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Physiology This vitamin exists in several forms that are interconverted. Retinol (vitamin A1) is a
primary alcohol and is present in the tissues of animals and marine fishes; 3-dehydroretinol (vitamin
A2) is present in freshwater fish; retinoic acid shares some but not all of the actions of retinol.
Carotene is provitamin A and is readily converted into retinol in the body. Vitamin Ahas many
physiological functions (Figure 35.1). Its deficiency retards growth and development, and causes
night blindness, keratomalacia, dry eyes and keratinization of the skin. Dietary sources of vitamin
Ainclude eggs, fish liver oil, liver, milk and vegetables.

Use Vitamin Ais used to prevent and treat deficiency states. Dietary supplementation with halibut
liver oil capsules BP(containing the daily requirement of vitamin A and vitamin D) is used to
Maintenance of epithelial cell integrity, Stabilization of membrane, Component of rhodopsin
(essential for normal vision) Cofactor for microsomal drug-metabolizing enzymes, Cofactor in
cholesterol synthesis, Cofactor in mucopolysaccharide synthesis, Normal soft tissue growth, Normal
skeletal growth

prevent vitamin A deficiency. Regular dietary or parenteral supplementation of vitamin A may be

necessary in patients with steatorrhoea. Adverse effects Long-term ingestion of more than double
the recommended daily intake of vitamin Acan lead to toxicity and chronic hypervitaminosis A.
Chronic toxicity includes: 1. anorexia and vomiting; 2. itching and dry skin; 3. raised intracranial
pressure (benign intracranial hypertension), irritability and headache; 4. tender hyperostoses in the
skull and long bones; 5. hepatotoxicity; 6. congenital abnormalities. Acute poisoning causes: 1.
headache, vomiting and papilloedema; 2. desquamation. Pharmacokinetics Gastro-intestinal
absorption of retinol via a saturable active transport mechanism is very efficient, but is impaired in
patients with steatorrhoea. Carotene is metabolized to vitamin Ain the intestine. Esterified retinol
reaches peak plasma concentrations four hours after ingestion. Retinol is partly conjugated to a
glucuronide and undergoes enterohepatic circulation. Clinical evidence of vitamin Adeficiency
usually appears only months after reduced intake, when hepatic stores have been depleted.
Contraindications Excess vitamin Aduring pregnancy causes birth defects (closely related compounds
are involved in controlling morphogenesis in the fetus). Therefore pregnant women should not take
vitamin Asupplements, and should also avoid liver in their diet.


RETINOIDS AND THE SKIN Vitamin Aderivatives, e.g. etretinate, are discussed in Chapter 51.

RETINOIDS AND CANCER This is discussed in Chapter 48.


Physiology All plant and animal cells require thiamine (in the form of thiamine pyrophosphate) for
carbohydrate metabolism, as it is a coenzyme for decarboxylases and transketolases. Thiamine
deficiency leads to the various manifestations of beriberi, including peripheral neuropathy and
cardiac failure. Increased carbohydrate utilization requires increased intake because thiamine is
consumed during carbohydrate metabolism. It is therefore useful to express thiamine needs in
relation to the calorie intake. Diets associated with beriberi contain less than 0.3mg thiamine per
1000kcal. If the diet provides more than this, the excess is excreted in the urine. Thus the
recommended daily intake of 0.4mg/1000kcal provides a considerable safety margin. The body
possesses little ability to store thiamine and with absolutely deficient intake, beriberi develops
within weeks. Acute thiamine deficiency may be precipitated by a carbohydrate load in patients who
have a marginally deficient diet. This is especially important in alcoholics and thiamine replacement
should precede intravenous dextrose in alcoholic patients with a depressed conscious level. Failure
to do this has historically been associated with worsening encephalopathy and permanent sequelae
(e.g. Korsakoffs psychosis). Thiamine is found in many plant and animal foods (e.g. yeast and pork).
Use Thiamine is used in the treatment of beriberi and other states of thiamine deficiency, or in their
prevention. Such conditions include alcoholic neuritis, Wernickes encephalopathy and the neuritis
of pregnancy, as well as chronic diarrhoeal states and after intestinal resection. The parenteral route
of administration is used in confused patients. Once the deficiency state has been corrected, the oral
route is preferred, unless gastrointestinal disease interferes with ingestion or absorption of the
vitamin. Adverse effects Anaphylactoid reactions following parenteral thiamine dosing have been
reported, so parenteral administration should be restricted to situations where it is essential.
Pharmacokinetics Absorption of thiamine following intramuscular injection is rapid and complete.
Thiamine is also well absorbed through the mucosa of the upper part of the small intestine by both
active and passive mechanisms, and surplus intake is excreted unchanged in the urine.


