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{{Short description|Vitamin, dietary supplement, and yellow food dye}}
{{Good article}}
{{Use dmy dates|date=August 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| IUPAC_name = 7,8-Dimethyl-10-[(2''S'',3''S'',4''R'')-2,3,4,5-tetrahydroxypentyl]benzo[''g'']pteridine-2,4-dione
| image = Riboflavin_v2.svg
| image_class = skin-invert-image
| width =
| alt =
| image2 = Riboflavin-based-on-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| width2 =
| alt2 =
| caption = Chemical structure
<!-- Clinical data -->
| pronounce =
| tradename = Many<ref name="drugs">{{cite web | title=Riboflavin | website=Drugs.com | date=22 July 2021 | url=https://www.drugs.com/monograph/riboflavin.html | access-date=8 October 2021 | archive-date=30 December 2016 | archive-url=https://web.archive.org/web/20161230231848/https://www.drugs.com/monograph/riboflavin.html | url-status=live }}</ref>
| Drugs.com = {{Drugs.com|monograph|Riboflavin}}
| MedlinePlus =
| DailyMedID = Riboflavin
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular]], [[intravenous]]
| class =
| ATC_prefix = A11
| ATC_suffix = HA04
| ATC_supplemental = {{ATC|S01|XA26}}
<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = OTC
| legal_US_comment = / Rx-only
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life = 66 to 84 minutes
| duration_of_action =
| excretion = Urine
<!-- Identifiers -->
| CAS_number = 83-88-5
| CAS_supplemental = {{cascite|correct|CAS}}
| PubChem = 493570
| PubChemSubstance =
| IUPHAR_ligand = 6578
| DrugBank = DB00140
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| ChemSpiderID = 431981
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = TLM2976OFR
| KEGG = D00050
| KEGG_Ref = {{keggcite|correct|kegg}}
| ChEBI = 17015
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1534
| ChEMBL_Ref = {{ebicite|correct|EMBL}}
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = lactochrome, lactoflavin, vitamin G<ref name=anm/>
<!-- Chemical and physical data -->
| C=17 | H=20 | N=4 | O=6
| SMILES = c12cc(C)c(C)cc1N=C3C(=O)NC(=O)N=C3N2C[C@H](O)[C@H](O)[C@H](O)CO
| StdInChI = InChI=1S/C17H20N4O6/c1-7-3-9-10(4-8(7)2)21(5-11(23)14(25)12(24)6-22)15-13(18-9)16(26)20-17(27)19-15/h3-4,11-12,14,22-25H,5-6H2,1-2H3,(H,20,26,27)/t11-,12+,14-/m0/s1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AUNGANRZJHBGPY-SCRDCRAPSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| specific_rotation =
}}
'''Riboflavin''', also known as '''vitamin B<sub>2</sub>''', is a [[vitamin]] found in food and sold as a [[dietary supplement]].<ref name="ods">{{Cite web|url=https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/|title=Riboflavin: Fact Sheet for Health Professionals|publisher=Office of Dietary Supplements, US National Institutes of Health|date=11 May 2022|access-date=20 August 2023|archive-date=24 February 2020|archive-url=https://web.archive.org/web/20200224044152/https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/|url-status=live}}</ref> It is essential to the formation of two major [[coenzyme]]s, [[flavin mononucleotide]] and [[flavin adenine dinucleotide]]. These coenzymes are involved in energy [[metabolism]], [[cellular respiration]], and [[antibody]] production, as well as normal growth and development. The coenzymes are also required for the metabolism of [[Niacin (nutrient)|niacin]], [[vitamin B6|vitamin B<sub>6</sub>]], and [[folate]]. Riboflavin is [[prescription drug|prescribed]] to treat [[Corneal ectatic disorders|corneal thinning]], and taken orally, may reduce the incidence of [[migraine headache]]s in adults.
[[Riboflavin deficiency]] is rare and is usually accompanied by deficiencies of other vitamins and nutrients. It may be prevented or treated by oral supplements or by injections. As a [[water-soluble]] vitamin, any riboflavin consumed in excess of nutritional requirements is not stored; it is either not absorbed or is absorbed and quickly [[clearance (pharmacology)|excreted in urine]], causing the urine to have a bright yellow tint. Natural sources of riboflavin include meat, fish and fowl, eggs, dairy products, green vegetables, mushrooms, and almonds. Some countries require its addition to [[food grains|grains]].<ref name=ods/>
In its purified, solid form, it is a water-soluble yellow-orange crystalline powder. In addition to its function as a vitamin, it is used as a [[food coloring|food coloring agent]]. Biosynthesis takes place in bacteria, fungi and plants, but not animals. Industrial synthesis of riboflavin was initially achieved using a chemical process, but current commercial manufacturing relies on [[Fermentation in food processing|fermentation]] methods using strains of [[fungus|fungi]] and [[Genetic engineering|genetically modified]] bacteria.
