 from food, allowing it to bind to other proteins, known as R proteins. In the alkaline environment of the small intestine, R proteins are degraded by pancreatic enzymes, freeing vitamin B12 to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach. Receptors on the surface of the small intestine take up the IF-B12 complex only in the presence of calcium, which is also supplied by the pancreas. Vitamin B12 can also be absorbed by passive diffusion, but this process is very inefficient, allowing only about 1% absorption of a vitamin B12 dose.

Causes of vitamin B12 deficiency

The most common causes of vitamin B12 deficiency are 1) an autoimmune condition known as pernicious anemia and 2) food-bound vitamin B12 malabsorption. Although both causes become more common with age, they are two separate conditions.

Pernicious anemia

Pernicious anemia has been estimated to be present in approximately 2 % of individuals over 60. Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach, resulting in destruction of stomach cells by one's own antibodies. Progressive destruction of the cells that line the stomach cause decreased secretion of acid and enzymes required to release food bound vitamin B12. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. If the body's vitamin B12 stores are adequate prior to the onset of pernicious anemia, it may take years for symptoms of deficiency to develop. About 20% of the relatives of pernicious anemia patients also have pernicious anemia, suggesting a genetic predisposition. Treatment of pernicious anemia generally requires injections of vitamin B12, bypassing intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 mcg (1 mg)/day of vitamin B12 orally should result in the absorption of about 10 mcg/day (about 1%) by passive diffusion.

Food-bound vitamin B12 malabsorption

Food-bound vitamin B12 malabsorption is defined as an impaired ability to absorb food or protein-bound vitamin B12, although the free form is fully absorbable. In the elderly, food-bound vitamin B12 malabsorption is thought to result mainly from atrophic gastritis, a chronic inflammation of the lining of the stomach, which ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production. Because stomach acid is required for the release of vitamin B12 from the proteins in food, vitamin B12 absorption is diminished. Decreased stomach acid production also provides an environment more conducive to the overgrowth of anaerobic bacteria in the stomach, interfering further with vitamin B12 absorption. Because vitamin B12 in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B12 is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B12 malabsorption do not have an increased requirement for vitamin B12; they simply need it in the form of a supplement rather than from food.

Atrophic gastritis

Atrophic gastritis is thought to affect 10% - 30% of people over 60 years of age, and is frequently associated with infection by the bacteria, Heliobacter pylori. H. pylori infection induces a chronic inflammation of the stomach which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals. The relationship of H. pylori infection to atrophic gastritis, gastric cancer, and vitamin B12 deficiency is presently an area of active research.

Other causes of vitamin B12 deficiency

Other causes of deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B12 complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B12 deficiency. Because the pancreas provides critical enzymes as well as calcium required for vitamin B12 absorption, pancreatic insufficiency may contribute to B12 deficiency. Since vitamin B12 is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B12 deficiency. In alcoholics, vitamin B12 intake and absorption are reduced, while elimination is increased. Individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B12 receptor to take up the IF-B12 complex. Long-term use of acid-reducing drugs has also been implicated in vitamin B12 deficiency (see Drug interactions).

Symptoms of vitamin B12 deficiency

Vitamin B12 deficiency results in impairment of the activities of B12-requiring enzymes. Impaired activity of methionine synthase may result in elevated homocysteine levels, while impaired activity of L-methylmalonyl-CoA mutase results in increased levels of a metabolite of methylmalonyl-CoA, called methylmalonic acid (MMA). Individuals with mild vitamin B12 deficiency may not experience symptoms, although blood levels of homocysteine and/or MMA may be elevated.

Megaloblastic anemia

Diminished activity of methionine synthase in vitamin B12 deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body (diagram), resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B12 deficiency, folate is unavailable to participate in DNA synthesis. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, hemoglobin-poor red blood cells. The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named. Supplementation of folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B12 deficiency was the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined.

Neurologic symptoms

The neurologic symptoms of vitamin B12 deficiency include numbness and tingling of the arms and more commonly the legs, difficulty walking, memory loss, disorientation, and dementia, with or without mood changes. Although the progression of neurologic complications is generally gradual, they are not always reversible with treatment of vitamin B12 deficiency, especially if they have been present for a long time. Neurologic complications are not always associated with megaloblastic anemia, and are the only clinical symptom of vitamin B12 deficiency in about 25% of cases. Although vitamin B12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in B12 deficiency are not well understood.

Gastrointestinal symptoms

A sore tongue, appetite loss, and constipation have also been associated with vitamin B12 deficiency. Their origins are unclear, but may be related to the stomach inflammation underlying some cases of B12 deficiency, or the increased vulnerability of the rapidly dividing cells along the gastrointestinal tract to impaired DNA synthesis.

