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A Review of Vitamin A
Roger Bloxham and Antony Wakeford explore vitamin A’s role
as a treatment for ageing and photodamaged skin
Introduction
Vitamins are organic compounds that the human body requires to effectively function, thus they have a direct affect on our health and
wellbeing. They are derived from the diet in small amounts, and, as such, are often referred to as micronutrients.1 An organic compound
is considered a vitamin if a lack of it results in clinical symptoms, known as vitamin deficiency.
Summary of vitamins
· Vitamin A is a term used for a group of fat-soluble compounds
known as retinoids; these include retinol, retinal and retinoic
acid. Their primary action is to affect gene expression and the
production of Messenger RNA (mRNA), resulting in the production
of proteins and the differentiation of epithelial cells and tissues,
which develop from the ectoderm. Vitamin A therefore plays
a key role in the development and integrity of the skin (the
epidermis in particular), and the outer membranes of sensory
organs such as the eye and neural membranes.1,2,
· Vitamin C, or ascorbic acid, is an electron donor and is the
primary and highly potent water-soluble non-enzyme antioxidant
present in plasma and tissues throughout the body. It also acts
as an electron donor for key enzymes involved in catecholamine
synthesis (hormones involved in collagen hydroxylation) and
subsequent collagen structure stabilisation as well as carnitine
synthesis and subsequent mitochondrial activity.1,3
· Vitamin E describes a group of fat soluble compounds known
as tocopherols. Vitamin E is a very effective antioxidant, which
prevents or helps to slow down lipid oxidation and subsequent
damage to cell membranes and membrane structures and
lipoproteins that transport fats through the blood stream.1,3
· Vitamin D is formed from cholesterol in the skin through a
photolysis reaction stimulated by exposure to UV light. This
fat-soluble compound plays a role in inducing protein synthesis
and calcium absorption in the intestine and associated optimum
calcium levels in the kidneys and bones.1,2
· Vitamin K is involved in the carboxylation of glutamic acid in a
number of vitamin K dependent proteins; during the process it is
converted to an epoxide form that can be regenerated to vitamin
K within the body. Many of the blood clotting factor proteins are
vitamin K dependent.1,2
· The B-complex vitamins are water soluble coenzymes:
Thiamine (B1) is involved in enzyme functions associated with
carbohydrate metabolism.1,2
Riboflavin (B2) is a precursor of coenzymes that are involved in
protein metabolism.1,2
Niacin is a coenzyme of dehydrogenases that plays a key role
in the metabolism of proteins and carbohydrates.1,2
Vitamin B6, of which the most stable form is pyridoxal, is a
coenzyme involved in protein metabolism.1,2
Pantothenic Acid (B5) is the main component of coenzyme-A
and a key requirement for cell metabolism, the synthesis of
essential fats, cholesterol and hormones, including melatonin.1,2
Biotin is the active site of five carboxylating enzymes
required for the biosynthesis of fatty acids and
gluconeogenesis.1,2
· Folates, including folic acid, are cofactors to enzymes that
facilitate the transfer of carbon units in transfer reactions,
particularly associated with the metabolism of DNA. Its effects
are most prevalent in rapidly dividing cells such as red blood
cells. It is also key to a process known as methylation and the
associated gene expression responsible for the processing of
proteins, phospholipids and cell differentiation.1,2,3
· Vitamin B12 plays a key role in the metabolism of folate and
coenzyme A; it is therefore closely linked to DNA metabolism
and expression.1,2
Given the primary role of vitamin A in the production and
differentiation of epithelial cells, which includes the skin and in
particular the epidermis, as well as the fact that a lack of vitamin
A causes observable changes in skin epithelial tissue, including
epidermal thickening and hyperkeratosis,2 it is no surprise that
retinoids became, and still are, a topic of dermatological research
for skin conditions and treatments. This is the focus of the
discussion below.
Vitamin A: How does our body get it and use it?