In 2023, riboflavin was the 294th most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=17 August 2025 | archive-date=17 August 2025 | archive-url=https://web.archive.org/web/20250817043812/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Riboflavin Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Riboflavin | access-date = 17 August 2025 }}</ref>
==Definition==
Riboflavin, also known as vitamin B<sub>2</sub>, is a water-soluble [[vitamin]] and is one of the [[B vitamins]].<ref name="ods"/><ref name=DRItext /><ref name=PKIN2020B2>{{cite book |vauthors=Merrill AH, McCormick DB |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Riboflavin |editor=BP Marriott |editor2=DF Birt |editor3=VA Stallings|editor4=AA Yates |publisher = Academic Press (Elsevier) |year=2020 |___location = London, United Kingdom |pages = 189–208 |isbn=978-0-323-66162-1}}</ref> Unlike [[folate]] and [[vitamin B6|vitamin B<sub>6</sub>]], which occur in several chemically related forms known as [[vitamer]]s, riboflavin is only one chemical compound. It is a starting compound in the synthesis of the coenzymes [[flavin mononucleotide]] (FMN, also known as riboflavin-5'-phosphate) and [[flavin adenine dinucleotide]] (FAD). FAD is the more abundant form of flavin, reported to bind to 75% of the number of flavin-dependent protein encoded genes in the all-species genome (the flavoproteome)<ref name=Lienhart_2013>{{cite journal | vauthors = Lienhart WD, Gudipati V, Macheroux P | title = The human flavoproteome | journal = Archives of Biochemistry and Biophysics | volume = 535 | issue = 2 | pages = 150–62 | date = Jul 2013 | pmid = 23500531 | doi = 10.1016/j.abb.2013.02.015 | pmc=3684772}}</ref><ref>{{cite journal | vauthors = Macheroux P, Kappes B, Ealick SE | title = Flavogenomics--a genomic and structural view of flavin-dependent proteins | journal = The FEBS Journal | volume = 278 | issue = 15 | pages = 2625–34 | date = Aug 2011 | pmid = 21635694 | doi = 10.1111/j.1742-4658.2011.08202.x | s2cid = 22220250 | doi-access = free}}</ref> and serves as a co-enzyme for 84% of human-encoded flavoproteins.<ref name=Lienhart_2013/>
In its purified, solid form, riboflavin is a yellow-orange [[crystal]]line powder with a slight odor and bitter taste. It is soluble in polar [[solvent]]s, such as water and aqueous sodium chloride solutions, and slightly soluble in alcohols. It is not soluble in non-polar or weakly polar organic solvents such as chloroform, benzene or acetone.<ref name=pubchem/> In solution or during dry storage as a powder, riboflavin is heat stable if not exposed to light. When heated to decompose, it releases toxic fumes containing [[nitric oxide]].<ref name=pubchem>{{cite web |title=Riboflavin |url=https://pubchem.ncbi.nlm.nih.gov/compound/493570 |publisher=PubChem, US National Library of Medicine |access-date=15 October 2021 |date=9 October 2021 |archive-date=21 March 2021 |archive-url=https://web.archive.org/web/20210321160141/https://pubchem.ncbi.nlm.nih.gov/compound/493570 |url-status=live }}</ref>
==Functions==
Riboflavin is essential to the formation of two major coenzymes, FMN and FAD.<ref name=ods/><ref name=Mewies>{{cite journal |doi=10.1002/pro.5560070102 |doi-access=free |title=Covalent attachment of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to enzymes: The current state of affairs |year=1998 |vauthors=Mewies M, McIntire WS, Scrutton NS |journal=Protein Science |volume=7 |issue=1 |pages=7–20 |pmid=9514256 |pmc=2143808 }}</ref> These coenzymes are involved in [[energy metabolism]], [[cell respiration]], [[antibody]] production, growth and development.<ref name=Mewies/> Riboflavin is essential for the metabolism of [[carbohydrate]]s, [[protein (nutrient)|protein]] and [[fat]]s.<ref name=ods/> FAD contributes to the conversion of [[tryptophan]] to [[Niacin (nutrient)|niacin]] (vitamin B<sub>3</sub>)<ref name=lpi/> and the conversion of vitamin B<sub>6</sub> to the coenzyme [[Pyridoxal phosphate|pyridoxal 5'-phosphate]] requires FMN.<ref name=lpi/> Riboflavin is involved in maintaining normal circulating levels of [[homocysteine]]; in riboflavin deficiency, homocysteine levels increase, elevating the risk of [[cardiovascular diseases]].<ref name="lpi">{{Cite web | title = Riboflavin | publisher = Micronutrient Information Center, Linus Pauling Institute, Oregon State University | year = 2013 | url = http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/ | access-date = 8 October 2021 | archive-date = 11 February 2010 | archive-url = https://web.archive.org/web/20100211034337/http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/ | url-status = live }}</ref>
===Redox reactions===
[[Redox|Redox reactions]] are processes that involve the [[electron transfer|transfer of electrons]]. The flavin coenzymes support the function of roughly 70-80 flavoenzymes in humans (and hundreds more across all organisms, including those encoded by [[Archaea|archeal]], bacterial and fungal [[genome]]s) that are responsible for one- or two-electron redox reactions which capitalize on the ability of flavins to be converted between oxidized, half-reduced and fully reduced forms.<ref name=ods/><ref name=PKIN2020B2 /> FAD is also required for the activity of [[glutathione reductase]], an essential enzyme in the formation of the [[Endogeny (biology)|endogenous]] [[antioxidant]], [[glutathione]].<ref name=lpi/>
===Micronutrient metabolism===
Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B<sub>6</sub>, and [[folate]].<ref name="DRItext" /> The synthesis of the niacin-containing coenzymes, [[Nicotinamide adenine dinucleotide|NAD]] and [[Nicotinamide adenine dinucleotide phosphate|NADP]], from tryptophan involves the FAD-dependent enzyme, [[kynurenine 3-monooxygenase]]. Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency.<ref name="DRItext" /> Conversion of vitamin B<sub>6</sub> to its coenzyme, [[pyridoxal 5'-phosphate]], involves the enzyme, [[pyridoxine 5'-phosphate oxidase]], which requires FMN.<ref name="DRItext" /> An enzyme involved in folate metabolism, [[5,10-methylenetetrahydrofolate]] [[reductase]], requires FAD to form the amino acid, [[methionine]], from homocysteine.<ref name="DRItext" />
Riboflavin deficiency appears to impair the metabolism of the [[Mineral (nutrient)|dietary mineral]], [[iron]], which is essential to the production of [[hemoglobin]] and [[red blood cell]]s. Alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effectiveness of [[iron supplement]]ation for treating [[iron-deficiency anemia]].<ref>{{cite journal |vauthors=Fishman SM, Christian P, West KP |title=The role of vitamins in the prevention and control of anaemia |journal=Public Health Nutr |volume=3 |issue=2 |pages=125–50 |date=June 2000 |pmid=10948381 |doi=10.1017/s1368980000000173 |url=|doi-access=free }}</ref>
==Synthesis==
===Biosynthesis===