Physiology Niacin is found in yeast, rice, liver and other meats. Its vital metabolic role is as a
component of nicotinamide adenine

dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin can be
generated in the body in small amounts from tryptophan. Deficiency of niacin causes pellagra, that
can manifest clinically as a syndrome complex which includes dementia, dermatitis and diarrhoea.

Uses 1. Niacin is used to treat and prevent pellagra. If oral treatment is not possible, intravenous
injections are available. 2. Nicotinic acid (or nicotinic acid analogues, e.g. acipomox) may be used to
treat dyslipidaemia (Chapter 27), but hypolipidaemic dosing is limited by vasodilatation/flushing.

Adverse effects In replacement therapy for pellagra, adverse effects are uncommon. High doses (as
used for hyperlipidaemia) cause the following: 1. vasodilatation due to prostaglandin D2 this can
be reduced by premedication with aspirin; 2. nausea, vomiting and itching; 3. hyperglycaemia; 4.
exacerbation of hyperuricaemia.

Pharmacokinetics Both niacin and nicotinamide are well absorbed via the intestine and are widely
distributed to tissues. When the usual dietary amounts are administered, a high proportion is
excreted as N-methyl nicotinamide and other metabolites. When increased doses are administered,
a higher proportion is excreted unchanged in the urine.


Physiology Vitamin B6 occurs naturally in three forms, namely pyridoxine, pyridoxal and
pyridoxamine. All three forms are converted in the body into pyridoxal phosphate, which is an
essential cofactor in several metabolic reactions, including decarboxylation, transamination and
other steps in amino acid metabolism. Pyridoxine is present in wheatgerm, yeast, bran, rice and
liver. Deficiency causes glossitis, seborrhoea, fits, peripheral neuropathy and sideroblastic anaemia.
Isoniazid prevents the activation of pyridoxal to pyridoxal phosphate by inhibiting the enzyme
pyridoxal kinase, and slow acetylators of isoniazidare at increased risk of developing peripheral
neuropathy for this reason (Chapters 14 and 44).

Use Pyridoxine hydrochloride is given to patients at risk (e.g. alcoholics) during long-term therapy
with isoniazid to prevent peripheral neuropathy, and in deficiency states. Large doses

are used in sideroblastic anaemia. Pyridoxine is also used to treat certain uncommon inborn errors
of metabolism, including primary hyperoxaluria. Large doses are sometimes used to treat
premenstrual syndrome, and there is a lobby of enthusiasts for this, despite a paucity of evidence.
Adverse effects There have been reports of ataxia and sensory neuropathy following administration
of large doses (2g/day) of pyridoxine for more than two months.


Physiology Ascorbic acid is present in large quantities in citrus fruits, tomatoes and green vegetables.
Vitamin C is essential to humans, monkeys and guinea pigs which, unlike other mammals, cannot
synthesize it from glucose. Dietary lack of vitamin C causes scurvy, which is characterized by bleeding
gums and perifollicular purpura. Ascorbic acid is involved in several metabolic processes (Figure
35.2). It is a potent watersoluble anti-oxidant. The nutritional status of vitamin C can be assessed by
measuring the intracellular leukocyte concentration, but this is not routinely performed or available.
Uses 1. Ascorbic acid is used in the prophylaxis and treatment of scurvy. (Perhaps the first recorded
clinical trial involved the distribution of citrus fruit to some, but not all, British naval vessels and
observation of the incidence of scurvy. The Admiralty were (after some prevarication) convinced and
British sailors were subsequently provided with limes whence the term limeys.) 2. Ascorbic acid
increases the absorption of orally administered iron. 3. The reducing properties of ascorbate may be
used in the treatment of methaemoglobinaemia. 4. In scorbutic patients, wound healing is delayed
and this is restored to normal by administration of ascorbic acid. Adverse effects Ascorbic acidis non
toxic in low doses. However, administration of
4g daily raises the urinary excretion of oxalate. Large


Anti-oxidant, Collagen biosynthesis, Steroid metabolism, Folic acid activation, CYP450 drug-
metabolizing enzyme function, Mitochondrial electron transport chain function.


