Download Nutrition and the deleterious side effects of nutritional supplements

Clinics in Dermatology (2010) 28, 371–379
Nutrition and the deleterious side effects of
nutritional supplements
Marcia S. Driscoll, MD a,⁎, Eun-Kyung M. Kwon, BA a , Hadas Skupsky, BA a ,
Soon-You Kwon, MD a , Jane M. Grant-Kels, MD b
a
Department of Dermatology, University of Maryland School of Medicine, 419 W Redwood St, Ste 160, Baltimore,
MD 21201, USA
b
Department of Dermatology, University of Connecticut Health Center, 21 South Rd, Farmington, CT 06030, USA
Abstract The potential adverse effects associated with some of the more common oral vitamin
supplements—vitamins A, D, and E and niacin (forms include nicotinic acid and nicotinamide), and
mineral supplements—zinc, copper, and iron, used in dermatology are manifold. Although the
dermatologist may be familiar with adverse effects of vitamins A and D, less well-known adverse
effects, such as hematologic and neurologic effects from zinc, are presented.
© 2010 Elsevier Inc. All rights reserved.
Introduction
The use of nutritional supplements to correct for
nutritional deficiencies, prevent birth defects, and treat
specific dermatologic conditions can undisputedly help
many patients and improve quality of life; however, if one
consumes supplements in amounts above the recommended
dietary allowance (RDA), potentially severe adverse effects
may occur. Multiple factors may enhance the risk for
excessive intake of nutritional supplements, including easy
accessibility and availability of supplements, patients' selfdiagnosis and treatment, and lack of knowledge of possible
deleterious effects. Patients who observe improvement in a
condition or symptom associated with a certain dose may
choose to increase their daily intake.
In dermatology, nutritional supplements are recommended for a wide variety of skin conditions and sometimes
are co-prescribed with other medications (eg, folic acid with
⁎ Corresponding author. Tel.: +1 410 328 3167; fax: +1 410 328 1323.
E-mail address: [email protected] (M.S. Driscoll).
0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2010.03.023
methotrexate). Specific nutrients are also included in the
formulations of certain medications that are prescribed. This
contribution presents an overview of the nutritional supplements most widely used in dermatology. We review their
relevance to dermatology, how to monitor patients who have
been prescribed these supplements, possible drug-drug
interactions, RDAs when applicable, and potential adverse
effects at therapeutic and toxic levels. We predominantly
focus on oral supplements and, therefore, topical nutrients
are only briefly discussed. Important information concerning
selected vitamins and minerals are summarized in Table 1.
Mineral supplements
Zinc
Zinc is a trace element used as a mineral supplement in the
treatment of certain dermatologic conditions, including
acrodermatitis enteropathica (AE), acquired bullous AE,
necrolytic acral erythema, rosacea, and acne vulgaris. AE is a
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Table 1
M.S. Driscoll et al.
Summary of vitamin and mineral use and doses
Nutrient Dermatologic conditions
RDA
UL
Zinc
Acrodermatitis enteropathica,
necrolytic acral erythema
Men: 11 mg/d; women: 8 mg/d Adults: 40 mg/d
Copper
Tissue formation and repair
Children: 340 μg/d; adults:
900 μg/d
Children: 1000 μg/d;
adults: 10,000 μg/d
Iron
Alopecia
Men: 8 mg/d; premenopausal
women: 18 mg/d
Adults: 45 mg/d
Vitamin Phrynoderma, pityriasis rubra
A
pilaris, wound healing
Men: 900 μg RAE/d
(3000 IU/d); women: 700 μg
RAE/d (2310 IU/d)
Adults: 3000 μg/d
(10,000 IU/d)
Niacin
Acne vulgaris, rosacea,
necrobiosis lipoidica,
dermatitis herpetiformis,
bullous pemphigoid
Vitamin Keratinocyte growth and
D
differentiation, acne, psoriasis,
immune modulation
Men: 16 mg/d; women:
Adults: 35 mg/d
14 mg/d (pregnancy: 18 mg/d)
Children: 5 μg/d (200 IU/d);
adults: 5-15 μg/d
(200-600 IU/d)
Children: 50 μg/d
(2000 IU/d); adults:
250 μg/d (10,000 IU/d)
Vitamin Antioxidant, immune
E
modulation, reduction
of erythema
Adults: 15 mg/d (22.4 IU/d)
Adults: 1000 mg/d
(1500 IU/d)
Adverse effects
Hypocupremia, sideroblastic
anemia, myelopathy,
GI symptoms
Weakness, lethargy, anorexia,
GI symptoms, cirrhosis, cardiac
and renal failure
Constipation, dark stools,
nausea, caution in pregnancy
and liver disease
Caution in liver disease and
hemodialysis, pseudotumor
cerebri, skeletal changes,
teratogenic
Flushing, GI symptoms,
caution in liver disease,
gout, diabetes
Hypercalcemia, weakness,
polyuria, anorexia, GI
symptoms, metastatic
calcification, renal failure
Stomatitis, fatigue,
thrombophlebitis, GI symptoms
GI, gastrointestinal; RDA, recommended dietary allowance. UL, tolerable upper intake level; RAE, retinol activity equivalents.
