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Summary

  • Riboflavin is the precursor of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). They act as electron carriers in a number of oxidation-reduction (redox) reactions involved in energy production and in numerous metabolic pathways. (More information)
  • Riboflavin deficiency can affect multiple pathways in the metabolism of vitamin B6, folate, niacin, and iron. (More information)
  • Riboflavin deficiency has been linked to preeclampsia in pregnant women. This condition may progress to eclampsia and cause severe bleeding and death. The risk of preeclampsia has recently been associated with the presence of a genetic variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme, which is FAD-dependent. (More information)
  • Oxidative stress can cause opacification of the eye lens, leading to cataracts in older individuals. While the results of some observational studies are promising, intervention studies are needed to assess a potential benefit of riboflavin in the prevention of cataracts. (More information)
  • Riboflavin (in the form, FAD) is required as a cofactor for the key folate-metabolizing enzyme, MTHFR. A low status of riboflavin status may interfere with the metabolism of folate, particularly in individuals homozygous for the MTHFR C677T gene variant; these individuals exhibit a higher risk of cardiovascular disease (CVD). Emerging evidence from intervention trials supports a protective role for riboflavin against hypertension in individuals with the MTHFR 677TT genotype. (More information)
  • Riboflavin has been evaluated as a prophylactic agent in studies with children and adults suffering from migraine headache. Riboflavin supplementation has been shown to decrease the frequency and severity of headache attacks in adults but not in children. (More information)
  • Case reports have shown that patients with autosomal recessive disorders of riboflavin metabolism may benefit from riboflavin supplementation. (More information)
  • Riboflavin has been evaluated as a potential adjunct therapy in cancer and certain eye disorders. (More information)

Riboflavin is a water-soluble B vitamin, also known as vitamin B2. In the body, riboflavin is primarily found as an integral component of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (1). Coenzymes derived from riboflavin are termed flavocoenzymes, and enzymes that use a flavocoenzyme are called flavoproteins (2).

Function

Oxidation-reduction (redox) reactions

Living organisms derive most of their energy from redox reactions, which are processes that involve the transfer of electrons. Flavocoenzymes participate in redox reactions in numerous metabolic pathways (3). They are critical for the metabolism of carbohydrates, lipids, and proteins. FAD is part of the electron transport (respiratory) chain, which is central to energy production. In conjunction with cytochrome P-450, flavocoenzymes also participate in the metabolism of drugs and toxins (4).

Antioxidant functions

Glutathione reductase is an FAD-dependent enzyme that participates in the redox cycle of glutathione. The glutathione redox cycle plays a major role in protecting organisms from reactive oxygen species, such as hydroperoxides. Glutathione reductase (GR) requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4). Measurement of GR activity in red blood cells is commonly used to assess riboflavin nutritional status (5). The erythrocyte glutathione reductase activation coefficient (EGRac) assay assesses riboflavin status by measuring the activity of GR before and after in vitro reactivation with its prosthetic group FAD; EGRac is calculated as the ratio of FAD-stimulated to unstimulated enzyme activity and indicates the degree of tissue saturation with riboflavin. EGRac is thus a functional measure of riboflavin status and has shown to be effective in reflecting biomarker status from severe deficiency to normal status (6).

Glutathione peroxidases, selenium-containing enzymes, require two molecules of reduced glutathione to break down hydroperoxides. GPx are involved in the glutathione oxidation-reduction (redox) cycle (Figure 1).

Figure 1. Glutathione Oxidation Reduction (Redox) Cycle. One molecule of hydrogen peroxide is reduced to 2 molecules of water while 2 molecules of glutathione (GSH) are oxidized in a reaction catalyzed by the selenoenzyme, glutathione peroxidase. Oxidized glutathione (GSSG) may be reduced by the flavin adenine dinucleotide (FAD)-dependent enzyme, glutathione reductase.

Xanthine oxidase, another FAD-dependent enzyme, catalyzes the oxidation of hypoxanthine and xanthine to uric acid. Uric acid is one of the most effective water-soluble antioxidants in the blood. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (7).

