Vitamin B2 (Riboflavin)


Article Author:
Basil Peechakara


Article Editor:
Mohit Gupta


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Kranthi Sitammagari
Mayank Singhal


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Saad Nazir
William Gossman
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Hussain Sajjad
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James Hughes
Beata Beatty
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Phillip Hynes


Updated:
8/1/2019 6:09:33 PM

Indications

Riboflavin or vitamin B2 is a member of the group of vitamins referred to as vitamin B complex, which makes it a water-soluble vitamin. As a drug, healthcare providers often prescribe it in a combined formulation consisting of other B complex vitamins as a prophylactic supplement to prevent the development of deficiency.

Riboflavin deficiency is rare as it is ubiquitous in a variety of food choices. However, individuals following a diet scarce in milk and meat, which are one of the best sources of riboflavin, and also some specific groups of individuals as discussed below may be prone to its deficiency.[1]

Milk and dairy products have very high riboflavin content; dairy intake is the most significant contributor of the vitamin in Western diets, making riboflavin deficiency uncommon among water-soluble vitamins. However, in developed countries, there is increased intake of semi-skimmed milk, depleting milk of its riboflavin content. Although relatively stable, it easily degrades by light exposure. Milk kept in a glass bottle may be susceptible to degradation through this route.

Grain products possess low natural amounts, but fortification practices ensure that certain breads and cereals have become sources of riboflavin. Therefore, according to an article by Morgan KJ et al., high riboflavin levels were found in those having cereals for breakfast.[2] Fatty fish are also excellent sources of riboflavin, and certain fruits and vegetables, especially dark green vegetables, contain reasonably high concentrations. Vegetarians with access to a variety of fruit and vegetables can avoid deficiency, although intake may be lower than omnivores, and elderly vegetarians are at a higher risk.[3]

Groups of Individuals at a Higher Risk for Low Riboflavin Intake

Pregnant/lactating women and infants

Pregnancy demands higher riboflavin intake as it crosses the placenta. If the maternal status is poor during gestation, the infant is likely to be born riboflavin deficient. Breast milk riboflavin content may reflect maternal intake and can be moderately increased by riboflavin concentration of the mother when maternal intake is low.

Schoolchildren

Riboflavin deficiency among children is present in many regions of the world where there are inadequate levels of milk and meat in their diet.[1] Riboflavin deficiency among children in the Western world seems to largely confine itself to adolescents, especially girls, because of increased metabolic demand.

The elderly

There is an increasing requirement of riboflavin with advancing age as a result of decreased efficiency of its absorption by the enterocytes.[4]

Athletes

Some studies report that vigorous exercise may deplete riboflavin due to its consumption in the metabolic pathways.[5]

Eating disorders

Young women practicing unorthodox eating habits accompanied by excessive exercise to lose weight have been shown to have low levels of riboflavin.[5]

Prominent Features of Riboflavin Deficiency

Although clinical features of some vitamin deficiencies are similar and often coexist, the following are more common features of riboflavin deficiency are as follows[6]:

  • Lips become red, dry, fissured or ulcerated.
  • Angular cheilitis is often a feature
  • The tongue gets dry, atrophic, magenta red or sometimes blackish
  • Seborrheic dermatitis may be present on the face
  • Scrotum or vulva may get hyperpigmented resembling zinc deficiency
  • Conjunctivitis can occur
  • Sore throat
  • Fatigue

Recommended Daily Allowance for Riboflavin[7]

  • Adults (age 19 to 70 years): Women: 0.9 to 1.1 mg/dl and Men: 1.1 to 1.3 mg/d. (These values are based on observing clinical evidence of deficiency in intake less than 0.6 mg/d)
  • Adolescents (Age 10 to 18 years): 0.9 to 1.3 mg/dl
  • Children (Age 1 to 9 years): 0.5 to 0.6 mg/d
  • Infants (Age: 0 to 12 mo): 0.3 to 0.4 mg/d

Apart from supplementation in deficiency, it is also prescribed in some clinical situations as follows: 

Migraine prophylaxis

Riboflavin may be effective for the prophylaxis of migraine (not FDA-approved) to minimize the frequency of attacks.[8]

Neonates undergoing phototherapy

Management of hyperbilirubinemia in the neonatal period is often with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in the newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.[9]

Antiretroviral induced lactic acidosis

This rare syndrome results from a group of antiretroviral drugs used to treat HIV infection called nonnucleoside reverse transcriptase inhibitors (NNRTI). Discontinuation of the drug along with treatment with riboflavin causes its reversal.[10]

Corneal ectasia

This condition consists of gradual corneal narrowing caused by an alteration in the collagen matrix in the stroma, resulting in protrusion of the cornea in an irregular pattern. Therapy aims at correcting the refractory error until 1990; however, now a radical approach targeting the pathophysiology of the disease by cross-linking the corneal fibers is undertaken where the superficial epithelium gets removed, 0.1% riboflavin is applied for 30 minutes,[11] and the cornea receives treatment with UVA for another 30 minutes.[12]

Mechanism of Action

Riboflavin is involved in the metabolism of macronutrients as well as the production of some other B complex vitamins. It is known to participate in redox reactions in the metabolic pathways through cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), derived from riboflavin, by acting as electron carriers.[13] Inadequate intake of riboflavin would be expected to lead to a disturbance in the intermediate steps of metabolism, with specific functional implications.

