Journal Reading

Dermopathy Degeneratif diinduksi oleh D-penisilamin

Oleh :
Mimi Fitriani
15100707360803117

Pembimbing:
Dr. H. Yosse Rizal, Sp.KK

ILMU KESEHATAN KULIT DAN KELAMIN

RSUD ACHMAD MOCHTAR BUKITTINGGI
FAKULTAS KEDOKTERAN UNIVERSITAS BAITURRAHMAH
2015

Journal of Indian Journal of Dermatology 2015; 60: 406-9.

CASE REPORT
D-penicillamine induced degenerative dermopathy
Sujay Khandpur1, Naresh Jain1, Shweta Singla2, Priti Chatterjee3, Madhuri Behari2
1
Department of Dermatology and Venereology, All India Institute of Medical Sciences,
New Delhi, India
2
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
3
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

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.
Keywords: Degenerative dermopathy, penicillamine, chronic therapy
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 g/dl
(normal - 70-140 g/dl), serum ceruloplasmin was 0.002 OD/unit (normal - 0.2-0.5
OD/unit), 24 h urinary copper was 87 g/day (normal - 20-50 g/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 dpenicillamine, 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 710 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 1]a 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 2]a and b]. Patient was also evaluated for other side effects of Dpenicillamine. Urine was normal without any proteinuria (0.02 gm/24 hour urine). CT
chest incidentally 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 g/day and serum copper was 31 g/dl. Echocardiography was normal. Since the
copper stores had significantly reduced, it was planned to decrease the dose of Dpenicillamine, 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 g/dl, serum ceruloplasmin of 0.058 OD/unit, and 24 h urinary copper of 71
g/day. He was diagnosed as Wilson's disease and started on zinc acetate and Dpenicillamine, 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.
Figure 3: Hemorrhagic vesicles and scarring over bony prominences with overlying milia
in upper limb in Case 2

In
both
cases, this
adverseevent 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 WHOUMC causality category and a level 4 ADR on the Hardwig's Severity Assessment scale.
[5],[6],[7]

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 (penicillamineinduced 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],[9],[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., 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.

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.
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.
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.

Dermopathy Degeneratif Diinduksi oleh D-Penisilamin

Abstrak
D-penisilamin mengganggu elastin dan metabolisme kolagen dan menghasilkan
beberapa efek samping kulit dan multi-sistemik. Kami menyajikan dua kasus penyakit
Wilson yang menggunakan terapi penisilamin jangka panjang berkembang menjadi
dermopathy degeneratif yang disebabkan karena obat penisilamin sebagai manifestasi
berupa kerapuhan kulit di atas tempat yang banyak mengalami penekanan dan perubahan
cutis-laxa.
Kata kunci: dermopathy, penisilamin, terapi kronis degeneratif.

Pengantar
Penisilamin adalah chelator logam berat, yang digunakan untuk mengobati beberapa
toksisitas logam berat termasuk timbal, merkuri, dan tembaga.Ini adalah modalitas terapi
yang penting untuk beberapa penyakit termasuk skleroderma, penyakit Wilson,
rheumatoid arthritis, dan sistinuria. [1] Efek samping yang umum dari D-penisilamin
termasuk gangguan pencernaan, ruam kulit, stomatitis, dysgeusia, sitopenia, proteinuria
karena nefritis membran, dan jarang, sindrom miastenia. [2] , [3] terapi penisilamin
berkepanjangan dapat juga menghasilkan spektrum perubahan kulit. [4] Kami menyajikan
dua kasus dengan dermopathy degeneratif berat akibat terapi penisilamin jangka panjang.
Laporan kasus
Kasus 1
Seorang gadis 15 tahun dirawat di departemen Neurologi rumah sakit kami dengan
masalah perilaku, lekas marah, penurunan akademik progresif dan dystonia umum juga
mempengaruhi bicara. Dia memiliki kornea cincin Kaiser Fleschner (KF). Tembaga
serum adalah 54 g / dl (normal 70-140 g / dl), seruloplasmin serum 0,002 OD / unit
(normal 0,2-0,5 OD / unit/24 jam) , tembaga urin adalah 87 g / hari (normal 20- 50 g /
hari) dan MRI otak menunjukkan T2 hiperintensitas di globus pallidus bilateral dan
substantia nigra. Tes fungsi hati normal. Dia didiagnosis memiliki penyakit Wilson dan
mulai d-penisilamin, awalnya 250 mg / hari, yang dititrasi selama beberapa bulan sampai
3 gm / hari bersama dengan zinc asetat. Dystonia ditingkatkan sebagian dan pasien
mampu berbicara. Setelah dua setengah tahun mengkonsumsi D-penisilamin, pasien
mengeluhkan tegang , lesi vesiko-bulosa penuh dengan cairan bening dan hemoragik di
atas tempat trauma mudah pecah dalam 7-10 hari dan sembuh dengan jaringan parut
dalam 1-2 bulan. Dia juga mengeluhkan peningkatan kelemahan kulit di daerah ini serta
semua lipatan kulit. Pada pemeriksaan, pasien memiliki dystonia umum berat yang
melibatkan wajah, rahang, leher, badan dan tungkai, dengan kekakuan, dan sulit
mereganggkan tendon. Pemeriksaan dermatologis mengungkapkan lesi vesicobullous dan
erosi simetris di distribusikan di bahu, siku, tangan, lutut, dan pergelangan kaki. Ada juga
bukti jaringan parut, hiperpigmentasi dan milia atas situs tersebut [Gambar 1] a dan b].
Ada peningkatan kelemahan kulit di daerah-daerah dan lebih lipatan tubuh (leher,
pangkal paha, cubiti dan poplitea fossae). Tzanck smear yang di buat dari lepuhan negatif
untuk sel acantholytic atau sel-sel inflamasi. Biopsi kulit dari lesi di atas sisi dinyatakan
menurun, serat elastis menebal dan terfragmentasi, disorot pada VVG pewarnaan
(dibandingkan dengan kontrol normal sampel kulit) bersifat elastolysis [Gambar 2] a dan
b]. Pasien juga dievaluasi untuk efek samping lain dari D-penisilamin. Urine normal
tanpa proteinuria (0,02 mg / 24 jam urin). CT dada tampak bayangan reticulonodular
bilateral menunjukkan fibrosis interstitial mulai menyebar. Pasien memiliki anemia
hipokromik sekunder anemia defisiensi besi dengan serum besi 11 ng / nl (normal - 50150 ug / dl). tembaga urin 24 jam adalah <5 g / hari dan tembaga serum adalah 31 g /
dl. Echocardiography normal. Karena tembaga telah berkurang secara signifikan,
direncanakan untuk mengurangi dosis D-penisilamin, dilanjutkan dengan seng asetat dan

