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Acta Dermatovenerol Croat
2012;20(3):181-186
CASE REPORT
Progressive Pigmented Purpuric Dermatitis and
Alopecia Areata as Unusual Skin Manifestations in
Recognizing Hereditary Hemochromatosis
Vesna Sredoja Tišma1, Stela Bulimbašić2, Morana Jaganjac3,
Marica Stjepandić4, Miljana Larma4
Polyclinic Department of Dermatology and Venereology, 2Department of Pathology,
Dubrava University Hospital; 3Divison of Molecular Medicine, Laboratory for Oxidative Stress, Ruđer Bošković Institute, Zagreb; 4Department of Internal Medicine, Pakrac
General Hospital, Pakrac, Croatia
1
Corresponding author:
Vesna Sredoja Tišma, MD, MSc
Polyclinic Department of Dermatology
and Venereology
Dubrava University Hospital
Avenija Gojka Šuška 6
HR-10000 Zagreb
Croatia
[email protected]
Received: September 2, 2011
Accepted: May 25, 2012
SUMMARY Hereditary hemochromatosis (HHC) is a common genetic disorder of iron overload, caused by mutations in the HFE gene. If untreated,
abnormal accumulation of iron may lead to organ damage and premature death. Significant changes in the symptomatology of HHC have been
observed in recent years, and its full clinical expression is rarely seen. The
disorder presents a large phenotypic heterogeneity. We report a case
of newly identified HHC in a 56-year-old man presenting as pigmented
purpuric dermatitis and alopecia areata affecting the beard, accompanied with elevated liver enzymes and elevated serum ferritin level on
screening chemistry panels. Histopathologic examination of skin biopsy
revealed changes consistent with the diagnosis of progressive pigmented purpuric dermatitis. The diagnosis of HHC was confirmed by genetic
testing, with compound heterozygosity for the C282Y/H63D mutation.
He had no signs of cardiomyopathy, gonadal insufficiency, arthropathy,
or glucose intolerance. The diagnosis of HHC in our patient was based on
clinical findings, laboratory findings, histopathologic examination of skin
biopsy and genetic tests. Early diagnosis and therapeutic phlebotomy
are very important in the prevention of all known complications of HHC,
and are the major determinants of survival. Pigmented purpuric dermatitis and alopecia areata may be unusual early clinical skin presentations of
HHC. The relation between inheritance of one or more hemochromatosis
genes and susceptibility for progressive pigmented purpuric dermatitis
or alopecia areata needs further investigation.
KEYWORDS: hemochromatosis, iron overload, pigmentation disorders,
alopecia areata, HFE mutation
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INTRODUCTION
The term hemochromatosis was first used in 1889
by von Recklinghausen, who believed that the disease resulted from decomposition of the blood and
deposition of hemosiderin in various tissues, structures, and organs (1).
Hereditary hemochromatosis (HHC) is an adultonset disorder that represents an error of iron metabolism characterized by inappropriately high iron
absorption resulting in progressive iron overload (2).
The first clinical symptoms appear generally about
age 40 years in males and later in females, approximately age 50 years, because of physiological iron
loss through menstruation and pregnancy. HHC is
the most common cause of severe iron overload (3).
The involved organs are the liver, heart, pancreas, pituitary, joints, and skin (4). Excess iron is dangerous
because it produces free radical formation (5). The
presence of free iron in biologic systems can lead to
the rapid formation of damaging reactive oxygen
metabolites, such as the hydroxyl radical and the superoxide radical. These can produce DNA cleavage,
impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and
fibrosis (6). Additionally, excessive iron metabolism is
associated with numerous diseases (7,8).
HHC is the most common inherited liver disease
in white persons and the most common autosomal
recessive genetic disorder in Europe (prevalence
1:400) (9). A crucial candidate gene for HHC has been
reported by Feder et al. (10). It was cloned on chromosome 6, at position 6p21.3. This gene, HFE, encodes
the HFE protein, which is a transmembrane glycoprotein implied in modulation of iron uptake. Two
most frequent mutations in the HFE gene have been
described (10). The first, C282Y, comprises the substitution of tyrosine for cysteine at amino acid position
282. In the second, H63D, aspartic acid is substituted
for histidine in position 63. C282Y homozygosity or
compound C282Y/H63D heterozygosity is found in
most patients with HHC (10).
