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Vitamin B Complex Deficiencies and Excess
Vitamin B complex includes a number of water-soluble nutrients, including thiamine (vitamin B 1 ), riboflavin (B 2 ), niacin (B 3 ), pyridoxine (B 6 ), folate, cobalamin (B 12 ), biotin, and pantothenic acid. Choline and inositol are also considered part of the B complex and are important for normal body functions, but specific deficiency syndromes have not been attributed to a lack of these factors in the diet.
B-complex vitamins serve as coenzymes in many metabolic pathways that are functionally closely related. Consequently, a lack of one of the vitamins has the potential to interrupt a chain of chemical processes, including reactions that are dependent on other vitamins, and ultimately can produce diverse clinical manifestations. Because diets deficient in any one of the B-complex vitamins are often poor sources of other B vitamins, manifestations of several vitamin B deficiencies usually can be observed in the same person. It is therefore a general practice in a patient who has evidence of deficiency of a specific B vitamin to treat with the entire B-complex group of vitamins.
Thiamine (Vitamin B 1 )
Keywords
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beriberi
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cardiopathy
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peripheral neuropathy
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thiamine deficiency
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Wernicke encephalopathy
Thiamine diphosphate, the active form of thiamine, serves as a cofactor for several enzymes involved in carbohydrate catabolism such as pyruvate dehydrogenase, transketolase, and α-ketoglutarate. These enzymes also play a role in the hexose monophosphate shunt that generates nicotinamide adenine dinucleotide phosphate (NADP) and pentose for nucleic acid synthesis. Thiamine is also required for the synthesis of acetylcholine (ACh) and γ-aminobutyric acid (GABA), which have important roles in nerve conduction. Thiamine is absorbed efficiently in the gastrointestinal (GI) tract and may be deficient in persons with GI or liver disease. The requirement of thiamine is increased when carbohydrates are taken in large amounts and during periods of increased metabolism, such as fever, muscular activity, hyperthyroidism, pregnancy, and lactation. Alcohol affects various aspects of thiamine transport and uptake, contributing to the deficiency in alcoholics.
Pork (especially lean), fish, and poultry are good nonvegetarian dietary sources of thiamine. Main sources of thiamine for vegetarians are rice, oat, wheat, and legumes. Most ready-to-eat breakfast cereals are enriched with thiamine. Thiamine is water soluble and heat labile; most of the vitamin is lost when the rice is repeatedly washed and the cooking water is discarded. The breast milk of a well-nourished mother provides adequate thiamine; breastfed infants of thiamine-deficient mothers are at risk for deficiency. Thiamine antagonists (coffee, tea) and thiaminases (fermented fish) may contribute to thiamine deficiency. Most infants and older children consuming a balanced diet obtain an adequate intake of thiamine from food and do not require supplements.
Thiamine Deficiency
Deficiency of thiamine is associated with severely malnourished states, including malignancy and following surgery. The disorder (or spectrum of disorders) is classically associated with a diet consisting largely of polished rice (oriental beriberi); it can also arise if highly refined wheat flour forms a major part of the diet, in alcoholic persons, and in food faddists (occidental beriberi). Thiamine deficiency has often been reported from inhabitants of refugee camps consuming the polished rice–based monotonous diets. Low thiamine concentrations are also noted during critical illnesses.
Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder characterized by megaloblastic anemia, diabetes mellitus, and sensorineural hearing loss, responding in varying degrees to thiamine treatment. The syndrome occurs because of mutations in the SLC19A2 gene, encoding a thiamine transporter protein, leading to abnormal thiamine transportation and cellular vitamin deficiency. Another dependency state, biotin and thiamine–responsive basal ganglia disease , results from mutations in the SLC19A3 gene; presents with lethargy, poor contact, and poor feeding in early infancy; and responds to combined treatment with biotin and thiamine. Thiamine and related vitamins may improve the outcome in children with Leigh encephalomyelopathy and type 1 diabetes mellitus.
Clinical Manifestations
Thiamine deficiency can develop within 2-3 mo of a deficient intake. Early symptoms of thiamine deficiency are nonspecific, such as fatigue, apathy, irritability, depression, drowsiness, poor mental concentration, anorexia, nausea, and abdominal discomfort. As the condition progresses, more-specific manifestations of beriberi develop, such as peripheral neuritis (manifesting as tingling, burning, paresthesias of the toes and feet), decreased deep tendon reflexes, loss of vibration sense, tenderness and cramping of the leg muscles, heart failure, and psychologic disturbances. Patients can have ptosis of the eyelids and atrophy of the optic nerve. Hoarseness or aphonia caused by paralysis of the laryngeal nerve is a characteristic sign. Muscle atrophy and tenderness of the nerve trunks are followed by ataxia, loss of coordination, and loss of deep sensation. Later signs include increased intracranial pressure, meningismus, and coma. The clinical picture of thiamine deficiency is usually divided into a dry ( neuritic ) type and a wet ( cardiac ) type. The disease is wet or dry depending on the amount of fluid that accumulates in the body because of cardiac and renal dysfunction, even though the exact cause for this edema is unknown. Many cases of thiamine deficiency show a mixture of both features and are more properly termed thiamine deficiency with cardiopathy and peripheral neuropathy .