Nutrient interactions

B-complex vitamins

Flavoproteins are involved in the metabolism of several other vitamins: (vitamin B6, niacin, and folate). Therefore, severe riboflavin deficiency may affect many enzyme systems. Conversion of most naturally available vitamin B6 to its coenzyme form, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (8). At least two studies in the elderly have documented significant interactions between indicators of vitamin B6 and riboflavin nutritional status (9, 10). The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid tryptophan, requires the FAD-dependent enzyme, kynurenine mono-oxygenase. Severe riboflavin deficiency can decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3). 5, 10-Methylenetetrahydrofolate reductase (MTHFR) is an FAD-dependent enzyme that plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (Figure 2). Along with other B vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine levels (11). Increased plasma riboflavin levels have also been associated with decreased plasma homocysteine levels, mainly in individuals homozygous for the C677T polymorphism in the MTHFR gene and in individuals with low folate intake (12). Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors (see Cardiovascular disease and Cancer).

Figure 2. Folate and Nucleic acid Metabolism. 5,10-Methylene tetrahydrofolate (TH4-folate) is required for the synthesis of nucleic acids, and 5-methyl TH4-folate is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many biological methylation reactions, including DNA methylation. Methylene TH4-folate reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylene TH4-folate to 5-methyl TH4-folate.

Iron

Riboflavin deficiency alters iron metabolism. Although the mechanism is not clear, research in animals suggests that riboflavin deficiency may impair iron absorption, increase intestinal loss of iron, and/or impair iron utilization for the synthesis of hemoglobin (Hb) (13). In humans, improving riboflavin nutritional status has been found to increase circulating Hb levels (14). Correction of riboflavin deficiency in individuals who are both riboflavin and iron deficient improves the response of iron-deficiency anemia to iron therapy (15). Anemia during pregnancy, a worldwide public health problem, is responsible for considerable perinatal morbidity and mortality (16, 17). The management of maternal anemia includes the supplementation with iron alone or iron in combination with folic acid (18), and it has been considered that riboflavin supplementation could enhance the iron-folic acid supplementation. Randomized, double-blind intervention trials conducted in pregnant women with anemia in Southeast Asia showed that a combination of folic acid, iron, vitamin A, and riboflavin improved Hb levels and decreased anemia prevalence compared to the iron-folic acid supplementation alone (19, 20).

Deficiency

Ariboflavinosis is the medical name for clinical riboflavin deficiency. Riboflavin deficiency is rarely found in isolation; it occurs frequently in combination with deficiencies of other water-soluble vitamins. Symptoms of riboflavin deficiency include sore throat, redness and swelling of the lining of the mouth and throat, cracks or sores on the outsides of the lips (cheliosis) and at the corners of the mouth (angular stomatitis), inflammation and redness of the tongue (magenta tongue), and a moist, scaly skin inflammation (seborrheic dermatitis). Other symptoms may involve the formation of blood vessels in the clear covering of the eye (vascularization of the cornea) and decreased red blood cell count in which the existing red blood cells contain normal levels of hemoglobin and are of normal size (normochromic normocytic anemia) (1, 3). Severe riboflavin deficiency may result in decreased conversion of vitamin B6 to its coenzyme form (PLP) and decreased conversion of tryptophan to niacin (see Nutrient interactions).

Preeclampsia is defined as the presence of elevated blood pressure, protein in the urine, and edema (significant swelling) during pregnancy. About 5% of women with preeclampsia progress to eclampsia, a significant cause of maternal and fetal death. Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (21). A study in 154 pregnant women at increased risk of preeclampsia found that those who were riboflavin deficient were 4.7 times more likely to develop preeclampsia than those who had adequate riboflavin nutritional status (22). The cause of preeclampsia-eclampsia is not known. Decreased intracellular levels of flavocoenzymes could cause mitochondrial dysfunction, increase oxidative stress, and interfere with nitric oxide release and thus blood vessel dilation—all of these changes have been associated with preeclampsia (22).

A recent meta-analysis of 51 studies found that the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism was associated with preeclampsia in Caucasian and East Asian populations (23). However an earlier meta-analysis reported that the MTHFR 677TT genotype carried a significantly greater risk of preeclampsia among Asian women only, while in Caucasian women the increased risk was not significant (24). Such heterogeneity among studies may suggest that the effect of MTHFR 677TT genotype could be modulated by riboflavin and other relevant dietary factors that may vary considerably among different populations. The reduction in the flavoprotein MTHFR activity observed in subjects with the C677T genetic variant leads to a slight increase in plasma homocysteine concentrations; increased homocysteine levels have been associated with preeclampsia (25). One small randomized, placebo-controlled, double-blind trial in 450 pregnant women at high risk for preeclampsia found that supplementation with 15 mg of riboflavin daily did not prevent the condition (26). However, studies are needed to assess the potential benefit of riboflavin supplementation in reducing perinatal complications specifically in preeclamptic women with the C677T genotype.