A total of 13 nutritionally essential trace elements are recognized, namely fluorine, silicon,
vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium, tin and iodine. These
are required in the human body at

0.01% of body weight. Most of them are highly reactive chemically and one or more of these
elements is present at the active site of many enzymes. They are present in small but adequate
amounts in a normal diet, but evidence is accumulating that in addition to iron, cobalt (Chapter 49)
and iodine (Chapter 38), zinc, doses of vitamin C taken chronically have resulted in calcium oxalate
urolithiasis. There is theoretical concern that high doses of vitamin C (in common with other anti-
oxidants) can have pro-oxidant actions.

Pharmacokinetics Ascorbic acid is well absorbed following oral administration and its sodium salt
may be given by intramuscular or intravenous injection. Ascorbic acid is mainly metabolized by
oxidation to oxalic acid. Normally about 40% of urinary oxalate is derived from ascorbic acid. When
the body stores of ascorbic acid are saturated, some ingested ascorbic acid is excreted in the urine


Vitamin E is found in many foods, including nuts, wheatgerm and bananas. Deficiency in animals
causes abortion and degeneration of the germinal epithelium of the testes. No defined deficiency
syndrome exists in humans, but low vitamin E intake is associated with anaemia in premature and
malnourished infants. Vitamin E protects erythrocytes against haemolysis, and is a fat-soluble anti-
oxidant and detoxifies free radicals. Free radicals cause membrane and epithelial injury and have
been implicated in the pathophysiology of numerous diseases, including cancer and atheroma.
Epidemiological studies suggested that reduced vitamin E intake is associated with increased
atherogenesis (Chapter 27). Large studies of vitamin E supplementation for a number of
cardiovascular disorders and cancers have not shown clear benefit, and there is a theoretical risk
that prolonged ingestion of high doses could be harmful.

Key points Vitamin deficiency and disease

In general, vitamin deficiencies are due to inadequate dietary intake or malabsorption. Vitamin B
deficiencies do not often occur in isolation. Vitamin A deficiency causes night blindness. Vitamin
B1 (thiamine) deficiency causes beriberi (neuropathy, paralysis, muscle wasting and cardiac failure).
Vitamin B3 (nicotinic acid) deficiency causes pellagra (photosensitive dermatitis, diarrhoea,
dementia and death (the 4 Ds)). Vitamin B12 deficiency causes megaloblastic anaemia, dementia
and neuropathy. Vitamin C deficiency causes scurvy (perifollicular petechiae, gingivitis and swollen
joints). Vitamin D deficiency causes rickets (in young) and osteomalacia (adults). Folate deficiency
causes megaloblastic anaemia and neural tube defects (in the developing fetus).

Key points Population groups at high risk for vitamin deficiency

Infants Pregnant women Elderly people, especially the elderly with chronic disease Alcoholics
and drug abusers Vegans and undernourished populations Patients taking long-term
anticonvulsants Patients with malabsorption syndromes.

Key points Vitamin toxicities

Vitamin A gastro-intestinal upsets, headache (raised intracranial pressure), desquamation,

hepatotoxicity and teratogenicity. Nicotinic acid flushing, vasodilatation and hepatotoxicity.
Vitamin C hyperoxaluria and oxalate stones. Vitamin D hypercalcaemia.
copper, selenium and molybdenum deficiencies can contribute to disease. Trace element
deficiencies are most commonly due to inadequate intake or to intestinal disease reducing
absorption; treatment is with adequate replacement. The features of copper and zinc deficiencies
are summarized in Table 35.1.