The classic clinical triad of Wernicke encephalopathy —mental status changes, ocular signs, and ataxia—is rarely reported in infants and young children with severe deficiency secondary to malignancies or feeding of defective formula. An epidemic of life-threatening thiamine deficiency was seen in infants fed a defective soy-based formula that had undetectable thiamine levels. Manifestations included emesis, lethargy, restlessness, ophthalmoplegia, abdominal distention, developmental delay, failure to thrive (malnutrition), lactic acidosis, nystagmus, diarrhea, apnea, seizures, and auditory neuropathy. An acute presentation with tachycardia, moaning, and severe metabolic acidosis responding to parenteral thiamine has been occasionally reported in infants of mothers consuming polished and frequently washed rice.
Death from thiamine deficiency usually is secondary to cardiac involvement. The initial signs are cyanosis and dyspnea, but tachycardia, enlargement of the liver, loss of consciousness, and convulsions can develop rapidly. The heart, especially the right side, is enlarged. The electrocardiogram (ECG) shows an increased QT interval, inverted T waves, and low voltage. These changes, as well as the cardiomegaly, rapidly revert to normal with treatment, but without prompt treatment, cardiac failure can develop rapidly and result in death. In fatal cases of beriberi, lesions are principally located in the heart, peripheral nerves, subcutaneous tissue, and serous cavities. The heart is dilated, and fatty degeneration of the myocardium is common. Generalized edema or edema of the legs, serous effusions, and venous engorgement are often present. Degeneration of myelin and axon cylinders of the peripheral nerves, with wallerian degeneration beginning in the distal locations, is also common, particularly in the lower extremities. Lesions in the brain include vascular dilation and hemorrhage.
Diagnosis
The diagnosis is often suspected based on clinical setting and compatible symptoms. A high index of suspicion in children presenting with unexplained cardiac failure may sometimes be lifesaving. Objective biochemical tests of thiamine status include measurement of erythrocyte transketolase activity and the thiamine pyrophosphate effect. The biochemical diagnostic criteria of thiamine deficiency consist of low erythrocyte transketolase activity and high thiamine pyrophosphate effect (normal range: 0–14%). Urinary excretion of thiamine or its metabolites (thiazole or pyrimidine) after an oral loading dose of thiamine may also be measured to help identify the deficiency state. MRI changes of thiamine deficiency in infants are characterized by bilateral symmetric hyperintensities of the basal ganglia and frontal lobe, in addition to the lesions in the mammillary bodies, periaqueductal region, and thalami described in adults.
Prevention
A maternal diet containing sufficient amounts of thiamine prevents thiamine deficiency in breastfed infants, and infant formulas marketed in all developed countries provide recommended levels of intake. During complementary feeding, adequate thiamine intake can be achieved with a varied diet that includes meat and enriched or whole-grain cereals. When the staple cereal is polished rice, special efforts need to be made to include legumes and/or nuts in the ration. Thiamine and other vitamins can be retained in rice by parboiling, a process of steaming the rice in the husk before milling. Improvement in cooking techniques, such as not discarding the water used for cooking, minimal washing of grains, and reduction of cooking time helps to minimize the thiamine losses during the preparation of food. Thiamine supplementation should be ensured during total parenteral nutrition (TPN).
Treatment
In the absence of GI disturbances, oral administration of thiamine is effective. Children with cardiac failure, convulsions, or coma should be given 10 mg of thiamine intramuscularly (IM) or intravenously (IV) daily for the 1st wk. This treatment should then be followed by 3-5 mg/day of thiamine orally (PO) for at least 6 wk. The response is dramatic in infants and in those having predominantly cardiovascular manifestations, whereas the neurologic response is slow and often incomplete. Epilepsy, mental disability, and language and auditory problems of varying degree have been reported in survivors of severe infantile thiamine deficiency.