Risk factors for riboflavin deficiency

Alcoholics are at increased risk for riboflavin deficiency due to decreased intake, decreased absorption, and impaired utilization of riboflavin. Interestingly, the elevated homocysteine levels associated with riboflavin deficiency rapidly decline during alcohol withdrawal (27). Additionally, anorexic individuals rarely consume adequate riboflavin, and lactose intolerant individuals may not consume milk or other dairy products that are good sources of riboflavin. The conversion of riboflavin into FAD and FMN is impaired in hypothyroidism and adrenal insufficiency (3, 4). Further, people who are very active physically (athletes, laborers) may have a slightly increased riboflavin requirement. However, riboflavin supplementation has not generally been found to increase exercise tolerance or performance (28).

Although clinical riboflavin deficiency (i.e., including signs such as angular stomatitis, cheilosis, and glossitis) is rare in the developed world, there is evidence suggesting that suboptimal riboflavin status (as determined by the functional biomarker EGRac) may be a widespread problem affecting many otherwise healthy populations within the developed world. For example, a high proportion of the British adult population was reported to have poor riboflavin status as determined from national survey data using EGRac (29). Dietary intakes however were generally found to compare favorably with recommended values, except in young women who had low intakes. The large proportion of the UK population with abnormal EGRac values, despite apparently adequate dietary intakes, requires further investigation.

The Recommended Dietary Allowance (RDA)

The RDA for riboflavin, revised in 1998, is based on the prevention of deficiency (Table 1). Clinical signs of deficiency in humans appear at intakes of less than 0.5-0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).

Table 1. Recommended Dietary Allowance (RDA) for Riboflavin
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months  0.3 (AI 0.3 (AI) 
Infants  7-12 months  0.4 (AI)  0.4 (AI) 
Children  1-3 years  0.5  0.5 
Children  4-8 years  0.6  0.6 
Children  9-13 years  0.9  0.9 
Adolescents  14-18 years  1.3  1.0 
Adults  19 years and older  1.3  1.1 
Pregnancy  all ages  1.4 
Breast-feeding  all ages  1.6

Disease Prevention

Cataracts

Age-related cataracts are the leading cause of visual disability in the US and other developed countries. Research has focused on the role of nutritional antioxidants because of evidence that light-induced oxidative damage of lens proteins may lead to the development of age-related cataracts. A case-control study found significantly decreased risk of age-related cataract (33% to 51%) in men and women in the highest quintile of dietary riboflavin intake (median of 1.6 to 2.2 mg/day) compared to those in the lowest quintile (median of 0.08 mg/day in both men and women) 30. Another case-control study reported that individuals in the highest quintile of riboflavin nutritional status, as measured by red blood cell glutathione reductase activity, had approximately one-half the occurrence of age-related cataract as those in the lowest quintile of riboflavin status, though the results were not statistically significant (31). A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of riboflavin intake were 50% less likely to have cataracts than those in the lowest quintile (32). A prospective study of more than 50,000 women did not observe a difference between rates of cataract extraction between women in the highest quintile of riboflavin intake (median of 1.5 mg/day) and women in the lowest quintile (median of 1.2 mg/day) (33). However, the range between the highest and lowest quintiles was small, and median intake levels for both quintiles were above the current RDA for riboflavin. A study in 408 women found that higher dietary intakes of riboflavin were inversely associated with a five-year change in lens opacification (34). Although these observational studies provide some support for the role of riboflavin in the prevention of cataracts, randomized, placebo-controlled intervention trials that include a response biomarker (such as EGRac) are needed to confirm the relationship.

Cardiovascular disease

For many years, elevated homocysteine levels in plasma have been considered to be a risk factor for cardiovascular disease (CVD), although this has recently become somewhat controversial (35). Plasma homocysteine is responsive to the lowering effects of interventions with folate and metabolically related B vitamins, including riboflavin. Riboflavin acts as a cofactor for MTHFR and is therefore needed to generate 5-methyltetrahydrofolate required in the remethylation of homocysteine to methionine (see Figure 2 above). These B vitamins, however, may have roles in the prevention of CVD that are independent of their effects on homocysteine.

