Metabolic functions of thiamin

The active form of this vitamin is thiamin diphosphate (also called thiamin pyrophosphate), which acts as a coenzyme for three multi-enzyme complexes important in central energy-yielding metabolic pathways and in the metabolism of branched chain amino acids. It is also the coenzyme for transketolase in the pentose phosphate pathway of carbohydrate metabolism.

Thiamin deficiency

Deficiency can develop rapidly during depletion. In deficiency there is impaired entry of pyruvate into the tricarboxylic acid cycle, especially on a relatively high carbohydrate diet, which results in increased plasma concentrations of lactate and pyruvate, which may lead to life-threatening acidosis. Thiamin deficiency can result in three distinct syndromes: a chronic peripheral neuritis, dry beriberi, which may or may not be associated with heart failure and oedema; acute pernicious beriberi, in which heart failure and metabolic abnormalities predominate, also called wet beriberi; and Wernicke’s encephalopathy, associated especially with alcoholism. Dry beriberi is associated with a more prolonged, and presumably less severe, deficiency, with a generally low food intake, while higher carbohydrate intake and physical activity predispose to oedema and hence wet beriberi.

Forms of thiamin in foods, and good food sources

In foods, most thiamin is present as the diphosphate. Thiamin is present in many foods of plant and animal origin, although pork, nuts and fish are especially rich sources.

Absorption and transport of thiamin

Thiamin is absorbed by active transport in the duodenum and proximal jejunum. There is active transport from the intestinal cells into the bloodstream; this is inhibited by alcohol, leading to thiamin deficiency in alcoholics. Much of the absorbed thiamin is phosphorylated in the liver, and both free thiamin and thiamin monophosphate circulate in plasma, bound to albumin. All tissues can take up both thiamin and thiamin monophosphate, and are able to phosphorylate them to the active di- and triphosphates.

Assessment of thiamin status and dietary requirements

The activation of apo-transketolase in erythrocyte lysate by thiamin diphosphate added in vitro is the most widely used index of thiamin nutritional status. An activation coefficient > 1.25 is indicative of deficiency, and < 1.15 is considered to reflect adequate thiamin nutrition.

Thiamin requirements depend largely on carbohydrate intake. In practice, requirements are calculated on the basis of total energy intake. For diets that are lower in fat, and hence higher in carbohydrate and protein, thiamin requirements will be higher. Depletion/repletion studies show that an intake of 0.3 mg/1000 kcal is required for a normal transketolase activation coefficient and this is the basis of the current recommended intakes.

Metabolic functions of riboflavin

This vitamin is important in a wide variety of oxidation and reduction reactions central to all metabolic processes, including the mitochondrial electron transport chain. The active forms of the vitamin are flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). Riboflavin contributes to antioxidant defences through a role in the synthesis of glutathione, an important antioxidant. Riboflavin is also important in folate and vitamin B₆ metabolism, and may play a role in iron utilization.

Riboflavin deficiency

Low intakes of riboflavin and associated biochemical riboflavin deficiency are common in many regions of the world including affluent Western countries. Clinically, deficiency is characterized by lesions of the margin of the lips and corners of the mouth and a painful desquamation of the tongue, so that it is red, and dry. However, the functional significance of riboflavin deficiency in humans is not completely understood. Impaired fatty acid oxidation has been reported in animals but this has not been substantiated in humans. Altered gastrointestinal development and impaired iron absorption are features of riboflavin deficiency in animals and there is some evidence to suggest that this may also be important in humans, but research is ongoing.

Forms of riboflavin in food and dietary sources

Apart from milk and eggs, which contain relatively large amounts of free riboflavin, most of the vitamin in foods is as the flavin coenzymes, FAD and FMN, bound to enzymes. Liver, milk, meat and fish are good sources of riboflavin; some green leafy vegetables also provide significant amounts. About one-third of riboflavin in Western diets comes from milk and milk products.