The retinoid compounds that the term vitamin A describes
are all lipid soluble, and are related to the preformed vitamin
A compound all-trans-retinol. This is the active bioavailable
form of vitamin A. There are four main physiologic functions of
retinoids in the body:4
1. To ensure normal embryonic development.
2. To facilitate normalised epithelial differentiation in varying tissue types, including the skin.
3. To maintain healthy vision through the production of rhodopsin, an 11-cis-retinaldehyde containing eye pigment that enables night vision.
4. To enable adequate immune function and lymphocyte survival.
Vitamin A and nutrition
Vitamin A levels within the body depend on levels of nutrition.
Preformed vitamin A, predominantly in the form of retinyl esters
(esterified retinol, mainly retinyl palmitate), is available from animalbased foods – liver, butter, cheese, egg yolks and oily fish are
known to have a high content. It is also possible to derive vitamin
A from vegetables and fruit via a relatively small sub-section of
the many carotenoid compounds present in plants, particularly
alpha and beta-carotenes. These are known as pro vitamin A
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compounds.3,5 In addition, some food items, such as margarine
and low-fat spreads, are fortified with vitamin A.
The different sources of vitamin A have different levels of potency
available in food items. For example, retinyl esters are membranebound within storage cells within the animal tissue. The pro-vitamin
A carotenoids are not only bound to lipids but are embedded in
complex cellular structures within the plant material. Therefore
the amount of the retinyl ester or carotenoid does not directly
reflect the amount of vitamin A (retinol) available. Because of this,
standardised units known as International Units (IU) or Retinol
Equivalents (RE) are often used to express the levels available per
compound, and to help provide a comparison across the different
food sources.2,3
There can be a wide variability in levels contained in the different
food sources, for example 100g of pork liver has been shown
to have 30,000 μg RE, whereas pork muscle has 6 μg RE and
oily fish has 40 μg RE.2 There are risks associated with taking
too much vitamin A. The UK National Health Service (NHS) has
advised that having more than an average of 1.5mg a day vitamin
A, over many years, may affect bones, making them more likely to
fracture.6 They point out that this is particularly important for older
people, especially women, who are already at risk of osteoporosis.
This is when bone density reduces and there is a higher risk of
fractures. Thus, women who have been through the menopause
and older men, who have a higher risk of osteoporosis, are
advised to avoid having more than 1.5mg of vitamin A per day from
food and supplements.6
Eating liver or liver pâté more than once a week may result in
too high a vitamin A intake, and it is advised that if liver is eaten
every week, supplements containing vitamin A should not be
taken. Additionally, if the dietary intake of vitamin D is too low, it is
possible that there will be more risk of the harmful effects of too
much vitamin A.6
In addition to the osteoporosis risks associated with taking too much
vitamin A detailed earlier, there are additional risks in pregnancy.6
Having large amounts of vitamin A can harm an unborn baby. It is
advised that women who are pregnant, or who are thinking about
becoming pregnant, should not eat liver or liver products, and should
not take supplements that contain vitamin A. It is recommended that
a GP or midwife be consulted for more information.6
Vitamin A and bioavailability
Once the food has been consumed, digestion frees the retinol
from the retinyl esters. The lipid soluble retinol is then inside a
predominantly aqueous environment in the intestines and gut,
with fatty acids and phospholipids and bile secretions. It then has
to pass through the lipid-rich intestinal mucosal cells. Enzymes
either cleave vegetable derived carotenoids as they pass through
the intestinal mucosa to form retinol, or they remain as they are.
