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Riboflavin Deficiency

Mark R Allee, MD, Associate Professor, Department of Medicine, University of Oklahoma Health Sciences Center
Mary Zoe Baker, MD, Professor, Department of Medicine, Section of Endocrinology, Metabolism and Hypertension, University of Oklahoma; Medical Director, University of Oklahoma Physicians, Medicine Specialty Clinic, General Medicine Clinic and Medicine Residents' Clinic

Updated: May 18, 2009

Introduction

Background

Riboflavin, or vitamin B-2, was initially isolated from milk whey in 1879. Originally called lactochrome, it was also once known as vitamin G. Riboflavin is important for energy production, enzyme function, and normal fatty acid and amino acid synthesis and is necessary for the reproduction of glutathione, a free radical scavenger. The water-soluble B factor consists of 2 separate ingredients; one is unstable when heated, while the other remains stable. The less stable factor was named vitamin F (thiamine), while the heat-stable product was labeled vitamin G. They were later renamed vitamins B-1 and B-2, respectively.

Pathophysiology

Riboflavin functions in several different enzyme systems. Two derivatives, riboflavin 5' phosphate (flavin mononucleotide [FMN]) and riboflavin 5' adenosine diphosphate (flavin adenine dinucleotide [FAD]), are the coenzymes that unite with specific apoenzyme proteins to form flavoprotein enzymes. Most of the flavin coenzyme systems help to regulate cellular metabolism, whereas others are specifically involved in carbohydrate or amino acid metabolism systems. Riboflavin also appears to have a role in fat metabolism.

Frequency

United States

Water-soluble riboflavin is not stored in ample amounts; minute reserves are stored in the liver, kidneys, and heart. A constant supply is needed. Deficiency in this vitamin is usually part of a multiple-nutrient deficiency and does not occur in isolation. Some authorities claim that riboflavin deficiency is the most common nutrient deficiency in America.

Milk and other dairy products make the greatest contributions of riboflavin in western diets. Other common dietary sources include cereals, meats, and dark green vegetables (spinach, asparagus, and broccoli). Deficiency can occur with a diet deficient in these riboflavin-rich foods. Glass milk containers promote degradation of the vitamin from exposure to light. Deficiency is uncommon in the United States with fortification of many food including grains and cereals. Daily consumption of breakfast cereal and milk would be expected to maintain an adequate intake of riboflavin.

The condition is more commonly seen in persons with such risk factors as pregnancy,1 lactation, phototherapy for hyperbilirubinemia (in premature infants), advanced age,2 low income, and/or depression. Riboflavin is absorbed in the proximal small intestine. Malabsorption from such conditions as celiac sprue, malignancies, and alcoholism can also promote deficiency of riboflavin. Riboflavin is transported in the bloodstream as a flavin-protein complex, which means that nonavailability of the carrier protein also leads to apparent riboflavin deficiency. Similarly, it is possible for antagonists to interfere with absorption and/or transport and thus create an apparent deficiency at receptor sites.


Clinical

History

Riboflavin deficiency is usually associated with other vitamin B complex deficiencies, and isolated deficiency is rare.3 However, it has been associated with multiple clinical manifestations.

  • Riboflavin deficiency most commonly associated with dermatologic conditions, such as the following:
    • Cheilosis, or chapping and fissuring of the lips (See image below and Image 1.)


Riboflavin deficiency is often associated with ch...

Riboflavin deficiency is often associated with cheilosis (chapping and fissuring of the lips).


    • A sore, red tongue
    • Oily, scaly skin rashes on the scrotum, vulva and philtrum
  • Deficiency can be associated with some developmental abnormalities, such as the following:
    • Cleft lip and palate deformities (See image below and Image 2.)


Riboflavin deficiency can be associated with vari...

Riboflavin deficiency can be associated with various developmental abnormalities, including cleft lip.


    • Growth retardation in infants and children - Results from the National Birth Defects Prevention Study, which included an investigation of 324 infants with transverse limb deficiency (TLD), indicated that low maternal dietary intake of riboflavin is a risk factor for TLD.4
    • Congenital heart defects - A study from the Netherlands indicated that a maternal diet that is high in saturated fats and low in riboflavin and nicotinamide may increase the risk for congenital heart defects.5
  • Other associations of deficiency include the following:
    • Red, itchy eyes
    • Night blindness
    • Cataracts
    • Migraines
    • Peripheral neuropathy
    • Mild anemia (secondary to interference with iron absorption)
    • Fatigue
    • Malignancy (esophageal and cervical dysplasia)

Differential Diagnoses

Pyridoxine Deficiency

Workup

Laboratory Studies

  • Measurement of RBC glutathione reductase activity may help in the detection of riboflavin deficiency.6  An increase in the stimulation of this enzymatic reaction confirms a low level of riboflavin.
  • Riboflavin can cause false elevations of urinary catecholamines and false-positive urine urobilinogen reactions (Ehrlich test).

Treatment

Medical Care

See Medication.

Medication

Treatment for riboflavin deficiency consists of riboflavin replenishment, with care taken not to overlook coexisting B-complex deficiencies. Multivitamins have no documented role, because the physician must establish the presence of individual vitamin deficiencies and correct them appropriately. This prevents toxicities and masking of the clinical picture.

Vitamins

Essential for normal deoxyribonucleic acid (DNA) synthesis and metabolism.