rare autosomal-recessive disorder that presents with diarrhea,
alopecia, and a periorificial and acral dermatitis at the time of
weaning from breast milk.1 The defect in AE causes
inadequate absorption of zinc from the diet. Vesiculobullous,
eczematous, and psoriasiform skin lesions are typical
manifestations of the disorder.2 Acquired bullous AE can
present at any age secondary to zinc deficiency and has
similar clinical findings as AE.3
Necrolytic acral erythema may be associated with
hepatitis C virus infection.4 Recent case reports have
indicated the effective treatment of necrolytic acral erythema
with oral zinc supplementation. Patients were treated with
210 to 220 mg of oral zinc sulfate twice daily, with resolution
of plaques by 7 to 8 weeks.5-7
Zinc is also found in Nicomide (Sirius Laboratories, Inc.
Vernon Hills, IL), which contains 750 mg nicotinamide,
25 mg zinc oxide, 1.5 mg cupric oxide, and 500 μg folic
acid, and has been recommended for acne vulgaris and
rosacea.8,9 In addition, zinc has been used for treatment of
wounds, oral ulcers, and viral warts.10-12
According to the Institute of Medicine of the National
Academy of Sciences, the RDA for zinc is 8 mg/d for women
and 11 mg/d for men.13 The median intake of zinc from food
in the United States of America is 9 mg/d for women and 14
mg/d for men. The tolerable upper intake level (UL), defined
as the maximal daily intake unlikely to cause adverse health
effects, is 40 mg/d for adults.
Zinc was included in two studies, describing the effects of
antioxidant supplementation on skin cancer risk.14,15 The
Supplementation in Vitamins and Mineral Antioxidants
(SUVIMAX) study examined the effects of nutritional
doses of antioxidants on reducing cancer and ischemic
heart disease risk in the general population.14 The SUVIMAX study randomized 7876 women and 5141 men who
were supplemented with 120 mg of vitamin C, 30 mg of
vitamin E, 6 mg of β-carotene, 100 μg of selenium, and
20 mg of zinc daily, or a matching placebo, and monitored
for a median of 7.5 years. A fourfold higher risk of
melanoma was reported in the women supplemented with
antioxidants, but not in the men.
The results of the recent large, population-based prospective cohort study, the Vitamins and Lifestyle (VITAL) study,
were inconsistent with the SUVIMAX study.15 In the
VITAL study, 69,671 men and women reported their intake
of multivitamins and supplemental antioxidants during the
previous 10 years and were evaluated for melanoma risk
factors based on a questionnaire. The results showed no
increase in melanoma risk in men and women who took
vitamin C, vitamin E, β-carotene, selenium, and zinc
supplementation in doses similar to the SUVIMAX study.
The authors emphasized that the SUVIMAX study had
methodologic flaws that may have accounted for the
enhanced risk of melanoma in women associated with
antioxidant supplementation.