Retinol is then re-esterified or is bound to a specific protein retinol
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binding protein (RBP), synthesised within the tissue, and passes
into the blood stream. Any carotenoids or retinol that has become
re-esterified in the intestinal cell wall is packaged in to lipoprotein
particles and enters into the blood stream via lymph channels.3
The next step is storage, predominantly within the liver, in
parenchymal cells. Retinol is detached from the RBP or the retinyl
ester is removed from the circulating lipoprotein particle and then
hydrolysed within the liver to produce retinol. The resulting retinol
is then esterified for storage. The liver can also take up carotenoids
from the lipoprotein particles for storage.3
Stored retinyl esters in the liver are mobilised by hydrolytic release
of retinol and binding to a RBP, produced in the liver, enabling it
to be transported in the aqueous environment of the plasma in
the blood stream to target tissues and cells. The levels of plasma
vitamin A are maintained at approximately 2μmol/L. The circulating
retinol RBP combination forms a further complex with a larger
protein transthyretin, to ensure the retinol is not filtered out through
the kidney.7 The bound retinol enters into the tissue through the
cellular membrane, where the retinol binds to an intracellular
binding protein (CRBP). Within the cell, retinol can be esterified,
most likely to form a localised store, and more importantly it can be
metabolised to form retinal (also known as retinaldehyde) and then
retinoic acid. The conversions of retinol to ester forms or retinal are
all reversible which, consequently, can regulate the levels of retinol
and retinoic acid in the cells.2,9
Vitamin A and biochemical activity
The cellular conversion of retinol to retinal and retinoic acid is
fundamental to its biological role and ultimately its role in the
treatment of ageing and photodamaged skin.
In ocular tissue and specifically the retina, retinol is converted to
retinal and then rhodopsin – the pigment required for low light
vision. For the control of cell growth and differentiation in all
other epithelial tissue retinol is converted to retinal and then to
retinoic acid (of which there are two primary isomers). These bind
to receptors in the nucleus (known as Retinoic Acid Receptor
(RAR) and Retinoid X Receptor (RXR) receptors), which in turn bind
to specific elements of DNA and consequently regulate gene
expression and transcription.8 As such, vitamin A is essential for the
biological functions previously mentioned.4,9
Vitamin A deficiency is rare in the western world but can be a major
problem in the developing world with specific symptoms including
night blindness and xerophthalmia, which can lead to permanent
blindness. Other significant negative effects associated with
deficiency include growth retardation in children, skin disorders
and impaired immune function. Deficiency in pregnancy can lead
to congenital malformation of the eyes, lung, cardiovascular and
urinary systems.5
In the environment of cosmetic dermatology and aesthetics, we
do not usually have to deal with such issues of deficiency. The
Table 1: Table comparing pre-formed and pro vitamin A compounds:
Molecule
Quantity
Retinol Equivalents (RE)
International Units (IU)
Retinol
1μg
1.00
3.3
Retinyl Palmitate
1μg
0.55
1.8
Beta-carotene
1μg
0.17
0.6
(data adapted)1,2,3
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clinical focus with respect to vitamin A is for use in the treatment
of physical and anatomical impairment of the epithelial tissues
and cells that occurs i.e in the skin, as part of the ageing process
and photodamage, and to treat other cosmetically impairing skin
conditions such as pigmentation and acne.
Vitamin A and the clinical enhancement of aged
and photodamaged skin
During skin ageing, the production and replacement of collagen,
elastin and hyaluronic acid slows down as there are fewer
dermal fibroblasts, and they operate less efficiently. Skin not
damaged by photo radiation will age as a result of this, and
become thinner, more lax and finely wrinkled.10,11 External factors,
including UV radiation and smoking, accelerate the natural ageing
process. In the 1990s, research showed that photodamaged
skin had premature damage of the collagen bundles and
amorphous amounts of elastotic material, which was likely due
to increased synthesis of matrix metalloproteinases (MMPs) and
subsequent collagen destruction.12,13 It was also demonstrated
that photodamaged skin has reduced capability to produce new
collagen.14 This prematurely reduces the elasticity, firmness, and
smoothness of the skin, resulting in coarser lines and wrinkles.
Photodamaged skin is also differentiated from naturally aged skin
by a thickened and rougher appearance.
With an understanding of the role of vitamin A within biological
processes, and the mechanisms and effects of skin ageing and
photodamage, it comes as no surprise that vitamin A is often
considered an essential component of an evidence-based antiageing skin management programme.
The role of oral retinoids
The consumption of vitamin A via food substances or supplements
could be considered to be a logical route to try and combat the
effects of intrinsic skin ageing and photodamage. However, vitamin
A deficiency is rare in the western world and it is known that average
daily intakes of preformed retinol within the EU are well above the
recommended reference intake.5 Despite this, aesthetic consultations
and treatments for skin ageing and photodamage continue to rise,
implying that dietary levels of vitamin A may have little correlation with
the impact of chronological or photo-induced ageing.