Pigmentation of the skin is present in about 90%
of patients with HHC at the time of diagnosis, but
in some individuals the color changes are minimal
(11). Usually, sun exposed areas of the body are most
prone and take on grayish or brownish-bronze hue
(12). Hyperpigmentation of mucous membranes
and conjunctival membranes occur in 15% to 20%
of patients (13). Bronze diabetes is found in more advanced cases.
HHC also results in hair loss, koilonychia, ichthyosiform alterations and skin atrophy (14,15). Thinning
or loss of hair is another classical sign, whereas cuta-
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neous atrophy and ichthyosis-like changes are rarely
reported (15). There can be a loss of axillary and pubic
hairs because of hepatotesticular insufficiency (13).
We report a case of newly identified HHC in a
56-year-old man presenting as pigmented purpuric
dermatitis and alopecia areata affecting the beard,
accompanied with abnormal liver function tests and
abnormal iron studies on screening chemistry panels.
CASE REPORT
A 56-year-old man, a worker in a chemical industry, presented to the outpatient clinic of the Polyclinic Department of Dermatology and Venereology,
Dubrava University Hospital, with irregularly shaped
orange-brown, speckled, cayenne pepper-like discoloration and mild phlebectasia on the legs (Fig. 1).
The irregular discolorations on the lower limbs were
present for two years with spreading to the knees and
upper legs in the last two months. The cutaneous lesions were asymptomatic.
Additionally, the patient’s dermatologic appearance included one smooth normal-colored alopecic
patch on the beard, around two centimeters in size.
The patient’s family history for skin diseases was not
significant. He had a medical history of hypertension,
for which he had been taking lisinopril.
We performed lesional skin biopsy from the upper
leg, under clinical suspicion of progressive pigmented
purpuric dermatitis. Histopathologic examination of
skin biopsy on routine hematoxylin and eosin (H&E)
stains showed mild to moderate perivascular lymphocytic infiltrate and rare extravasated red blood
cells in the upper dermis, while the overlying epidermis showed just mild and focal spongiotic changes
(Fig. 2). Additionally performed Prussian blue stain
highlighted rare dermal siderophages.
Further investigations included complete blood
cell count, liver function tests and coagulation screening to exclude other possible causes of purpura, and
routine screening for most common underlying diseases in association with alopecia areata.
Laboratory studies showed elevation of serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum gamma-glutamyltransferase
(GGT), and increased iron parameters. Serum transferrin saturation was greater than 45 percent and serum
ferritin level was 982.4 μg/L (normal range: 30-400
μg/L). On evaluating these findings at the third visit,
the patient said that he had known about elevated
liver enzymes for several years. Ten years before, he
had been diagnosed at another hospital with toxic
ACTA DERMATOVENEROLOGICA CROATICA
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Unusual manifestations of hereditary hemochromatosis
Acta Dermatovenerol Croat
2012;20(3):181-186
Figure 1. Irregularly shaped orange-brown, speckled, cayenne pepper-like discoloration and mild phlebectasia on
the legs of a 56-year-old patient with hereditary hemochromatosis.
hepatitis of unknown etiology. He was not controlled
by gastroenterologist for the last ten years. He denied
any alcohol intake, any history of jaundice, blood
transfusions, intravenous drug use, or family history
of liver disease. Complete blood cell count, coagulogram, renal function tests, serum glucose level, urine
analyses, thyroid profile and antistreptolysin O titer
(AST-O) were within the normal limits. Hepatitis A,
hepatitis B and hepatitis C serologic markers were
negative.
The features of iron overload in the skin and abnormal iron studies on screening chemistry panels
accompanied with elevated liver enzymes were indicative of the diagnosis of HHC. After consulting
an internal medicine specialist, genetic testing for
HHC was performed. Genetic testing revealed that
he was compound heterozygous for the C282Y and
H63D mutations of the HFE gene. He was referred to
gastroenterologist for additional tests and diagnosis.
Abdominal ultrasound showed hyperechogenic and
inhomogeneous structure of the liver. The patient underwent liver biopsy. The material was sent for histopathologic examination, on the basis of which further
procedures were to be chosen.
