MICRONUTRIENTS, MINERALS AND THEIR DISEASES

Vitamins
Vitamins are organic substances with key roles in certain
metabolic pathways, and are categorised into those that
are fat-soluble (vitamins A, D, E and K) and those that
are water-soluble (vitamins of the B complex group and
vitamin C). Recommended daily intakes of micronutrients
(Box ) vary between countries. Additional amounts of some
micronutrients may be required in pregnancy and lactation.
Vitamin deficiency diseases are most prevalent
in developing countries but still occur in developed
countries. Older people (and alcoholics) are at risk of
deficiencies in B vitamins and in vitamins D and C.
Summary of clinically important vitamins
Darker-skinned individuals living at higher latitude, and
those who cover up or do not go outside are at increased
risk of vitamin D deficiency due to inadequate sunlight
exposure. Deficiencies of fat-soluble vitamins are seen in
conditions of fat malabsorption .Some vitamins also have
pharmacological actions when given at
supraphysiological doses, e.g. the use of vitamin A for
acne. Taking vitamin supplements is fashionable in many
countries, although there is no evidence of benefit.
Toxic effects are most serious with high dosages of
vitamins A, B6 and D. Investigation of vitamin deficiency or
excess may involve biochemical assessment of body stores .
However, measurements in blood should be interpreted
carefully in conjunction with the clinical presentation.
Nutrition in pregnancy and lactation
• Energy requirements: increased in mother and fetus.
• Micronutrient requirements: adaptive mechanisms ensure
increased uptake of minerals in pregnancy, but extra
increments of some are required during lactation.
Additional increments of some vitamins are
recommended during pregnancy and lactation:
— Vitamin A: for growth and maintenance of the fetus, and
toprovide some reserve (important in some countries to prevent blindness
associated with vitamin A deficiency).Teratogenic in excessive amounts.
— Vitamin D: to ensure bone and dental development in
the infant. Higher incidences of hypocalcaemia,
hypoparathyroidisim and defective dental enamel have
been seen in infants of women not taking vitamin D
supplements at > 50° latitude.
— Folate: to avoid neural tube defects .
— Vitamin B : in lactation only.
12

— Thiamin: to meet increased fetal energy demands.

— Riboflavin: to meet extra demands.
— Niacin: in lactation only.
— Vitamin C: for the last trimester to maintain maternal
stores as fetal demands increase.
— Iodine: in countries with high consumption of staple
foods (e.g. brassicas, maize, bamboo shoots) that contain
goitrogens (thiocyanates or perchlorates) that interfere
with iodine uptake, supplements prevent infants being
born with cretinism.
Periconceptual folate supplementation and neural
tube defects
Biochemical assessment of vitamin status
Fat-soluble vitamins
Vitamin A (retinol)
Pre-formed retinol is found only in foods of animal origin.
Vitamin A can also be derived from carotenes, which are
present in green and coloured vegetables and some fruits.
Carotenes provide most of the total vitamin A in the UK,
and constitute the only supply in vegans. Retinol is
converted to several other important molecules:
• 11-cis retinaldehyde is part of the photoreceptor
complex in rods of the retina.
• Retinoic acid induces differentiation of epithelial cells by
binding to specific nuclear receptors, which induce
responsive genes. In vitamin A deficiency, mucus-secreting
cells are replaced by keratinproducing cells.
• Retinoids are necessary for normal growth, fetal
development, fertility, haematopoiesis and immune
function. Globally, the most important consequence of
vitamin A deficiency is irreversible blindness in young
children. Adults are not usually at risk because liver stores
can supply vitamin A when foods containing vitamin A are
unavailable. Early deficiency causes impaired adaptation
to the dark (night blindness). Keratinisation of the cornea
(xerophthalmia) gives rise to characteristic Bitot’s spots,
and progresses to keratomalacia, with corneal ulceration,
scarring and irreversible blindness . In countries where
vitamin A deficiency is endemic, pregnant women should be
advised to eat dark-green, leafy vegetables and yellow
fruits (to build up stores of retinol in the fetal liver), and
infants should be fed the same.
WHO is according high priority to prevention in
communities where xerophthalmia occurs, giving single
prophylactic oral doses of 60 mg retinyl palmitate (providing
200 000 U retinol) to pre-school children. This also reduces
mortality from gastroenteritis and respiratory infections.
Repeated moderate or high doses of retinol can cause
liver damage, hyperostosis and teratogenicity. Women
in countries where deficiency is not endemic are
therefore advised not to take vitamin A supplements in
pregnancy.Retinol intake may also be restricted in those at
risk of osteoporosis. Acute overdose leads to nausea and
headache, increased intracranial pressure and skin
desquamation. Excessive intake of carotene can cause
pigmentation of the skin (hypercarotenosis); this gradually
fades when intake is reduced.
