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406Indian Journal of Dermatology 2015; 60(4)
CASE REPORT
Abstract
D-penicillamine interferes with elastin and collagen metabolism and produces several
cutaneous and multi-systemic side-effects. We present two cases of Wilson’s disease who on
long-term penicillamine therapy developed drug-induced degenerative dermopathy manifesting
as skin fragility over pressure sites and cutis laxa-like changes.
Key Words: Degenerative dermopathy, penicillamine, chronic therapy
D-penicillamine Induced Degenerative Dermopathy
Sujay Khandpur, Naresh Jain, Shweta Singla1, Priti Chatterjee2, Madhuri Behari1
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DOI: 10.4103/0019‑5154.160498
Introduction
Penicillamine is a heavy metal chelator, used to treat
several heavy metal toxicities including lead, mercury,
and copper. It is an important therapeutic modality
for several diseases including scleroderma, Wilson’s
disease, rheumatoid arthritis, and cystinuria.[1] Common
side effects of D-penicillamine include gastrointestinal
upset, skin rash, stomatitis, dysgeusia, cytopenia,
proteinuria due to membranous nephritis, and
uncommonly, myasthenic syndrome.[2,3] Prolonged
penicillamine therapy can also produce a spectrum
of skin changes.[4] We present two cases with severe
degenerative dermopathy due to prolonged penicillamine
therapy.
Case Reports
Case 1
A 15-year-old girl presented to the Neurology department
of our hospital with behavioral problems, irritability,
progressive academic decline and generalized dystonia
also affecting speech. She had corneal Kaiser Fleschner
(KF) ring. Serum copper was 54 µg/dl (normal –
70-140 µg/dl), serum ceruloplasmin was 0.002 OD/
unit (normal – 0.2-0.5 OD/unit), 24 h urinary copper
was 87 µg/day (normal – 20-50 µg/day) and MRI brain
showed T2 hyperintensities in bilateral globus pallidus
and substantia nigra. Liver function test was normal.
She was diagnosed to have Wilson’s disease and started
on d-penicillamine, initially 250 mg/day, which was
titrated over months to 3 gm/day along with zinc
acetate. Dystonia improved partially and the patient was
able to take orally. After two and half years of starting
D-penicillamine, she developed tense vesico-bullous
lesions filled with clear and hemorrhagic fluid over
trauma- prone sites that ruptured in 7-10 days and healed
with scarring in 1-2 months. She also complained of
increased laxity of skin over these areas as well as all skin
folds. On examination, the patient had severe generalized
dystonia involving face, jaw, neck, trunk and limbs, with
rigidity, and the deep tendon jerks were difficult to elicit.
Dermatological examination revealed vesicobullous lesions
and erosions symmetrically distributed over shoulders,
elbows, hands, knee, and ankles. There was also evidence
of scarring, hyperpigmentation and milia over these
sites [Figure 1a and b]. There was increased skin laxity
in these areas and over body folds (neck, groin, cubital
and popliteal fossae). Tzanck smear made from a blister
was negative for acantholytic cells or inflammatory
cells. Skin biopsy from a lesion over the hand revealed
decreased, thickened and fragmented elastic fibers,
highlighted on vVG staining (compared to control–normal
skin sample) suggestive of elastolysis [Figure 2a and b].
Patient was also evaluated for other side effects
of D-penicillamine. Urine was normal without any
proteinuria (0.02 gm/24 hour urine). CT chest incidentally
From the Departments of
Dermatology and Venereology,
1Neurology, 2Pathology, All India
Institute of Medical Sciences,
New Delhi, India
Address for correspondence:
Dr. Sujay Khandpur,
Department of Dermatology and
Venereology, All India Institute of
Medical Sciences,
New Delhi, India.
E-mail: sujay_khandpur@yahoo.
com
What was known?
Prolonged d-penicillamine administration can produce skin fragility.
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Khandpur, et al.: Penicillamine induced dermopathy
407 Indian Journal of Dermatology 2015; 60(4)
revealed bilateral reticulonodular shadows suggesting
early diffuse interstitial fibrosis. She had microcytic
hypochromic anemia secondary to iron deficiency anemia
with serum iron 11 ng/nl (normal – 50-150 ug/dl).
Recent 24 hour urine copper was < 5 µg/day and serum
copper was 31 µg/dl. Echocardiography was normal.
Since the copper stores had significantly reduced, it was
planned to decrease the dose of D-penicillamine, continue
zinc acetate and keep the patient on follow up. After
decreasing the dose to 1.5 gm her skin lesions improved
dramatically (70-80%) over a period of 4-6 months.