It is also known for its role as an antioxidant due to its involvement in the regeneration of glutathione, a free radical scavenger.

Additionally, it is involved in growth and development, especially during fetal life, reproduction, and lactation.

Administration

A small amount of riboflavin is present in foods as free riboflavin, a majority as its derivative flavin adenine dinucleotide (FAD), and a smaller amount as flavin mononucleotide (FMN). A small amount, however, is also produced by the intestinal bacteria.[14]

For the absorption of dietary riboflavin, a prerequisite is the conversion of FAD and FMN to free riboflavin, catalyzed by enzymes called phosphatases in the enterocyte.[15] Absorption of the vitamin takes place predominantly in the proximal small intestine through a saturable, active, carrier-mediated transport process.

Adverse Effects

Riboflavin is relatively safe to administer as excess as enterocytes do not absorb the excess. Caution is necessary with the administration of large doses in pregnant women. It may cause urine discoloration (yellow-orange).

Contraindications

There are no absolute contraindications to riboflavin intake.

Monitoring

Blood levels and urinary excretion are not sensitive markers of riboflavin deficiency, and the preferred method for assessment of riboflavin status is stimulation of the FAD-dependent erythrocyte glutathione reductase. The results express as an activation coefficient (erythrocyte glutathione reductase activation coefficient) such that the poorer the riboflavin status, the higher is the activation coefficient.[4]

Toxicity

Toxicity is infrequent when consumed orally from the diet; however, deleterious effects like hepatotoxicity, cytotoxicity, and damage to lenticular and retinal proteins, which always incur light exposure, can occur due to repeatedly taken pharmacologic doses.[7]

Enhancing Healthcare Team Outcomes

An Interprofessional Approach Can Prevent Riboflavin Deficiency

The body does not store riboflavin in large amounts; only small reserves exist in the liver, heart, and kidneys. Most people obtain riboflavin from their diet. There are many individuals on restricted diet plans, and many who do not consume dairy; these individuals are prone to developing riboflavin deficiency. Other risk factors for riboflavin deficiency include pregnancy, poverty, old age, depression, breastfeeding, use of phototherapy, and poor cognition. Riboflavin deficiency can present with many clinical features, and the quality of life can be poor. Hence, given these facts, an interprofessional team approach is required to prevent this nutritional deficiency. Pharmacists play a key role in patient education as they are the first-line professionals to see them, and can also make dosing recommendations to the prescribing physician based on the indication. Nutritionists should emphasize the importance of adequate nutrition, exercise, and maintaining a healthy weight. The nurse also plays a critical role in educating pregnant mothers on the possibility of riboflavin deficiency when breastfeeding and the need to take supplements. Nurses who look after newborns who receive phototherapy for hyperbilirubinemia should be aware that this treatment can also cause riboflavin breakdown, and hence the need for supplements, and alert the prescribing clinician. For outpatients, a dietitian or nurse educator should be consulted to teach patients about foods that are rich in riboflavin. Most cases of riboflavin deficiency are preventable by taking a proactive, interprofessional team approach; this not only leads to a healthy population but also decreases healthcare costs.[7][16][17] [Level V]

Outcomes

When treating riboflavin deficiency, the outcomes are good. The majority of symptoms improve within a few weeks or months. However, those who develop neurological abnormalities may have residual deficits that last a long time.[18] [Level V]


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Vitamin B2 (Riboflavin) - Questions

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A 29-year-old patient presents to the clinic with the complaint of persistent headache for three months. She has had no headache for a week but fears it is recurrent and will recur in the future. She describes the headache on the left side of her head, dull, 5/10 in intensity, and sees flashes of light before the episodes. She has used ibuprofen but with no significant relief. Her vital signs are within normal limits. On examination, she appears in no distress but is worried about the possibility of a headache in the future. Her pupils are 3 mm in size and reactive to light. She does not have any weakness or sensory limitations. Reflexes are normal. The doctor prescribes sumatriptan for the episodes and a drug which is also a vitamin ordinarily present in the body to help prevent future attacks. Which of the following vitamins has a role in preventing such relapsing headaches?