The gastroenterologist suggested cardiologist
consultation and ultrasound of the heart to exclude or
confirm any of cardiac manifestations of HHC. Electrocardiography and echocardiographic evaluation were
normal. He had no signs of cardiomyopathy. Furthermore, there were no symptoms of gonadal insufficiency, arthropathy or glucose intolerance in our patient.
ACTA DERMATOVENEROLOGICA CROATICA
Figure 2. Moderate perivascular lymphocytic infiltrate with extravasated red blood cells in the upper
dermis and focal mild spongiosis of the overlying epidermis (HE; X400).
The diagnosis of HHC in our patient was based on
clinical findings, laboratory findings (elevated liver
enzymes, elevated serum ferritin levels, elevated serum iron and high transferrin saturation), histopathologic examination of skin biopsy (the features of iron
overload in the skin) and genetic tests (compound
heterozygosity for the C282Y and H63D mutations of
the HFE gene).
He underwent therapeutic phlebotomy immediately after the diagnosis had been established. In the
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induction phase, phlebotomy was performed with
removal of 500 mL of blood every two weeks. In the
maintenance phase, phlebotomy will be performed
less frequently (the interval between the procedures
will be determined by the level of ferritin). The patient
was advised not to consume foods that contain large
concentrations of bioavailable iron, such as red meats
and organ meats, alcohol, vitamin C, and iron supplements including multivitamins with iron.
On the alopecic patch of the beard, high potency
corticosteroid creams were applied for several weeks.
Regrowth was seen 6 weeks after therapy initiation.
Dermatological treatment of skin changes on the
legs included topical weak potency corticosteroid
creams and emollients. We also recommended him
to avoid sunlight exposure that can exacerbate the
condition.
DISCUSSION
Many skin disorders are associated with a change
in skin color. Following a systematic diagnostic procedure is essential (16). Information should be obtained
from the patient on the family history, onset and development of pigmentary changes. Patients should
also be asked about any related impact on overall
health as well as any pathology involving other organs. A medication history should also be taken and
should include occupational contacts (16).
Cutaneous changes may also be the first clue
that the patient has liver disease. If we can recognize
these manifestations early, we are able to promptly
diagnose and treat the underlying liver disease (17).
Although not considered a consistent sign of HHC by
some authors (18,19), abnormal pigmentation is generally recognized to be very frequent by most authors
(20-22). Hyperpigmentation of the skin is, on the one
hand, caused by increased melanin in the epidermis
and in dermal melanophages, and on the other hand
by iron deposits in the deeper dermis (16). However,
the mechanism is not fully understood.
Tsuji found that hyperpigmentation of the skin
occurred after iron injections in hairless mice. This hyperpigmentation was accompanied by hemosiderin
accumulation in the skin. Stronger pigmentation of
the facial skin rather than the dorsal skin corresponded with elevated iron accumulation in the facial part
of the skin. The study suggests that the brownish discoloration of the skin in HHC may be dependent to
some degree on hemosiderin accumulation. Hemosiderin is supposed to increase activation of melanocytes (23). On the other hand, in 1978, Smith et al. (24)
found normal levels of immunoreactive beta-MSH
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(beta-melanocyte-stimulating hormone) in patients
with HHC and concluded that elevation of beta-MSH
played no role in the pathogenesis of hyperpigmentation.
Structures of the skin are injured by iron deposits
and increased synthesis of melanin in melanocytes.
The rapid tanning with minimal sun exposure reflects
the synergistic effects of iron accumulation and sun
exposure, but is the result of melanin, rather than the
iron itself (17,24). Hyperpigmentation is often enhanced during exacerbations of the disease (17,24).
The cutaneous hyperpigmentation in patients with
HHC should be differentiated from drug-induced hyperpigmentation and actinic reticuloid.
The diagnosis of hemochromatosis is based on
clinical features of the disease accompanied with
biochemical abnormalities of iron metabolism and
genotypic investigation. Laboratory studies show
high ferritin levels, high transferrin saturation and
elevated levels of iron. Measuring serum iron has
no value in the diagnosis, but measuring transferrin
saturation is necessary. Transferrin saturation corresponds to the ratio of serum iron and total iron-binding capacity (TIBC). High transferrin saturation is the
earliest evidence of hemochromatosis. High ferritin
level may be an indicator of iron overload, especially
if accompanied with elevated liver enzymes. Liver
biopsy and histological evaluation of tissue iron accumulation was considered the criterion standard for
the diagnosis of HHC until testing of the HFE gene
was introduced (25).