Biosynthesis takes place in bacteria, fungi and plants, but not animals.<ref name=PKIN2020B2 /> The biosynthetic precursors to riboflavin are [[ribulose 5-phosphate]] and [[guanosine triphosphate]]. The former is converted to L-3,4-dihydroxy-2-butanone-4-phosphate. Guanosine is degraded to [[4-Hydroxy-2,4,5-triaminopyrimidine|4-hydroxy-2,4,5-triaminopyrimidine]], which is transformed into 5-amino-6-(D-ribitylamino)uracil. These two compounds are then the substrates for the penultimate step in the pathway, catalysed by the enzyme [[lumazine synthase]] in reaction {{EC number|2.5.1.78}}.<ref name=Bacher>{{cite journal |doi=10.1016/j.abb.2008.02.008 |title=Biosynthesis of vitamin B2: Structure and mechanism of riboflavin synthase |year=2008 |vauthors=Fischer M, Bacher A |journal=Archives of Biochemistry and Biophysics |volume=474 |issue=2 |pages=252–265 |pmid=18298940 }}</ref><ref name=Metacyc>{{cite web |url=https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-6168&detail-level=2 |title=Pathway: flavin biosynthesis III (fungi) |vauthors=Caspi R |publisher=MetaCyc Metabolic Pathway Database |date=17 March 2009 |access-date=21 November 2021 |archive-date=21 November 2021 |archive-url=https://web.archive.org/web/20211121162528/https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-6168&detail-level=2 |url-status=live }}</ref><ref>{{Cite journal|vauthors=Wei Y, Kumar P, Wahome N, Mantis NJ, Middaugh CR|date=2018|title=Biomedical Applications of Lumazine Synthase|url=https://www.researchgate.net/publication/325109792|journal=Journal of Pharmaceutical Sciences|volume=107|issue=9|pages=2283–96|doi=10.1016/j.xphs.2018.05.002|pmid=29763607|bibcode=2018JPhmS.107.2283W |s2cid=21729139|access-date=29 December 2021|archive-date=20 March 2024|archive-url=https://web.archive.org/web/20240320024255/https://www.researchgate.net/publication/325109792_Biomedical_Applications_of_Lumazine_Synthase|url-status=live}}</ref>
:[[File:Lumazine synthase reaction.svg|upright=2|class=skin-invert-image]]
In the final step of the biosynthesis, two molecules of [[6,7-dimethyl-8-ribityllumazine]] are combined by the enzyme [[riboflavin synthase]] in a [[dismutation]] reaction. This generates one molecule of riboflavin and one of 5-amino-6-(D-ribitylamino) uracil. The latter is recycled to the previous reaction in the sequence.<ref name=Bacher /><ref name=Metacyc />
:[[File:Riboflavin synthase dismutation.svg|upright=2|class=skin-invert-image]]
Conversions of riboflavin to the [[Cofactor (biochemistry)|cofactors]] FMN and FAD are carried out by the enzymes [[riboflavin kinase]] and [[FMN adenylyltransferase|FAD synthetase]] acting sequentially.<ref name=Metacyc /><ref>{{cite book | vauthors = Devlin TM | title = Textbook of Biochemistry: with Clinical Correlations | date = 2011 | publisher = John Wiley & Sons | ___location = Hoboken, NJ | isbn = 978-0-470-28173-4 | edition = 7th }}</ref>
:[[File:FAD Synthesis.png|thumb|class=skin-invert-image|Riboflavin is the biosynthetic precursor of FMN and FAD]]
===Industrial synthesis===
[[File:Micrococcus riboflavin.jpg|thumb|Cultures of ''Micrococcus luteus'' growing on pyridine (left) and succinic acid (right). The pyridine culture has turned yellow from the accumulation of riboflavin.<ref name="Sims1992"/>]]
The industrial-scale production of riboflavin uses various microorganisms, including [[Mold (fungus)|filamentous fungi]] such as ''[[Ashbya gossypii]]'', ''[[Candida famata]]'' and ''Candida flaveri'', as well as the [[bacteria]] ''[[Corynebacterium]] ammoniagenes'' and ''[[Bacillus subtilis]]''. ''B. subtilis'' that has been genetically modified to both increase the production of riboflavin and to introduce an antibiotic ([[ampicillin]]) resistance marker, is employed at a commercial scale to produce riboflavin for [[animal feed|feed]] and food fortification.<ref name=Stahmann>{{cite journal | vauthors = Stahmann KP, Revuelta JL, Seulberger H | title = Three biotechnical processes using Ashbya gossypii, Candida famata, or Bacillus subtilis compete with chemical riboflavin production | journal = Applied Microbiology and Biotechnology | volume = 53 | issue = 5 | pages = 509–16 | date = May 2000 | pmid = 10855708 | doi = 10.1007/s002530051649 | s2cid = 2471994 }}</ref> By 2012, over 4,000 tonnes per annum were produced by such fermentation processes.<ref name=Anie>{{cite journal | vauthors = Eggersdorfer M, Laudert D, Létinois U, McClymont T, Medlock J, Netscher T, Bonrath W | title = One hundred years of vitamins-a success story of the natural sciences | journal = Angewandte Chemie | volume = 51 | issue = 52 | pages = 12960–12990 | date = December 2012 | pmid = 23208776 | doi = 10.1002/anie.201205886 | bibcode = 2012ACIE...5112960E }}</ref>
In the presence of high concentrations of hydrocarbons or aromatic compounds, some bacteria overproduce riboflavin, possibly as a protective mechanism. One such organism is ''[[Micrococcus luteus]]'' ([[American Type Culture Collection]] strain number ATCC 49442), which develops a yellow color due to production of riboflavin while growing on pyridine, but not when grown on other substrates, such as succinic acid.<ref name="Sims1992">{{cite journal | vauthors = Sims GK, O'loughlin EJ | title = Riboflavin Production during Growth of Micrococcus luteus on Pyridine | journal = Applied and Environmental Microbiology | volume = 58 | issue = 10 | pages = 3423–5 | date = October 1992 | pmid = 16348793 | pmc = 183117 | doi = 10.1128/AEM.58.10.3423-3425.1992 | bibcode = 1992ApEnM..58.3423S }}</ref>
===Laboratory synthesis===
The first [[total synthesis]] of riboflavin was carried out by [[Richard Kuhn]]'s group.<ref name=Anie/><ref>{{cite journal |doi=10.1002/cber.19350680922 |title=Über die Synthese des Lactoflavins (Vitamin B 2 ) |year=1935 | vauthors = Kuhn R, Reinemund K, Weygand F, Ströbele R |journal=Berichte der Deutschen Chemischen Gesellschaft (A and B Series) |volume=68 |issue=9 |pages=1765–1774|language=de }}</ref> A substituted [[aniline]], produced by [[reductive amination]] using [[D-ribose]], was [[condensation reaction|condensed]] with [[alloxan]] in the final step:
:[[File:Riboflavin synthesis.svg|upright=2|class=skin-invert-image]]
==Uses==
===Treatment of corneal thinning===
[[Keratoconus]] is the most common form of [[corneal ectasia]], a progressive thinning of the cornea. The condition is treated by [[Corneal cross-linking|corneal collagen cross-linking]], which increases corneal stiffness. Cross-linking is achieved by applying a [[topical medication|topical]] riboflavin solution to the cornea, which is then exposed to [[Ultraviolet#UVA|ultraviolet A]] light.<ref>{{cite journal | vauthors = Mastropasqua L | title = Collagen cross-linking: when and how? A review of the state of the art of the technique and new perspectives | journal = Eye and Vision | volume = 2 | article-number = 19 | date = 2015 | pmid = 26665102 | pmc = 4675057 | doi = 10.1186/s40662-015-0030-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sorkin N, Varssano D | title = Corneal collagen crosslinking: a systematic review | journal = Ophthalmologica | volume = 232 | issue = 1 | pages = 10–27 | date = June 2014 | pmid = 24751584 | doi = 10.1159/000357979 | s2cid = 32696531 | doi-access = free }}</ref>
===Migraine prevention===
