We present a 27-year-old female Caucasian patient, who initially presented with extensive fragility and blistering of mainly the dorsal side of both hands. Histology and urine porphyrin analysis confirmed the diagnosis of porphyria cutanea tarda. Internal screening for underlying disease revealed C282Y mutation-associated primary hemochromatosis, a hereditary iron-overload syndrome that may cause toxicity of a variety of organs. Hemochromatosis and porphyria cutanea tarda are pathogenetically linked as iron interferes with heme synthesis pathway. Patient was successfully treated with phlebotomy and low-dose hydroxychloroquine

Bovenschen, H Jorn

Vissers, Wynand H P M

English

PubMed

H Bovenschen

Wynand Vissers

Crossref

Primary hemochromatosis presented by porphyria cutanea tarda: a case report

Item does not contain fulltextWe present a 27-year-old female Caucasian patient, who initially presented with extensive fragility and blistering of mainly the dorsal side of both hands. Histology and urine porphyrin analysis confirmed the diagnosis of porphyria cutanea tarda. Internal screening for underlying disease revealed C282Y mutation-associated primary hemochromatosis, a hereditary iron-overload syndrome that may cause toxicity of a variety of organs. Hemochromatosis and porphyria cutanea tarda are pathogenetically linked as iron interferes with heme synthesis pathway. Patient was successfully treated with phlebotomy and low-dose hydroxychloroquine

Bovenschen, H.J.

Vissers, W.H.P.M.

Radboud Repository

Primary hemochromatosis presented by porphyria cutanea tarda: a case report.

