B-Complex Vitamin Deficiency and Supplementation

Home , Biotin, Dihydrofolic acid, Vitamin deficiency

REVIEW B-complex vitamin deficiency and supplementation

Gustav Schellack, BCur, AdvUnivDiplNursSc(HSM), HonsBSc(Pharmacology) Clinical Research Manager and Training Specialist in the Pharmaceutical Industry with a Special Interest in Clinical Research and Applied Pharmacology Pamela Harirari, BPharm, Academic Intern; Natalie Schellack, BCur, BPharm, PhD (Pharmacy) Associate Professor, Department of Pharmacy, Faculty of Health Sciences, Sefako Makgatho Health Sciences University Correspondence to: Natalie Schellack, [email protected] Keywords: vitamin B, B-complex vitamins, thiamine, riboflavin, niacin, pyridoxine, pantothenic acid, biotin, inositol, folic acid, folate, cobalamin, Wernicke-Korsakoff syndrome, beriberi, pellagra, pernicious anaemia, megaloblastic anaemia, intrinsic factor, haematinic, peripheral neuropathy

Abstract Vitamins are either fat- or water-soluble micronutrients that are derived from a healthy, well-balanced diet. The B-complex vitamins are well-known examples of water-soluble nutrients that are readily absorbed from a healthy gut, and easily eliminated via renal excretion. They are required for their vital physiological functions and are significant contributors to the maintenance of optimal health. Multiple B-vitamin deficiencies are quite common. Therefore, a balanced diet, including a full spectrum of B vitamins, is usually needed when any of them are found to be deficient. Conversely, their therapeutic value is limited to supplementation during states of deficiency since they have no additional benefits in the presence of an adequate dietary intake. In general, their active supplementation should only be used to correct deficiencies. This article provides an overview of B-complex vitamin deficiencies and their supplementation.

Introduction Table I: Water-soluble versus fat-soluble vitamins6,7

Vitamins are essential nutrients that are sourced from food. Water-soluble vitamins Fat-soluble vitamins They are required for their vital physiological functions, and are B complex • Vitamin A (retinol) 1 significant contributors to the maintenance of optimal health. • Vitamin B1 (thiamine) • Vitamin D (ergocalciferol and cholecalciferol) The B-group (or B-complex) vitamins, specifically, assist with the • Vitamin B2 (riboflavin) • Vitamin E (a-tocopherol) production of energy and the biosynthesis of many physiologically • Vitamin B3 (niacin) • Vitamin K (phytonadione) vital molecules in cells. They are water soluble and are not stored • Vitamin B5 (pantothenic acid) in the body. Therefore, daily replenishment is possible through • Vitamin B6 (pyridoxine) 1 dietary intake. Cereals, mainly in their purest and unrefined form, • Vitamin B12 (cobalamin) 2 are a common source of these vitamins. However, the practice • Folic acid (vitamin B9) of excessively refining and polishing cereals strips them of a • Para-aminobenzoic acid significant amount of vitamin B.3 Multiple B-vitamin deficiencies • Choline are quite common. Therefore, a balanced diet, including a full • Inositol (vitamin B8) • Biotin (vitamin B ) spectrum of B vitamins, is usually needed when any of them are 7 found to be deficient.4 In other words, if at least one B vitamin is Vitamin C (ascorbic acid) found to be deficient, the full spectrum should be considered to Notes be deficient, unless proven otherwise. • The water-soluble vitamins • These vitamins require binding are readily absorbed from the to ingested lipids to facilitate What are vitamins? gastrointestinal tract, and merely their absorption from the require passage in conjunction gastrointestinal tract. It is Vitamins are organic compounds that are characterised by high with water. (The notable important to note that any exception is vitamin B12, which condition that interferes with fat levels of potency. Therefore, they are only required in very small also needs to bind to intrinsic absorption will necessarily also amounts. They are classified as nutrients, and most of them are factor that is derived from the interfere with the absorption of obtained via dietary intake (hence the reason why several vitamins stomach) the fat-soluble vitamins become depleted in patients with a poor nutritional status). Some • These vitamins are excreted • These vitamins are stored in in the urine and are not the body, with the noteworthy of the B vitamins are also synthesised by the intestinal bacteria, stored in the body in any exception of vitamin K, and but in insufficient quantities. Vitamins are typically categorised as significant quantities. Therefore, toxicities are well-known, either being water soluble or fat soluble, as shown in Table I.5,6 hypervitaminosis is quite rare. e.g. hypervitaminosis A.