In its 2012 guidelines, the [[American Academy of Neurology]] stated that high-dose riboflavin (400 mg) is "probably effective and should be considered for migraine prevention,"<ref name="Holland">{{cite journal | vauthors = Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E | title = Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society | journal = Neurology | volume = 78 | issue = 17 | pages = 1346–53 | date = April 2012 | pmid = 22529203 | pmc = 3335449 | doi = 10.1212/wnl.0b013e3182535d0c }}</ref> a recommendation also provided by the UK National Migraine Centre.<ref name="nmc">{{cite web |title={{-'}}Natural' remedies for migraine – should I try them? |url=https://www.nationalmigrainecentre.org.uk/migraine-and-headaches/migraine-and-headache-factsheets/natural-remedies-for-migraine-should-i-try-them/ |publisher=UK National Migraine Centre |access-date=8 October 2021 |date=2021 |archive-date=8 October 2021 |archive-url=https://web.archive.org/web/20211008155921/https://www.nationalmigrainecentre.org.uk/migraine-and-headaches/migraine-and-headache-factsheets/natural-remedies-for-migraine-should-i-try-them/ |url-status=live }}</ref> A 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of [[migraine]] headaches in adults.<ref name="Thompson2017">{{cite journal | vauthors = Thompson DF, Saluja HS | title = Prophylaxis of migraine headaches with riboflavin: A systematic review | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 42 | issue = 4 | pages = 394–403 | date = August 2017 | pmid = 28485121 | doi = 10.1111/jcpt.12548 | s2cid = 29848028 | doi-access = free }}</ref> Research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and so supplements are not recommended.<ref name=drugs/><ref name=ods/><ref name="Sherwood">{{cite journal | vauthors = Sherwood M, Goldman RD | title = Effectiveness of riboflavin in pediatric migraine prevention | journal = Canadian Family Physician | volume = 60 | issue = 3 | pages = 244–6 | date = March 2014 | pmid = 24627379 | pmc = 3952759 }}</ref>
===Food coloring===
Riboflavin is used as a [[food coloring]] (yellow-orange crystalline powder),<ref name=pubchem/> and is designated with the [[E number]], E101, in Europe for use as a [[food additive]].<ref name=UKFSA>{{cite web|url=https://www.food.gov.uk/business-guidance/approved-additives-and-e-numbers|title=Approved additives and E numbers|website=food.gov.uk|access-date=20 August 2023|date=10 August 2023|publisher=UK Food Standards Agency|archive-date=26 September 2020|archive-url=https://web.archive.org/web/20200926032802/https://www.food.gov.uk/business-guidance/approved-additives-and-e-numbers/|url-status=live}}</ref>
==Dietary recommendations==
The [[National Academy of Medicine]] updated the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for riboflavin in 1998. {{As of|1998|alt=The EARs}} for riboflavin for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.3 mg/day, respectively. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy is 1.4 mg/day and the RDA for lactating females is 1.6 mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.3–0.4 mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day. As for safety, the IOM sets [[tolerable upper intake level]]s (ULs) for vitamins and minerals when evidence is sufficient. In the case of riboflavin there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as [[Dietary Reference Intake]]s (DRIs).<ref name="DRItext">{{cite book | author = Institute of Medicine | title =Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B<sub>6</sub>, Folate, Vitamin B<sub>12</sub>, Pantothenic Acid, Biotin, and Choline | chapter = Riboflavin | publisher = The National Academies Press | year = 1998 | ___location = Washington, DC | pages = 87–122 | chapter-url = http://www.nap.edu/openbook.php?record_id=6015&page=87 | access-date = 29 August 2017 | isbn = 978-0-309-06554-2 | url-status = live | archive-url = https://web.archive.org/web/20150717032627/http://www.nap.edu/openbook.php?record_id=6015&page=87 | archive-date = 17 July 2015 | author-link =Institute of Medicine }}</ref><ref name="Gropper S.S. 2009, P329-333"/>
The [[European Food Safety Authority]] (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men aged 15 and older the PRI is set at 1.6 mg/day. The PRI during pregnancy is 1.9 mg/day and the PRI for lactating females is 2.0 mg/day. For children aged 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. These PRIs are higher than the U.S. RDAs.<ref>{{cite journal |vauthors=Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, Hirsch-Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Van Loveren H, Vinceti M, Willatts P, Lamberg-Allardt C, Przyrembel H, Tetens I, Dumas C, Fabiani L, Forss AC, Ioannidou S, Neuhäuser-Berthold M |title=Dietary Reference Values for riboflavin |journal=EFSA J |volume=15 |issue=8 |pages=e04919 |date=August 2017 |pmid=32625611 |pmc=7010026 |doi=10.2903/j.efsa.2017.4919 |url=}}</ref><ref name="EFSA PRI">{{cite web| title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| url-status = live| archive-url = https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| archive-date = 28 August 2017}}</ref> The EFSA also considered the maximum safe intake and like the U.S. National Academy of Medicine, decided that there was not sufficient information to set an UL.<ref>{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| url-status = live| archive-url = https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| archive-date = 16 March 2016}}</ref>
{| class="wikitable" style="float: right; font-size: 80%; text-align: center; margin-left: 2em"
|-
| colspan="2" style="background: blue; color: white; font-size: 110%; text-align: center;" | Recommended Dietary Allowances '''United States'''
|-
! scope="col" width="8em" | Age group (years)
! scope="col" width="8em"| RDA for riboflavin (mg/d)<ref name=DRItext />
|-
| 0–6 months || 0.3*
|-
| 6–12 months || 0.4*
|-
| 1–3 || 0.5
|-
| 4–8 || 0.6
|-
| 9–13 || 0.9
|-
| Females 14–18 || 1.0
|-
| Males 14–18 || 1.3
|-
| Females 19+ || 1.1
|-
| Males 19+ || 1.3
|-
| Pregnant females || 1.4
|-
| Lactating females || 1.6
|-
| colspan="2" style="text-align: center;" | * Adequate intake for infants, no RDA/RDI yet established<ref name=DRItext />
|-
| colspan="2" style="background: blue; color: white; font-size: 110%; text-align: center;" | Population Reference Intakes '''European Union'''
|-
! scope="col" width=8em | Age group (years)
! scope="col" width=8em | PRI for riboflavin (mg/d)<ref name="EFSA PRI"/>
|-
| 7–11 months || 0.4
|-
| 1–3 || 0.6
|-
| 4–6 || 0.7
|-
| 7–10 || 1.0
|-
| 11–14 || 1.4
|-
| 15–adult || 1.6
|-
| Pregnant females || 1.9
|-
| Lactating females || 2.0
|-
|}
===Safety===
In humans, there is no evidence for riboflavin toxicity produced by excessive intakes and absorption becomes less efficient as dosage increases. Any excess riboflavin is excreted via the [[kidney]]s into [[urine]], resulting in a bright yellow color known as flavinuria.<ref name=PKIN2020B2/><ref name="Gropper S.S. 2009, P329-333">{{cite book | vauthors = Gropper SS, Smith JL, Groff JL |chapter= Ch. 9: Riboflavin |title=Advanced Nutrition and Human Metabolism |edition=5th |___location=Wadsworth |publisher=CENGAG Learning |year=2009 |pages=329–33|isbn= 9780495116578}}</ref><ref name="MayoClinic"/> During a clinical trial on the effectiveness of riboflavin for treating the frequency and severity of migraines, subjects were given up to 400 mg of riboflavin orally per day for periods of 3–12 months. Abdominal pains and [[diarrhea]] were among the [[side effect]]s reported.<ref name="Thompson2017"/>
===Labeling===
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For riboflavin labeling purposes 100% of the Daily Value was 1.7 mg, but as of 27 May 2016, it was revised to 1.3 mg to bring it into agreement with the RDA.<ref name="FedReg">{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982. |url-status=live |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-date=8 August 2016 }}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}</ref> A table of the old and new adult daily values is provided at [[Reference Daily Intake]].