A review of clinical studies on PubMed reveals oral vitamin A
supplement studies relating to skin are relatively low in number and
the data that was sourced relates primarily to skin cancer. This data
is briefly reviewed here, as it can reasonably be considered to have
some correlation to the impact of UV in photodamaged skin.
A recently published review of vitamin A in photocarcinogenesis
stated that relatively high oral doses of prescription only medicines
(POMs), isotretinoin and acitretin, resulted in a significant
reduction of new skin cancers in high-risk patients.15 Whilst many
medical aesthetic treatments crossed over from their initial
use in more clinical areas, it would be difficult (based on a risk/
benefit assessment) to attempt to adapt this approach with these
medications for skin ageing treatments.
One study showed daily supplementation of 25,000 IU of retinol,
more than 10 times the recommended daily dose, for a median period
of 3.8 years, did significantly reduce the incidence of squamous cell
carcinoma.16 However a four-year follow up prospective study of
73,336 women showed that their diet, including vitamin A intake, or
supplementation with vitamins including vitamin A and multivitamins,
had no significant impact on the incidence of basal cell carcinoma.17
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Similarly, a study of men taking 50mg of beta-carotene on alternative
days for 12 years, again more than 10 times the recommended
daily intake, showed that it had no effect on the incidence of nonmelanoma skin cancer when compared to the placebo group and
there was no beneficial link associated with plasma levels of betacarotene, vitamin A or vitamin E.18
Based on this, it is logical to conclude that oral intake of vitamin A is
going to play a minimal role in treating ageing and photodamaged
skin and, therefore, for an evidence-based approach, we need to
focus on topical retinoids.
The role of topical pharmaceutical retinoids
As early as 1962, the effect of topical vitamin A in the form of tretinoin
(all-trans-retinoic acid) was shown to affect epidermal differentiation
and keratinization, and was used clinically in the treatment of
ichthyoses.19 In 1969, Kligman published the first clinical paper clearly
demonstrating its clinical efficacy in the treatment of acne20 and
in the early 1970s tretinoin was approved by the Food and Drugs
Administration (FDA) in the USA as a prescription only medicine, the
first retinoid approved as a medicine, for the treatment of mild to
moderate acne.19
However, it took some time before the skin physiology-changing
attributes of tretinoin were appreciated in the treatment of
photodamaged and aged skin. In 1986 Kligman published a study
showing that in photoaged skin, topical tretinoin 0.05% induced a
normalisation of keratinocyte exfoliation and proliferation, along with
improvement in keratinocyte morphology and function, extracellular
matrix structure and formation, and angiogenesis.21
A review of clinical studies available for tretinoin summarised
that the shorter-term studies of four to 16 weeks demonstrated
physiological changes in the epidermis and significant enhancements
in appearance but with minimal dermal changes. Longer-term
studies of approximately six months showed that these clinically
significant improvements in fine and coarse wrinkles, sallowness,
hyperpigmentation, roughness and epidermal structure continued,
and that these improvements were maintained after the study
periods. Interestingly, it was the studies of 12 months or more that
showed clinical changes in the dermis, with new collagen production
and the regulation of damaged tissue.9,22
Topical tretinoin presented some potential adverse events, such as
erythema and inflammation in the areas of application, as well as
increased photosensitisation. It was for this reason that lower strength
tretinoin was assessed and showed good results. 0.025% and 0.1%
tretinoin produced statistically equivalent results after 48 weeks’ use,
with significantly less adverse events in the lower strength group.22
In the USA, the FDA review of products containing tretinoin has, to
date, designated them to be POMs.24 The same is true in the UK
with respect to the Medicines and Healthcare products Regulatory
Agency (MHRA)25, and the EU Cosmetics Regulation26 lists tretinoin as
a substance prohibited in all cosmetic products.
The electronic medicines compendium (eMC) website27 shows that
there are two topical medicinal products containing tretinoin available
in the UK. Both are combined with an antibiotic and indicated for the
treatment of acne. There are currently no forms of tretinoin suitable
for use in the rejuvenation of aged and photodamaged skin with an
MHRA approved marketing application (MA).
