Iron In Skin Disease
ironjustice
clinicopathological correlations.
Englander, Laura; Friedman, Adam
Journal of Drugs in Dermatology
Jun 1, 2010
Abstract
Iron levels are tightly regulated in the body to maintain homeostasis.
When homeostatic mechanisms malfunction, excess iron accumulation in
the body has deleterious effects with important health consequences
worldwide. Different degrees of iron accumulation complicate
pathological conditions such as hereditary hemochromatosis (HH),
porphyria cutanea tarda (PCT), venous stasis ulcers, diabetic wounds,
skin cancer and sunburn. Despite the known association of systemic
iron excess with cutaneous findings, little is known about the
mechanism by which a surplus of systemic iron affects the skin. This
paper explores the link between excess iron and dermatologic findings
in the conditions listed above in order to illustrate potential
mechanisms by which iron overload exacerbates the cutaneous
manifestations associated with each disease.
Introduction
Iron overload associated with tissue injury, or hemochromatosis, has
important health consequences worldwide. (1) Different degrees of iron
accumulation complicate a variety of pathological conditions such as
hereditary hemochromatosis (HH), porphyria cutanea tarda (PCT), venous
stasis ulcers, diabetic wounds, skin cancer and sunburn. Despite the
known association of systemic iron excess with cutaneous findings,
little is known about the mechanism by which a surplus of systemic
iron affects the skin. Furthermore, the assumption that iron overload
is the culprit of skin findings in various diseases has yet to been
proven with certainty. The question remains; with the exception of
pigmentary changes, are the skin changes in different instances of
iron overload caused directly by the local effect of iron or are they
caused indirectly by iron's toxicity on internal organs that in some
way contribute to skin pathology?
This paper explores the link between excess iron and dermatologic
findings by reviewing (1) normal iron metabolism, (2) dermatologic
diseases associated with iron excess and (3) the potential mechanisms
by which iron overload may contribute and exacerbate the cutaneous
manifestations associated with each disease.
Brief Review of Normal Iron Metabolism
Normal Iron Distribution in the Body
A 70 kg adult male has an average iron content of about 4 g. Seventy-
five to 80 percent of iron is contained within hemoglobin, myoglobin
and enzymes. (1) The remaining 20-25 percent is in the storage forms,
ferritin and hemosiderin, located in skeletal muscle, macrophages of
the spleen and bone marrow and parenchymal cells of the liver. (1) A
small amount of iron (~3 mg) circulates in the plasma bound to the
iron transport protein transferrin. (1)
Iron Homeostasis
Dietary iron absorption, iron recycling and mobilization of stored
iron are tightly controlled to maintain iron homeostasis. (2)
Enterocytes regulate iron absorption locally by hypoxia inducible
factor (HIF) signaling and iron regulatory proteins (IRPs). (2) The
liver, however, is the central regulator of iron homeostasis,
systemically modulating iron levels by means of a central iron-
regulatory hormone, hepcidin. (2) In response to iron overload or
inflammation, hepcidin controls the rate of intestinal iron absorption
as well as reduces iron mobilization from stores by binding and down-
regulating ferroportin, a cellular iron exporter. (2), (3) Hepcidin
expression is regulated in the liver by various proteins, including
hemochromatosis gene (HFE), the HH protein. (2)
Dermatologic Diseases Associated With Iron Overload
Hereditary Hemochromotosis (HH)
HH refers to a group of autosomal recessive inherited disorders of
iron metabolism that lead to tissue iron overload. HH is mainly
attributed to a mutation in the hereditary hemochromatosis protein,
HFE--a protein involved in hepatic hepcidin expression. (3)
HFE-associated hemochromatoses generally occur as a result of a single
nucleotide substitution in amino acid 282 (C282Y) or in amino acid 63
(H63D) that disrupts proper folding of the HFE protein. (2), (3) This
disruption leads to a defect in intestinal iron absorption. (4) C282Y
homozygosity is found in most patients with hereditary hemochromatosis
with a prevalence of one in 200 in European populations, (3) however
clinical penetrance of this genotype is incomplete, (3) suggesting
that other inherited or acquired factors in addition to iron surplus
are necessary to develop iron-induced pathology.