Disease Prevention

Homocysteine and cardiovascular disease

Evidence is mounting that an elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases, including heart disease, stroke, and peripheral vascular disease. The amount of homocysteine in the blood is regulated by at least three vitamins: folate, vitamin B12, and vitamin B6 (diagram). Analysis of the results of 12 homocysteine-lowering trials showed folic acid supplementation (0.5-5 mg/day) to have the greatest lowering effect on blood homocysteine levels (25%), with vitamin B12 (0.5 mg/day or 500 mcg/day) providing an additional 7% reduction. The results of a sequential supplementation trial in 53 men and women indicated that after folic acid supplementation, vitamin B12 became the major determinant of plasma homocysteine. Some evidence indicates that vitamin B12 deficiency is a major cause of elevated homocysteine levels in people over the age of 60. Two studies found blood methylmalonic acid (MMA) levels to be elevated in more than 60 % of elderly individuals with elevated homocysteine levels. An elevated MMA level in conjuction with elevated homocysteine suggests either a vitamin B12 deficiency, or a combined B12 and folate deficiency, in the absence of impaired kidney function. Thus, it is important to evaluate vitamin B12 status as well as kidney function in older individuals with elevated homocysteine levels, prior to initiating homocysteine-lowering therapy. For more information regarding homocysteine and cardiovascular diseases, see folic acid.

Cancer

Folate is required for synthesis of DNA, and there is evidence that decreased availability of folate results in strands of DNA that are more susceptible to damage. Deficiency of vitamin B12 traps folate in a form that is unusable by the body for DNA synthesis. Both vitamin B12 and folate deficiencies result in a diminished capacity for methylation reactions (diagram). Thus, vitamin B12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA, both of which are important risk factors for cancer. A recent series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B12 in the blood were associated with a biomarker of chromosome breakage in white blood cells. In a double blind, placebo-controlled study the same biomarker of choromosome breakage was minimized in young adults who were supplemented with 700 mcg of folic acid and 7 mcg of vitamin B12 daily in cereal for two months.

Breast cancer

A case-control study compared prediagnostic levels of serum folate, vitamin B6, and vitamin B12 in 195 women later diagnosed with breast cancer and 195 age-matched women who were not diagnosed with breast cancer. Among women who were postmenopausal at the time of blood donation, the association between blood levels of vitamin B12 and breast cancer suggested a threshold effect. The risk of breast cancer was more than doubled in those women with serum vitamin B12 levels in the lowest quintile (1/5) compared to those women in the four highest quintiles. The investigators found no relationship between breast cancer and serum levels of vitamin B6, folate, or homocysteine. Because this study was observational, it cannot be determined whether decreased serum levels of vitamin B12 were a cause or a result of breast cancer. Previously, there has been little evidence to suggest a relationship between vitamin B12 status and breast cancer risk. However, the above studies point to a need for further investigation of the relationship between vitamin B12 status and cancer risk.

Neural tube defects

Neural tube defects (NTD) may result in anencephaly or spina bifida, devastating and sometimes fatal birth defects. The defects occur between the 21st and 27th days after conception, a time when many women do not realize they are pregnant. Randomized controlled trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the month before and the month after conception. Increasing evidence indicates that the homocysteine-lowering effect of folic acid plays a critical role in lowering the risk of NTD. Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B12 for effective functioning of the methionine synthase enzyme. Decreased vitamin B12 levels in the blood and amniotic fluid of pregnant women have been associated with an increased risk of NTD, suggesting that adequate vitamin B12 intake in addition to folic acid may be beneficial in the prevention of NTD.

Alzheimer's disease and dementia

Individuals with Alzheimer's disease often have low blood levels of vitamin B12. One study found lower vitamin B12 levels in the cerebrospinal fluid of patients with Alzheimer's disease than in patients with other types of dementia, though blood levels of vitamin B12 did not differ. The reason for the association of low vitamin B12 status with Alzheimer's disease is not clear. Vitamin B12 deficiency, like folate deficiency, may lead to decreased synthesis of methionine and S-adenosylmethionine, adversely affecting methylation reactions essential for the metabolism of components of the myelin sheath of nerve cells, as well as neurotransmitters. Moderately increased homocysteine levels, as well as decreased folate and vitamin B12 levels have also been associated with Alzheimer's disease and vascular dementia. A case-control study of 164 patients with dementia of Alzheimer's type included 76 cases in which the diagnosis of Alzheimer's disease was confirmed by examination of the brain cells after death. Compared to 108 control subjects without evidence of dementia, subjects with dementia of Alzheimer's type and confirmed Alzheimer's disease had higher blood homocysteine levels and lower folate and vitamin B12 levels. Measures of general nutritional status indicated that the association of increased homocysteine levels and diminished vitamin B12 status with Alzheimer's disease was not due to dementia-related malnutrition. Low serum vitamin B12 (< 150 pmol/L) or folate (< 10 nmol/L) levels were associated with a doubling of the risk of developing Alzheimer's disease in 370 elderly men and women followed over 3 years. In a sample of 1092 men and women without dementia followed for an average of 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia. Those with plasma homocysteine levels greater than 14 mmol/L had nearly double the risk of developing Alzheimer's disease.