Riboflavin (vitamin B-2)

Except in malabsorption syndromes, riboflavin is readily absorbed from the upper GI tract. The extent of GI absorption is increased when the drug is administered with food and is decreased in patients with hepatitis, cirrhosis, and biliary obstruction. Free riboflavin is present in the retina. In blood, about 60% of FAD and FMN are protein bound. The biologic half-life is about 66-84 min following PO or IM administration of a single large dose in healthy individuals. Only about 9% of the drug is excreted unchanged; the fate of the remainder is unknown. Excretion appears to involve renal tubular secretion as well as glomerular filtration. Amounts in excess of the body's needs are excreted in urine.

Dosing

Adult

6-30 mg PO divided daily for replacement when deficiency is suspected

Pediatric

<3 years: Not established
3-12 years: 3-10 mg PO divided daily
>12 years: Administer as in adults

Interactions

Tricyclic antidepressants, phenothiazines, probenecid antimalarial drugs, and alcohol decrease effects; tobacco decreases absorption of (smokers may require supplemental riboflavin); contraceptives increase catabolism

Contraindications

None reported

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

As a photosynthesizing agent, riboflavin is destroyed by light; combination of light, oxygen, and riboflavin can lead to formation of free radicals and, consequently, cataracts; patients with cataracts are advised to use no more than 10 mg daily; riboflavin is a water-soluble vitamin and is considered nontoxic and with no known adverse effects; because of light-sensitivity, fruits and vegetables stored in clear glass or uncovered lose riboflavin content rather quickly; should be taken with food since only about 15% is absorbed when taken alone on an empty stomach; excess riboflavin is excreted in urine, giving the urine a fluorescent yellow-green tint

Follow-up

Further Inpatient Care

None recommended

Miscellaneous

Medicolegal Pitfalls

  • Be aware of unnecessary over-the-counter supplements.
    • The recommended nutrient intake (RNI) of riboflavin is 0.6 mg/5000 kJ daily.
    • The daily RNI ranges are 0.3-0.6 mg for infants, 0.7-1.1 mg for children, 1.1-1.4 mg for adolescents, and 1-1.6 mg for adults.
    • Recommended increased requirements for pregnant and lactating women are as follows:
      • Additional 0.1 mg/d in the first trimester
      • Additional 0.3 mg/d in the second and third trimesters
      • Additional 0.4 mg/d during lactation
    • Oral riboflavin doses of 1-4 mg daily are usually considered sufficient as a nutritional supplement in patients with normal GI absorption. These doses should be present in the normal diet. Doses for deficiency treatment are slightly higher.

Multimedia

Riboflavin deficiency is often associated with ch...

Media file 1: Riboflavin deficiency is often associated with cheilosis (chapping and fissuring of the lips).

Riboflavin deficiency can be associated with vari...

Media file 2: Riboflavin deficiency can be associated with various developmental abnormalities, including cleft lip.

References

  1. Ma AG, Schouten EG, Zhang FZ, et al. Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements. J Nutr. Oct 2008;138(10):1946-50. [Medline].

  2. Yazdanpanah N, Uitterlinden AG, Zillikens MC, et al. Low dietary riboflavin but not folate predicts increased fracture risk in postmenopausal women homozygous for the MTHFR 677 T allele. J Bone Miner Res. Jan 2008;23(1):86-94. [Medline].

  3. McNulty H, Scott JM. Intake and status of folate and related B-vitamins: considerations and challenges in achieving optimal status. Br J Nutr. Jun 2008;99 Suppl 3:S48-54. [Medline].

  4. Robitaille J, Carmichael SL, Shaw GM, et al. Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997-2003. Birth Defects Res A Clin Mol Teratol. Apr 6 2009;[Medline].

  5. Smedts HP, Rakhshandehroo M, Verkleij-Hagoort AC, et al. Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects. Eur J Nutr. Oct 2008;47(7):357-65. [Medline].

  6. Hoey L, McNulty H, Strain J. Studies of biomarker responses to intervention with riboflavin: a systematic review. Am J Clin Nutr. Apr 29 2009;[Medline].

  7. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr. Jun 2003;77(6):1352-60. [Medline]. [Full Text].

  8. Russell, RM. Vitamin and trace mineral deficiency and excess. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:403-11.

  9. Schoenen J, Lenaerts M, Bastings E. High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study. Cephalalgia. Oct 1994;14(5):328-9. [Medline].

  10. Winters LR, Yoon JS, Kalkwarf HJ. Riboflavin requirements and exercise adaptation in older women. Am J Clin Nutr. Sep 1992;56(3):526-32. [Medline]. [Full Text].

Keywords

riboflavin deficiency, vitamin deficiency, riboflavin, vitamin B2, vitamin B-2, B complex, vitamin B complex, vitamin B deficiency, B complex vitamins, vitamin G, riboflavin 5' phosphate, flavin mononucleotide, FMN, riboflavin 5' adenosine diphosphate, flavin adenine dinucleotide, apoenzyme proteins, flavoprotein enzymes, cheilosis, lactochrome, vitamin F, thiamine, vitamin B-1, vitamin B1

Contributor Information and Disclosures

Author

Mark R Allee, MD, Associate Professor, Department of Medicine, University of Oklahoma Health Sciences Center
Mark R Allee, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Mary Zoe Baker, MD, Professor, Department of Medicine, Section of Endocrinology, Metabolism and Hypertension, University of Oklahoma; Medical Director, University of Oklahoma Physicians, Medicine Specialty Clinic, General Medicine Clinic and Medicine Residents' Clinic
Mary Zoe Baker, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Chemical Society, and American College of Physicians-American Society of Internal Medicine
Disclosure: Nothing to disclose.

Medical Editor

Stanley Wallach, MD, Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine
Stanley Wallach, MD is a member of the following medical societies: American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

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