Genetic studies provide convincing evidence to support a link between suboptimal B-vitamin status and CVD risk. A meta-analysis of such studies showed that individuals who are homozygous for the MTHFR C677T gene variant had a significantly higher risk of CVD (by 14 to 21%) compared to those without this polymorphism, but there was a large amount of geographical variation in the increased CVD risk (36), strongly suggesting that dietary factors can modulate the disease risk related to this genetic factor.

Accumulating evidence links this common folate polymorphism with hypertension (defined as a blood pressure of 140/90 mm Hg or greater), a major risk factor for CVD, particularly stroke. The emerging evidence that blood pressure in patients homozygous for this polymorphism is highly responsive to low-dose riboflavin (see Disease Treatment) raises the possibility that improving riboflavin status will have an important role in preventing hypertension. This in turn could potentially reduce the risk of stroke specifically in individuals with the relevant genotype. Notably, the reported frequency of the MTHFR 677TT genotype is 10% worldwide, ranging from 4-26% in Europe, 20% in Northern China, and as high as 32% in Mexico (37).

Cancer

The flavoprotein, methylenetetrahydrofolate reductase (MTHFR), plays a pivotal role in folate-mediated homocysteine metabolism. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is necessary for the re-methylation of homocysteine to methionine (see Figure 2 above). The conversion of homocysteine to methionine is of importance for homocysteine detoxification and for the production of S-adenosylmethionine (SAM), the methyl donor for the methylation of DNA and histones. Folate deficiency and elevated homocysteine concentrations may increase cancer risk (see the article on Folate). Aberrant methylation changes are also known to alter the structure and function of DNA and histones during cancer development (38). Since MTHFR controls the detoxification of homocysteine and the supply of methyl groups for SAM synthesis, a reduction in its activity can affect homocysteine metabolism and disturb cellular methylation processes. The substitution of a cytosine by a thymine in position 677 (c.677C>T) in the MTHFR gene is a polymorphism that affects the binding of FAD and leads to an increased propensity for MTHFR to lose its flavin coenzyme (39). Individuals homozygous for this mutation (i.e., MTHFR 677TT genotype) exhibit reduced MTHFR activity, and some evidence shows that such individuals are at increased risk of cancer at various sites (40-42); however, the nature of the association between this common polymorphism and cancer risk remains unclear.

As mentioned above (see B-complex vitamins), riboflavin intake is a determinant of homocysteine concentration. This suggests that riboflavin status can influence MTHFR activity and the metabolism of folate, thereby potentially affecting cancer risk (42). In a randomized, double-blind, placebo-controlled study, 93 subjects with colorectal polyps and 86 healthy subjects were given either a placebo, folic acid (400 or 1,200 mcg/day), or folic acid (400 mcg/day) plus riboflavin (5 mg/day) for 45 days. These interventions significantly improved folate and riboflavin status in vitamin-supplemented individuals compared to those taking the placebo. Interestingly, riboflavin enhanced the effect of 400 mcg folic acid on circulating 5-methyl tetrahydrafolate (5-MeTH4) specifically in the polyp patients with the C677T genetic variant (43). This suggests that riboflavin may improve response to folic acid supplementation in individuals with a reduced MTHFR activity. Additionally, a prospective cohort study of 88,045 postmenopausal women found total (dietary plus supplemental) intake of riboflavin to be inversely correlated with colorectal cancer risk when comparing the highest (>3.97 mg) and lowest (<1.80 mg) quartiles of daily intake (44); intake in the reference group was well above the RDA of 1.1 mg/day. The subjects in this study were not prescreened to identify those with the C677T genotype, and the association between the C677T polymorphism and colorectal cancer is unclear, with reports suggesting a reduction in the risk with the T allele (45).

