The Vitamins 139different tissues, and at different stages in develop-
ment, and retinoic acid is essential for the normal
responses to vitamin D, thyroid hormone and long-
chain PUFA derivatives.
Unoccupied RXRs can form dimers with calcitriol
and other receptors; these bind to hormone response
elements on DNA, but do not lead to activation of
transcription. This means that vitamin A defi ciency
will impair responses to vitamin D and thyroid
hormone more markedly than might be expected
simply from lack of 9-cis-retinoic acid to form active
heterodimers.
Vitamin A in excess may also impair responsiveness
to vitamin D and other hormones, since high concen-
trations of 9-cis-retinoic acid will lead to the forma-
tion of RXR–RXR homodimers, leaving too few RXRs
to form heterodimers with vitamin D and other
receptors. There is epidemiological evidence that
habitually high intakes of vitamin A are associated
with poor bone health in later life as a result of
impaired responsiveness to vitamin D.
The antioxidant function of carotenes
At least in vitro, and under conditions of low oxygen
availability, carotenes can act as radical-trapping anti-
oxidants. There is epidemiological evidence that high
intakes of carotene are associated with a low incidence
of cardiovascular disease and some forms of cancer,
although the results of intervention trials with β-
carotene have been disappointing, with an increased
incidence of lung cancer among those taking carotene
supplements.
The problem is that although carotene is an anti-
oxidant at a low partial pressure of oxygen, as occurs
in most tissues, at a high partial pressure of oxygen,
as occurs in the lungs, it is an autocatalytic pro-
oxidant, acting as a source of oxygen radicals. The UK
Food Standards Agency specifi cally advises smokers
not to take carotene supplements.
Vitamin A defi ciency: night blindness
and xerophthalmia
Worldwide, vitamin A defi ciency is a major public
health problem and the most important preventable
cause of blindness; the WHO estimates that some 256
million children under 5 years old show subclinical
defi ciency and 2.7 million have xerophthalmia.
The earliest signs of clinical defi ciency are associ-
ated with vision. Initially, there is a loss of sensitivity
to green light; this is followed by impairment of the
ability to adapt to dim light, then an inability to see
at all in dim light: night blindness. More prolonged
or severe defi ciency leads to the condition called
xerophthalmia: keratinization of the cornea, followed
by ulceration – irreversible damage to the eye that
causes blindness. At the same time there are changes
in the skin, with excessive formation of keratinized
tissue.
Vitamin A also plays an important role in the dif-
ferentiation of immune system cells, and mild defi -
ciency, not severe enough to cause any disturbance of
vision, leads to increased susceptibility to a variety of
infectious diseases. At the same time, the synthesis of
RBP is reduced in response to infection (it is a nega-
tive acute-phase protein), so that there is a reduction
in the circulating concentration of the vitamin, and
hence further impairment of immune responses.
Signs of vitamin A defi ciency also occur in protein–
energy malnutrition, regardless of whether or not the
intake of vitamin A is adequate. This is due to impair-
ment of the synthesis of plasma RBP; functional
vitamin A defi ciency can occur secondary to protein–
energy malnutrition; even if liver reserves of the
vitamin are adequate, it cannot be mobilized.Vitamin A requirements and
reference intakes
There have been relatively few studies of vitamin A
requirements in which subjects have been depleted of
the vitamin for long enough to permit the develop-
ment of clear defi ciency signs. Current estimates of
requirements are based on the intakes required to
maintain a concentration in the liver of 70 μmol
retinol/kg, as determined by measurement of the rate
of metabolism of isotopically labeled vitamin A. This
is adequate to maintain normal plasma concentra-
tions of the vitamin, and people with this level of liver
reserves can be maintained on a vitamin A-free diet
for many months before they develop any detectable
signs of defi ciency.
The average requirement to maintain a concentra-
tion of 70 μmol/kg of liver is 6.7 μg retinol equiva-
lents/kg body weight, and this is the basis for
calculation of reference intakes.Assessment of vitamin A status
The only direct assessment of vitamin A status is by
liver biopsy and measurement of retinyl ester reserves.