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The various B vitamins Vitamin B1 (thiamine) Thiamine is essential for glucose metabolism in the body.9 It Vitamins are essential for normal growth, metabolism and reproduction. However, their therapeutic value is limited to functions as a co-enzyme in the metabolism of carbohydrates 2 supplementation during states of deficiency since they have no and branched-chain amino acids. It is also essential for a normal additional benefits in the presence of an adequate dietary intake. appetite and plays a crucial role in maintaining the proper In general, their active supplementation should only be used to functioning of the nervous system.1 correct deficiencies, after which a well-balanced diet should be A thiamine deficiency may manifest itself in any of the following:2,10 able to provide all of the necessary nutrients.5 • Beriberi, which can be wet (oedematous) or dry (paralytic) As already mentioned, the B-complex vitamins are water soluble, • Wernicke’s encephalopathy, which is characterised by confusion, and the vitamins in this group are easily eliminated from the body ataxia and nystagmus via renal excretion. Typical members of this complex are thiamine • Korsakoff’s psychosis, which is characterised by confabulation, (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), folic lack of insight, retrograde and anterograde amnesia, and 6 10 acid (vitamin B9) and cobalamin (vitamin B12). Some authors apathy. The latter two are also referred to as the Wernicke- also include inositol, para-aminobenzoic acid and choline in this Korsakoff syndrome. Korsakoff’s psychosis is associated with group.7 Among a diverse array of functions, they act as important chronic alcoholism, following a thiamine deficiency in these co-factors or co-enzymes in a wide variety of metabolic processes patients.5 in the body. It is noteworthy that many different vitamins play a role in the formation and normal functioning of red blood cells.8 Treatment is invariably via thiamine supplementation (Table II).11 Furthermore, vitamin C and E act as antioxidants, and vitamin A Table II provides a summary of B-complex vitamin functions, and D as hormones.5 deficiencies and the treatment thereof. Also refer to Figure 1.

Table II: A summary of B-complex vitamin functions, deficiencies and their treatment4,5,11-14

Vitamin Functions Results of a deficiency Treatment of deficiency

Vitamin B1 (thiamine) • Functions as a co-enzyme Beriberi, polyneuritis and Thiamine is given as follows: in the metabolism of Wernicke-Korsakoff syndrome • For mild polyneuropathy: 10-20 mg orally, once daily, for carbohydrates and branched- 2 weeks chain amino acids in the body. • For moderate or advanced neuropathy: 20-30 mg once daily, • It catalyses the continued for several weeks after the symptoms disappear decarboxylation of a-ketoacids • For congestion and oedema due to cardiovascular beriberi: 100 mg intravenously, once daily, for several days • For Wernicke-Korsakoff syndrome: 50-100 mg intramuscularly or intravenously, twice daily, usually for several days, followed by 10-20 mg once daily, until a therapeutic response is obtained11 • Neuropathy will not respond to treatment if the nerve cells have died off • Prophylactic thiamine should be used in patients with chronic diarrhoea and those who have undergone intestinal resection5 • 100 mg of thiamine should be given intravenously before the administration of intravenous glucose* to alcoholic patients, or to any other patients who are at risk of having a thiamine deficiency11

Vitamin B2 (riboflavin) Functions as a co-enzyme in Cheilosis, angular stomatitis, lip • Riboflavin 5-10 mg orally, once daily, until recovery. Other several oxidation and reduction fissures and dermatitis (fissures B vitamins should also be administered11 reactions in the body may become infected with • Dosages up to 50 mg orally or intravenously may need to be Candida albicans), as well as considered5 normochromic or normocytic anaemia