Associations between riboflavin intake and cancer risk have been evaluated in other types of cancer. A seven-year intervention study evaluated the use of riboflavin-fortified salt in 22,093 individuals at high risk for esophageal cancer in China. Riboflavin status and esophageal pathology (percent normal, dysplastic, and cancerous tissues) improved in the intervention group compared to the control group, but the lower incidence of esophageal cancer found in the intervention group was not statistically significant (46). Additionally, the Melbourne Collaborative Cohort Study, which followed 41,514 men and women over a 15-year period, found weak inverse associations between riboflavin intake and lung cancer (47) and breast cancer (48) and no association with prostate cancer (49). However, a 10-year follow up of an intervention trial in patients at high risk for gastric (stomach) cancer found that dietary supplementation with minerals and vitamins, including riboflavin (3.2 mg/day) and niacin (40 mg/day), for five years failed to decrease the incidence or mortality rate of gastric cancer (50).

Disease Treatment

Migraine headaches

Some evidence indicates that impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraine headaches. Since riboflavin is the precursor of the two flavocoenzymes (FAD and FMN) required by the flavoproteins of the mitochondrial electron transport chain, supplemental riboflavin has been investigated as a treatment for migraine. A randomized, placebo-controlled trial examined the effect of 400 mg/day of riboflavin for three months on migraine prevention in 54 men and women with a history of recurrent migraine headaches (51). Riboflavin was significantly better than placebo in reducing attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment. Another study by the same investigators found that treatment with either a medication called a β-blocker or high-dose riboflavin (400 mg/day) for four months resulted in clinical improvement, but each therapy appeared to act on a distinct pathological mechanism: β-blockers on abnormal cortical information processing and riboflavin on decreased brain mitochondrial energy reserve (52). A small study in 23 patients reported a reduction in median migraine attack frequency after supplementation with 400 mg of riboflavin daily for three months (53). However, a three-month randomized, double-blind, placebo-controlled study that administered a combination of riboflavin (400 mg/day), magnesium, and feverfew to migraine sufferers reported no therapeutic benefit beyond that associated with taking a placebo containing 25 mg/day of riboflavin (54). Compared to baseline measurements in this trial, both the placebo and treatment groups experienced some benefits with respect to the mean number of migraines, migraine days, or migraine index (54). Although these findings are preliminary, data from most studies to date suggest that riboflavin supplementation in adults might be a useful adjunct to pharmacologic therapy in migraine prevention.

Two randomized, double-blind, placebo-controlled trials investigated the effect of riboflavin supplementation on the frequency and severity of headache attacks in children with migraines. The first study evaluated riboflavin at 200 mg/day for 12 weeks in 48 children aged 5 to 15 years old (55). The second study was a cross-over trial with half of the 42 children, aged 6 to 13, receiving 50 mg/day riboflavin for 16 weeks then placebo (100 mg/day carotene) for 16 weeks with a four-week washout period in between, while the other half were first given the placebo then riboflavin (56). Both studies showed no differences in the frequency, duration, or intensity of migraines between treatments. The effectiveness of riboflavin supplementation in children with migraine is yet to be established, and future research should first determine the most appropriate riboflavin dosage for this population.

Metabolic disorders

Increasing evidence indicates that patients with autosomal recessive disorders caused by defective FAD-dependent enzymes could benefit from riboflavin supplementation.

Multiple acyl-CoA dehydrogenase deficiency (MADD)

MADD, also known as type II glutaric aciduria (or acidemia), is a fatty acid metabolism disorder characterized by the accumulation of short-, medium-, and long-chain acyl-carnitines in various tissues. Neonatal and late onset forms of MADD show a wide spectrum of clinical severity and variable presentations, including episodic encephalopathy, periodic vomiting, hepatopathy, and rhabdomyolysis (57). MADD is caused by mutations in genes that impair the activity of enzymes involved in the transfer of electrons from acyl-Coenzyme A (acyl-CoA) to Coenzyme Q10/Ubiquinone inside mitochondria (Figure 3). ETFA, ETFB, and ETFDH code for the two subunits of the electron transfer flavoprotein (ETF-A and -B), and for ETF dehydrogenase/ubiquinone oxidoreductase (ETFDH/ETFQO), respectively.