Deleterious side effects of nutritional supplements
Chronic toxic effects of zinc have been reported in
patients who consume well beyond the UL of 40 mg/d. Case
reports describe acne patients self-medicating with zinc at
doses ranging from 300 up to 1000 mg/d for 1 to 2 years.16-18
These patients were found to have hypocupremia, anemia,
sideroblastic anemia, neutropenia, and leukopenia.
The most likely mechanism for zinc-induced copper
deficiency can be explained by the competitive absorption
between zinc and copper in enterocytes of the small intestine.
Metallothionein is a protein that binds both zinc and copper,
with a higher affinity for copper. Excess zinc intake
stimulates the production of metallothionein. Enterocytes
are then shed, causing the excess zinc bound to metallothionein to be excreted. Copper, however, has a higher affinity for
metallothionein, so it displaces zinc and is subsequently
excreted, leading to hypocupremia. Copper as a ceruloplasmin is important for enzymatic reactions in red blood cells for
iron transport and utilization. Because iron is needed for
hemoglobin synthesis, copper deficiency would subsequently
cause anemia.
Several cases of zinc-induced copper deficiency have
been described. A patient diagnosed with AE was prescribed
a daily dose of 50 to 150 mg of zinc, but he took
approximately 600 mg/d to “control his symptoms.”
Hematologic monitoring and bone marrow biopsy revealed
neutropenia and anemia with vacuolization of granulocytic
and erythroid precursors and the presence of ringed
sideroblasts.2 Sideroblastic anemia and neutropenia developed in a 19-year-old woman with Hallervorden-Spatz
syndrome who took 50 mg of zinc twice daily for 5 years.19
In addition to hematologic syndromes, neurologic
adverse effects due to zinc excess have also been reported.
Myelopathy and demyelination has been associated with
zinc-induced copper deficiency. 20-22 A 52-year-old
woman presented with myelopathy with spastic paraparesis and dorsal column loss manifest by a generalized
lower motor neuron deficit with atrophy and paralysis of
muscles below the knee and weakness of the proximal legs
and distal hand muscles.22 The patient's serum copper was
less than 200 μg/L and her serum zinc was 2108 μg/L
(normal, 58-1060 μg/L), with a 24-hour urine zinc
excretion level of 19,290 μg/d (normal, 75-530 μg/d).
These levels suggested that she ingested or was exposed to
50 to 200 mg of zinc daily, an amount of zinc well above
the average daily intake of 10 to 15 mg. Therapy with 2.5
mg/d of oral copper improved the patient's anemia and
neutropenia. The neurologic symptoms persisted 1 year
later, however, along with enhanced levels of urine zinc
excretion. The authors concluded that the zinc-induced
copper deficiency was the probable cause of the patient's
neurologic abnormalities.
Another study reported four additional patients who
experienced numbness, weakness, spastic gait, ataxia, and
significant dorsal column deficits secondary to hyperzincemia and hypocupremia due to inadvertent ingestion of
denture cream.23
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Clinical signs and symptoms of acute zinc toxicity include
epigastric pain, diarrhea, nausea, vomiting, and dizziness.17
Among the other deleterious side effects are gastric erosion,
proconvulsant effects, tumor growth, and genitourinary
complications.17,24-27
Copper
Copper is a component of several vital metalloenzymes,
including tyrosinase, that function in melanin production.
Beyond melanin pigmentation, copper is also essential for
the production of mature collagen and elastin.28 Copper has a
stimulating effect on the proliferation of keratinocytes and
fibroblasts in monolayers, has a vital role in the activation of
key enzyme systems specific to tissue formation and repair,
and participates in the cross-linking and maturation of
collagen in healing wounds.29-31 In addition, copper has
antimicrobial and anti-inflammatory properties that have led
to the use of topical preparations to enhance wound healing.