==Sources==
The [[United States Department of Agriculture]], Agricultural Research Service maintains a food composition database from which riboflavin content in hundreds of foods can be searched.<ref name="USDA-NDL">{{cite web|url=https://fdc.nal.usda.gov/fdc-app.html#/|title=USDA Food Composition Databases; Food Search; SR Legacy Foods|date=7 May 2019|publisher=United States Department of Agriculture, Agricultural Research Service. Release 28|access-date=28 November 2021|archive-date=3 April 2019|archive-url=https://web.archive.org/web/20190403171801/https://fdc.nal.usda.gov/fdc-app.html#/|url-status=dead}}</ref>
{|
|valign=top|
{|class="wikitable"
|-
!Source<ref name="USDA-NDL" />
!Amount (mg)<br /> (per 100 grams)
|-
|[[Beef]] liver, pan-fried || 3.42
|-
|[[Chicken]] liver, pan-fried || 2.31
|-
|[[Whey]] protein powder || 2.02
|-
|[[Salmon]], cooked, wild/farmed || 0.49/0.14
|-
|Cows' [[milk]], whole || 0.41 (one cup)
|-
|[[Turkey bird|Turkey]], cooked, dark/breast || 0.38/0.21
|-
|[[Pork]], cooked, chop || 0.23
|-
|[[Egg as food|Chicken egg]]s, fried || 0.23 (one, large)
|-
|[[Chicken]], cooked, thigh/breast || 0.19/0.11
|-
|[[Beef]], ground, cooked || 0.18
|}
|valign=top|
{|class="wikitable"
|-
!Source<ref name="USDA-NDL" />
!Amount (mg)<br /> (per 100 grams)
|-
|[[Cheese]], cheddar || 0.43
|-
|[[Yogurt]], whole milk || 0.25 (one cup)
|-
|[[Almond]]s || 1.14
|-
|[[Mushroom]]s, white, raw || 0.40
|-
|[[Spinach]], boiled || 0.24
|-
|[[Bread]], baked, fortified || 0.25
|-
|[[Pasta]], cooked, fortified || 0.14
|-
|[[Grits|Corn grits]] || 0.06
|-
|[[Rice]], cooked, brown/white || 0.05/0.00
|}
|valign=top|
{|class="wikitable"
|-
!Source<ref name="USDA-NDL" />
!Amount (mg)<br /> (per 100 grams)
|-
|[[Avocado]] || 0.14
|-
|[[Kale]], boiled || 0.14
|-
|[[Sweet potato]] baked || 0.11
|-
|[[Peanut]]s, roasted || 0.11
|-
|[[Tofu]], firm || 0.10
|-
|[[Bean]]s, green || 0.10
|-
|[[Brussels sprout]]s, boiled || 0.08
|-
|[[Romaine lettuce]] || 0.07
|-
|[[Potato]], baked, with skin || 0.05
|-
|[[Bean]]s, baked || 0.04
|}
|}
The white [[flour]] produced after milling of wheat has only 67% of its original riboflavin amount left,<ref>{{cite journal | vauthors = Batifoulier F, Verny MA, Chanliaud E, Rémésy C, Demigné C | title=Variability of B vitamin concentrations in wheat grain, milling fractions and bread products | journal=European Journal of Agronomy | volume=25 | issue=2 | date=2006 | doi=10.1016/j.eja.2006.04.009 | pages=163–69| bibcode=2006EuJAg..25..163B }}</ref> so white flour is enriched in some countries.<ref name="NutrientsAdded"/> Riboflavin is also added to ready-to-eat [[breakfast cereal]]s.<ref name=Cereal>{{cite web |url=https://www.webmd.com/diet/foods-high-in-riboflavin |title=Healthy Foods High in Riboflavin | vauthors = Sachdev P |date=23 November 2022 |website=WebMD |access-date=31 July 2024}}</ref> It is difficult to incorporate riboflavin into liquid products because it has poor solubility in water, hence the requirement for [[riboflavin-5'-phosphate]] (FMN, also called [[E number|E101 when used as colorant]]), a more soluble form of riboflavin.<ref name=UKFSA/> The enrichment of bread and ready-to-eat breakfast cereals contributes significantly to the dietary supply of the vitamin. Free riboflavin is naturally present in animal-sourced foods along with protein-bound FMN and FAD. Cows' milk contains mainly free riboflavin, but both FMN and FAD are present at low concentrations.<ref>{{cite journal | vauthors = Kanno C, Kanehara N, Shirafuji K, Tanji R, Imai T | title = Binding form of vitamin B2 in bovine milk: its concentration, distribution and binding linkage |journal = Journal of Nutritional Science and Vitaminology |volume=37 |issue=1 |pages=15–27 |date=February 1991 |pmid=1880629 |doi = 10.3177/jnsv.37.15|doi-access=free }}</ref>
===Fortification===
Some countries require or recommend fortification of grain foods.<ref name="NutrientsAdded">{{Cite web|url=https://www.ffinetwork.org/from-nutritionists-faq?rq=riboflavin|publisher=Food Fortification Initiative|title=What nutrients are added to flour and rice in fortification?|date=2021|access-date=8 October 2021|archive-date=8 October 2021|archive-url=https://web.archive.org/web/20211008135516/https://www.ffinetwork.org/from-nutritionists-faq?rq=riboflavin|url-status=live}}</ref> As of 2024, 57 countries, mostly in North and South America and southeast Africa, require food fortification of [[wheat]] flour or [[maize]] (corn) flour with riboflavin or riboflavin-5'-phosphate sodium. The amounts stipulated range from 1.3 to 5.75 mg/kg.<ref name=FortifMap>{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange|access-date=31 July 2024}}</ref> An additional 16 countries have a voluntary fortification program.<ref name=FortifMap/> For example, the Indian government recommends 4.0 mg/kg for [[Maida (flour)|"maida" (white)]] and [[Atta flour|"atta" (whole wheat)]] flour.<ref>{{cite web |url=https://fssai.gov.in/upload/advisories/2018/03/5a97968275a36206.pdf |title=Direction under Section 16(5) of Foods Safety and Standards Act, 2006 regarding Operationalisation of Food Safety & Standards (Fortification of Foods) Regulations, 2017 relating to standards for fortification of food |date=19 May 2017 |website=Food Safety & Standards Authority of India (FSSAI) |access-date=30 November 2021 |archive-date=17 December 2021 |archive-url=https://web.archive.org/web/20211217054313/https://www.fssai.gov.in/upload/advisories/2018/03/5a97968275a36206.pdf |url-status=live }}</ref>
==Absorption, metabolism, excretion==
More than 90% of riboflavin in the diet is in the form of protein-bound FMN and FAD.<ref name=ods/> Exposure to [[gastric acid]] in the stomach releases the coenzymes, which are subsequently enzymatically hydrolyzed in the proximal [[small intestine]] to release free riboflavin.<ref name="zempleni">{{cite journal |vauthors=Zempleni J, Galloway JR, McCormick DB |title=Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans |journal=American Journal of Clinical Nutrition |volume=63 |issue=1 |pages=54–66 |date=January 1996 |pmid=8604671 |doi=10.1093/ajcn/63.1.54 |url=|doi-access=free }}</ref>