If a tretinoin product is made available within the UK without an
MA it must be done under the section of the Human Medicines
Regulations 2012 (SI 2012 No. 1916)28 concerning unlicensed medicinal
products for individual patient use. Regulation 167 of the Regulations
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requires that there is a bona fide unsolicited order, that the product is
formulated in accordance with the requirement of a doctor or dentist,
nurse independent prescriber, pharmacist independent prescriber
or supplementary prescriber registered in the UK, and the product
is for use by one of their individual patients (on the basis of ‘special
need’) on the practitioner’s direct personal responsibility. In addition,
guidance from the prescriber’s governing body should be considered.
For example, the Nursing and Midwifery Council (NMC) provide such
guidance accessible via their website.29
The most recent generation of medicinal retinoids are
synthetically produced. They were developed to have a
more selective mechanism of action and better tolerability.
Adapalene, the first synthetic retinoid, is readily taken up by the
pilosebaceous unit (hair shaft, hair follicle, sebaceous gland)
and was shown to directly bind to RAR receptors and regulate
keratinisation and inflammation.9 There are cream and gel
formulation POMs approved by the MHRA for the treatment of
mild to moderate acne.14 Their short-term use over four weeks
and longer-term use of up to nine months, have shown significant
improvements in photoaged skin,30 although such use is not
in accordance with the approved indications, and would be
considered to be ‘off-label’ with respect to the currently available
and approved medicines. Tazarotene is another synthetically
produced retinoid approved in the UK in a gel form for the
treatment of psoriasis.14
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Specific retinoids are also available for use as cosmetic
ingredients in compliance with the Cosmetic Product Regulations
and the EU Cosmetic Directive. With respect to their use in
ageing and photodamaged skin, retinol has had established
evidence-based cosmetic use since 1984, and is accorded
‘generally recognized as safe’ (GRAS) status by the FDA.
Retinaldehyde (retinal) has generated clinical data supporting its
use and the retinol derivatives such as retinyl palmitate are widely
used due to their stability and ease of formulation, although less
clinical evidence of their efficacy as a monotherapy is available.9
All of the retinoids referred to above require a biological
conversion within the skin to form retinoic acid.9,31 The advantage
of the cosmetic retinoids is that they are more widely available for
use than medicinal products, and their skin tolerance has been
shown to be significantly greater than tretinoin.32 The fact that
they are also cosmetics allows greater flexibility with respect to
formulation.
The evidence of the clinical efficacy of retinol is compelling. Kang
et al showed that 1.6% retinol induced similar effects to 0.025%
retinoic acid, without similar measurable skin irritation.33 The
retinol caused epidermal thickening and enhanced expression
of retinol binding protein mRNA, similar to that of retinoic acid.
However, the erythema produced by retinol application was
significantly less. Interestingly, they discovered that the retinoic
acid levels found in the epidermis were approximately a thousand
times less in the retinol treated skin compared to the retinoic acid
treated skin, despite seeing similar clinical effects and markers.
They postulated that the retinol was being converted to retinoic
acid in a tightly controlled manner at physiologically relevant
sites; the right amount at the right location within the skin.
Further studies have shown that retinol is safe and effective in
the treatment of photodamaged skin.31,34,35 It is acknowledged,
however, that formulation is key as retinol-based products can be
unstable, particularly on exposure to light and air.9
Because of the clinical value of retinol and the fact that its efficacy
Figure 1:
Figure 2:
The role of topical cosmetic retinoids
Before
Before
After
A 42-year-old female before (left) and after (right) eight weeks of treatment
with Retinol (0.5%) aqeuous protein-rich suspension. Images courtesy of
Dr Michael Gold.
Figure 3:
Before
After
After
A 69-year-old female before (top) and after (bottom) eight weeks of
treatment with Retinol (1.0%) aqeuous protein-rich suspension. Images
courtesy of Dr Vivian Bucay.