Eye signs of vitamin A
deficiency.
A Bitot’s spots in xerophthalmia,
showing the white triangular
plaques (arrows).
B Keratomalacia in a 14-
month-old child. There is
liquefactive necrosis
affecting the greater part of
the cornea, with typical sparing
of the superior aspect.
Vitamin D
The natural form of vitamin D, cholecalciferol or vitamin
D3, is formed in the skin by the action of UV light on
7-dehydrocholesterol, a metabolite of cholesterol. Few
foods contain vitamin D naturally and skin exposure to
sunlight is the main source. Moving away from the
equator, the intensity of UV light decreases, so that at
a latitude above 50° (including northern Europe), vitamin D
is not synthesised in winter, and even above 30° there is
seasonal variation. The body store accumulated during the
summer is consumed during the winter. Vitamin D is
converted in the liver to 25-hydroxy vitamin D (25(OH)D),
which is further hydroxylated in the kidneys to 1,25-
dihydroxy-vitamin D (1,25 (OH)2D), the active form .
1,25(OH)2D activates specific intracellular receptors which
influence calcium metabolism, bone mineralization and
tissue differentiation. The synthetic form, ergocalciferol, or
vitamin D2, is considered to be less potent than the
endogenous D3.
There is increasing evidence that vitamin D is important for
immune and muscle function, and may reduce falls in the
elderly. Margarines are fortified with vitamin D in the UK,
and milk is fortified in some parts of Europe and in North
America. An analogue of vitamin D (calcipotriol) is used for
treatment of skin conditions such as psoriasis. Excessive
doses of cholecalciferol, ergocalciferol or the hydroxylated
metabolites cause hypercalcaemia.
Vitamin E
There are eight related fat-soluble substances with
vitamin E activity. The most important dietary form is α-
tocopherol.
Vitamin E has many direct metabolic actions:
• It prevents oxidation of polyunsaturated fatty acids
in cell membranes by free radicals.
• It helps maintain cell membrane structure.
• It affects DNA synthesis and cell signalling.
• Involved in the anti-inflammatory and immune systems.
Human deficiency is rare and has only been described
in premature infants and in malabsorption. It can
cause a mild haemolytic anaemia, ataxia and visual
scotomas. Vitamin E intakes are considered safe up to
3200 mg/day (1000-fold greater than recommended
intakes). Diets rich in vitamin E are consumed in countries
with lower rates of coronary heart disease. However,
randomised controlled trials have not demonstrated
cardioprotective effects of vitamin E or other antioxidants.
Vitamin K
Vitamin K is supplied in the diet mainly as vitamin K1
(phylloquinone) in the UK, or as vitamin K2 (menaquinone)
from fermented products in parts of Asia. Vitamin
K2 is also synthesised by bacteria in the colon. Vitamin
K is a co-factor for carboxylation reactions: in particular,
the production of γ-carboxyglutamate (gla). Gla residues
are found in four of the coagulation factor proteins (II, VII,
IX and X), conferring their capacity to bind to phospholipid
surfaces in the presence of calcium. Other important gla
proteins are osteocalcin and matrix gla protein, which are
important in bone mineralisation.
Vitamin K deficiency leads to delayed coagulation
and bleeding. In obstructive jaundice, dietary vitamin K
is not absorbed and it is essential to administer the
vitamin in parenteral form before surgery. Warfarin and
related anticoagulants act by antagonising
vitamin K. Vitamin K is given routinely to newborn
babies to prevent haemorrhagic disease. Symptoms of
excess have been reported only in infants, with synthetic
preparations linked to haemolysis and liver damage.
Water-soluble vitamins
Thiamin (vitamin B1 )
Thiamin is widely distributed in foods of both vegetable
and animal origin. Thiamin pyrophosphate (TPP) is
a co-factor for enzyme reactions involved in the
metabolism of macronutrients (carbohydrate, fat and
alcohol), including:
• decarboxylation of pyruvate to acetyl-co-enzyme A,
which bridges between glycolysis and the
tricarboxylic acid (Krebs) cycle
• transketolase activity in the hexose monophosphate
shunt pathway
• decarboxylation of α-ketoglutarate to succinate in
the Krebs cycle.
In thiamin deficiency, cells cannot metabolise glucose
aerobically to generate energy as ATP. Neuronal cells
are most vulnerable, since they depend almost exclusively
on glucose for energy requirements. Impaired
glucose oxidation also causes an accumulation of
pyruvic and lactic acids, which produce vasodilatation
and increased cardiac output.
Deficiency – beri-beri
In the developed world Thiamin deficiency is mainly
encountered in chronic alcoholics. Poor diet, impaired
absorption, storage in the liver, and the increased
requirements for thiamin to metabolise ethanol all
contribute. In the developing world, deficiency usually
arises as a consequence of a diet based on polished rice.