Absorption occurs via a rapid [[active transport]] system, with some additional [[passive transport|passive diffusion]] occurring at high concentrations.<ref name=zempleni/> Bile salts facilitate uptake, so absorption is improved when the vitamin is consumed with a meal.<ref name="DRItext" /><ref name=PKIN2020B2/> The majority of newly absorbed riboflavin is taken up by the liver on the first pass, indicating that [[prandial|postprandial]] appearance of riboflavin in [[blood plasma]] may underestimate absorption.<ref name=PKIN2020B2/> Three riboflavin transporter proteins have been identified: RFVT1 is present in the small intestine and also in the placenta; RFVT2 is highly expressed in brain and salivary glands; and RFVT3 is most highly expressed in the small intestine, testes, and prostate.<ref name=PKIN2020B2/><ref name="Jaeger2016">{{cite journal |vauthors=Jaeger B, Bosch AM |title=Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience |journal=Journal of Inherited Metabolic Disease |volume=39 |issue=4 |pages=559–64 |date=July 2016 |pmid=26973221 |pmc=4920840 |doi=10.1007/s10545-016-9924-2 |url=}}</ref> Infants with mutations in the genes encoding these transport proteins can be treated with riboflavin administered orally.<ref name="Jaeger2016"/>
Riboflavin is reversibly converted to FMN and then FAD. From riboflavin to FMN is the function of zinc-requiring [[riboflavin kinase]]; the reverse is accomplished by a phosphatase. From FMN to FAD is the function of magnesium-requiring FAD synthase; the reverse is accomplished by a [[pyrophosphatase]]. FAD appears to be an inhibitory end-product that down-regulates its own formation.<ref name=PKIN2020B2 />
When excess riboflavin is absorbed by the small intestine, it is quickly removed from the blood and excreted in urine.<ref name=PKIN2020B2/> Urine color is used as a hydration status biomarker and, under normal conditions, correlates with [[urine specific gravity]] and [[urine osmolality]].<ref>{{cite journal |vauthors=Ellis LA, Yates BA, McKenzie AL, Muñoz CX, Casa DJ, Armstrong LE |title=Effects of Three Oral Nutritional Supplements on Human Hydration Indices |journal=Int J Sport Nutr Exerc Metab |volume=26 |issue=4 |pages=356–62 |date=August 2016 |pmid=26731792 |doi=10.1123/ijsnem.2015-0244 |url=}}</ref> However, riboflavin supplementation in large excess of requirements causes urine to appear more yellow than normal.<ref name="MayoClinic">{{cite web |url=https://www.mayoclinic.org/drugs-supplements/riboflavin-oral-route/side-effects/drg-20065810 |title=Riboflavin (Oral Route) |date=February 2021 |website=Mayo Clinic |access-date=28 October 2021 |archive-date=28 October 2021 |archive-url=https://web.archive.org/web/20211028125749/https://www.mayoclinic.org/drugs-supplements/riboflavin-oral-route/side-effects/drg-20065810 |url-status=live }}</ref> With normal dietary intake, about two-thirds of urinary output is riboflavin, the remainder having been partially metabolized to hydroxymethylriboflavin from oxidation within cells, and as other metabolites. When consumption exceeds the ability to absorb, riboflavin passes into the large intestine, where it is catabolized by bacteria to various metabolites that can be detected in [[feces]].<ref name=PKIN2020B2/> There is speculation that unabsorbed riboflavin could affect the large intestine [[microbiome]].<ref>{{cite journal |vauthors=Steinert RE, Sadaghian Sadabad M, Harmsen HJ, Weber P |title=The prebiotic concept and human health: a changing landscape with riboflavin as a novel prebiotic candidate? |journal=Eur J Clin Nutr |volume=70 |issue=12 |pages=1348–1353 |date=December 2016 |pmid=27380884 |doi=10.1038/ejcn.2016.119 |s2cid=29319823 |url=|doi-access=free }}</ref>
==Deficiency==
===Prevalence===
Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs.<ref name=FortifMap /> From data collected in biannual surveys of the U.S. population, for ages 20 and over, 22% of women and 19% of men reported consuming a supplement that contained riboflavin, typically a vitamin-mineral multi-supplement. For the non-supplement users, the dietary intake of adult women averaged 1.74 mg/day and men 2.44 mg/day. These amounts exceed the RDAs for riboflavin of 1.1 and 1.3 mg/day respectively.<ref>{{cite web |url=https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1718/Table_37_SUP_GEN_17.pdf |title=Total Nutrient Intakes: Percent Reporting and Mean Amounts of Selected Vitamins and Minerals from Food and Beverages and Dietary Supplements, by Gender and Age, What We Eat in America, NHANES 2017-2018 |date=2020 |website=U.S. Department of Agriculture, Agricultural Research Service |access-date=24 October 2021 |archive-date=21 October 2021 |archive-url=https://web.archive.org/web/20211021154439/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1718/Table_37_SUP_GEN_17.pdf |url-status=live }}</ref> For all age groups, on average, consumption from food exceeded the RDAs.<ref>{{cite web |url=https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1718/Table_1_NIN_GEN_17.pdf |title=Nutrient Intakes from Food and Beverages: Mean Amounts Consumed per Individual, by Gender and Age, What We Eat in America, NHANES 2017-2018 |date=2020 |website=U.S. Department of Agriculture, Agricultural Research Service |access-date=24 October 2021 |archive-date=2 November 2021 |archive-url=https://web.archive.org/web/20211102164736/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/1718/Table_1_NIN_GEN_17.pdf |url-status=live }}</ref> A 2001-02 U.S. survey reported that less than 3% of the population consumed less than the [[Estimated Average Requirement]] of riboflavin.<ref>{{cite web |url=https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/0102/usualintaketables2001-02.pdf |title=What We Eat in America 2001-2002: Usual Nutrient Intakes from Food Compared to Dietary Reference Intakes |vauthors=Moshfegh A, Goldman J, Cleveland L |date=September 2005 |website=U.S. Department of Agriculture, Agricultural Research Service |access-date=24 October 2021 |archive-date=24 October 2021 |archive-url=https://web.archive.org/web/20211024150207/https://www.ars.usda.gov/ARSUserFiles/80400530/pdf/0102/usualintaketables2001-02.pdf |url-status=live }}</ref>
===Signs and symptoms===