Vitamin B3 (niacin, Functions as a co-substrate or Pellagra with dermatitis, Nicotinamide 250-500 mg daily orally, in divided dosages nicotinic acid or co-enzyme for hydrogen transfer diarrhoea and dementia, as 3-4 times a day or 100 mg 8 hourly5,11 nicotinamide) with several dehydrogenases well as secondary to diarrhoea, cirrhosis of the liver, alcoholism and carcinoid syndrome

Vitamin B5 Functions as a component Fatigue, sleep disturbances, The recommended daily allowance has not been established (pantothenic acid) of co-enzyme A and impaired coordination and with certainty, but 5-10 mg daily provided by a balanced diet is phosphopantetheine and is nausea probably adequate12 involved in fatty acid metabolism

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Table II: A summary of B-complex vitamin functions, deficiencies and their treatment4,5,11-14

Vitamin Functions Results of a deficiency Treatment of deficiency

Vitamin B6 Functions as a co-enzyme Nasolateral seborrhoea, glossitis • Specific causes, e.g. the use of pyridoxine-inactivating drugs, (pyridoxine, pyridoxal (pyridoxal phosphate) in the and peripheral neuropathy such as isoniazid, and malabsorption, should be corrected for phosphate or metabolism of amino acids, (and epileptiform convulsions, secondary deficiency4 pyridoxamine) glycogen and sphingoid bases especially in infants, which may • Pyridoxine 50-100 mg orally, once daily be refractory to treatment with • Dosages may be as low as 2 mg per day5 anticonvulsive agents), as well as normocytic, microcytic or • An amount larger than the daily recommended intake may be sideroblastic anaemia required for deficiency due to increased metabolic demand4 • High dosages of pyridoxine may be effective in most cases of inborn errors of metabolism4

Vitamin B7 (biotin) Has co-enzyme functions • Fatigue, conjunctivitis, • Biotin 150 µg intramuscularly, once daily. Symptoms should in bicarbonate-dependent alopecia, nausea, dermatitis, begin to resolve within 3-5 days, and should be absent within carboxylation reactions muscular pain, depression, 3-5 months hallucinations and • Biotin 5-20 mg per day. The symptoms may resolve much paraesthesia of the extremities faster with a larger dosage13 • Patients who are receiving long-term total parenteral nutrition may develop an exfoliative dermatitis if biotin is not supplemented as part of their total nutrition

Vitamin B8 (inositol) Functions include cell membrane Atherosclerosis, alopecia, Treatment is difficult to establish as inositol is not recognised synthesis, the maintenance eczema, increased blood as a true vitamin, but a recommended dietary allowance of of healthy hair, control of cholesterol levels, skin disorders, approximately 1 000 mg can be given14 oestrogen levels and cholesterol eye disorders, declining brain metabolism function, mood swings and constipation

Vitamin B9 (folic acid, • Functions include aiding Megaloblastic anaemia and Folate 400-1 000 μg orally, once daily. The normal requirement is folate and folacin) protein metabolism, neural tube defects 400 μg per day4 promoting red blood cell formation and maturation, and purine and pyrimidine synthesis • Folic acid is converted to folinic acid

Vitamin B12 Functions include aiding in Megaloblastic anaemia, fatigue, • Cobalamin 1 000-2 000 μg orally, once daily, in patients who (cobalamin) nucleic acid metabolism, methyl neurological disorders and the do not have severe deficiency or neurological symptoms or transfer, myelin synthesis and degeneration of nerves, resulting signs repair, as well as red blood cell in peripheral neuropathy • Cobalamin 1 mg intramuscularly, 1-4 times per week, for production several weeks, until the haematological abnormalities are corrected, then given once per month for severe deficiency4