The body has very limited stores of thiamin, so deficiency
is manifest after only 1 month on a thiamin-free diet.
There are two forms of the disease in adults:
• Dry (or neurological) beri-beri manifests with chronic peripheral
neuropathy and with wrist and/or foot drop, and may cause
Korsakoff’s psychosis and Wernicke’s encephalopathy .
• Wet (or cardiac) beri-beri causes generalised oedema
due to biventricular heart failure with pulmonary congestion.
In dry beri-beri, response to thiamin administration
is not uniformly good. However, multivitamin therapy
seems to produce some improvement, suggesting
that other vitamin deficiencies may be involved.
Wernicke’s encephalopathy and wet beri-beri should
be treated without delay with intravenous vitamin B
and C mixture (‘Pabrinex).
Korsakoff’s psychosis is irreversible and does not
respond to thiamin treatment.
Riboflavin (vitamin B2 )
Riboflavin is required for the flavin co-factors involved
in oxidation–reduction reactions. It is widely distributed
in animal and vegetable foods. Levels are low in staple
cereals but germination increases its content. It is
destroyed under alkaline conditions by heat and by
exposure to sunlight.
Deficiency is rare in developed countries. It mainly
affects the tongue and lips and manifests as glossitis,
angular stomatitis and cheilosis. The genitals may be
affected, as well as the skin areas rich in sebaceous
glands, causing nasolabial or facial dyssebacea. Rapid
recovery usually follows administration of riboflavin
10 mg daily by mouth.
Niacin (vitamin B3 )
Niacin encompasses nicotinic acid and nicotinamide.
Nicotinamide is an essential part of the two pyridine
nucleotides, nicotinamide adenine dinucleotide (NAD)
and nicotinamide adenine dinucleotide phosphate (NADP),
which play a key role as hydrogen acceptors
and donors for many enzymes.
Niacin can be synthesized in the body in limited amounts
from the amino acid tryptophan.
Deficiency – pellagra
Pellagra was formerly endemic among poor people who
subsisted chiefly on maize, which contains niacytin, a
form of niacin that the body is unable to utilise. Pellagra
can develop in only 8 weeks in individuals eating diets
that are very deficient in niacin and tryptophan. It
remains a problem in parts of Africa, and is occasionally
seen in alcoholics and in patients with chronic small
intestinal disease in developed countries. Pellagra can
occur in Hartnup’s disease, a genetic disorder
characterised by impaired absorption of several amino
acids, including tryptophan. It is also seen occasionally in
carcinoid syndrome ,when tryptophan is consumed in the
excessive production of 5-hydroxytryptamine (5-HT).
Pellagra has been called the disease of the
three Ds:
• Dermatitis. Characteristically, there is erythema
resembling severe sunburn, appearing symmetrically over
the parts of the body exposed to sunlight, particularly the
limbs and especially on the neck, but not the face (Casal’s
necklace). The skin lesions may progress to vesiculation,
cracking, exudation and secondary infection.
• Diarrhoea. This is often associated with anorexia, nausea,
glossitis and dysphagia, reflecting the presence of a non-
infective inflammation that extends throughout the
gastrointestinal tract.
• Dementia. In severe deficiency, delirium occurs acutely
and dementia develops in chronic cases.
Treatment is with nicotinamide, given in a dose of
100 mg 3 times daily orally or parenterally. The response
is usually rapid. Within 24 hours, the erythema diminishes,
the diarrhoea ceases and a striking improvement
occurs in the patient’s mental state.
Toxicity
Excessive intakes of niacin may lead to reversible
hepatotoxicity. Nicotinic acid is a lipid-lowering agent,
but at doses above 200 mg a day gives rise to
vasodilatory symptoms (‘flushing’ and/or hypotension).
Pyridoxine (vitamin B6 )
Pyridoxine, pyridoxal and pyridoxamine are different
forms of vitamin B6 that undergo phosphorylation to
produce pyridoxal 5-phosphate (PLP). PLP is the
co-factor for a large number of enzymes involved in the
metabolism of amino acids. Vitamin B6 is available in
most foods.
Deficiency is rare, although certain drugs, such as
isoniazid and penicillamine, act as chemical antagonists
to pyridoxine. Pyridoxine administration is effective
in isoniazid-induced peripheral neuropathy and some
cases of sideroblastic anaemia.
Large doses of vitamin B6 have an antiemetic effect in
radiotherapy-induced nausea.
Although vitamin B6 supplements have become
popular in the treatment of nausea in pregnancy, carpal
tunnel syndrome and premenstrual syndrome, there is
no convincing evidence of benefit.
Very high doses of vitamin B6 taken for several months
can cause a sensory polyneuropathy.