menjaga pasien di follow up. Setelah mengurangi dosis 1,5 gram lesi kulit membaik
secara dramatis (70-80%) selama 4-6 bulan.

Kasus 2
Seorang pria 29 tahun, dirawat di departemen neurologi dengan kekakuan secara
bertahap progresif keempat anggota badan, tremor pada tungkai atas dan sering jatuh. Dia
memiliki riwayat penyakit kuning pada usia 14 tahun yang konservatif berhasil. Pada
pemeriksaan, tidak ada bukti anemia, penyakit kuning atau tanda-tanda gagal hati tapi ia
memiliki tawa yang tidak pantas. Pemeriksaan Status Mental Mini nya 17/24 dan cincin
KF hadir. Ada dystonia umum dan kekakuan dari semua anggota badan dan batang tubuh
dan kesulitan dalam menulis karena tremor yang berat. Penyelidikan menunjukkan
tembaga serum 25 g / dl, seruloplasmin serum 0,058 OD / unit, dan 24 jam tembaga urin
dari 71 g / hari. Ia didiagnosis sebagai penyakit Wilson dan diterapi denagn seng asetat
dan D-penisilamin, yang secara bertahap meningkat dari 1 sampai 3 mgr/ hari. Hanya ada
perbaikan parsial dalam kekakuan dan dystonia. Setelah 4 tahun terapi penisilamin, ia
berkembang menjadi lesi vesicobullous atas wilayah trauma rawan yang sembuh dengan
pembentukan milia dan jaringan parut [Gambar 3] . Biopsi kulit mengungkapkan serat
elastis terfragmentasi dalam dermis reticular. Fitur-fitur ini konsisten dengan penisilamin
diinduksi kerapuhan kulit. Investigasi terhadap efek samping sistemik D-penisilamin
mengungkapkan tidak ada kelainan. Dosis penisilamin diturunkan menjadi 1 mg/ hari,
lesi kulit meningkat secara signifikan setelah 6 bulan.
Figure 3: Hemorrhagic vesicles and scarring over bony prominences with overlying milia
in upper limb in Case 2

Dalam
kedua
kasus,
penyakit
yang

menrugikan ini untuk penisilamin menghasilkan skor 9 dari reaksi obat yang merugikan
Naranjo (ADR) skala probabilitas (yang pasti ADR jika skor 9). Itu adalah 'ADR
tertentu' menurut WHO-UMC kategori kausalitas dan tingkat 4 ADR pada skala Hardwig
ini penilaian berat. [5] , [6] , [7]
Diskusi
Kasus kami membahas contoh dermopathy degeneratif diinduksi penisilamin,
pertama dijelaskan oleh Sternleib dan Scheinberg pada tahun 1964 pada pasien penyakit
Wilson. [4] Kedua kasus dikembangkan akibat induksi obat terjadi kerapuhan kulit di atas
tonjolan tulang dan situs tekanan mewujudkan sebagai lecet hemoragik, jaringan parut ,
dan pembentukan milia sementara satu kasus kutis juga terkait perubahan Laxa .
Administrasi jangka panjang D-penisilamin telah terbukti menghasilkan dermopathy
pada 20 sampai 33% dari pasien selain hematologi, imunologi, dan keterlibatan sistem