Riboflavin deficiency (also called ariboflavinosis) results in [[stomatitis]], symptoms of which include chapped and fissured lips, inflammation of the corners of the mouth ([[Angular cheilitis|angular stomatitis]]), sore throat, painful red tongue, and hair loss.<ref name=ods/> The eyes can become itchy, watery, bloodshot, and sensitive to light.<ref name=ods/> Riboflavin deficiency is associated with [[anemia]].<ref>{{cite journal |vauthors=Thakur K, Tomar SK, Singh AK, Mandal S, Arora S |title=Riboflavin and health: A review of recent human research |journal=Crit Rev Food Sci Nutr |volume=57 |issue=17 |pages=3650–3660 |date=November 2017 |pmid=27029320 |doi=10.1080/10408398.2016.1145104 |s2cid=205692748 |url=}}</ref> Prolonged riboflavin insufficiency may cause degeneration of the liver and nervous system.<ref name=ods/><ref name="DRItext"/> Riboflavin deficiency may increase the risk of [[preeclampsia]] in pregnant women.<ref name=ods/><ref name=lpi/> Deficiency of riboflavin during pregnancy can result in [[fetus|fetal]] [[birth defect]]s, including heart and limb deformities.<ref>{{cite journal | vauthors = Smedts HP, Rakhshandehroo M, Verkleij-Hagoort AC, de Vries JH, Ottenkamp J, Steegers EA, Steegers-Theunissen RP | title = Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects |journal = European Journal of Nutrition |volume = 47 |issue = 7 |pages = 357–65 |date = October 2008 |pmid = 18779918 |doi = 10.1007/s00394-008-0735-6 |s2cid = 25548935 }}</ref><ref>{{cite journal | vauthors = Robitaille J, Carmichael SL, Shaw GM, Olney RS | title = Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997-2003 | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 85 | issue = 9 | pages = 773–9 | date = September 2009 | pmid = 19350655 | doi = 10.1002/bdra.20587 | url = https://zenodo.org/record/1229129 | access-date = 17 December 2019 | archive-date = 13 June 2020 | archive-url = https://web.archive.org/web/20200613114554/https://zenodo.org/record/1229129 | url-status = live }}</ref>
===Risk factors===
People at risk of having low riboflavin levels include [[alcoholism|alcoholics]], [[vegetarianism|vegetarian]] athletes, and practitioners of [[veganism]].<ref name=ods/> Pregnant or lactating women and their infants may also be at risk, if the mother avoids meat and dairy products.<ref name=ods/><ref name=lpi/> [[Anorexia]] and [[lactose intolerance]] increase the risk of riboflavin deficiency.<ref name=lpi/> People with physically demanding lives, such as athletes and laborers, may require higher riboflavin intake.<ref name=lpi/> The conversion of riboflavin into FAD and FMN is impaired in people with [[hypothyroidism]], [[adrenal insufficiency]], and riboflavin [[Membrane transport protein|transporter]] deficiency.<ref name=lpi/>
===Causes===
Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble [[vitamin]]s.<ref name=ods/> A deficiency of riboflavin can be primary (i.e. caused by poor vitamin sources in the regular diet) or secondary, which may be a result of conditions that affect absorption in the intestine. Secondary deficiencies are typically caused by the body not being able to use the vitamin, or by an increased rate of excretion of the vitamin.<ref name=lpi/> Diet patterns that increase risk of deficiency include [[veganism]] and low-dairy [[vegetarianism]].<ref name=PKIN2020B2/> Diseases such as cancer, [[heart disease]] and [[diabetes]] may cause or exacerbate riboflavin deficiency.<ref name=DRItext />
There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or use by flavoproteins.<ref name=Jaeger2016/><ref name="cali">{{cite journal |vauthors=Cali E, Dominik N, Manole A, Houlden H |title=Riboflavin transporter deficiency |journal=GeneReviews (Adam MP, Ardinger HH, Pagon RA, et Al., Editors) |volume= |issue= |pages= |date=8 April 2021 |pmid=26072523 |doi= |url=https://www.ncbi.nlm.nih.gov/books/NBK299312/ |publisher=University of Washington, Seattle |access-date=20 November 2021 |archive-date=6 December 2021 |archive-url=https://web.archive.org/web/20211206220900/https://www.ncbi.nlm.nih.gov/books/NBK299312/ |url-status=live }}</ref> One of these is riboflavin transporter deficiency, previously known as [[Brown–Vialetto–Van Laere syndrome]].<ref name=Jaeger2016/><ref name=cali/> Variants of the genes SLC52A2 and [[SLC52A3]] which code for [[Transport protein|transporter proteins]] RDVT2 and RDVT3, respectively, are defective.<ref name=Jaeger2016/><ref name=cali/> Infants and young children present with muscle weakness, [[cranial nerve]] deficits including hearing loss, sensory symptoms including sensory [[ataxia]], feeding difficulties, and respiratory distress caused by a [[Sensorimotor network|sensorimotor]] [[axon]]al [[neuropathy]] and cranial nerve pathology.<ref name=cali/> When untreated, infants with riboflavin transporter deficiency have labored breathing and are at risk of dying in the first decade of life. Treatment with oral supplementation of high amounts of riboflavin is lifesaving.<ref name=Jaeger2016/><ref name=cali/>
Other inborn errors of metabolism include riboflavin-responsive multiple [[acyl-CoA dehydrogenase]] deficiency, also known as a subset of [[glutaric acidemia type 2]], and the C677T variant of the [[methylenetetrahydrofolate reductase]] enzyme, which in adults has been associated with risk of high blood pressure.<ref name=PKIN2020B2/>
===Diagnosis and assessment===
The assessment of riboflavin status is essential for confirming cases with non-specific symptoms whenever deficiency is suspected. Total riboflavin excretion in healthy adults with normal riboflavin intake is about 120 [[microgram]]s per day, while excretion of less than 40 micrograms per day indicates deficiency.<ref name=ods/><ref name="hoey">{{cite journal | vauthors = Hoey L, McNulty H, Strain JJ | title = Studies of biomarker responses to intervention with riboflavin: a systematic review | journal = The American Journal of Clinical Nutrition | volume = 89 | issue = 6 | pages = 1960S–1980S | date = June 2009 | pmid = 19403631 | doi = 10.3945/ajcn.2009.27230b | doi-access = free }}</ref> Riboflavin excretion rates decrease as a person ages, but increase during periods of [[chronic stress]] and the use of some [[prescription drug]]s.<ref name=ods/>