The RDA for copper is 340 μg/d for young children and rises
to 900 μg/d for adults. The UL is 1000 μg/d in young
children and 10,000 μg/d for adults.13
Chronic copper toxicity primarily affects the liver and
may lead to hepatocellular necrosis as well as damage to
renal tubules, the brain, and other organs. Symptoms can
progress to coma, hepatic necrosis, vascular collapse, and
death.32 Acute copper poisoning causes gastrointestinal
symptoms, including abdominal pain, diarrhea, and vomiting, along with weakness, lethargy, and anorexia in the early
stages. Subsequent erosion of the epithelial lining of the
gastrointestinal tract, hepatocellular necrosis, and acute
tubular necrosis in the kidney may occur. In more severe
overdosage, progressive cardiac, liver, and renal failure,
encephalopathy, and ultimately, death may ensue. The
estimated lethal dose of copper in an untreated adult is
about 10 to 20 g.33
Several mechanisms have been proposed to explain
copper-induced cellular toxicity. The propensity of free
copper ions to participate in the formation of reactive
oxygen species is the most likely etiology.33 No correlation
was found between plasma copper concentrations and
prognosis.34 Although serum ceruloplasmin levels rise in
patients with acute copper toxicity due to increased hepatic
synthesis as an acute-phase reactant, the ceruloplasmin level
cannot be used to predict toxicity.35 Therefore, clinical
monitoring of the patient is vital when there is a suspicion of
copper overdosage.
Iron
Iron deficiency has been associated with hair loss as
in alopecia areata, androgenetic alopecia, and telogen
effluvium.36-38 Some patients with pruritus may have
abnormal iron or ferritin levels, or both, and restoration to
normal levels of serum ferritin with iron supplementation
may lead to improvement.39 The RDA for iron is 8 mg/d for
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men and postmenopausal women and 18 mg/d for premenopausal women.13 The UL is 45 mg/d of iron for adults.
Various complications associated with iron supplementation have been reported. Gastrointestinal side effects of
excess iron include constipation, dark stools, and nausea.
Oral liquid forms of iron supplementation may cause teeth
stains. Excess iron supplementation may also cause pregnant
women to have an increased risk for hypertension and
newborns with low birth weight.40 In a randomized, doubleblinded, placebo-controlled study, 370 pregnant women with
a hemoglobin level of 13.2 g/dL or higher during the second
trimester ingested one 50-mg tablet of elemental iron daily
and were compared with 357 controls. The study group had a
greater incidence of hypertension during pregnancy, and
newborns considered small for gestational age compared
with controls.40 Some have questioned this study and
suggested assessing hematic ferritin concentrations rather
than iron status using hemoglobin concentration.41
Another potential adverse effect of iron supplementation
is an increased risk of type 2 diabetes mellitus in women.42
Iron can also potentially interact with other minerals, such as
copper and zinc, resulting in decreased serum copper and
zinc levels.43
Finally, dermatologists should be cautious when prescribing iron supplementation for patients with liver diseases
and hemochromatosis. Iron accumulation can cause cirrhosis
of the liver and hepatocellular carcinoma in HFE-related
hemochromatosis.44 HFE-related hereditary hemochromatosis is an inherited iron overload disorder in which patients are
homozygous for the C282Y mutation in the HFE gene.45
These patients have increased levels of serum ferritin and
transferrin saturation and, therefore, iron supplementation
should be avoided.46
Vitamin supplements
Vitamin A
Dermatologic conditions for which vitamin A supplementation has been indicated include phrynoderma, pityriasis rubra pilaris, and wound healing. Phrynoderma is a form
of follicular hyperkeratosis associated with nutritional
deficiency. These lesions have been shown to resolve after
treatment with vitamin A.47-50 Before the introduction of
retinoids, vitamin A was used as therapy for pityriasis rubra
pilaris.51,52 The antioxidant effects of vitamin A have made it
efficacious as a topical application in the treatment of
photoaging, inflammatory dermatoses, acne vulgaris, pigmentation disorders, and wound healing in combination with
other antioxidants.53
The RDA for vitamin A is 900 μg retinol activity
equivalents (RAE)/d for men and 700 μg RAE/d for
women.13 The UL for preformed vitamin A is 3,000 μg/d
for adults. Acute hypervitaminosis A occurs at greater than
500,000 IU (100× RDA). Hepatitis and dialysis patients are
M.S. Driscoll et al.
at increased risk for vitamin A toxicity with doses as low as
25,000 IU/d.