Excess deposition of iron in the parenchymal tissues of several organs
(liver, heart, pancreas, joints, endocrine glands) can lead to
considerable morbidity including liver cirrhosis, arthritis and
diabetes mellitus, (6) but the mechanism by which this occurs is
poorly understood. (3) There are several postulated mechanisms of iron-
induced liver injury including increased lysosomal and mitochondrial
fragility mediated by iron-induced lipid peroxidation, (7) direct
interference of collagen biosynthesis or a combination of the above.
(1)
Various skin changes are observed in HH. Bluish-gray or bronze
discoloration of the skin, particularly in sun-exposed areas, is an
early sign of hemochromatosis and affects up to 90 percent of
patients. (4) Hyperpigmentation of mucous membranes and conjunctival
membranes also occurs in 15-20 percent of patients. (5) The bronze
coloration is thought to be secondary to the surplus of cutaneous iron
deposits that damage vital skin structures and initiate a process that
culminates in enhanced melanin production by melanocytes. (4) Exposure
to UV light likely has a synergistic effect with iron, accelerating
the process of hyperpigmentation. The bluish-gray reflects iron
deposition in the basal layers of the epidermis. (1)
Ichthyosiform changes in which the skin manifests a dry scaly
appearance, loss of body hair and koilonychia are also observed in
hemochromotosis. (4) That phlebotomy treatment to lower serum iron
levels can reverse the cutaneous manifestations and minimize the risk
of organ failure (6) indicates that iron is a causal factor in the
organ level damage present in this disorder.
Porphyria Cutanea Tarda (PCT)
PCT is a disorder of the fifth enzyme of the heme biosynthetic
pathway, uroporphyrinogen decarboxylase (URO-D). The subsequent
decrease in URO-D activity results in a build-up of circulating
porphyrins, in particular uroporphyrin. Porphyrins in the skin
interact with light to create reactive oxygen species that account for
the main cutaneous symptoms of the disease: fragility, erosions,
bullae, milia and scars on sun-exposed skin. (8)
There are two main types of PCT, sporadic (type 1) and familial (type
2). Sporadic PCT is likely caused by combination of acquired and
genetic factors, such as an inhibitor of URO-D generated in liver
cells that inactivates normal enzyme activity in the liver. Familial
PCT is an autosomal dominant trait, caused by a genetic mutation in
the URO-D gene located at chromosome 1p34 that inactivates normal URO-
D enzyme activity in all cells. (9) Sporadic PCT accounts for 80
percent of PCT cases, whereas familial PCT accounts for the remaining
20 percent. (8), (9) The penetrance of PCT is dependent on
precipitating factors that include alcohol, estrogens, polyhalogenated
aromatic hydrocarbons (PAH), hepatotrophic viruses and iron. (8), (9)
Iron plays a significant role in the pathogenesis of PCT At least 80
percent of patients with PCT have some degree of hepatic
hemosiderosis, ranging from mild to severe, (8), (10) and phlebotomy
to decrease iron stores improves clinical outcome. (3) Conversely,
administration of iron accelerates disease and produces relapse in
phlebotomy-induced remissions.
A prevailing theory hypothesizes that excess iron exerts it damaging
effect by increasing production of peroxides and free radicals that
convert uroporphyringen to porphyrin in the cell, thereby blocking URO-
D function either by direct modification of URO-D or by the production
of oxidized metabolites that indirectly inhibit URO-D. (8), (11) More
recent research has confirmed the hypothesis that iron induced
oxidized metabolites inhibit URO-D. Uroporphomethane, a competitive
inhibitor of URO-D, was isolated from liver extracts in mice with PCT
and demonstrated its inhibition of the URO-D enzyme. The oxidation
reactions of uropophyrinogen to the inhibitor uroporphomethane is iron
dependent, supporting the concept that iron is a co-factor in PCT.
(12)
Studies have also confirmed the relationship between hereditary
hemochromatosis and PCT, further implicating iron in its pathogenesis.
(8), (9), (13) In the United Kingdom, the Netherlands, the U.S. and
Australia, the C282Y mutation was found in approximately 44 percent of
patients with sporadic PCT (8) Studies have shown that homozygosity
for the C282Y mutation is associated with earlier onset of skin
lesions in both familial and sporadic PCT. (10) The precipitating
effect of HH on PCT is likely secondary to the accumulation of iron.