Figure 3. Fatty-Acid Beta-Oxidation and the Electron Transfer Flavoprotein System. Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is caused by mutations in the genes coding for the electron transfer flavoprotein (ETF) and the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). These flavoproteins are essential for electron transfer from the fatty-acid beta-oxidation (beta-oxidation) pathway to the respiratory chain: FAD is the electron acceptor for acyl-CoA dehydrogenase (first step in fatty acid beta-oxidation), and it donates electrons to ETF-FAD, reducing it to ETF-FADH2. The flavoprotein is restored to its oxidized form by ETF-QO, which transfers the electrons to coenzyme Q10, via its iron-sulfur (Fe-S) cluster and FAD.

Deficiencies in these enzymes (ETF or ETFDH) lead to a decrease in oxidized FAD, which becomes unavailable for FAD-dependent dehydrogenation reactions, including the first step in β-oxidation—a major fatty acid catabolic process that takes place in the mitochondria. A defect in fatty acid β-oxidation causes lipid accumulation in skeletal muscles, leading to lipid storage myopathy characterized by muscle pain and weakness and exercise intolerance. Together with a low-fat and high-carbohydrate diet, riboflavin supplementation has led to significant clinical improvements in patients with ETFDH mutations. The specific type of the mutation in ETF/ETFDH contributes to age of onset, severity, and responsiveness to riboflavin treatment (58). Additionally, the recent report of a 20-year-old man with riboflavin-responsive MADD failed to find mutations in ETF and ETFDH genes, suggesting that other sites of mutation should not be excluded (57). Finally, secondary deficiencies in the respiratory chain are observed in MADD and appear to respond favorably to riboflavin supplementation (58, 59).

Acyl-CoA dehydrogenase 9 deficiency (ACAD9)

Recessive mutations in the ACAD9 gene coding for a FAD-dependent acyl CoA dehydrogenase were found in patients with mitochondrial complex I deficiency, a respiratory chain disorder (60). ACAD9 deficiency has not been linked to fatty acid β-oxidation defects, suggesting instead a role in complex I assembly for ACAD9 (61). Complex I carries electrons from NADH to Coenzyme Q10 in the electron transport chain. Defective oxidative phosphorylation (ATP synthesis by the respiratory chain) due to complex I deficiency has been linked to a broad variety of clinical manifestations from neonatal death to late-onset neurodegenerative diseases. The symptoms of complex I deficiency due to ACAD9 mutations include muscle weakness, exercise intolerance, lactic acidosis, encephalopathy, and cardiomyopathy. Riboflavin supplementation (100-300 mg/day) increased complex I activity in patients with childhood-onset clinical forms of ACAD9 deficiency. Improvements in muscle strength and exercise tolerance have also been associated with riboflavin supplementation (62-64).

Defective riboflavin transport-associated disorders

SLC52A1, SLC52A3, and SLC52A2 genes code for the human riboflavin transporters hRTF1, hRTF2, and hRTF3, respectively. Mutations in these genes have been linked with Brown-Vialetto-Van Laere syndrome (BVVL), a rare neurodegenerative disorder characterized by variable age onsets. The syndrome includes bulbar palsy with hypotonia and facial weakness, sensorineural deafness, and respiratory insufficiency. Lack of hearing loss in the clinical description of BVVL symptoms is known as Fazio-Londe syndrome (FL). Transient clinical and biochemical features of MADD were described in a newborn of a riboflavin-deficient mother; this mild deficiency, caused by a mutation in hRTF1, was promptly corrected by riboflavin supplementation (65, 66). A recent review of the literature, which analyzed reports of 74 patients affected by the BVVL/FL syndrome, found that 8 of the 13 patients given supplemental riboflavin (average dose of 10 mg/kg/day) experienced clinical improvements, and the treated individuals had a survival rate of 100% (67). Riboflavin also restored normal flavin and acylcarnitine levels in patients presenting abnormal profiles.

Riboflavin-responsive trimethylaminuria

Primary trimethylaminuria is caused by defective oxidation of trimethylamine by a liver flavoprotein called flavin containing mono-oxygenase 3 (FMO3). Individuals with FMO3 deficiency have increased levels of trimethylamine in urine, sweat, and breath (68). This socially distressing condition is known as "fish odor syndrome" due to the fishy odor and volatile nature of trimethylamine. FMO3 gene mutations are usually associated with mild or intermittent trimethylaminuria; the condition is sometimes limited to peri-menstrual periods in female subjects or to the consumption of trimethylamine-rich food. The clinical management of the condition includes dietary restriction of trimethylamine and its precursors, such as foods rich in choline and seafood, as well as cruciferous vegetables that contain both trimethylamine precursors and FMO3 antagonists (69). The use of riboflavin supplements was recently reported in a 17-year-old female patient affected by pyridoxine non-responsive homocystinuria (70). The disease was initially treated with betaine (a choline derivative), which caused body odor secondary to FMO3 deficiency. Riboflavin supplementation (200 mg/day) reduced trimethylamine excretion and betaine treatment-related body odor. The data suggest that riboflavin might help maximize residual FMO3 enzyme activity in patients with primary trimethylaminuria.