Patients have been reported to overdose on vitamin A
supplements prescribed for dermatologic disorders in the
past, particularly in the early 1970s. Ready availability of
vitamins and publicity about vitamin A for the treatment and
prevention of acne vulgaris, aging skin, skin cancers, and
other dermatologic conditions has led to patients' selfmedicating and overdosing.54 In recent years, the dermatologist who prescribes systemic retinoids must also ask
patients about their vitamin intake. Avoidance of supplemental vitamin A during treatment with retinoids is
important to minimize the incidence and severity of
adverse effects.
Deleterious side effects associated with vitamin A toxicity
vary according to whether the patient ingested an extremely
high dose of vitamin A (N5× RDA) in a short period (2 to
3 weeks; ie, acute hypervitaminosis A), or continuously for a
longer period (months to years; ie, chronic hypervitaminosis
A). In acute hypervitaminosis A, infants may present with
bulging fontanels and adults may present with headaches
secondary to increased intracranial pressure. Nausea, vomiting, fever, vertigo, visual disorientation, and desquamation
of the skin may occur.55 Once excess vitamin A intake is
discontinued, levels return to normal and the symptoms, for
the most part, resolve.54
A variety of systemic and cutaneous manifestations are
associated with chronic hypervitaminosis A. Many of these
are well known to dermatologists who prescribe systemic
retinoids. Systemic adverse effects include anorexia, increased intracranial pressure, hepatomegaly (children),
pseudotumor cerebri, fatigue, menstrual disturbances in
women, and elevated blood lipid levels. In children,
hepatomegaly and bone changes associated with pain and
tenderness can occur.
Vitamin A has also been shown to cause anxiety and
depression in humans and animal models.54,55 One possible
mechanism for psychologic effects is the elevation in caspase3 activity in rat cerebral cortex reported after 28 days of
vitamin A supplementation at 1000 to 9000 IU/kg/d .56
Hypervitaminosis A has been observed to induce bone
resorption, hypercalcemia, bone abnormalities, low bone
density, osteoporosis, and increased fracture risk. 57-60
Serum levels of retinol greater than 86 μg/dL may increase
the risk of fracture.59 Chronic vitamin A intake may also
lead to hypercalcemia, which can also potentially lead
to osteoporosis.61
Another deleterious effect of hypervitaminosis A is
hepatotoxicity. The liver contains 50% to 80% of the body's
total vitamin A stores, and 90% of the total vitamin A stores
in the liver are transferred to and reside within hepatic stellate
cells.62 Vitamin A activation causes the hepatic stellate cells
to acquire a myofibroblast-like phenotype and produce a
large amount of extracellular matrix. An association has been
shown between daily vitamin A intake and severity of
perisinusoidal fibrosis.63
Deleterious side effects of nutritional supplements
Teratogenicity associated with systemic retinoids as well
as with hypervitaminosis A in pregnant women is well
established.64,65 Birth defects associated with hypervitaminosis A include an increased risk of abnormalities in a wide
range of organ systems, including musculoskeletal, craniofacial, central nervous system, thymic, cardiac, neural tube,
urogenital, and gastrointestinal.66
Some of the common cutaneous signs and symptoms of
chronic vitamin A toxicity include alopecia, desquamation,
erythema and exanthems of skin, brittle nails, cheilitis,
petechiae, and pruritus.54,55,67
Niacin
Nicotinic acid and nicotinamide are the two common
forms of the vitamin most often referred to as niacin.
Through a series of biochemical reactions in the mitochondria, niacin, nicotinamide, and tryptophan form nicotinamide
adenine dinucleotide (NAD) and NAD phosphate (NADP).
NAD and NADP are the active forms of niacin. As essential
components of oxidation-reduction reactions and hydrogen
transport, NAD and NADP are crucial in the synthesis and
metabolism of carbohydrates, fatty acids, and proteins.28 In
moderate to high doses (1 to 3 g/d) niacin is a wellestablished antihyperlipidemic agent, decreasing total and
low-density lipoprotein cholesterol.68 A deficiency of this
vitamin manifests clinically as pellagra, with the triad of
diarrhea, dermatitis, and dementia. The dermatitis manifests
as a photodistributed hyperpigmented skin eruption.28
Nicotinamide has several therapeutic uses in dermatology.