Absorption and transport

FAD and FMN in foods are hydrolysed to riboflavin in the gastrointestinal tract and riboflavin is taken up into the gastrointestinal mucosa. Much of the absorbed riboflavin is phosphorylated in the intestinal mucosa, and enters the bloodstream as riboflavin phosphate. Free riboflavin and FAD are the main forms in plasma. Most riboflavin in tissues is as FAD or FMN, bound to enzymes. There is no evidence of any significant storage of riboflavin, and intake in excess of tissue requirements is excreted rapidly in the urine.

Assessment of riboflavin status and dietary requirements

On the basis of depletion/repletion studies, the minimum adult requirement is 0.5–0.8 mg/day. Because of the central role of flavin coenzymes in energy yielding metabolism, reference intakes are sometimes calculated on the basis of energy intake: 0.6–0.8 mg/1000 kcal (0.14–0.19 mg/MJ).

The most commonly used method for determining riboflavin status is the activation of the erythrocyte enzyme glutathione reductase by FAD added in vitro, known as EGRAC. With decreasing intakes of riboflavin EGRAC values increase and values of about 1.40 and above are considered to indicate riboflavin deficiency.

Metabolic functions of niacin

In general, NAD is involved as an electron acceptor in energy-yielding metabolism, and the resultant NADH is oxidized by the mitochondrial electron transport chain. The major coenzyme for reactions of biosynthesis is NADPH. NAD is also the precursor of messengers that act to increase the release of calcium from intracellular stores in response to hormones.

Effects of niacin deficiency and excess

Niacin deficiency can lead to the deficiency disease pellagra, which is characterized by a photosensitive dermatitis, like severe sunburn, affecting regions of the skin that are exposed to sunlight. Advanced pellagra is also accompanied by a ‘dementia’ or depressive psychosis, and there may be diarrhoea. Untreated pellagra is fatal.

The synthesis of NAD from tryptophan requires both riboflavin and vitamin B₆, and deficiency of either may lead to the development of secondary pellagra when intakes of tryptophan and preformed niacin are marginal.

High intakes of niacin through supplements cause liver damage. Sustained release preparations are associated with more severe liver damage and clinical liver failure.

Forms in foods and good food sources of niacin

Meat and fish are good sources of preformed niacin and nuts and some fruits and vegetables provide significant amounts. Most of the niacin in cereals is biologically unavailable. Because synthesis of niacin from tryptophan is more important than dietary preformed niacin, foods that are good sources of protein are also good sources of niacin. Total niacin intakes are calculated as mg niacin equivalents: the sum of preformed niacin plus 1/60 of tryptophan (the average equivalence of dietary tryptophan and niacin).

Absorption and transport of preformed niacin

Niacin is present within cells largely as the nicotinamide coenzymes. Both nicotinic acid and nicotinamide are absorbed from the small intestine by a sodium-dependent saturable process. The coenzymes NAD and NADP are synthesized from these compounds in tissues. In the liver, NAD can be synthesized from tryptophan, and then hydrolysed to release nicotinamide, which is exported to other tissues.

Assessment of niacin status and dietary requirements

There is no wholly satisfactory biochemical measurement of niacin status. The two methods in current use are measurement of blood nicotinamide nucleotides and the urinary excretion of niacin metabolites. Because of the central role of the nicotinamide nucleotides in energy-yielding metabolism, niacin requirements are conventionally expressed per unit of energy expenditure. The average niacin requirement has been estimated to be 5.5 mg/1000 kcal (1.3 mg/MJ). Allowing for individual variation, reference intakes are set at 6.6 mg niacin equivalents. The tolerable upper limit of niacin intake is 35 mg/day for adults.

Metabolic functions of vitamin B₆

Pyridoxal phosphate is involved in many reactions of amino acid metabolism, is a cofactor for glycogen mobilization, and plays a role in lipid metabolism and in steroid hormone action. Vitamin B₆-dependent enzymes catalyse several types of reactions involving amino acids including transamination, which is central both to the utilization of amino acid carbon skeletons for gluconeogenesis or ketogenesis and also the synthesis of non-essential amino acids, and decarboxylation, to form a variety of biologically active amines such as the neurotransmitter serotonin (see chapter 4).