Springer - Publisher Connector

Case report
Open Access
Primary hemochromatosis presented by porphyria cutanea tarda:
a case report
H Jorn Bovenschen* and Wynand H P M Vissers
Address: Department of Dermatology, Radboud University Nijmegen Medical Center, René Descartes dreef 1, P.O Box 9101, 6525 GL, Nijmegen,
The Netherlands
Email: HJB* - H.Bovenschen@derma.umcn.nl; WHPMV - w.vissers@derma.umcn.nl
*Corresponding author
Received: 15 April 2009 Accepted: 12 June 2009 Published: 17 June 2009
Cases Journal 2009, 2:7246 doi: 10.4076/1757-1626-2-7246
This article is available from: http://casesjournal.com/casesjournal/article/view/7246
© 2009 Bovenschen and Vissers; licensee Cases Network Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
We present a 27-year-old female Caucasian patient, who initially presented with extensive fragility
and blistering of mainly the dorsal side of both hands. Histology and urine porphyrin analysis
confirmed the diagnosis of porphyria cutanea tarda. Internal screening for underlying disease revealed
C282Y mutation-associated primary hemochromatosis, a hereditary iron-overload syndrome that
may cause toxicity of a variety of organs. Hemochromatosis and porphyria cutanea tarda are
pathogenetically linked as iron interferes with heme synthesis pathway. Patient was successfully
treated with phlebotomy and low-dose hydroxychloroquine.
Introduction
Primary hemochromatosis is a hereditary iron-overload
syndrome with enhanced intestinal absorption of iron
and potentially noxious iron in the peripheral tissue.
Two separate gene mutations in the hemochromatosis
gene (C282Y and H63D) have recently been identified
that are responsible for the disease [1]. However, other
inherited, acquired or environmental triggering factors
are necessary to develop pathology. Secondary hemo-
chromatosis may be due to alcohol use, excessive iron
and vitamin C intake, oral contraceptives and blood
transfusions [2,3]. Early recognition of hemochromato-
sis is essential for preventing destructive organ damage.
The initial signs and symptoms are quite diverse, as
multiple organs may be affected. We present a patient
with sunlight-aggravated fragile skin on the hands and
wrists with bullae formation, diagnosed as porphyria
cutanea tarda (PCT), which was the first sign of under-
lying hemochromatosis.
Case presentation
A 27-year-old female Caucasian patient presented with
suddenly appearing blisters and fragility of the extensor
sides of both hands since May 2007. The lesions were
progressive and not directly sensitive to light. Patient was
otherwise healthy and used only an oral contraceptive:
Diane-35. There was no atopy. There was no skin disease
or similar skin symptoms in family members. There was
only modest alcohol use and no smoking. Dermatological
examination revealed multiple active blisters, erosions,
erythematous macules, dyspigmentation, atrophic scarring
and milia on the extensor sides of both hands (Figure 1).
Histopathology of lesional and perilesional skin showed a
partial normal epidermis with bullae formation at the
Page 1 of 4
(page number not for citation purposes)
basal membrane. Herein, fibrin deposition and granulo-
cytes were observed in addition to a perivascular infiltrate
and a vasculopathic reaction pattern deep in the dermis
(Figure 2). Blood analysis revealed: CRP 34 (n < 10), ASAT
91 (n < 40), ALAT 141 (n < 45), Fe 41 (10-25) and ferritin
783 (6-80). Differential diagnosis at this time included
PCT, epidermolysis bullosa acquisita, bullous pemphi-
goid, perniones, drug eruption. Urine porphyrin screening
showed a raised uroporphyrin (1642 nmol/mmol creati-
nin (n < 2.5)) and heptaporphyrins, in combination with
relative normal other porphyrins. There was normal serum
protoporphyrin. With the selective abnormal laboratory
parameters, normal autoimmune laboratory analysis,
negative hepatitis and HIV serology and normal liver
ultrasonography, suspicion had been raised of a primary
hemochromatosis. Gene analysis ultimately showed a
homozygous C282Y missense mutation of the hemochro-
matosis (HFE) gene, in the absence of a H63D mutation.
The final diagnosis was porphyria cutanea tarda due to
primary hemochromatosis and the course was as follows.
Patient was instructed to stop using alcohol, which she
already sparingly used. She was advised to stop using her
contraceptive medication as well. The patient was repeti-
tively treated with phlebotomy which resulted in a
decrease in ferritin levels (783 to 100) in three months
time. Adjuvant low-dose hydroxychloroquine (200 mg
daily) was started afterwards to prevent the possibility of a
relapse. Four months later, the porphyria symptoms were
still in remission. However, she rapidly developed three
ulcers on the lateral side of the left lower leg in 5 days
varying from 6 mm to 2 cm in diameter (Figure 1).
Histology was consistent with ecthyma and not with
vasculitis or venous ulceration (Figure 2). Bacterial
cultures revealed massive growth of beta-hemolytic
Streptococci Group A and Staphylococcus aureus. With a
diagnosis of ecthyma patient was treated with local
mupirocin (Bactroban®) ointment and compression
(Tubigrips®). Clearance of the infection was reached in
10 days.
Discussion
In our patient, fragile skin and bullae formation on the
dorsal side of the hands related to PCT is the presenting
symptom of underlying primary hemochromatosis. Hemo-
chromatosis is themost common inherited liver disease and
the most common autosomal recessive genetic disorder [4].
From epidemiological point of view there is a clearcut
association between PCT and hemochromatosis [5]. The
question rises how porphyria, hemochromatosis and/or the
hemolytic streptococcal infection can be linked together.
Most patients with heriditary hemochromatosis have a
mutation in one of the mentioned HFE genes located on
Figure 1. Skin abnormalities in our patient. Erosive
erythematous patches, bullae and milia on the dorsal side of
both hands (1, 2, 4). Ulcerations on the lower left leg caused
by beta-hemolytic streptococci group A (3).
Figure 2. Histopathology of the skin lesions. Histopathology (hematoxylin-eosin staining) of active PCT lesions on the dorsal
aspect of the hands (A), milia formation (B) and the non-specific ecthyma (C) developing in our patient. (Magnification 100x)
Page 2 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:7246 http://casesjournal.com/casesjournal/article/view/7246