It has been used for acne vulgaris as an alternative to
antimicrobial agents because of its anti-inflammatory properties without promotion of antimicrobial resistance. One
study found topically applied 4% nicotinamide gel was
equivalent in efficacy to 1% clindamycin gel in patients with
moderate inflammatory acne vulgaris.69 Nicotinamide has
also been used systemically for the treatment of other
cutaneous disorders, including necrobiosis lipoidica and
dermatitis herpetiformis.70-72
The combination of nicotinamide (500 mg three times
daily) and tetracycline (500 mg four times daily) has been
promoted as an alternative to systemic steroids in the
treatment of bullous pemphigoid.73 Together these agents
may act by inhibiting the chemotaxis of eosinophils and
neutrophils in pemphigoid. Nicotinamide may also act by
electron scavenging, inhibiting the release of proteases from
granulocytes, and blocking degranulation of mast cells and
their release of histamine.70,73,74 The vasodilatory action of
nicotinamide has been used therapeutically in peripheral
vascular disorders such as Raynaud syndrome.75
The RDA for niacin is 16 mg/d for men and 14 mg/d for
women, rising to 18 mg/d during pregnancy and 17 mg/d
during lactation.76 These doses are far below the antihyperlipidemic doses of niacin and are not associated with
toxicity. The risks associated with a daily dose exceeding 1
gram of nicotinic acid may be tolerable when it is used as an
375
antihyperlipidemic drug under the care and monitoring of a
physician. Higher doses of nicotinic acid for the treatment
of dermatologic conditions should be reserved for recalcitrant disease, and patients must be cautioned against
unsupervised use.
The most common adverse effect of niacin is a flushing
reaction associated with the crystalline nicotinic acid. Mild
flushing can be experienced even when doses are as small as
10 mg/d. Despite the patient's concern about this reaction,
there are no serious sequelae from flushing.77 In pharmacologic doses (1 to 3 g/d), other common adverse effects of
niacin in addition to flushing include nausea, vomiting,
pruritus, urticaria, elevation in serum aminotransferases, and
constipation.78 A niacin-induced myopathy has also been
described.79 Caution should be used in patients with a history
of gout, because niacin is also known to elevate serum uric
acid concentration.80
Although most reported adverse reactions to niacin have
occurred with ingestion of 2 to 6 g/d,81 nicotinic acid toxicity
has been reported with less than 1 g/d.82 A long-acting vs
short-acting formula of niacin was studied in two groups of
participants, with each group starting at 500 mg/d. When the
niacin dose was raised every 6 weeks by about 500 mg, there
was no gastrointestinal or liver toxicity at doses below 1000
mg/d. The extent of the toxicity was minimal and mostly
gastrointestinal in the immediate-release group, whereas
mild liver enzyme elevation was noticed only in the slowrelease niacin group.83
Nicotinamide usually lacks the vasodilatory, gastrointestinal, hepatic, and hypolipemic effects described for nicotinic
acid and niacin. Flushing, gastrointestinal upset, pruritus,
and hepatotoxicity are not typically associated with nicotinamide administration at doses usually prescribed by
dermatologists (750 to 1500 mg/d). At higher doses,
however, adverse effects similar to nicotinic acid and niacin
may occur.
