Continuing Education Activity

Riboflavin is a medication used in the management and treatment of deficiency of vitamin B2. It is part of the B complex group of vitamins. This activity will highlight the mechanism of action, adverse event profile, and other vital factors, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional team in the treatment of patients with riboflavin deficiency and related conditions.

Objectives:

• Explain the indications for riboflavin.
• Outline the potential adverse effects of riboflavin.
• Review the mechanism of action of riboflavin.
• Summarize the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with riboflavin deficiency.

Indications

Riboflavin or vitamin B2 is a member of the group of vitamins referred to as vitamin B complex, which is 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 some specific groups of individuals, as discussed below, may be prone to its deficiency.[1]

Milk and dairy products have very high riboflavin content; the dairy intake is the most significant contributor of the vitamin in Western diets, making riboflavin deficiency uncommon among water-soluble vitamins. However, there is an increased intake of semi-skimmed milk in developed countries, 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. Therefore, 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 the riboflavin concentration of the mother when maternal intake is low.

Children

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. Moreover, rare inborn errors of metabolism, such as glutaric acidemia type 1 or multiple acyl-coenzyme A (CoA) dehydrogenase deficiencies (MADD), in which there is a defect in the formation of riboflavin-dependent enzymes, or Brown-Vialetto-Van Laere syndrome, in which there is a defect in a riboflavin transporter.

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 with anorexia nervosa or patients with malignancies, malabsorption syndromes, like celiac disease and short bowel syndrome, have been shown to have low riboflavin levels.[5] Patients with lactose intolerance are likely to have suboptimal intake since dairy products are a good source of riboflavin.

Long-term Use of Barbiturates

Long-term use of phenobarbital, as well as other barbiturates, can impair riboflavin due to oxidation.

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

Mechanism of Action

Riboflavin is involved in the metabolism of macronutrients and 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.[7] Inadequate riboflavin intake 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.[8]

For the absorption of dietary riboflavin, a prerequisite is converting FAD and FMN to free riboflavin, catalyzed by enzymes called phosphatases in the enterocyte.[9] Absorption of the vitamin takes place predominantly in the proximal small intestine through a saturable, active, carrier-mediated transport process.

It is often available in conjugation with other water-soluble multi-vitamins. It is also available as single-ingredient oral tablets of 25 mg, 50 mg, 100 mg, and oral capsules of 400 mg strengths.

Recommended Daily Allowance for Riboflavin[10]

• Adults (age 19 to 70 years): Women: 0.9 to 1.1 mg per day and Men: 1.1 to 1.3 mg per day. (These values have their basis on clinical evidence of deficiency in intake less than 0.6 mg per day). During pregnancy and lactation, the recommended daily allowance increases to 1.4 to 1.6 mg per day.
• Adolescents (Age 10 to 18 years): 0.9 to 1.3 mg per day.
• Children (Age 1 to 9 years): 0.5 to 0.6 mg per day.
• Infants (Age: 0 to 12 mo): 0.3 to 0.4 mg per day.

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 migraines (not FDA-approved) to minimize the frequency of attacks.[11]

Neonates Undergoing Phototherapy

Management of hyperbilirubinemia in the neonatal period is often done with phototherapy. But it has been shown to degrade riboflavin and cause a deficiency in newborns. A prophylactic daily oral dose of riboflavin prevents the development of the deficiency.[12]

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.[13]

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.[14] The cornea receives treatment with UVA for another 30 minutes.[15]

Adverse Effects

Riboflavin is relatively safe to administer as it has limited water solubility and excess as enterocytes do not absorb the excess. However, caution is necessary with the administration of large doses in pregnant women. It may cause benign 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 assessing 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

There are no observable toxicities with intakes of riboflavin from food sources that are many folds the recommended daily allowance. Riboflavin has high water solubility and limited absorption. There are no adverse effects from high riboflavin intakes from foods or supplements up to 400 mg daily for at least three months. The food and nutrition board has not established the upper limit for riboflavin as it has a good safety profile.

Enhancing Healthcare Team Outcomes

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. Those on restricted diet plans and many individuals who do not consume dairy are prone to developing riboflavin deficiency. Other risk factors for riboflavin deficiency include pregnancy, poverty, old age, depression, breastfeeding, 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 relevant role in patient education. 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 the need for supplements and alert the prescribing clinician. For outpatients, a dietitian or nurse educator should be consulted to teach patients about rich riboflavin foods. Most cases of riboflavin deficiency are preventable by taking a proactive, interprofessional team approach; this leads to a healthy population and decreases healthcare costs.[10][16][17] [Level 5]

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 5]