Hypertension

Although the etiology of hypertension is unclear, the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is the main determinant of homocysteine concentrations and has been related to elevated blood pressure (a marker of hypertension) (71) and increased risk of coronary heart disease and vascular accident (72-74). Since this genetic variant leads to decreased MTHFR activity, individuals with the 677TT genotype may benefit from riboflavin supplementation. In an initial randomized, double-blind, placebo-controlled trial in 77 healthy subjects who had been pre-screened for MTHFR genotype, riboflavin supplementation (1.6 mg/day for 12 weeks) lowered homocysteine levels in the MTHFR 677TT genotype group but not in the age-matched 677CC and 677CT groups that exhibited normal plasma homocysteine levels at baseline (75). Two subsequent randomized, double-blind, placebo-controlled trials investigated the possibility of riboflavin modulating hypertension in premature cardiovascular disease (CVD) patients (pre-screened for the MTHFR 677C→T polymorphism) (76, 77). Results showed a significant lowering of blood pressure only in the patients with the 677TT genotype supplemented with riboflavin (1.6 mg/day for 16 weeks) compared to placebo, both on initial examination (69) and when the same cohort of high-risk CVD patients was reinvestigated four years after the original trial (70). Another study investigated the effect of riboflavin in 88 hypertensive patients (but without overt CVD) with the MTHFR 677TT genotype, the majority of whom were being treated with antihypertensive therapy. At baseline, 60% of participants had failed to achieve target BP levels (≤ 140/90 mm Hg), despite taking three or more antihypertensive medications. The reduction in blood pressure following riboflavin supplementation (1.6 mg/day for 16 weeks) in these patients suggested that the excess risk of hypertension linked to this genetic variation could be overcome by optimizing riboflavin status (78).

Cancer

Anti-cancer agents often display various side effects that may force patients to limit the dose or to discontinue the treatment. The antioxidant effect of co-administering riboflavin (10 mg/day), niacin (50 mg/day), and coenzyme Q10 (100 mg/day) was evaluated in 78 postmenopausal breast cancer patients treated with Tamoxifen for 90 days. This supplementation effectively prevented the oxidative stress associated with tamoxifen treatment (79). Riboflavin can also act as a photosensitizer, and this property may have value in photodynamic therapy of cancer. A mouse model was used to assess the effect of riboflavin in combination with cisplatin, one of the most effective anti-cancer agents. Under light exposure, riboflavin administration reduced cisplatin-induced DNA damage in the liver and kidneys (80). These results are promising, but human studies are needed to examine whether riboflavin might be an effective adjunct to chemotherapy.

Corneal disorders

Corneal ectasia is an eye condition characterized by irregularities of the cornea that affect vision. Corneal cross-linking—a new procedure used by professionals to limit the progression of corneal damage—involves the use of riboflavin in conjunction with ultraviolet light irradiation. Cross-linking modifies the properties of the cornea and strengthens its architecture (81).

Sources

Food sources

Most plant- and animal-derived foods contain at least small quantities of riboflavin. In the US, wheat flour and bread have been enriched with riboflavin (as well as thiamin, niacin, and iron) since 1943. Data from large dietary surveys indicate that the average intake of riboflavin for men is about 2 mg/day and for women is about 1.5 mg/day; both intakes are well above the RDA. Intake levels were similar for a population of elderly men and women (1). Riboflavin is easily destroyed upon exposure to light. For instance, up to 50% of the riboflavin in milk contained in a clear glass bottle can be destroyed after two hours of exposure to bright sunlight (7). Some foods with substantial amounts of riboflavin are listed in Table 2, along with their riboflavin content in milligrams (mg). For more information on the nutrient content of food, search the USDA food composition database.