Vitamin D
The biologically active vitamin D metabolite, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), regulates calcium
and bone metabolism. Skin is the only site of vitamin D
photosynthesis, and plays a key role in attaining sufficient
vitamin D levels. In keratinocytes and other cell types, 1,25
(OH)2D3 regulates growth and differentiation.84 Consequently, vitamin D analogues have been introduced for the
treatment of the hyperproliferative skin diseases, such as
psoriasis.85 Recent identification of sebocytes as 1,25(OH)
2D3-responsive target cells suggests a potential role for
vitamin D analogues in the treatment of acne.86 Additional
emerging functions of vitamin D analogues include
immune modulation, and protection against cancer and
autoimmune and infectious diseases.84 Evidence is accumulating that the vitamin D pathway may play a
chemoprotective role in melanoma.87 Epidemiologic studies of the association of vitamin D and melanoma risk have
376
shown conflicting results, however.88-90 In the recent
VITAL study, the risk of melanoma was not affected by
Vitamin D supplementation. 91
As a fat-soluble vitamin, vitamin D can be toxic in excess
doses. Vitamin D intoxication is characterized by hypercalcemia and the resultant loss of appetite, nausea, weight loss,
weakness, polyuria, polydipsia, mental depression, and
calcific keratitis. Metastatic calcification can be seen in the
skin as calcinosis cutis. Generalized calcinosis can ensue.28
Renal calcification can lead to kidney failure and death. The
intake at which the dose of vitamin D becomes toxic is not
clear. Previous data suggested that the UL for vitamin D is
50 μg/d (2000 IU/d) for healthy adults, children 1 to
18 years, and pregnant and lactating women92; however,
newer data indicates that higher doses may be safe.
An analysis of the vitamin D intoxication literature and
the recent controlled dosing studies show that essentially no
cases of confirmed intoxication have been reported at serum
25(OH)D levels below 500 nmol/L.93 Correspondingly, the
oral intake needed to produce such levels are in excess of
20,000 IU/d (and usually above 50,000 IU/d) in otherwise
healthy adults.94 These findings have led some to select
10,000 IU/d as the tolerable UL.93 A higher intake could
probably be defended, but 10,000 IU/d is substantially
more than is apparently needed for any recognized efficacy
end point.94 It is noteworthy that one minimum erythema
dose of total body solar exposure, such as might be achieved
in a few minutes on a summer day, produces a vitamin D
input in the range of 10,000 to 20,000 IU, depending upon
skin type.95,96 Despite such cutaneous synthesis, there has
never been a case of vitamin D intoxication reported as a
result of sun exposure.96 Patients with systemic sarcoidosis,
mycobacterial infections, and those treated with thiazide
diuretics are reported to have increased sensitivity to
excessive vitamin D.97-99
Vitamin E
Vitamin E is a family of eight antioxidants derived from
tocopherols and tocotrienols. The main form of vitamin E in
human tissues is α-tocopherol, which functions as the main
lipid-soluble, membrane-preserving antioxidant. Additional
functions of vitamin E include immune modulation,
inhibition of platelet aggregation, and vasodilatation.100
Vitamin E is a commonly used supplement, taken daily,
usually as 400 IU α-tocopherol, by 22% of American adults
aged older than 55 years.
In human skin, vitamin E is the predominant physiologic
barrier antioxidant.101 Vitamin E and synergistic antioxidants such as vitamin C are commonly added to sunscreens
to enhance photoprotection.102 Several studies have demonstrated a reduction in erythema, edema, and sunburn cell
formation with topical vitamin E application before ultraviolet light exposure.103
Pure topical vitamin E has an emollient effect on the skin and
is thought to enhance barrier function.104 Topical vitamin E
M.S. Driscoll et al.
preparations have been promoted to prevent scar formation,
presumably due to inhibition of collagen synthesis and
reduction of fibroblast proliferation and inflammation.105,106
In vivo studies of topical vitamin E, however, have yielded
conflicting results with respect to the prevention and treatment
of scars.104,106,107 Use of topical vitamin E for the enhancement
of wound healing is supported by evidence from studies on
diabetic mouse models.108,109 A significant improvement of
melasma and hyperpigmentation secondary to contact dermatitis was reported with a combination of topical vitamins E and
C in a double-blinded controlled study. The combination of
these topical antioxidants was superior to treatment with a
single vitamin.110
Although numerous topical skin care products claim to
contain vitamin E, the formulations can include active
vitamin E as well as several esters and other derivatives in
various concentrations and vehicles. Dose-response studies
defining the optimal dosage of vitamin E are lacking. One
recent study found that topical formulations containing 0.1%
to 1% α-tocopherol are likely to be effective for enhancing
protection against lipid peroxidation in the stratum corneum.111 Vitamin E esters, such as vitamin E acetate, are
commonly present in over-the-counter topicals for improved
shelf life, but their photoprotective effects appear to be less
pronounced than α-tocopherol.112 Vitamin E esters act as a
prodrug and are converted to the active α-tocopherol upon
penetration into the stratum corneum. The extent to which
this conversion takes place is controversial.113
Clinical side effects have been described with the use
topicals containing vitamin E, including local and generalized contact dermatitis, contact urticaria, and eruptions
resembling erythema multiforme.112 In 1992, approximately
1000 cases of allergic contact dermatitis were attributed to αtocopherol linoleate in a Swiss cosmetic line.114 Therefore, it
would be prudent to avoid topical vitamin E in patients who
have recently undergone dermabrasion or chemical peels.