As pyridoxal phosphate, vitamin B₆ also plays a role in the control of the nuclear action of steroid hormones. In animals, vitamin B₆ deficiency results in increased and prolonged nuclear uptake and retention of steroid hormones in target tissues, and enhanced end-organ responsiveness to low doses of hormones.

Effects of vitamin B₆ deficiency and excess

Vitamin B₆ is widely distributed in foods and is synthesized by intestinal flora so clinical deficiency is rare, although biochemical deficiency is reported in 10–20% of the population of developed countries. Although clinical and physiological effects of vitamin B₆ deficiency in animals have been well-characterized there is relatively little documented about clinical deficiency in humans, except for neurological abnormalities in acute deficiency. Studies suggest that low vitamin B₆ status increases the risk of cardiovascular disease, probably independent of an associated elevation of plasma homocysteine.

Vitamin B₆ deficiency may result from the prolonged administration of drugs that antagonize the metabolism of the vitamin, such as penicillamine and the antitubercular drug isoniazid which reacts with pyridoxal phosphate, making it unavailable.

High dose supplements of vitamin B₆ are consumed for a variety of conditions, including premenstrual syndrome, depression, morning sickness in pregnancy, hypertension and carpal tunnel syndrome, although the evidence of efficacy is slight. High doses of the vitamin, of the order of 100 times requirements, cause peripheral sensory neuropathy.

Forms of vitamin B₆ in foods and good food sources

Meat, fish, potatoes and bananas are good sources of vitamin B₆ and milk, nuts, beans and vegetables also make a useful contribution to dietary vitamin B₆. All forms of the vitamin are found in foods but pyridoxal phosphate predominates.

Absorption and transport of vitamin B₆

Phosphorylated forms of the vitamin are hydrolysed in the intestinal mucosa and the non-phosphorylated vitamers, pyridoxal, pyridoxamine and pyridoxine, are all absorbed rapidly by carrier-mediated diffusion. Vitamin B₆ is retained in tissues by conversion to pyridoxal phosphate. Pyridoxal and pyridoxal phosphate constitute the main plasma forms of the vitamin, together with the oxidation product pyridoxic acid, which is excreted in the urine.

Assessment of vitamin B₆ status and dietary requirements

Vitamin B₆ status is usually assessed from the measurement of plasma concentrations of either total vitamin B₆ or pyridoxal phosphate, or urinary pyridoxic acid or as the activation coefficient of vitamin B₆-dependent red blood cell enzymes.

In view of the important role for vitamin B₆ in amino acid metabolism, requirements for this vitamin can be expressed relative to protein intake. On the basis of depletion/repletion studies in adults, reference intakes for the UK population range from 8 μg/g protein per day in infants to 15 μg/g protein per day in adults, which approximates to 0.2–1.5 mg per day.

Metabolic functions of folate

Folate is central to reactions involving the transfer of one-carbon units, in biosynthetic and catabolic processes. It plays an important role in the synthesis of purines and pyrimidines for nucleic acid synthesis, and acts as a methyl group donor to various substrates, including DNA. There is evidence that the role for folate in DNA methylation is important for gene expression and may influence carcinogenesis. Folate plays a key role in the regulation of concentrations of the amino acid homocysteine in cells and in the plasma, through its conversion to methionine by methylation. This is important because raised plasma homocysteine is considered to be a risk factor for cardiovascular disease. Certainly increasing folate intake will reduce plasma homocysteine levels, but the role for homocysteine in determining cardiovascular disease risk is still uncertain. A commonly occurring polymorphism (see chapter 11) in the gene expressing methylene tetrahydrofolate reductase, which generates the methyl group essential for methylation of homocysteine, is associated with a reduced concentration of red blood cell and plasma folate and an increased plasma homocysteine concentration, particularly in people with low folate intake.

Effects of folate deficiency and excess

Low dietary intakes of folate are common in many countries of the world, in affluent countries as well as low-income countries. Folate status is also compromised in patients using the drug methotrexate, an anti-cancer drug also used to treat rheumatoid arthritis and psoriasis. Deficiency results in megaloblastic anaemia which involves the release into the circulation of immature red blood cells due to a failure of the normal process of maturation in the bone marrow. Deficiency is frequently accompanied by depression, insomnia, forgetfulness and irritability, and sometimes cognitive impairment and dementia. Low folate status can lead to elevated plasma homocysteine levels and there is some evidence that low folate status may alter the methylation profile of DNA.