Patients with beriberi often have other B-complex vitamin deficiencies; therefore, all other B-complex vitamins should also be administered. Treatment of TRMA and other dependency states require higher dosages (100-200 mg/day). The anemia responds well to thiamine administration, and insulin for associated diabetes mellitus can also be discontinued in many patients with TRMA syndrome.
Thiamine Toxicity
There are no reports of adverse effects from consumption of excess thiamine by ingestion of food or supplements. A few isolated cases of pruritus and anaphylaxis have been reported in patients after parenteral administration of vitamin B 1 .
Bibliography
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Beshlawi I, Al Zadjali S, Bashir W, et. al.: Thiamine responsive megaloblastic anemia: the puzzling phenotype. Pediatr Blood Cancer 2014; 61: pp. 528-531.
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Dabar G, Harmouche C, Habr B, et. al.: Shoshin beriberi in critically-ill patients: case series. Nutr J 2015; 14: pp. 51.
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Frank LL: Thiamin in clinical practice. JPEN J Parenter Enteral Nutr 2015; 39: pp. 503-520.
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Qureshi UA, Sami A, Altaf U, et. al.: Thiamine responsive acute life threatening metabolic acidosis in exclusively breast-fed infants. Nutrition 2016; 32: pp. 213-216.
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Tabarki B, Alfadhel M, AlShahwan S, et. al.: Treatment of biotin-responsive basal ganglia disease: open comparative study between the combination of biotin plus thiamine versus thiamine alone. Eur J Paediatr Neurol 2015; 19: pp. 547-552.
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Wani NA, Qureshi UA, Jehangir M, et. al.: Infantile encephalitic beriberi: magnetic resonance imaging findings. Pediatr Radiol 2016; 46: pp. 96-103.
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Ygberg S, Naess K, Eriksson M, et. al.: Biotin and thiamine responsive basal ganglia disease: a vital differential diagnosis in infants with severe encephalopathy. Eur J Paediatr Neurol 2016; 20: pp. 457-461.
Riboflavin (Vitamin B 2 )
Keywords
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ariboflavinosis
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angular cheilosis
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glossitis
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riboflavin deficiency
Riboflavin is part of the structure of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide, which participate in oxidation-reduction (redox) reactions in numerous metabolic pathways and in energy production via the mitochondrial respiratory chain. Riboflavin is stable to heat but is destroyed by light. Milk, eggs, organ meats, legumes, and mushrooms are rich dietary sources of riboflavin. Most commercial cereals, flours, and breads are enriched with riboflavin.
Riboflavin Deficiency
The causes of riboflavin deficiency ( ariboflavinosis ) are mainly related to malnourished and malabsorptive states, including GI infections. Treatment with some drugs, such as probenecid, phenothiazine, or oral contraceptives (OCs), can also cause the deficiency. The side chain of the vitamin is photochemically destroyed during phototherapy for hyperbilirubinemia, since it is involved in the photosensitized oxidation of bilirubin to more polar excretable compounds.
Isolated complex II deficiency , a rare mitochondrial disease manifesting in infancy and childhood, responds favorably to riboflavin supplementation and thus can be termed a dependency state. Brown-Vialetto-Van Laere syndrome (BVVLS) , a rare, potentially lethal neurologic disorder characterized by rapidly progressive neurologic deterioration, peripheral neuropathy, hypotonia, ataxia, sensorineural hearing loss, optic atrophy, pontobulbar palsy, and respiratory insufficiency, responds to treatment with high doses of riboflavin if treated early in the disease course. Mutations in SLC52A2 gene (autosomal recessive), encoding riboflavin transporter proteins, have been identified in children with BVVLS.
Clinical Manifestations
Clinical features of nutritional riboflavin deficiency include cheilosis, glossitis, keratitis, conjunctivitis, photophobia, lacrimation, corneal vascularization, and seborrheic dermatitis. Cheilosis begins with pallor at the angles of the mouth and progresses to thinning and maceration of the epithelium, leading to fissures extending radially into the skin ( Fig. 62.1 ). In glossitis the tongue becomes smooth, with loss of papillary structure ( Fig. 62.2 ). Normochromic, normocytic anemia may also be seen because of the impaired erythropoiesis. A low riboflavin content of the maternal diet has been linked to congenital heart defects, but the evidence is weak.
Diagnosis
Most often, the diagnosis is based on the clinical features of angular cheilosis in a malnourished child, who responds promptly to riboflavin supplementation. A functional test of riboflavin status is done by measuring the activity of erythrocyte glutathione reductase (EGR), with and without the addition of FAD. An EGR activity coefficient (ratio of EGR activity with added FAD to EGR activity without FAD) of >1.4 is used as an indicator of deficiency. Urinary excretion of riboflavin <30 µg/24 hr also suggests low intakes.