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A 55-year-old patient with chronic pancreatitis is found to be deficient in a few vitamins. On further evaluation, it was found that a deficiency of pancreatic enzymes resulted in the impaired absorption of the vitamins. The absorption of which of the following vitamins is unaffected by the aforementioned pathophysiology?



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A patient with a history of depression is brought to the emergency department by his family. The patient appears to be in no acute distress. He explains that he ingested 20 tablets of vitamin B2. His family insisted on taking him to the emergency department just to be sure. Which of the following could be one of the signs or symptoms seen in this patient?



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A 34-year-old immigrant from China comes with fissures on the angle of the mouth, sore throat and fatigue. For the past month, his diet has consisted of only rice, without vegetables, meat, or milk. Testing results show a riboflavin deficiency. Which of the following test must have been done to arrive at this diagnosis?



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A 67-year-old patient presents to the clinic with 'mouth sores'. On examination, the lips appear dry and ulcerated. Angular stomatitis is also noted. The patient is found to have low levels of vitamin B2 via erythrocyte glutathione reductase activation coefficient. Which of the following is most likely deficient in the patient's diet?



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A 16-year-old male presents to the clinic with fatigue. After evaluation, he is found to have low levels of riboflavin. Which of the following would be a finding expected on physical examination of the patient?



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Vitamin B2 (Riboflavin) - References

References

Oppenheimer SJ,Bull R,Thurnham DI, Riboflavin deficiency in Madang infants. Papua and New Guinea medical journal. 1983 Mar     [PubMed]
Morgan KJ,Zabik ME,Leveille GA, The role of breakfast in nutrient intake of 5- to 12-year-old children. The American journal of clinical nutrition. 1981 Jul     [PubMed]
Woo J,Kwok T,Ho SC,Sham A,Lau E, Nutritional status of elderly Chinese vegetarians. Age and ageing. 1998 Jul     [PubMed]
Pinto JT,Zempleni J, Riboflavin. Advances in nutrition (Bethesda, Md.). 2016 Sep     [PubMed]
Boisvert WA,Mendoza I,Casta�eda C,De Portocarrero L,Solomons NW,Gershoff SN,Russell RM, Riboflavin requirement of healthy elderly humans and its relationship to macronutrient composition of the diet. The Journal of nutrition. 1993 May     [PubMed]
Belko AZ,Obarzanek E,Roach R,Rotter M,Urban G,Weinberg S,Roe DA, Effects of aerobic exercise and weight loss on riboflavin requirements of moderately obese, marginally deficient young women. The American journal of clinical nutrition. 1984 Sep     [PubMed]
Prentice AM,Bates CJ, A biochemical evaluation of the erythrocyte glutathione reductase (EC 1.6.4.2) test for riboflavin status. 1. Rate and specificity of response in acute deficiency. The British journal of nutrition. 1981 Jan     [PubMed]
IINUMA S, Synthesis of riboflavin by intestinal bacteria. The Journal of vitaminology. 1955 Feb 10     [PubMed]
Daniel H,Binninger E,Rehner G, Hydrolysis of FMN and FAD by alkaline phosphatase of the intestinal brush-border membrane. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition. 1983     [PubMed]
Schoenen J,Jacquy J,Lenaerts M, Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998 Feb     [PubMed]
Tan KL,Chow MT,Karim SM, Effect of phototherapy on neonatal riboflavin status. The Journal of pediatrics. 1978 Sep     [PubMed]
Posteraro AF 3rd,Mauriello M,Winter SM, Riboflavin treatment of antiretroviral induced lactic acidosis and hepatic steatosis. Connecticut medicine. 2001 Jul     [PubMed]
Barthelemy H,Chouvet B,Cambazard F, Skin and mucosal manifestations in vitamin deficiency. Journal of the American Academy of Dermatology. 1986 Dec     [PubMed]
Mastropasqua L, Collagen cross-linking: when and how? A review of the state of the art of the technique and new perspectives. Eye and vision (London, England). 2015     [PubMed]
Dror DK,Allen LH, Dairy product intake in children and adolescents in developed countries: trends, nutritional contribution, and a review of association with health outcomes. Nutrition reviews. 2014 Feb     [PubMed]
Chan M,Kelly J,Batterham M,Tapsell L, A high prevalence of abnormal nutrition parameters found in predialysis end-stage kidney disease: is it a result of uremia or poor eating habits? Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2014 Sep     [PubMed]
Barile M,Giancaspero TA,Brizio C,Panebianco C,Indiveri C,Galluccio M,Vergani L,Eberini I,Gianazza E, Biosynthesis of flavin cofactors in man: implications in health and disease. Current pharmaceutical design. 2013     [PubMed]
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