organ lain. [2] Insiden efek samping berkisar dari 30 sampai 60% dan tingkat penarikan
obat karena efek samping dapat mencapai 30%. [2] , [3] efek samping Cutaneous dapat
diklasifikasikan menjadi empat kelompok yang berbeda; Reaksi sensitivitas akut
(misalnya urtikaria akut), efek toksik-metabolik pada jaringan ikat atau dermopathy
degeneratif (penisilamin yang disebabkan kerapuhan kulit, kutis Laxa, elastosis perforans
serpiginosa-EPS, anetoderma, pseudoxanthoma elasticum-PXE), manifestasi kulit
autoimun (misalnya pemfigus , lupus erythematosus dan dermatomyositis) dan orangorang karena mekanisme yang tidak diketahui (misalnya lichen planus, hipertrikosis). [4]
Pada dosis tinggi, penisilamin mengganggu elastin dan kolagen metabolisme yang
bermanifestasi sebagai: Cutis Laxa, anetoderma, PXE, ecchymosis, dan
lymphangiectasis. [8] , [9] ,[10] D-penisilamin mengikat langsung ke prekursor aldehida yang
penting untuk elastin dan kolagen dan menghambat enzim oksidase lysyl tergantung
tembaga, yang mengkatalisis reaksi silang. [11]Bagaimanapun ini, tidak berpengaruh pada
kematangan, kolagen larut, karena itu menjelaskan jangka waktu yang panjang sebelum
dermopathy terjadi. Jumlah yang tepat dari penisilamin diperlukan untuk menghasilkan
kerusakan serat elastis tidak diketahui, tetapi diperkirakan bahwa minimal 1 g setiap hari
untuk lebih dari 5 tahun yang diperlukan untuk menginduksi perubahan ini. [12]Namun,
sebuah studi oleh Dalziel et al., menunjukkan bahwa kerusakan serat elastis terjadi pada
pasien rheumatoid arthritis yang menerima terapi penisilamin dosis rendah (0,25-1 g
sehari), bahkan setelah minimal 1 tahun pengobatan. [13]
Kasus kami mengembangkan kerapuhan kulit dan kutis Laxa seperti perubahan
setelah 3-4 tahun pengobatan. Mereka tidak memiliki fitur EPS, yang tampak sebagai
pink ke merah plak annular keratotik pada leher, aksila dan ante-cubiti fossae, PXE yang
memanifestasikan papula kekuningan kecil penggabungan untuk membentuk plak di
leher, atau efek samping sistemik D- penisilamin, yang terjadi karena kerusakan serat
elastis di berbagai organ termasuk atas dan pernapasan bawah saluran, kapsul sendi dan
pembuluh darah. [12] , [13]
Histopatologi karakteristik kerusakan serat elastis yang diinduksi penisilamin adalah
bahwa menebal bundel elastis dengan tonjolan lateral yang menonjol memberikan apa
yang disebut 'semak-semak duri' penampilan dengan atau tanpa kalsifikasi serat elastis,
dan peradangan kadang-kadang granulomatosa. Transepidermal penghapusan serat elastis
dapat terjadi yang bermanifestasi klinis sebagai EPS. [14] Dalam kasus kami VVG noda
baik pada biopsi kulit menunjukkan serat elastis menebal dan terfragmentasi.
Peningkatan manifestasi dermatologi memerlukan penghentian atau pengurangan
dosis D-penisilamin. [4] Pasien-pasien ini dapat dimulai pada seng asetat dan trientine
(senyawa pengkhelat untuk menghilangkan kelebihan tembaga dari tubuh) untuk penyakit
Wilson karena tidak ada perubahan kulit terjadi dengan agen ini. Seperti kebanyakan
kasus penisilamin diinduksi dermopathy degeneratif, lesi pasien kami meningkat secara
signifikan pada pengurangan dosis penisilamin. Hal ini dapat dipertimbangkan bahwa
intervensi dini akan membantu meminimalkan lanjut perluasan penisilamin menginduksi
elastolysis.
Kesimpulannya, penggunaan jangka panjang dari dosis tinggi penisilamin

berhubungan dengan kerusakan jaringan elastis yang dapat terwujud dalam kulit sebagai
kerapuhan kulit, milia dan purpura, seperti yang digambarkan dalam kasus ini. awal
pengenalan dari perubahan kulit yang diinduksi penisilamin penting karena kelainan ini
tidak dapat dibatasi hanya pada kulit, tetapi mungkin dapat lebih luas berupa keterlibatan
multi-sistemik.