*: Intravenous glucose can worsen a thiamine deficiency

Vitamin B2 (riboflavin) Vitamin B3 (niacin) Riboflavin functions as a co-enzyme in several oxidation and Also known as nicotinic acid, niacin is a vitamin that is mainly reduction reactions in the body.2 It is essential for the release involved in energy production, normal enzyme functioning, of energy from food and the conversion of the amino acid, digestion, and the promotion of a normal appetite, healthy skin 1 tryptophan, into niacin. and nerves.1 It functions as a co-substrate or co-enzyme for 2 A riboflavin deficiency may lead to cheilosis (fissuring and dry hydrogen transfer with several dehydrogenases. scaling of the vermilion surface of the lips and angles of the A niacin deficiency may result in pellagra, which is characterised mouth), angular stomatitis (inflammation of the corners of the by dermatitis, diarrhoea and dementia (the so-called three “Ds” of mouth, associated with a wrinkled or fissured epithelium that pellagra).5,15 Nicotinamide is usually used for treatment because does not involve the mucosa), and dermatitis (inflammation of the unlike nicotinic acid, the most common form of niacin, it does not skin), mucosal crusts and even a magenta-coloured tongue.2,5 cause flushing, itching, burning, or tingling sensations, owing to Treatment is usually via riboflavin supplementation (Table II). intense vasodilatation (Table II).4,5

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A vitamin B6 deficiency is also rarely seen, and is usually associated with a deficiency in other B-complex vitamins.16 Deficiency is associated with anaemia, abnormalities on the electroencephalograph, dermatitis with cheilosis and glossitis (a swollen tongue), nasolateral seborrhoea, depression, confusion, weakened immune function, peripheral neuropathy and seizures, especially in infants, which may be refractory to treatment with anticonvulsive agents, as well as normocytic, microcytic or sideroblastic anaemia.2

Treatment usually involves the elimination of risk factors, where possible, and the administration of pyridoxine (Table II).

Vitamin B7 (biotin) Biotin is required for the release of energy from carbohydrates and for the metabolism of fat, protein and carbohydrates.1 Vitamin

B7 functions as a co-enzyme in bicarbonate-dependent carboxylation reactions.2 Deficiency presents with fatigue, conjunctivitis, alopecia, nausea, dermatitis (the erythematous and seborrhoeic types), muscular pain and central nervous system abnormalities, such as hypotonia, lethargy Figure 1: Simplified summary of the B-complex vitamins and their major areas of physiological and stunted development in children; and 5,6,8 functioning depression, hallucinations and paraesthesia of the extremities in adults.2 Vitamin B5 (pantothenic acid) Treatment is usually via biotin supplementation, and in cases Pantothenic acid is important for the production of energy, where there is a secondary cause, e.g. eating raw eggs (owing hormone synthesis and the metabolism of fat, protein and to the fact that avidin, a glycoprotein contained in raw egg carbohydrates.1 It functions as a component of co-enzyme A and white, binds to biotin and effectively prevents its absorption 2 phosphopantetheine, and is involved in fatty acid metabolism. from the gastrointestinal tract) or anticonvulsant therapy, e.g. Vitamin B deficiency occurs very rarely, but if it does occur, it is phenobarbital, phenytoin and primidone. The secondary cause 5 should be eliminated, where possible, or substituted in the case of typically accompanied by deficits in other nutrients.4 Deficiency anticonvulsant therapy (Table II).13,17 is usually characterised by fatigue, sleep disturbances, impaired coordination, irascibility (a bad temper), postural hypotension, Vitamin B8 (inositol) a rapid heart rate on exertion, epigastric distress with anorexia, constipation and nausea, as well as numbness and tingling Strictly speaking, inositol is not a true vitamin because it is 18 of the hands and feet (so-called burning feet syndrome).2 The biosynthesised in the body. It is involved in cell membrane synthesis, the maintenance of healthy hair, the control of oestrogen recommended daily allowance has not been established with levels and in cholesterol metabolism.18 Deficiency, although rare, certainty, but 5-10 mg daily provided by a balanced diet is may result in atherosclerosis, alopecia, eczema, increased blood probably adequate (Table II).12 cholesterol levels, skin disorders, eye disorders, declining brain function, mood swings and constipation.7 Treatment is with Vitamin B (pyridoxine) 6 the recommended dietary allowance, which is quite difficult to Pyridoxine, also known as pyridoxal phosphate or pyridoxamine, establish, of approximately 1 000 mg (Table II).14 is required for the synthesis of the neurotransmitters, serotonin Vitamin B (folic acid) and noradrenaline, and for myelin formation.16 It functions as a co- 9 enzyme, as pyridoxal phosphate, in the metabolism of amino acid, Folic acid, also known as folate or folacin, is a vitamin that glycogen and sphingoid bases.2 assists with protein metabolism, the promotion of red blood cell