Folate deficiency and neural tube defects

The neural tube, which runs from the brain to the lower end of the spinal cord, normally closes in embryonic development in the third and fourth weeks after fertilization. A failure of this process leads to a range of severe fetal malformations collectively known as neural tube defects. There is evidence that low folate status in women increases the risk of neural tube defects in their offspring and that supplements of 400 μg/day of folic acid, begun before conception, significantly reduce risk. Women who are planning a pregnancy are advised to take folic acid supplements.

Two groups of people are at risk of adverse effects of high folic acid intakes that might result from widespread enrichment of foods with folic acid or indiscriminate use of supplements. High intakes of folic acid may mask the development of vitamin B₁₂ deficiency, which is prevalent among the elderly; this increases the risk of the deficiency progressing to irreversible neurological damage. High intakes of folic acid also antagonize the anticonvulsants used in treatment of epilepsy, leading to an increase in fit frequency.

Forms of folate in food and good food sources

All forms of folate can be present in foods, although folic acid only occurs as a food fortificant and it is in this form that folate is typically taken as a supplement. Folates are present naturally in a wide variety of foods; liver is an especially rich source, green leafy vegetables, beans, nuts and some fruits are also good sources. In some countries, including the USA, folic acid is added as a fortificant to flour and therefore many foods contain appreciable amounts of folate in this form.

Absorption and transport of folate

In the small intestine, folate polyglutamates are hydrolysed to the monoglutamate which is absorbed in the jejunum. Methyl-tetrahydrofolate (MeTHF) is the main form of the vitamin in the plasma and is taken up by tissues. Efficiency of absorption of folate from foods varies, such that folate in cereals is relatively poorly absorbed whilst that in milk appears to be well absorbed. Folic acid appears to be absorbed readily, although at single doses greater than about 200 μg it appears in the circulation in this form and there are suggestions that there may be adverse effects. Folate absorption is depressed in people who take the anti-inflammatory drug sulfasalazine, which is one reason why patients with inflammatory bowel disease often present with poor folate status.

Assessment of folate status and daily requirements

The plasma or red blood cell concentration of folate can be measured by protein-binding, radioimmunoassay, chromatography and microbiological assays but there is a lack of standardization of methodology. Folate is incorporated into red blood cells (erythrocytes) during their formation in the bone marrow, and does not enter the cells in the circulation to any significant extent. For this reason erythrocyte folate is generally considered to give an indication of folate status over 1–3 months (the lifespan of erythrocytes in the circulation is 120 days), rather than reflecting recent intake. Folate concentration can also be measured in white blood cells.

Because of the problems of determining the availability of the mixed folates in foods, reference intakes allow a wide margin of safety. Current reference daily intakes for the UK population range from 50 μg in infants to 200 μg in adults, with an increment of 100 μg during pregnancy. Dietary reference values for Europe and USA are higher, rising to 400 μg and 600 μg respectively, in pregnancy.

Metabolic functions of vitamin B₁₂

Vitamin B₁₂ plays a role in the metabolism of methionine, fatty acids with an odd number of carbon atoms, and the amino acid leucine. In each case vitamin B₁₂ acts as an enzyme cofactor. Its role in methionine metabolism is linked with the conversion of folate from the Me THF form to tetrahydrofolate and therefore vitamin B₁₂ deficiency is associated with the ‘trapping’ of folate in its methylated form in cells, which can lead to secondary folate deficiency.