(8)
Hepatitis C also precipitates symptoms of PCT. (9) Much like iron, the
role of hepatitis C in the pathogenesis of PCT is unknown, but the
most likely hypothesis is that hepatitis C triggers an increase in
hepatocellular iron, which as mentioned above, increases oxidative
stress in liver cells, reducing URO-D activity, and increasing
hepatocyte production of a URO-D inhibitor.
Chronic Venous Disease (CVD)
Chronic venous disease (CVD) is the most common vascular disorder
affecting 20-50 percent of the population. (14) In 10 percent of
patients, CVD progresses to chronic venous leg ulcerations. However,
the extent of venous hemodynamic damage is insufficient to explain the
progression of CVD to skin lesions. Further study of the causative
factors of venous ulceration revealed that CVD leads to local iron
overload. Corroborating that finding, individuals with HFE mutations
were also found to have an increased risk of venous ulcer development.
(14), (15)
One explanation for local iron overload in limbs affected with CVD is
the extravasation of erythrocytes that enter the interstitial space
under conditions of chronic venous stasis. (14), (15) It is also
possible that hypoxic tissue leads to up-regulation of iron, by
interfering with HIF regulatory mechanisms (see Iron Homeostasis).
Local ferric ions are important inducers of reactive oxygen species.
(15) Therefore, some hypothesize that the mechanism of tissue injury
is excessive oxidative stress from iron deposition. This causes
release of free radicals and subsequent activation of the proteolytic
hyperactivity of matrix matalloproteinases or down-regulation of
tissue inhibitors of metalloproteinases. (14), (15)
Simka et al. offer an alternative mechanism by which iron leads to
venous leg ulceration that implicates T-cell proliferation and
apoptosis as the main mechanism of tissue injury. T cells are
susceptible to many factors that determine their proliferation or
degradation. Among these regulators are interferon-gamma (IFN-[squire
box]) and nitric oxide (NO), which interact to control unrestrained
proliferation of T cells and macrophages. Both of these regulators can
be influenced by local concentration of iron. Great amounts of
intracellular iron induce the refractoriness of IFN-[squire box]
mediated T-cell apoptosis (15) and inhibit macrophage expression of
inducible nitric oxide synthase (iNOS). This blunting of IFN-[squire
box] and iNOS, likely disturbs the NO-dependent negative feedback loop
between macrophages and T cells resulting in cells which are resistant
to NO-mediated apoptosis. Therefore, the deleterious role of iron in
the development of venous leg ulcers may be due to proliferation of T
cells that mediate injury to the skin.
Some patients with a high concentration of iron do not have
ulceration. This suggests ulcer development is a multifactorial
process, and more likely to happen among patients with a genetic
susceptibility. A positive C282Y genetic test demonstrated elevated
specificity in predicting ulcer development. (14) Therefore, HFE
mutation appears to increase the risk of chronic venous leg ulceration
in patients affected by primary CVD and this risk was shown to be more
significant than any other predictive parameter for venous ulcer
reported to date. (14) This finding suggests new prospects for
prevention and treatment.
Diabetic Wounds
Diabetic wounds constitute a significant health burden, with slow or
non-healing diabetic foot ulcers representing the leading cause of non-
traumatic lower limb amputation. (16) Iron has been implicated in the
pathogenesis of chronic ulcers in diabetic patients. Vascular
endothelial growth factor (VEGF) is produced by normal fibroblasts in
response to tissue injury and is necessary for the formation of blood
vessels that reconnect wounded tissue to the bloodstream. Decreased
hypoxia-induced VEGF expression in diabetes results from impaired
transactivation of hypoxia inducible factor-1 (HIF-1), which mediates
the cellular response to hypoxia. (16) Covalent modification of p300
by carbonyl metabolite methylglyoxal prevents HIF-1a/p300 association
leading to the defect in HIF-1 transactivation.
Use of the iron chelator deferoxamine mesylate (DFO) corrected HIF-1
activity in hyperglycemic culture. This restoration of activity
implicates iron as a key factor in the failure of diabetic wounds to
heal properly. It was proposed that DFO corrected iron-catalyzed
reactive oxygen species generation, thereby curtailing methylglyoxal
formation.
In vivo, topical application of DFO also normalized healing of
humanized diabetic wounds in mice. (16) Mice treated with the drug
healed in 10 days faster and produced almost threefold more vascular
endothelial growth factor than untreated mice.
Skin Cancer
It is surprising that iron, a molecule indispensible to DNA synthesis,
should play a role in a major pathologic process such as cancer.