Table 2. Some Food Sources of Riboflavin
Food Serving Riboflavin (mg)
Fortified, wheat, puffed cereal 1 cup 0.22
Milk (nonfat) 1 cup (8 ounces) 0.45
Cheddar cheese 1 ounce 0.11
Egg (cooked, hard-boiled) 1 large 0.26
Almonds 1 ounce 0.29
Salmon (cooked) 3 ounces* 0.13
Halibut (Greenland, cooked, dry-heat) 3 ounces 0.09
Chicken, light meat (roasted) 3 ounces 0.08
Chicken, dark meat (roasted) 3 ounces 0.16
Beef (ground, cooked) 3 ounces 0.15
Broccoli (boiled) ½ cup chopped 0.10
Asparagus (boiled) 6 spears 0.13
Spinach (boiled) ½ cup 0.21
Bread, whole-wheat 1 slice 0.06
Bread, white (enriched) 1 slice 0.09
*A 3-ounce serving of meat is about the size of a deck of cards.

Supplements

The most common forms of riboflavin available in supplements are riboflavin and riboflavin 5'-monophosphate. Riboflavin is most commonly found in multivitamin and vitamin B-complex preparations (82).

Safety

Toxicity

No toxic or adverse effects of high riboflavin intake in humans are known. Studies in cell culture indicate that excess riboflavin may increase the risk of DNA strand breaks in the presence of chromium (VI), a known carcinogen (83). This may be of concern to workers exposed to chrome, but no data in humans are available. High-dose riboflavin therapy has been found to intensify urine color to a bright yellow (flavinuria), but this is a harmless side effect. The Food and Nutrition Board did not establish a tolerable upper intake level (UL) when the RDA was revised in 1998 (1).

Drug interactions

Several early reports indicated that women taking high-dose oral contraceptives (OC) had diminished riboflavin nutritional status. However, when investigators controlled for dietary riboflavin intake, no differences between OC users and non-users were found (1). Phenothiazine derivatives like the anti-psychotic medication chlorpromazine and tricyclic antidepressants inhibit the incorporation of riboflavin into FAD and FMN, as do the anti-malarial medication, quinacrine, and the cancer chemotherapy agent, adriamycin (4). Long-term use of the anti-convulsant, phenobarbitol may increase destruction of riboflavin by liver enzymes, increasing the risk of deficiency (3). Additionally, chronic alcohol consumption has been associated with riboflavin deficiency. In rats chronically fed alcohol, the inhibition of riboflavin transporters caused impairment in intestinal absorption and renal re-uptake of the vitamin (84).

Linus Pauling Institute Recommendation

The RDA for riboflavin (1.3 mg/day for men and 1.1 mg/day for women), which should prevent deficiency in most individuals, is easily met by eating a varied diet. Consuming a varied diet should supply 1.5 mg to 2 mg of riboflavin a day. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the Daily Values (DV) will ensure an intake of at least 1.7 mg/day of riboflavin.

Older adults (>50 years)

Some experts in nutrition and aging feel that the RDA (1.3 mg/day for men and 1.1 mg/day for women) leaves little margin for error in people over 50 years of age (85, 86). A study of independently living people between 65 and 90 years of age found that almost 25% consumed less than the recommended riboflavin intake, and 10% had biochemical evidence of deficiency (87). Epidemiological studies of cataract prevalence indicate that riboflavin intakes of 1.6 to 2.2 mg/day may reduce the risk of developing age-related cataracts. Additionally, older people suffering from acute ischemic stroke were found to be deficient for riboflavin (88), and riboflavin deficiency has been linked to a higher risk of fracture in postmenopausal women with the MTHFR 677T variant (89). Individuals whose diets may not supply adequate riboflavin, especially those over 50 years of age, should consider taking a multivitamin/mineral supplement, which generally provides at least 1.7 mg/day of riboflavin.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in December 2013 by: 
Helene McNulty, Ph.D., R.D. 
Professor of Human Nutrition and Dietetics 
Northern Ireland Centre for Food and Health (NICHE) 
University of Ulster 
Coleraine, United Kingdom

Reviewed in December 2013 by: 
Adrian McCann, Ph.D. 
Research Associate 
Northern Ireland Centre for Food and Health (NICHE) 
University of Ulster 
Coleraine, United Kingdom

Copyright 2000-2015  Linus Pauling Institute


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