Effects of deficiency and excess of vitamin B₁₂

The involvement of vitamin B₁₂ in folate metabolism is the basis of the megaloblastic anaemia that can develop during depletion, which, as we have seen, is also a feature of folate deficiency. Megaloblastic anaemia of vitamin B₁₂ deficiency is known as pernicious anaemia, and is associated with spinal cord degeneration and peripheral neuropathy; this is because vitamin B₁₂ is essential for making the fatty myelin sheath that covers nerve fibres. Vitamin B₁₂ deficiency is commonly due to poor absorption because of a failure to secrete intrinsic factor (IF) into the stomach, as this compound is essential for absorption. Pernicious anaemia is most common among the elderly, among whom it is typically treated with vitamin B₁₂ injections.

There is no evidence of adverse effects of high oral doses of vitamin B₁₂.

Forms of vitamin B₁₂ in foods and good food sources

Vitamin B₁₂ is found only in foods of animal origin, there are no plant sources. Rich sources include liver, fish and meat.

Absorption and transport

The major route of vitamin B₁₂ absorption is by way of binding to intrinsic factor, a glycoprotein secreted by cells of the gastric mucosa. There is an increased likelihood of impaired absorption in the elderly due to atrophic gastritis, which can lead to impaired secretion of intrinsic factor. The vitamin B₁₂–intrinsic factor complex is absorbed from the ileum into the mucosal cells. Inside the mucosal cells, the vitamin is released from IF and is bound to a protein carrier called transcobalamin, for transport into the bloodstream. The vitamin–transcobalamin complex is taken up from plasma by tissues, after which the vitamin is released as hydroxocobalamin, and converted to other vitamers. Vitamin B₁₂ undergoes entero-hepatic circulation, in which the vitamin is secreted in the bile and reabsorbed in the intestine.

Assessment of vitamin B₁₂ status and dietary requirements

Vitamin B₁₂ status is usually determined by measuring plasma total vitamin B₁₂, although there is general agreement that it does not always adequately reflect tissue depletion, especially in people with impaired renal function. Plasma holotranscobalamin (transcobalamin saturated with vitamin B₁₂), is currently under scrutiny as a marker of vitamin B₁₂ status. Methylmalonic acid accumulates in cells during vitamin B₁₂ depletion because of a block in a metabolic pathway, and plasma and urinary concentrations of this compound offer potential as functional markers of deficiency.

Reference nutrient intakes have been set at between 0.3–1.5 μg per day from infancy to adulthood, for the UK population, compared with an average intake of some 5 μg/day by non-vegetarians in most countries.

Metabolic functions of vitamin C

Vitamin C contributes to the synthesis of collagen and the catecholamines noradrenaline and adrenaline through its role as a cofactor in enzyme-catalysed reactions. The presence of ascorbic acid in a meal containing non-haem iron can significantly affect iron absorption, through reduction from the ferric to ferrous form, and binding of the iron. This reducing effect appears also to be important in mobilizing iron from the plasma iron transport protein, transferrin. The vitamin can protect cells from damage caused by free radicals because it can react with such radicals and convert them to less damaging species. Ascorbic acid is also thought to reduce the vitamin E radical α-tocopheroxyl, formed in cell membranes and plasma lipoproteins during the oxidation of vitamin E, so sparing vitamin E. However, it can also increase the rate of production of free radicals, via a chemical reduction of transition metals like iron or copper. The normally high concentration of vitamin C in white blood cells probably contributes to an appropriate inflammatory response to stress whilst minimizing oxidant damage to surrounding tissue.

Vitamin C deficiency and excess

Various biochemical and clinical changes result from vitamin C depletion, eventually resulting in the deficiency disease scurvy. Deficiency is associated with tiredness and general malaise, and is often accompanied by anaemia. In scurvy, skin changes reflect effects on collagen synthesis, and include haemorrhage of the gum capillaries and poor wound healing. High dose supplements of vitamin C can lead to unabsorbed ascorbate in the intestinal lumen, which becomes a substrate for bacterial fermentation, and can be associated with diarrhoea.

Forms in foods and good food sources

Ascorbic acid is the physiologically important form of the vitamin. It can oxidize to dehydroascorbic acid but this retains biological activity because it can be reduced to ascorbic acid. Fruits and vegetables are rich sources of ascorbate; blackcurrants and guava provide about five times the reference intake in a single serving, and potatoes are an important source in many countries.

Absorption and transport of vitamin C

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