Prevention
Table 62.1 lists the recommended daily allowance of riboflavin for infants, children, and adolescents. Adequate consumption of milk, milk products, and eggs prevents riboflavin deficiency. Fortification of cereal products is helpful for those who follow vegan diets or who are consuming inadequate amounts of milk products for other reasons.
Table 62.1
Water-Soluble Vitamins
From Dietary reference intakes (DRIs): Recommended dietary allowances and adequate intakes, vitamins, Food and Nutrition Board, Institute of Medicine, National Academies. http://www.nationalacademies.org/hmd/~/media/Files/Activity%20Files/Nutrition/DRI-Tables/2_%20RDA%20and%20AI%20Values_Vitamin%20and%20Elements.pdf?la=en .
| NAMES AND SYNONYMS | BIOCHEMICAL ACTION | EFFECTS OF DEFICIENCY | TREATMENT OF DEFICIENCY | CAUSES OF DEFICIENCY | DIETARY SOURCES | RDA * BY AGE |
|---|---|---|---|---|---|---|
| Thiamine (vitamin B 1 ) | Coenzyme in carbohydrate metabolism Nucleic acid synthesis Neurotransmitter synthesis |
Neurologic (dry beriberi): irritability, peripheral neuritis, muscle tenderness, ataxia Cardiac (wet beriberi): tachycardia, edema, cardiomegaly, cardiac failure |
3-5 mg/day PO thiamine for 6 wk | Polished rice–based diets Malabsorptive states Severe malnutrition Malignancies Alcoholism |
Meat, especially pork; fish; liver Rice (unmilled), wheat germ; enriched cereals; legumes |
0-6 mo: 0.2 mg/day 7-12 mo: 0.3 mg/day 1-3 yr: 0.5 mg/day 4-8 yr: 0.6 mg/day 9-13 yr: 0.9 mg/day 14-18 yr:
|
| Riboflavin (vitamin B 2 ) | Constituent of flavoprotein enzymes important in redox reactions: amino acid, fatty acid, and carbohydrate metabolism and cellular respiration | Glossitis, photophobia, lacrimation, corneal vascularization, poor growth, cheilosis | 3-10 mg/day PO riboflavin | Severe malnutrition Malabsorptive states Prolonged treatment with phenothiazines, probenecid, or OCPs |
Milk, milk products, eggs, fortified cereals, green vegetables | 0-6 mo: 0.3 mg/day 7-12 mo: 0.4 mg/day 1-3 yr: 0.5 mg/day 4-8 yr: 0.6 mg/day 9-13 yr: 0.9 mg/day 14-18 yr:
|
| Niacin (vitamin B 3 ) | Constituent of NAD and NADP, important in respiratory chain, fatty acid synthesis, cell differentiation, and DNA processing | Pellagra manifesting as diarrhea, symmetric scaly dermatitis in sun-exposed areas, and neurologic symptoms of disorientation and delirium | 50-300 mg/day PO niacin | Predominantly maize-based diets Anorexia nervosa Carcinoid syndrome |
Meat, fish, poultry Cereals, legumes, green vegetables |
0-6 mo: 2 mg/day 7-12 mo: 4 mg/day 1-3 yr: 6 mg/day 4-8 yr: 8 mg/day 9-13 yr: 12 mg/day 14-18 yr:
|
| Pyridoxine (vitamin B 6 ) | Constituent of coenzymes for amino acid and glycogen metabolism, heme synthesis, steroid action, neurotransmitter synthesis | Irritability, convulsions, hypochromic anemia Failure to thrive Oxaluria |
5-25 mg/day PO for deficiency states 100 mg IM or IV for pyridoxine-dependent seizures |
Prolonged treatment with INH, penicillamine, OCPs | Fortified ready-to-eat cereals, meat, fish, poultry, liver, bananas, rice, potatoes | 0-6 mo: 0.1 mg/day 7-12 mo: 0.3 mg/day 1-3 yr: 0.5 mg/day 4-8 yr: 0.6 mg/day 9-13 yr: 1.0 mg/day 14-18 yr:
|
| Biotin | Cofactor for carboxylases, important in gluconeogenesis, fatty acid and amino acid metabolism | Scaly periorificial dermatitis, conjunctivitis, alopecia, lethargy, hypotonia, and withdrawn behavior | 1-10 mg/day PO biotin | Consumption of raw eggs for prolonged periods Parenteral nutrition with infusates lacking biotin Valproate therapy |
Liver, organ meats, fruits | 0-6 mo: 5 µg/day 7-12 mo: 6 µg/day 1-3 yr: 8 µg/day 4-8 yr: 12 µg/day 9-13 yr: 20 µg/day 14-18 yr: 25 µg/day |
| Pantothenic acid (vitamin B 5 ) | Component of coenzyme A and acyl carrier protein involved in fatty acid metabolism | Experimentally produced deficiency in humans: irritability, fatigue, numbness, paresthesias (burning feet syndrome), muscle cramps | Isolated deficiency extremely rare in humans | Beef, organ meats, poultry, seafood, egg yolk Yeast, soybeans, mushrooms |