S Afr Pharm J 18 2016 Vol 83 No 4 REVIEW formation and maturation (folic acid is a haematinic, together likelihood exists that multiple B vitamins are actually lacking. The with iron, vitamin B6, vitamin B12, ascorbic acid and epoietin), B-complex vitamins are essential for normal growth, metabolism and the synthesis of purines and pyrimidines.4,5 It also lowers the and reproduction. However, their therapeutic value is limited to risk for neural tube birth defects, e.g. spina bifida, and helps to supplementation during states of deficiency since they have no control homocysteine levels, thus potentially reducing the risk of additional benefits in the presence of an adequate dietary intake. coronary heart disease.1 Deficiency causes megaloblastic anaemia, In general, their active supplementation should only be applied to which cannot be distinguished from that caused by vitamin B12 correct actual deficiencies. deficiency.4 Maternal deficiency increases the risk of neural tube birth defects (there is an increased demand for folate during Several disease states are associated with one or more B-vitamin pregnancy). Folic acid is converted to folinic acid, a metabolically deficiency, including a nutritional deficit, i.e. beriberi and active folate, which may also be used to treat folic acid deficiency pellagra, various forms of anaemia, suppressed metabolic and in patients taking dihydrofolic acid reductase inhibitors, such nervous system functioning and a weakened immune system. as methotrexate, trimethoprim and pyrimethamine.5 General Therefore, their major areas of physiological functioning extend treatment is with folate supplements (Table II). to metabolism, including the normal metabolic conversion of homocysteine to methionine, as well as neurological and blood-