Because vitamin E is now ubiquitous in over-the-counter
topical preparations, and use is widespread, it is fortunate
that the adverse effects of topical vitamin E are minimal.
There are a few reported uses of systemic vitamin E in
dermatology. Systemic vitamin E for melasma has shown
some benefit, although studies are limited to combination
therapies. A recent double-blinded, placebo-controlled trial
of oral procyanidin with vitamins A, C, and E reported this
regimen was safe and effective for the treatment of melasma
among Filipino women. 115 Small trials and case reports
support the use of systemic vitamin E supplementation in
the treatment of yellow-nail syndrome, vibration disease,
epidermolysis bullosa, cancer prevention, claudication,
cutaneous ulcers, and wound healing.116 Oral vitamin E
has also been shown to be an effective therapeutic adjunct
for atopic dermatitis. In a placebo-controlled study of
96 atopic dermatitis patients, oral supplementation with 400
IU/d for 8 months resulted in a 62% decrease in serum
immunoglobulin E and near-remission of atopic dermatitis
in the treatment group.117
Deleterious side effects of nutritional supplements
Evidence for the contribution of oxidative stress in the
pathogenesis of melanoma and nonmelanoma skin cancer
has led to speculation that antioxidants, such as vitamin E,
may have a role in the prevention and treatment of
malignancy.118 Despite these and other promising results,
well-designed controlled trials are sparse, and further
research is needed to clarify the role of vitamin E in
dermatologic diseases.
The RDA of oral vitamin E is 15 mg/d with a UL of
1000 mg/d, although recent literature suggests that this UL
may be too high.119 An important change in the paradigm
since the early trials of antioxidant supplements is that highdose oral antioxidants can no longer be assumed to be safe.
This was an unexpected outcome in the Alpha-Tocopherol
Beta-Carotene Trial, and subsequent trials have confirmed
this finding.119,120 A meta-analysis of 19 randomized
controlled trials involving more than 135,000 participants
showed that high-dose oral supplementation with vitamin E
(N400 IU/d for N1 year) resulted in a small but statistically
significant increase in all-cause mortality.121 In 10 of the 19
studies analyzed, vitamin E was included with other
nutritional supplements, thereby limiting conclusions
concerning the effects of this nutrient alone. Subsequent
studies, however, have consistently shown that large doses
of vitamin E should be prescribed with caution. 122,123
Concomitant use of vitamin E and anticoagulants can
increase the risk of bleeding complications.124 Excess intake
of vitamin E supplements can result in thrombophlebitis,
pulmonary embolism, hypertension, fatigue, gastrointestinal
effects, and gynecomastia. Dermatologic manifestations of
hypervitaminosis E include stomatitis, cheilitis, urticaria, and
impaired wound healing.28 The plasma concentration of αtocopherol (normal, 6-14 μg/mL) can be measured to
confirm excess levels of vitamin E in the blood.
Conclusions
Supplements of minerals and vitamins may enhance
health, improve some cutaneous diseases, and result in a
sense of well-being. They are often believed to be benign
because they are readily available without prescription;
however, deleterious side effects have been reported
with these supplements. It is prudent for physicians to
be aware of the supplements' recommended dietary
allowance, upper limits, and acute and chronic manifestations of excess intake.
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