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Table of Contents 
Year : 2015  |  Volume : 60  |  Issue : 4  |  Page : 406-409
D-penicillamine induced degenerative dermopathy

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

Date of Web Publication10-Jul-2015

Correspondence Address:
Dr. Sujay Khandpur
Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.160498

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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

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

How to cite this URL:
Khandpur S, Jain N, Singla S, Chatterjee P, Behari M. D-penicillamine induced degenerative dermopathy. Indian J Dermatol [serial online] 2015 [cited 2022 Oct 1];60:406-9. Available from:

What was known?
Prolonged d-penicillamine administration can produce skin fragility.

   Introduction Top

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 Top

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 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 D-penicillamine. 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 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.
Figure 1

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Figure 2

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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.
Figure 3: Hemorrhagic vesicles and scarring over bony prominences with overlying milia in upper limb in Case 2

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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],[6],[7]

   Discussion Top

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],[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 Top

Jha SK, Behari M, Ahuja GK. Wilson's disease: Clinical and radiological features. J Assoc Physicians India 1998;46:602-5.  Back to cited text no. 1
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.  Back to cited text no. 2
Grasedyck K. D-penicillamine-side effects, pathogenesis and decreasing the risks. [Article in German]. Z Rheumatol 1988;47 (Suppl 1):17-9.  Back to cited text no. 3
Levy RS, Fisher M, Alter JN. Penicillamine: Review and cutaneous manifestations. J Am Acad Dermatol 1983;8:548-58.  Back to cited text no. 4
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.  Back to cited text no. 5
Meyboom RH, Royer RJ. Causality classification in pharmacovigilance centres in the european community. Pharmacoepidemiol Drug Safety 1992;1:87-97.  Back to cited text no. 6
Srinivasan R, Ramya G. Adverse drug reaction-causality assessment. Int J Res Pharma Chem 2011;1:606-12.  Back to cited text no. 7
Faghini G, Ali A, Wali A. Cutaneous side effects of D-penicillamine. Indian J Dermatol 2003;48:133-6.  Back to cited text no. 8
  Medknow Journal  
Davis W. Wilson's disease and penicillamine-induced anetoderma. Arch Dermatol 1977;113:976.  Back to cited text no. 9
Bolognia JL, Braverman I. Pseudoxanthoma-elasticum-like skin changes induced by penicillamine. Dermatol 1992;184:12-8.  Back to cited text no. 10
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.  Back to cited text no. 11
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.  Back to cited text no. 12
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.  Back to cited text no. 13
Poon E, Mason GH, Oh C. Clinical and histological spectrum of elastotic changes induced by penicillamine. Australas J Dermatol 2002;43:147-50.  Back to cited text no. 14

What is new?

  • D-Penicillamine-induced degenerative dermopathy can manifest as a 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.
  • Stoppage of D-penicillamine can significantly improve the features of degenerative dermopathy.


  [Figure 1], [Figure 2], [Figure 3]

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