Biotin
Biotin is a co-enzyme in the synthesis of fatty acids,
isoleucine and valine and is also involved in
gluconeogenesis.
Deficiency results from consuming very large
quantities of raw egg whites (> 30% energy intake)
because the avidin they contain binds to and inactivates
biotin in the intestine. It may also be seen after long
periods of total parenteral nutrition.
The clinical features of deficiency include scaly dermatitis,
alopecia and paraesthesia.
Folate (folic acid)
Folates exist in many forms. The main circulating form
is 5-methyltetrahydrofolate. The natural forms are prone
to oxidation. Folic acid is the stable synthetic form.
Folate works as a methyl donor for cellular methylation
and protein synthesis. It is directly involved in DNA
and RNA synthesis, and requirements increase during
embryonic development. Folate deficiency may cause three
major birth defects (spina bifida, anencephaly and encephalocele)
resulting from imperfect closure of the neural tube, which
takes place 3–4 weeks after conception. Women who
have experienced a pregnancy affected by a neural tube
defect should take 5 mg of folic acid daily from before
conception and throughout the first trimester.
The UK Department of Health advises that All
women planning a pregnancy are advised to include
good sources of folate in their diet, and to take folate
supplements throughout the first trimester. Liver is the
richest source of folate but an alternative source (e.g.
leafy vegetables) is advised in early pregnancy because
of the high vitamin A content of liver . Folate deficiency
has also been associated with heart disease, dementia
and cancer. There is mandatory fortification of flour with
folic acid in the US and voluntary fortification of many
foods across Europe. There are now concerns that this may
contribute to the increased incidence of colon cancer
through promotion of the growth of polyps.
Hydroxycobalamin (vitamin B12 )
Vitamin B12 is a co-factor in folate co-enzyme recycling
and nerve myelination. Vitamin B12 and folate are
particularly important in DNA synthesis in red blood cells.
Vitamin B12 , but not folate, is needed for the integrity of
myelin, so that vitamin B12 deficiency is also associated
with neurological disease.
Neurological consequences of vitamin B12 deficiency
In older people and chronic alcoholics, B12 deficiency
arises from insufficient intake and/or from malabsorption.
Several drugs, including neomycin, can render vitamin B12
inactive. Adequate intake of folate maintains erythropoiesis
and there is a concern that fortification of foods with
folate may mask underlying vitamin B12 deficiency.
In severe deficiency there is insidious, diffuse and
uneven demyelination. It may be clinically manifest as
peripheral neuropathy or spinal cord degeneration
affecting both posterior and lateral columns (‘subacute
combined degeneration of the spinal cord’), or there
may be cerebral manifestations (resembling dementia)
or optic atrophy. Vitamin B12 therapy improves
symptoms in most cases.
Vitamin C (ascorbic acid)
Ascorbic acid is the most active reducing agent in
the aqueous phase of living tissues and is involved
in intracellular electron transfer. It takes part in the
hydroxylation of proline and lysine in protocollagen to
hydroxyproline and hydroxylysine in mature collagen.
It is very easily destroyed by heat, increased pH and
light, and is very soluble in water; hence many traditional
cooking methods reduce or eliminate it. Claims
that high-dose vitamin C improves immune function
(including resistance to the common cold) and cholesterol
turnover remain unsubstantiated.
Deficiency – scurvy
Vitamin C deficiency causes defective formation of
collagen with impaired healing of wounds, capillary
haemorrhage and reduced platelet adhesiveness (normal
platelets are rich in ascorbate) . Precipitants and clinical
features of scurvy are shown in Box.
A dose of 250 mg vitamin C 3 times daily by mouth should
saturate the tissues quickly. The deficiencies of the
patient’s diet also need to be corrected and other vitamin
supplements given if necessary. Daily intakes of more
than 1 g/day have been reported to cause diarrhoea and
the formation of renal oxalate stones.
 Scurvy –
vitamin C
deficiency

Scurvy.
A Gingival swelling
and bleeding.
B Perifollicular
hyperkeratosis.
Other dietary organic compounds
There are a number of non-essential organic compounds
with purported health benefits such as reducing risk of
heart disease or cancer. Groups of compounds such as
the flavonoids and phytoestrogens show bioactivity through
their respective antioxidant and oestrogenic or
anti-oestrogenic activities.
Flavonoids (of which there are a number of different
classes of compound) are found in fruit and vegetables, tea
and wine; phytoestrogens are found in soy products (with
higher intakes in parts of Asia compared to Europe and the
US) and pulses.
Caffeine from tea and coffee and carbonated
beverages affects the nervous system and can improve
mental performance in the short term, with adverse
effects seen at higher intakes. Intake of non-carbonic
organic acids (which are not metabolised to carbon
dioxide), e.g. oxalates, may be restricted in individuals
prone to kidney stones.
Vitamin deficiency in old age