Genetic tests for the C282Y and H63D mutations
are widely available. A single C282Y mutation in the
HFE gene is present in a homozygous state in 85%90% of patients with hereditary hemochromatosis.
Less than 10% of patients are compound heterozygous for the C282Y and H63D. The YY genotype is
highly penetrant and most commonly associated
with phenotypic expression of the disease, while
double heterozygous genotype (CY/HD) shows very
low penetration.
The treatment of choice is phlebotomy (26-28).
Although organ function can improve immediately
with phlebotomy, skin hyperpigmentation does not
immediately resolve (12,23).
HHC is a multisystem disease with relentless course.
Early diagnosis and therapeutic phlebotomy to maintain low normal body stores is crucial and can prevent
all known complications of HHC. If untreated, HHC may
lead to death from cirrhosis, diabetes, malignant hepatoma, or cardiac disease (26,27). Adequate phlebotomy treatment is the major determinant of survival, and
it markedly improves prognosis (29,30).
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Sredoja Tišma et al.
Unusual manifestations of hereditary hemochromatosis
Since the condition is inherited in an autosomalrecessive pattern, family members of patients should
consider being screened (31). The high prevalence of
the disorder, the opportunity to detect phenotypic
expression, to intervene and prevent subsequent disease justifies screening.
If the patient develops a cutaneous lesion, the
question is whether it is a sign of dermatosis or of
another underlying disease (32). HHC is one of the
many metabolic diseases, often presenting with specific cutaneous signs. However, the symptomatology
of HHC has changed in recent years, and its full clinical expression is seen only in the minority of patients
(33). The disorder presents large phenotypic heterogeneity, and its expression can be influenced by environmental factors (34).
The overlap of C282Y mutations and other skin
conditions has been reported in the literature (35,36).
Sporadic porphyria cutanea tarda is a skin disease associated with hepatic siderosis. Some homozygotes
for the C282Y mutation present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with hemochromatosis (36).
The most widely accepted hypothesis is that alopecia areata is a T-cell-mediated autoimmune condition that is most likely to occur in genetically predisposed individuals (37). Unusual localization of alopecia areata in our patient did not fit into the classic loss
of axillary and pubic hairs, usually associated with
HHC. The possible mechanism includes direct toxicity
of iron to hair metabolism because hair participates
in its excretion and contains increased amounts of
iron in HHC (12).
The pigmented purpuric dermatoses are a group
of chronic diseases of mostly unknown etiology that
have a very distinctive clinical appearance. They are
characterized by extravasation of erythrocytes in the
skin with marked hemosiderin deposition. Rare familial cases of pigmented purpuric dermatitis have been
reported in the literature, implying a genetic cause in
the minority of patients (38). Chronic venous disease
is associated with local iron overload in the affected
legs. In case of our patient, who had mild phlebectasia on the legs, venous hypertension might also be an
important cofactor that appears to influence disease
presentation. Zamboni et al. (35) report that hemochromatosis C282Y gene mutation could increase the
risk of chronic venous leg ulceration.
CONCLUSION
Pigmented purpuric dermatitis and alopecia areata affecting the beard, accompanied with elevated
ACTA DERMATOVENEROLOGICA CROATICA
Acta Dermatovenerol Croat
2012;20(3):181-186
liver enzymes and elevated iron levels in our patient,
are unusual early clinical skin presentation of HHC.
We found no such case in the literature. Careful clinical and diagnostic evaluation of these two skin conditions may be very important in recognizing such
a serious disease. All physicians are encouraged to
further evaluate patients with cutaneous signs, abnormal iron studies and abnormal liver function tests
on screening chemistry panels. Early detection and
treatment of this common iron overload can prevent
development of any organ damage, end stage complications of cirrhosis, diabetes, hepatocellular cancer, and premature death. Therefore, follow-up and
interdisciplinary approach is highly recommended.
The relation between inheritance of one or more
hemochromatosis genes and susceptibility for progressive pigmented purpuric dermatitis or alopecia
areata needs further investigation.
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