0-6 mo: 1.7 mg/day 7-12 mo: 1.8 mg/day 1-3 yr: 2 mg/day 4-8 yr: 3 mg/day 9-13 yr: 4 mg/day 14-18 yr: 5 mg/day |
|
| Folic acid | Coenzymes in amino acid and nucleotide metabolism as an acceptor and donor of 1-carbon units | Megaloblastic anemia Growth retardation, glossitis Neural tube defects in progeny |
0.5-1 mg/day PO folic acid | Malnutrition Malabsorptive states Malignancies Hemolytic anemias Anticonvulsant therapy |
Enriched cereals, beans, leafy vegetables, citrus fruits, papaya | 0-6 mo: 65 µg/day 7-12 mo: 80 µg/day 1-3 yr: 150 µg/day 4-8 yr: 200 µg/day 9-13 yr: 300 µg/day 14-18 yr: 400 µg/day |
| Cobalamin (vitamin B 12 ) | As deoxyadenosylcobalamin, acts as cofactor for lipid and carbohydrate metabolism As methylcobalamin, important for conversion of homocysteine to methionine and folic acid metabolism |
Megaloblastic anemia, irritability, developmental delay, developmental regression, involuntary movements, hyperpigmentation | 1,000 µg IM vitamin B 12 | Vegan diets Malabsorptive states Crohn disease Intrinsic factor deficiency (pernicious anemia) |
Organ meats, sea foods poultry, egg yolk, milk, fortified ready-to-eat cereals | 0-6 mo: 0.4 µg/day 7-12 mo: 0.5 µg/day 1-3 yr: 0.9 µg/day 4-8 yr: 1.2 µg/day 9-13 yr: 1.8 µg/day 14-18 yr: 2.4 µg/day |
| Ascorbic acid (vitamin C) | Important for collagen synthesis, metabolism of cholesterol and neurotransmitters Antioxidant functions and nonheme iron absorption |
Scurvy manifesting as irritability, tenderness and swelling of legs, bleeding gums, petechiae, ecchymoses, follicular hyperkeratosis, and poor wound healing | 100-200 mg/day PO ascorbic acid for up to 3 mo | Predominantly milk-based (non–human milk) diets Severe malnutrition |
Citrus fruits and fruit juices, peppers, berries, melons, tomatoes, cauliflower, leafy green vegetables | 0-6 mo: 40 mg/day 7-12 mo: 50 mg/day 1-3 yr: 15 mg/day 4-8 yr: 25 mg/day 9-13 yr: 45 mg/day 14-18 yr:
|
PO, Orally, IM, intramuscularly; IV, intravenously; INH, isoniazid; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; OCP, oral contraceptive pill; RDA, recommended dietary allowance.
* For healthy breastfed infants, the values represent adequate intakes, that is, the mean intake of apparently “normal” infants.
Treatment
Treatment includes oral administration of 3-10 mg/day of riboflavin, often as an ingredient of a vitamin B–complex mix. The child should also be given a well-balanced diet, including milk and milk products.
Riboflavin Toxicity
No adverse effects associated with riboflavin intakes from food or supplements have been reported, and the upper safe limit for consumption has not been established. Although the photosensitizing property of vitamin B 2 suggests some potential risks, limited absorption in high-intake situations precludes such concerns.
Bibliography
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Foley AR, Menezes MP, Pandraud A, et. al.: Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014; 137: pp. 44-56.
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Nichols EK, Talley LE, Birungi N, et. al.: Suspected outbreak of riboflavin deficiency among populations reliant on food assistance: a case study of drought-stricken Karamoja, Uganda, 2009–2010. PLoS ONE 2013; 8: pp. e62976.
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Sherwood M, Goldman RD: Effectiveness of riboflavin in pediatric migraine prevention. Can Fam Physician 2014; 60: pp. 244-246.
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Swaminathan S, Thomas T, Kurpad AV: B-vitamin interventions for women and children in low-income populations. Curr Opin Clin Nutr Metab Care 2015; 18: pp. 295-306.
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