Bhasin et al. tested the effect of iron overload on tumor promoters
(various free radical generating peroxides and hyper-oxides) and
demonstrated that iron-overload enhanced stage-1 and stage-2 tumor
promoters to initiate cutaneous tumors. (17), (18) Bhasin et al.
concluded that the iron-overload has a corroborative effect with the
tumor promoters in augmenting oxidative stress.
To further test the dependence of iron on skin tumor development,
Bhasin et al. demonstrated that a low iron diet in mice had a
protective effect, reducing the potency of known tumor promoter, 12-O-
tetradecanoylphorbol-13-acetate (TPA). (17) This promoter was
previously shown to accelerate cutaneous tumor appearance as well as
increase cutaneous tumor burden 2.5 fold in iron overloaded mice.
(17), (19)
Sunburn
While it is well understood that sunlight contributes to skin damage,
it is not well known that iron plays a role in this injurious process.
Exposure to UVA radiation leads to a harmful increases in "free" iron
that augment UVA-induced oxidative damage to lysosomal, mitochondrial
and plasma membranes with resultant cell membrane damage and necrotic
cell death. (20) The source of the iron following UVA-irradiation is
from ferritin, released following proteolytic degradation by lysosomal
proteases that leak from damaged lysosomes in the cytosol. (20), (21)
Iron is particularly geared for cellular targets such as cell
membranes because it can undergo redox cycling generating toxic
oxidants such as hydroxyl radical and lipid-derived alkyl and peroxyl
radicals. (22)
Under normal circumstances the iron regulatory protein-1 (IRP-1)
closely controls the ferritin bound pool, preventing iron from acting
as a catalyst in reactions between reactive oxygen species and
biomolecules. (21) Pathological conditions, however, such as exposure
to UVA radiation, alter iron homeostasis leading to oxidative cell
injury. (20)
If iron contributes to oxidative cell damage than conversely drugs
that reduce iron should blunt the affect of iron-mediated damage. In
fact, iron chelators have been shown to decrease the intracellular
labile iron pool (LIP) and subsequent necrotic cell death of human
skin fibroblasts upon exposure to physiologically relevant doses of
UVA. (20) The strong iron chelator, DFO, was capable of suppressing
both cell damage and iron release provoked by UVA, (20) clearly
demonstrating iron's essential role in promoting pro-oxidant
conditions in cells. (22)
Conclusion
Maintenance of iron homeostasis is an elegant process controlled by an
interplay of key molecules, namely HIF, IRP's and hepcidin. These
regulatory proteins react to conditions of low or excess iron to
maintain proper concentration of iron in the body. Injury to
regulatory molecules of iron balance, or organs that contribute to
iron homeostasis initiate a harmful cascade altering physiologic
levels of iron that promote oxidative damage and release of free
radicals.
The oxidative capacity of iron plays a key role in the exacerbation of
many skin disorders. Its upregulation in HH and PCT triggers symptoms
by promoting hepatic injury or contributing to enzyme dysfunction
thereby eliciting or exacerbating symptoms, respectively. The
evolution of chronic venous stasis to ulcer development or failure of
diabetic wounds to heal is also negatively impacted by excess iron.
Improper iron excess also augments tumorigenesis and damage already
inflicted by UVA irradiation so that increased release of free
radicals and reactive oxygen species become amplified in exercising
their injurious effects on cells.
Clarification of the mechanisms of cell injury in the above cutaneous
diseases and the knowledge that iron contributes to the pathogenesis
of many disease processes will allow more targeted treatment and
prevention of organ damage and symptom development. Many studies are
exploring the correction of iron levels as a means of restoring normal
physiology. Despite the exciting prospects of these studies there is a
need for further elucidation of how iron plays a role in the complex
breakdown of disease.
References
(1.) Bacon BR, Britton RS. Hepatic injury in chronic iron overload.
Role of lipid peroxidation. Chem Biol Interact. 1989;70:183-226.
(2.) Zhang A, Enns CA. Molecular mechanisms of normal iron
homeostasis. Hematology Am Soc Hematol Educ Program. 2009;1:207-214.
(3.) Wallace DF, Subramaniam VN. Co-factors in liver disease: The role
of HFE-related hereditary hemochromatosis and iron. Biochim Bio-
physActa. 2009;1790:663-670.