Case 2
A 29-year-old man, presented to neurology department
with gradually progressive stiffness of all four limbs,
action tremors in the upper limbs and history of
frequent falls. He had history of jaundice at the age
of 14 years which was conservatively managed. On
examination, there was no evidence of anemia, jaundice
or any sign of hepatic failure but he had inappropriate
laughter. His Mini Mental status Examination was 17/24
and KF ring was present. There was generalized dystonia
and rigidity of all the limbs and trunk and difficulty in
writing because of severe action tremor. Investigations
showed serum copper as 25 µg/dl, serum ceruloplasmin
of 0.058 OD/unit, and 24 h urinary copper of 71 µg/
day. He was diagnosed as Wilson’s disease and started on
zinc acetate and D-penicillamine, which was gradually
increased from 1 to 3 gm/day. There was only partial
improvement in the rigidity and dystonia. After 4 years
of penicillamine therapy, he developed vesicobullous
lesions over trauma-prone area that healed with milia
formation and scarring [Figure 3]. Skin biopsy revealed
fragmented elastic fibers in the reticular dermis. These
features were consistent with penicillamine-induced skin
fragility. Investigations toward systemic side-effects of
D-penicillamine revealed no abnormality. The dose of
penicillamine was decreased to 1 gm/day, skin lesions
improved significantly after 6 months.
In both cases, this adverse-event to penicillamine yielded
a score of 9 on the Naranjo adverse drug reaction (ADR)
probability scale (definite ADR if score ≥ 9). It was a
‘certain ADR’ according to WHO-UMC causality category
and a level 4 ADR on the Hardwig’s Severity Assessment
scale.[5-7]
Figure 1a: Erythematous to hyperpigmented atrophic plaques with milia over dorsa
of hands in case 1
Figure 1b: Erythematous scarred plaques topped by milia over shins, feet and knees
in Case 1
Figure 2a: Photomicrograph from site of skin fragility showing multiple short,
fragmented elastic fibers (black color) in the dermis (vVG stain ×40)
Figure 2b: Photomicrograph from healthy skin (control) showing normal elastic
fibres (black colour) between collagen bundles (vVG stain ×40)
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Khandpur, et al.: Penicillamine induced dermopathy
408Indian Journal of Dermatology 2015; 60(4)
Discussion
Our cases were striking examples of penicillamine-induced
degenerative dermopathy, first described by Sternleib and
Scheinberg in 1964 in a patient of Wilson’s disease.[4]
Both cases developed drug-induced skin fragility over
bony prominences and pressure sites manifesting as
hemorrhagic blisters, scarring, and milia formation while
one case also had associated cutis laxa-like changes.
Long term administration of D-penicillamine has been
shown to produce a dermopathy in 20 to 33% of
patients in addition to hematological, immunological,
and other organ system involvement.[2] The incidence
of side effects ranges from 30 to 60% and the rate
of drug withdrawal due to side effects may go upto
30%.[2,3] Cutaneous side effects can be classified into four
distinct groups; acute sensitivity reactions (e.g. acute
urticaria), a toxic-metabolic effect on connective tissue
or degenerative dermopathy (penicillamine-induced skin
fragility, cutis laxa, elastosis perforans serpiginosa-EPS,
anetoderma, pseudoxanthoma elasticum-PXE),
autoimmune skin manifestations (e.g. pemphigus,
lupus erythematosus and dermatomyositis) and those
due to unknown mechanisms (e.g. lichen planus,
hypertrichosis).[4] At high doses, penicillamine interferes
with elastin and collagen metabolism which manifests
as: Cutis laxa, anetoderma, PXE, ecchymosis, and
lymphangiectasis.[8-10] D-penicillamine binds directly to
the aldehyde precursors which are essential for elastin
and collagen cross-linking and inhibits copper-dependent
enzyme lysyl oxidase, that catalyses the cross-linking
reaction.[11] It, however, has no effect on mature,
insoluble collagen, therefore explaining the long period
before dermopathy sets in. The precise amount of
penicillamine required to produce elastic fiber damage is
unknown, but it has been estimated that a minimum of
1 g daily for more than 5 years is necessary to induce
these changes.[12] However, a study by Dalziel et al.,
Figure 3: Hemorrhagic vesicles and scarring over bony prominences with overlying
milia in upper limb in Case 2
showed that elastic fiber damage occurred in rheumatoid
arthritis patients receiving low-dose penicillamine
therapy (0.25 to 1 g daily), even after as little as 1 year
of treatment.[13]
Our cases developed skin fragility and cutis laxa-like
changes after 3-4 years of treatment. They did not have
features of EPS, which presents as pink to red keratotic
annular plaques on the neck, axillae and ante-cubital
fossae, PXE which manifests as small yellowish papules
coalescing to form plaques over neck, or any systemic
side effects of D-penicillamine, which occurs due to
damage to elastic fibers in various organs including
upper and lower respiratory tract, joint capsules and
blood vessels.[12,13]
The characteristic histopathology of penicillamine-induced
elastic fiber damage is that of thickened elastic bundles
with prominent lateral protrusions giving the so-called
‘bramble-bush’ appearance with or without calcification
of elastic fibers, and sometimes granulomatous
inflammation. Transepidermal elimination of elastic
fibers may occur that manifests clinically as EPS.[14] In
both our cases vVG stain on skin biopsies demonstrated
thickened and fragmented elastic fibers.