Vitamin B12 (cobalamin) forming effects. Furthermore, there are a number of medicines that contribute to B-vitamin depletion. For example, methotrexate Cobalamin is another vital haematinic agent. It is also important in nucleic acid metabolism and methyl transfer, as well as and trimethoprim, as well as cholestyramine, may cause a folic myelin synthesis and repair.1 Deficiency most commonly acid deficiency. Knowledge of the B-complex vitamins contributes affects strict vegetarians, infants of vegan mothers and the to an understanding of their role, individual functions, deficiency elderly.1 It is characterised by fatigue, megaloblastic anaemia, states and the judicious use of their supplementation. neurological disorders and the degeneration of nerves which results in peripheral neuropathy, i.e. numbness and tingling.4 References Treatment is with suitable cobalamin supplementation, for which 1. Bellows L, Moore R. Water-soluble vitamins: B-complex and vitamin C. Fort Collins: Colo- hydroxocobalamin is preferred over cyanocobalamin because the rado State University, 2012. 2. World Health Organization, Food and Agriculture Organization of the United Nations. Thia- former is excreted more slowly than the latter (Table II).4,5 min, riboflavin, niacin, vitamin 6B , pantothenic acid and biotin: human vitamin and mineral requirements. Geneva: WHO, 2002. A few important points to ponder 3. Chin RL. Neuropathy and the gastrointestinal system. The Neuropathy Association [homepage on the Internet]. c2015. Available from: http://www.neuropathy.org/site/DocServer/ nutritionGI-RussellCMD.pdf?docID=1601 A specific B-vitamin deficiency is not likely to occur in isolation. 4. Porter RS, Kaplan JL. Nutritional disorders. The Merck manual of diagnosis and therapy. 19th When megaloblastic anaemia is detected, both vitamin B and ed. Whitehouse Station: Merck, Sharp & Dohme Corp, 2011. 12 st folic acid should be supplemented. Medicines that could deplete 5. Sommers De K. Sommers’ pharmacology. 1 ed. Pretoria: Sommers, 2000. 6. Marieb EN. Human anatomy and physiology. 5th ed. San Francisco: Benjamin Cummings, folic acid include methotrexate, trimethoprim and pyrimethamine. 2001. Those that could potentially hamper its absorption from the 7. Presser A. B-vitamins: literature education series on dietary supplements. Huntington Col- gut include cholestyramine and certain anticonvulsants, such as lege of Health Sciences [homepage on the Internet]. 2009. c2015. Available from: http:// www.hchs.edu/literature/B-Vitamins.pdf phenytoin. Folic acid is essential for normal cell proliferation and 8. Brenner GM, Stevens CW. Pharmacology. 4th ed. Philadelphia: Saunders, 2013. erythropoiesis, and is in increased demand during pregnancy.5,8,12 9. Ramsey D, Muskin PR. Vitamin deficiencies and mental health: How are they linked? Cur- rent Psychiatry. 2013;12(1):37-43. Lifelong parenteral supplementation is required in patients who 10. World Health Organization. Thiamine deficiency and its prevention and control in major develop pernicious anaemia, secondary to a deficiency in intrinsic emergencies. Geneva: WHO, 1999. 11. Johnson LE. Vitamin deficiency, dependency and toxicity. Merck Manuals [homepage on factor, and therefore also a deficiency in vitamin B12. Lastly, vitamin the Internet]. 2014. c2015. Available from: http://www.merckmanuals.com/professional/ B prophylaxis is recommended in high-risk patients, i.e. those at nutritional_disorders/vitamin_deficiency_dependency_and_toxicity.html 6 th high risk of the development of neurotoxicity, who need to take 12. Rossiter D, editor. South African medicines formulary. 10 ed. Rondebosch: Health and Medical Publishing Group, 2012. isoniazid to treat tuberculosis. Such patients include those who 13. Scheinfeld NS, Freilich SB. Biotin deficiency treatment and management: drugs and diseas- are malnourished, alcoholics, pregnant women or those who es. Medscape [homepage on the Internet]. 2015. c2015. Available from: http://emedicine. suffer from diabetes mellitus or human immunodeficiency virus medscape.com/article/984803-treatment 14. Health Supplements Nutritional Guide. Inositol. Health Supplements Nutritional Guide: infection. A dose of 10-25 mg per day is sufficient in these patients. Nutritional Health Resource [homepage on the Internet]. 2010. c2015. Available from: However, higher dosages should be considered in those who http://www.healthsupplementsnutritionalguide.com/vitamin-deficiency-symptoms. already have an established neuropathy.5,12 html#Inositol 15. Rull G. Pellagra. Patient.co.uk [homepage on the Internet]. 2011. c2015. Available from: http://www.patient.co.uk/doctor/Pellagra.htm 16. National Institutes of Health. Dietary supplement fact sheet: vitamin B . NIH [homepage Conclusion 6 on the Internet]. 2011. c2015. Available from: http://ods.od.nih.gov/factsheets/VitaminB6- HealthProfessional/ The B-complex vitamins play a vital role in the maintenance of an 17. Biotin supplements can help counteract epilepsy drug side effects and seizures. Biotin.com optimal health status. A diverse group of micronutrients that are [homepage on the Internet]. c2015. Available from: http://www.biotin.com/neurological/ normally derived from the intake of a healthy and well-balanced biotin-supplements-can-help-counteract-epilepsy-drug-side-effects-and-reduce-seizures 18. Miller D. Inositol for healthy nervous system. Disabled World [homepage on the Internet]. diet is included within this group of water-soluble vitamins. 2013. c2015.Available from: http://www.disabled-world.com/medical/supplements/vita- However, when a deficiency is detected or diagnosed, the mins/inositol.php

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