Visia brown spot analysis of a 41-year-old female before (left) and after
(right) eight weeks of treatment with Retinol (0.5%) aqueous protein-rich
suspension. Images courtesy of Dr Michael Gold.
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depends greatly on its stability and bioavailability, research and
formulation developments continue. Gold et al demonstrated in
2013 the efficacy and tolerability of such a product, reporting a
pilot study of a serum with retinol 1% in a novel oil-free aqueous
protein rich suspension, showing improved visible signs of
photodamage after eight and 12 weeks of daily use. Their
subsequent study using 0.5% retinol in the same formulation
showed that hyperpigmentation, telangiectasias, skin laxity,
roughness and actinic keratosis showed significant improvement
from baseline after four and eight weeks daily use of the
formulation. Skin tolerability was reported to be good.33
Conclusion
When it comes to aged skin, and skin whose ageing process,
structure and appearance has been worsened by photodamage,
topical vitamin A plays a key role in its treatment and visible and
physical enhancement. There are robust double blind placebo
controlled clinical studies regarding the use of tretinoin (retinoic
acid) in the treatment of aged and photodamaged skin.21,22,23,32
Whilst clinically visible effects can be seen after four weeks, the
greatest physiological effects are seen after daily use of 12 months
or more, and the studies show the treatment has a good safety
profile over such periods. This indicates that on-going long-term
treatment is desirable, although skin tolerability issues were often
reported particularly in the early phases of treatment.
In the UK, the availability of tretinoin in topical formulations
suitable for use in treating aged and photodamaged skin is
currently limited to unlicensed medicinal products. These may
only be supplied in accordance with the Human Medicines
Regulations concerning unlicensed medicines for individual
patient use and by prescribers able to prescribe such medicines,
and in accordance with their governing body / council such as
the General Medical Council. There is also compelling data for
the efficacy of retinoids, available in cosmetics for the clinical
improvement of aged and photodamaged skin.33, 34, 35, 36 Cosmetics
containing these ingredients are more widely available and
generally display better skin tolerability than prescription-only
tretinoin-based topical medicines. Within this category, retinolbased formulations are supported by a high level of clinical data,
although formulations need to address the inherent instability
of retinol as an ingredient.9,31,33,34,36 On-going research and novel
formulation enhancements means that retinol-based cosmetics
can and will continue to play a significant role in the clinical
management of aged and photodamaged skin.
Roger Bloxham is the managing director of Ferndale
Pharmaceuticals Ltd and AesthetiCare, with a BSc
(Hons) in Applied Biology and over 28 years of
commercial, technical and regulatory experience in the
pharmaceutical, medical device and cosmetic industries.
In the last 18 years, his focus has been on the dermatology sector.
Antony Wakeford is a chartered chemist and member
of the Royal Society of Chemistry. As the owner
and managing director of QP-Services UK Ltd., an
independent provider of technical, quality, safety and
regulatory services to the pharmaceutical, medical device
and cosmetic industry, he has over 32 years experience in the industry. Aesthetics
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33. Kang et al, ‘Application of Retinol to Human Skin In Vivo Induces Edipermal Hyperplasia and Cellular Retinoid Binding Proteins Characteristic of Retinoic Acid but Without Measurable Retinoic Acid Levels or Irritation’, Soc Investig Drmatol, 105(4) (1995), p. 549-556.
34. Duell EA et al, ‘Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid’, J Investig Dermatol, 106 (1997) p. 316-320.
35. Tucker-Samaras et al, ‘A stabilized 0.1% retinol facial moisturizer improves the appearance of photodamaged skin in an eight-week, double-blind, vehicle-controlled study’, Journal of Drugs in Dermatology, 8(10) (2009), p. 932-936.
36. Gold et al, ‘Treatment of facial photdamage using a novel retinol formulation’, Journal of Drugs in Dermatology, 12(5) (2013) p. 533-510.
Ferndale Pharmaceuticals Ltd / AesthetiCare market products containing
vitamin A ingredients and QP-Services UK Ltd are technical and regulatory
service providers to Ferndale Pharmaceuticals Ltd.
Reproduced from Aesthetics | Volume 2/Issue 6 - May 2015