chromosome 6 [6]. Hemochromatosis interferes with the
transferrin receptor and causes a clear decrease in the
affinity with which the receptor binds transferrin. This
interaction also may modulate cellular iron uptake and
decrease ferritin levels. When a mutant or nonfunctional
variant of the HFE gene is present, ferritin levels are not
under influence of a normal and functional HFE gene,
which leads to enhanced accumulation of iron in
peripheral tissues [7].
The term “porphyria cutanea tarda” originally described
the dermatological manifestations of various chronic
porphyrias. Its usage now is usually restricted to disorders
associated with a deficiency of uroporphyrinogen decar-
boxylase (UROD). It is UROD that is responsible for an
essential step in the heme synthesis pathway: the conver-
sion of uroporhyrinogen III into coproporphyrinogen III
[7]. This is reflected in Figure 3.
Iron overload and in particular the cellular modifications
of the iron status secondary to hemochromatosis muta-
tions affect the quantity and activity of UROD [8]. Iron, by
catalyzing the formation of reactive oxygen species, can
enhance uroporphyrin formation by increasing the rate at
which uroporphyrinogen is oxidized to uroporphyrin.
Iron may also act indirectly to inhibit UROD activity by
enhancing the formation of non-porphyrin products of
porphyrinogen oxidation that are themselves direct
inhibitors of the enzyme. Finally, iron can act to increase
urophorphyrin production by inducing δ-aminolevulinic
acid synthase, the precursor to uroporphyrinogen, inside
the cell [4]. With the deficiency in UROD activity heme
precursor uroporphyrinogen accumulates in the skin. This
molecule is highly photosensitive, causing blistering and
fragility on the UV-exposed skin and subsequent comple-
ment activation and histamine release. Since a consider-
able amount of iron is required to produce symptoms, this
type of PCT most often starts in the third decade of life.
Secondary causes contributing to the disease, such as
alcohol use, excessive iron and vitamin C intake, oral
contraceptives and blood transfusions, are often observed
and should also be eliminated. From epidemiological
point of view PCT and hemochromatosis are also heavily
linked together.
The ecthyma caused by group A beta-hemolytic strepto-
cocci our patient developed could not be explained by
either hemochromatosis or PCT. One report highlights
the increased risk of venous leg ulceration in patients with
the C282Y mutation [9]. However, given the rapid
development of three ulcers, the bacterial cultures that
revealed beta-hemolytic streptococci group A and a rapid
response to local treatment, a venous origin of the leg
ulcerations in this young patient is not likely.
Treatment of PCT is based on recurrent phlebotomies and
low-dose (hydroxy)chloroquine. Our patient had an
excellent response to these treatments [2,4,6]. However,
there is evidence that patients that are homozygotes for the
C282Y mutation suboptimally respond to (hydroxy)
chloroquine therapy in contrast to their heterozygote
and wild-type counterparts [6].
Conclusion
In conclusion, PCT may be the presenting symptom of
underlying primary hemochromatosis. Urine analysis is
necessary to confirm the diagnosis of PCT. DNA analysis
may reveal HFE mutations, where iron and ferritin values
in peripheral blood are relevant screening parameters for
hemochromatosis activity. Treatment consists of removing
probable secondary disease aggravating factors, photo
protection, recurrent phlebotomies and low-dose
hydroxychloroquine.
List of abbreviations
PCT, Porphyria cutanea tarda; HFE, hemochromatosis;
URDO, Uroporphyrinogen decarboxylase.
Consent
Written informed consent was obtained from the patient
for publication of this case report and accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Figure 3. Heme synthesis, enzymes and porphyrias.
Page 3 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:7246 http://casesjournal.com/casesjournal/article/view/7246
Authors’ contributions
Both JB and WV had direct patient contact and were
directly responsible for all the work carried out for this
paper. JB wrote the paper, WV approved and changed the
paper.
References
1. McCune CA, Ravine D, Worwood M, Jackson HA, Evans HM,
Hutton D: Screening for hereditary haemochromatosis within
families and beyond. Lancet 2003, 362:1897-1898.
2. De Geus HR, Dees A: Sporadic porphyria cutanea tarda due to
haemochromatosis. Neth J Med 2006, 64:307-309.
3. Bulaj ZJ, Phillips JD, Ajioka RS, Franklin MR, Griffen LM, Guinee DJ,
Edwards CQ, Kushner JP: Hemochromatosis genes and other
factors contributing to the pathogenesis of porphyria cutanea
tarda. Blood 2000, 95:1565-1571.
4. Lambrecht RW, Bonkovsky HL: Hemochromatosis and por-
phyria. Semin Gastrointest Dis 2002, 13:109-119.
5. Frank J, Poblete-Gutiérrez P, Weiskirchen R, Gressner O, Merk HF,
Lammert F: Hemochromatosis gene sequence deviations in
German patients with porphyria cutanea tarda. Physiol Res
2006, 55:S75-S83.
6. Toll A, Celis R, Ozalla MD, Ercilla MG, Herrero C: Haemochro-
matosis gene mutations and response to chloroquine in
sporadic porphyria cutanea tarda. Acta Derm Venereol 2006,
86:279-280.
7. Moore MR: The biochemistry of heme synthesis in porphyria
and in the porphyrinurias. Clin Dermatol 1998, 16:203-223.
8. Sampietro M, Fiorelli G, Fargion S: Iron overload in porphyria
cutanea tarda. Haematologica 1999, 84:248-253.
9. Zamboni P, Tognazzo S, Izzo M, Pancaldi F, Scapoli GL, Liboni A,
Gemmati D: Hemochromatosis C282Y gene mutation
increases the risk of venous leg ulceration. J Vasc Surg 2005,
42:309-314.
Page 4 of 4
(page number not for citation purposes)
Cases Journal 2009, 2:7246 http://casesjournal.com/casesjournal/article/view/7246
Do you have a case to share?
Submit your case report today
• Rapid peer review
• Fast publication
• PubMed indexing
• Inclusion in Cases Database
Any patient, any case, can teach us
something
www.casesnetwork.com


NARCIS 

file:///data/remote/core/dit/data/Springer-OA/pdf/c6b/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjQwNzYvMTc1Ny0xNjI2LTItNzI0Ni5wZGY=.pdf

Primary hemochromatosis presented by porphyria cutanea tarda: a case report

Abstract

Similar works

Full text

Available Versions

Crossref

Radboud Repository

Springer - Publisher Connector

NARCIS

Springer - Publisher Connector