(4.) Hazin R, Abu-Rajab Tamimi Tl, Abuzetum JY, Zein NN. Recognizing
and treating cutaneous signs of liver disease. Clev Clin J Med.
2009;76:599-606.
(5.) Kostler E, Porst H, Wollina U. Cutaneous manifestations of
metabolic diseases: Uncommon presentations. Clin Dermatol.
2005;23:457-64.
(6.) Utzschneider KM, Kowdly KV. Hereditary hemochromatosis and
diabetes mellitus: Implications for clinical practice. Nat Rev
Endocrinol. 2010;6:26-33.
(7.) Ceccarelli D, Trenti T Muscatello U, Masini A. Possible
involvement of mitochondrial calcium transport in causing cell injury
in experimental hepatic chronic iron overload. Bioelectrochem
Bioenerg. 1990;23:325-336.
(8.) Bleasel NR, Varigos GA. Porphyria cutanea tarda. Au J Dermatol.
2000;41:197-208.
(9.) Bygum A, Christiansen L, Petersen NE, et al. Familial and
sporadic porphyria cutanea tarda: Clinical, biochemical and genetic
features with emphasis on iron status. Acta Derm Venereol.
2003;83:115-120.
(10.) Brady JJ, Jackson HA, Roberts AG, et al. Co-inheritance of
mutations in the uroporphyrinogen decarboxylase and hemochromatosis
genes accelerated the onset of porphyria cutanea tarda. J Invest
Dermatol. 2000;115:868-874.
(11.) Mogl MT, Pascher A, Presser SJ, et al. An unhappy triad:
Hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-
A case report. World J Gastroenterol. 2007;13:1998-2001.
(12.) Phillips JD, Bergonia HA, Reilly CA, et al. A porphomethene
inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea
tarda. Proc Natl Acad Sci. 2007;104:5079-5084.
(13.) Roberts AG, Whatley SD, Morgan RR, et al. Increased frequency of
the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea
tarda. Lancet. 1997;349:321-23.
(14.) Zamboni P Tognazzo S, Izzo M, et al. Hemochromatosis C282Y gene
mutation increases the risk of venous leg ulceration. J Vasc Surg.
2005;42:309-314.
(15.) Simka M, Rybak Z. Hypothetical molecular mechanism by which
local iron overload facilitates the development of venous leg ulcers
and multiple sclerosis lesions. Med Hypothesis. 2008;71:293-297
(16.) Thangarajah H, Vial IN, Grogan RH. HIF-1[squire box] dysfunction
in diabetes. Cell Cycle. 2010;9:75-79.
(17.) Bhasin G, Kauser H, Athar M. Iron augments stage-l and stage-ll
tumor promotion in murine skin. Cancer Lett. 2002;183:113-122.
(18.) Bhasin G, Kauser H, Athar M. Iron-induced Oxidative Stress
Augments UVB-mediated tumor promotion. J Nutr. 2004;3546S-3547S.
(19.) Rezazadeh H, Julka PK, Athar M. Iron Overload Augments 7,12-
Dimethyl-benz(a)anthracene-lnitiated and 12-O-Tetradecanoylphorbol-13-
Acetate-Promoted Skin Tumrigenesis. Skin Pharmacol Appl Skin Physiol.
1998;11:98-103.
(20.) Yiakouvaki A, Savovic J, Al-Qenaei A, et al. Caged-lron
chelators a novel approach towards protecting skin cells against UVA-
Induced necrotic cell death. J Invest Dermatol. 2006;126:2287-2295.
(21.) Pourzand C, Watkin RD, Brown JE, Tyrrell RM. Ultraviolet-A
radiation induces immediate release of iron in human primary skin
fibroblasts: The role of ferritin. Proc Natl Acad Sci.
1999;96:6751-6756.
(22.) Zhong JL, Yiakouvaki A, Holley P, et al. Susceptibility of skin
cells to UVA-induced necrotic cell death reflects the intracellular
level of labile iron. J Invest Dermatol. 2004;123:771-780.
News, Views and Reviews provides focused updates, topic reviews and
editorials concerning the latest developments in dermatologic
therapy.
Laura Englander BS (a) and Adam Friedman MD (b)
(a) Albert Einstein College of Medicine,
(b) Department of Medicine, Division of Dermatology, Bronx, NY
Journal of Drugs in Dermatology, Inc.
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