Depression

Observational studies have found as many as 30% of patients hospitalized for depression to be deficient in vitamin B12. A recent cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B12 deficient women were twice as likely to be severely depressed as non-deficient women. The reasons for the relationship between vitamin B12 deficiency and depression are not clear. Vitamin B12 and folate are required for the synthesis of S-adenosylmethionine, a methyl group donor essential for the metabolism of neurotransmitters, whose bioavailability has been related to depression. Because few studies have examined the relationship of vitamin B12 status and the development of depression over time, it cannot yet be determined if vitamin B12 deficiency plays a causal role in depression. However, due to the high prevalence of vitamin B12 deficiency in older individuals, it may be beneficial to screen them for vitamin B12 deficiency as part of a medical evaluation for depression.

Safety

Toxicity

No toxic or adverse effects have been associated with large intakes of vitamin B12 from food or supplements in healthy people. Doses as high as 1 mg (1000 mcg) daily by mouth or 1 mg monthly by intramuscular (IM) injection have been used to treat pernicious anemia, without significant side effects. When high doses of vitamin B12 are given orally only a small percentage can be absorbed, which may explain its low toxicity. Because of the low toxicity of vitamin B12, no tolerable upper intake level (UL) was set by the Food and Nutrition Board in 1998 when the RDA was revised.

Drug interactions

A number of drugs reduce the absorption of vitamin B12. Proton pump inhibitors (e.g., omeprazole and lansoprazole), used for therapy of Zollinger-Ellison syndrome and gastroesophageal reflux disease (GERD), markedly decrease stomach acid secretion required for the release of vitamin B12 from food but not supplements. Long-term use of proton pump inhibitors has been found to decrease blood vitamin B12 levels. However, vitamin B12 deficiency does not generally develop until after at least three years of continuous therapy. Another class of gastric acid inhibitors known as H2-receptor antagonists (e.g., Tagamet, Pepsid, Zantac), often used to treat peptic ulcer disease, has also been found to decrease the absorption of vitamin B12 from food. Because inhibition of gastric acid secretion is not as prolonged as with proton pump inhibitors H2-receptor antagonists have not been found to cause overt vitamin B12 deficiency even after long-term use. Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B12 in the form of a supplement, because gastric acid is not required for its absorption. Other drugs found to inhibit the absorption of vitamin B12 from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol, neomycin (antibiotics), and colchicine (anti-gout). Metformin, a medication for individuals with type 2 (non-insulin dependent) diabetes, decreases vitamin B12 absorption by tying up free calcium required for absorption of the IF- B12 complex. This effect is correctable by drinking milk or taking calcium carbonate tablets along with food or supplements. Previous reports that megadoses of vitamin C resulted in the destruction of vitamin B12 have not been supported and may have been an artifact of the assay used to measure vitamin B12 levels.

Nitrous oxide, a commonly used anesthetic inhibits both vitamin B12 dependent enzymes and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy. Because nitrous oxide is commonly used for surgery in the elderly, some experts feel vitamin B12 deficiency should be ruled out prior to its use.

Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. For this reason the Food and Nutrition Board of the Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1000 mcg (1 mg) daily.

Linus Pauling Institute Recommendation

A varied diet should provide enough vitamin B12 to prevent deficiency in most individuals 50 years of age and younger. Individuals over the age of 50, strict vegetarians, and women planning to become pregnant should take a multivitamin tablet daily or eat a fortified breakfast cereal, which would ensure a daily intake of 6 to 30 mcg of vitamin B12 in a form that is easily absorbed.

Older adults (65 years and over)

Because vitamin B12 malabsorption and vitamin B12 deficiency are more common in older adults, some respected nutritionists recommend 100 to 400 mcg/day of supplemental vitamin B12, an amount provided by a number of vitamin B-complex supplements.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/