Indicators used in humans are [[erythrocyte]] [[glutathione reductase]] (EGR), erythrocyte flavin concentration and urinary excretion.<ref name=DRItext /><ref name=PKIN2020B2/> The ''erythrocyte glutathione reductase activity coefficient'' (EGRAC) provides a measure of tissue saturation and long-term riboflavin status.<ref name=hoey/><ref name=ods/> Results are expressed as an activity coefficient ratio, determined by enzyme activity with and without the addition of FAD to the culture medium. An EGRAC of 1.0 to 1.2 indicates that adequate amounts of riboflavin are present; 1.2 to 1.4 is considered low, greater than 1.4 indicates deficient.<ref name=ods/><ref name=PKIN2020B2/> For the less sensitive "erythrocyte flavin method", values greater than 400 nmol/L are considered adequate and values below 270 nmol/L are considered deficient.<ref name=DRItext /><ref name=hoey/> Urinary excretion is expressed as nmol of riboflavin per gram of [[creatinine]]. Low is defined as in the range of 50 to 72 nmol/g. Deficient is below 50 nmol/g. Urinary excretion load tests have been used to determine dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg, there was a modest linear increase in urinary riboflavin, reaching 100 micrograms for a subsequent 24-hour urine collection.<ref name=DRItext /> Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of 2.5 mg, urinary output was 800 micrograms for a 24-hour urine collection.<ref name=DRItext />
==History==
The name "riboflavin" comes from "[[ribose]]" (the sugar whose [[reduction (chemistry)|reduced]] form, [[ribitol]], forms part of its structure) and "[[Flavin group|flavin]]", the ring-moiety that imparts the yellow color to the oxidized molecule (from Latin ''flavus'', "yellow").<ref name=PKIN2020B2 /> The reduced form, which occurs in metabolism along with the oxidized form, appears as orange-yellow needles or crystals.<ref name=pubchem/> The earliest reported identification, predating any concept of vitamins as essential nutrients, was by Alexander Wynter Blyth. In 1879, Blyth isolated a water-soluble component of cows' milk whey, which he named "lactochrome", that [[fluorescence|fluoresced]] yellow-green when exposed to light.<ref name="anm"/>
In the early 1900s, several research laboratories were investigating constituents of foods, essential to maintain growth in rats. These constituents were initially divided into fat-soluble "vitamine" A and water-soluble "vitamine" B. (The "e" was dropped in 1920.<ref name=Rosenfeld>{{cite journal | vauthors = Rosenfeld L | title = Vitamine—vitamin. The early years of discovery | journal = Clinical Chemistry | volume = 43 | issue = 4 | pages = 680–685 | date =1997 | pmid = 9105273 | doi = 10.1093/clinchem/43.4.680 | doi-access = free }}</ref>) Vitamin B was further thought to have two components, a heat-labile substance called B<sub>1</sub> and a heat-stable substance called B<sub>2</sub>.<ref name="anm">{{cite journal | vauthors = Northrop-Clewes CA, Thurnham DI | title = The discovery and characterization of riboflavin | journal = Annals of Nutrition & Metabolism | volume = 61 | issue = 3 | pages = 224–30 | year = 2012 | pmid = 23183293 | doi = 10.1159/000343111 | s2cid = 7331172 }}</ref> Vitamin B<sub>2</sub> was tentatively identified to be the factor necessary for preventing [[pellagra]], but that was later confirmed to be due to [[Niacin (nutrient)|niacin]] (vitamin B<sub>3</sub>) deficiency. The confusion was due to the fact that riboflavin (B<sub>2</sub>) deficiency causes [[stomatitis]] symptoms similar to those seen in pellagra, but without the widespread peripheral skin lesions. For this reason, early in the history of identifying riboflavin deficiency in humans the condition was sometimes called "pellagra sine pellagra" (pellagra without pellagra).<ref>{{Cite journal | doi = 10.2307/4583104 |volume = 54 |issue = 48 |pages = 2121–31 | vauthors = Sebrell WH, Butler RE |title = Riboflavin Deficiency in Man (Ariboflavinosis) |journal = Public Health Reports |date = 1939 |jstor = 4583104}}</ref>
In 1935, [[Paul Gyorgy]], in collaboration with chemist [[Richard Kuhn]] and physician T. Wagner-Jauregg, reported that rats kept on a B<sub>2</sub>-free diet were unable to gain weight.<ref>{{cite journal | vauthors = György P | title = Investigations on the vitamin B(2) complex: The differentiation of lactoflavin and the 'rat antipellagra' factor | journal = The Biochemical Journal | volume = 29 | issue = 3 | pages = 741–759 | date = March 1935 | pmid = 16745720 | pmc = 1266542 | doi = 10.1042/bj0290741 }}</ref> Isolation of B<sub>2</sub> from yeast revealed the presence of a bright yellow-green fluorescent product that restored normal growth when fed to rats. The growth restored was directly proportional to the intensity of the fluorescence. This observation enabled the researchers to develop a rapid chemical bioassay in 1933, and then isolate the factor from egg white, calling it ovoflavin.<ref name=anm/> The same group then isolated the a similar preparation from whey and called it lactoflavin. In 1934, Kuhn's group identified the chemical structure of these flavins as identical, settled on "riboflavin" as a name, and were also able to synthesize the vitamin.<ref name=anm/>
Circa 1937, riboflavin was also referred to as "Vitamin G".<ref>{{cite journal |vauthors=Levine H, Remington RE |title=The Vitamin G Content of Some Foods |journal=J Nutr |volume=13 |issue=5 |pages=525–42 |date=May 1937 |doi=10.1093/jn/13.5.525 |url=https://doi.org/10.1093/jn/13.5.525 |access-date=5 October 2021 |archive-date=20 March 2024 |archive-url=https://web.archive.org/web/20240320024336/https://www.sciencedirect.com/science/article/abs/pii/S0022316623128598?via%3Dihub |url-status=live |url-access=subscription }}</ref> In 1938, Richard Kuhn was awarded the [[Nobel Prize in Chemistry]] for his work on vitamins, which had included B<sub>2</sub> and B<sub>6</sub>.<ref>{{cite web|url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1938/index.html|title=The Nobel Prize in Chemistry 1938|access-date=5 July 2018|website=Nobelprize.org|archive-date=8 July 2018|archive-url=https://web.archive.org/web/20180708045113/https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1938/index.html|url-status=live}}</ref> In 1939, it was confirmed that riboflavin is essential for human health through a clinical trial conducted by William H. Sebrell and Roy E. Butler. Women fed a diet low in riboflavin developed stomatitis and other signs of deficiency, which were reversed when treated with synthetic riboflavin. The symptoms returned when the supplements were stopped.<ref name=anm/>
== References ==
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[[Category:World Health Organization essential medicines]]
[[Category:Ophthalmology drugs]]
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