Improvement in dermatologic manifestations requires
stoppage or reducing the dose of D-penicillamine.[4] These
patients can be started on zinc acetate and trientine
(a chelating compound for the removal of excess copper
from the body) for Wilson’s disease since no skin
changes occur with these agents. As with most cases
of penicillamine-induced degenerative dermopathy, our
patients’ lesions improved significantly on reduction
of penicillamine dose. It can be envisaged that early
intervention will help minimize further widespread
penicillamine-induced elastolysis.
In conclusion, prolonged use of high-dose penicillamine
is associated with elastic tissue damage that can
manifest in the skin as cutaneous fragility, milia and
purpura, as illustrated in these cases. Early recognition
of penicillamine-induced skin changes is important
since these abnormalities may not be restricted only
to the skin, but may be markers of more widespread,
multi-systemic involvement.
What is new?
•D-Penicillamine-induceddegenerativedermopathycanmanifestasa
combination of manifestations of skin fragility over bony prominences and
pressure areas and cutis laxa-like features, as was seen in one of our case.
•StoppageofD-penicillaminecansignicantlyimprovethefeaturesof
degenerative dermopathy.
References
1. Jha SK, Behari M, Ahuja GK. Wilson’s disease: Clinical and
radiological features. J Assoc Physicians India 1998;46:602-5.
2. Iozumi K, Nakagawa H, Tamaki K. Penicillamine-induced
degenerative dermatoses. Report of a case and brief review of
such dermatoses. J Dermatol 1997;24:458-65.
[Downloaded free from http://www.e-ijd.org on Tuesday, November 24, 2020, IP: 158.46.131.246]
Khandpur, et al.: Penicillamine induced dermopathy
409 Indian Journal of Dermatology 2015; 60(4)
3. Grasedyck K. D-penicillamine-side effects, pathogenesis
and decreasing the risks. [Article in German]. Z Rheumatol
1988;47 (Suppl 1):17-9.
4. Levy RS, Fisher M, Alter JN. Penicillamine: Review and
cutaneous manifestations. J Am Acad Dermatol 1983;8:548-58.
5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA,
et al. A method for estimating the probability of adverse drug
reactions. Clin Pharmacol Ther 1981;30:239-45.
6. Meyboom RH, Royer RJ. Causality classification in
pharmacovigilance centres in the european community.
Pharmacoepidemiol Drug Safety 1992;1:87-97.
7. Srinivasan R, Ramya G. Adverse drug reaction-causality
assessment. Int J Res Pharma Chem 2011;1:606-12.
8. Faghini G, Ali A, Wali A. Cutaneous side effects of
D-penicillamine. Indian J Dermatol 2003;48:133-6.
9. Davis W. Wilson’s disease and penicillamine-induced
anetoderma. Arch Dermatol 1977;113:976.
10. Bolognia JL, Braverman I. Pseudoxanthoma-elasticum-like skin
changes induced by penicillamine. Dermatol 1992;184:12-8.
How to cite this article: Khandpur S, Jain N, Singla S, Chatterjee P,
Behari M. D-penicillamine induced degenerative dermopathy. Indian J
Dermatol 2015;60:406-9.
Received: June, 2013. Accepted: September, 2013.
Source of support: Nil, Conflict of Interest: Nil.
11. Light N, Meyrick Thomas RH, Stephens A, Kirby JD,
Fryer PR, Avery NC. Collagen and elastin changes in
D-penicillamine-induced pseudoxanthoma elasticum-like skin.
Br J Dermatol 1986;114:381-8.
12. Meyrick Thomas RH, Kirby JD. Elastosis perforans serpinginosa
and pseudoxanthoma elasticum-like skin change due to
D-penicillamine. Clin Exp Dermatol 1985;10:386-91.
13. Dalziel KL, Burge SM, Frith PA, Ryan TJ, Mowat A. Elastic fibre
damage induced by low-dose D-penicillamine. Br J Dermatol
1990;123:305-12.
14. Poon E, Mason GH, Oh C. Clinical and histological spectrum
of elastotic changes induced by penicillamine. Australas J
Dermatol 2002;43:147-50.
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