Wilson disease (WD) is an autosomal recessive disorder caused by a mutation in the gene ATP7B that encodes a protein expressed on hepatocytes and involved in the excretion of copper into the bile (1). The deficient excretion of copper causes an accumulation primarily in the liver, brain, and eye. An early and lifelong therapy with chelators (penicillamine, trientine) or zinc is necessary to prevent disease evolution. Indeed, if WD is not adequately treated, hepatic and neurological damage can progress rapidly and acute liver failure can also occur. Unfortunately, all of the available drugs for WD may induce adverse reactions, especially d-penicillamine whose use is associated with both early (cutaneous eruptions, lymphadenopathy, neutropenia, thrombocytopenia, proteinuria, neurological worsening) and late (nephrotoxicity, lupus-like syndrome, Goodpasture syndrome) adverse effects (2). In approximately 30% of patients with penicillamine-related severe adverse effects, the drug must be discontinued.
In the present article, we present a WD adolescent with elastosis perforans serpiginosa (EPS), induced by penicillamine, which did not disappear following penicillamine withdrawal and persisted unchanged on zinc monotherapy during 3 years of observation. On the basis of this case, the potential role of zinc monotherapy in WD, as maintenance treatment, to reduce the risk of penicillamine severe adverse effects is discussed.
A 15-year-old white boy was admitted to our University Hospital with irregular proximal tremulousness, dysarthria, micrographia, labile mood, inappropriate behavior, and hepatomegaly associated with splenomegaly. The patient was diagnosed as having WD on the basis of low ceruloplasmin (0.06 g/L; reference range, 0.2–0.5), high 24-hour urinary copper (165 μg per 24 hours; normal values <40 μg), high liver copper (970 μg per gram of dry tissue; normal values <50 μg), and bilateral eye Kayser-Fleischer rings. Molecular analysis confirmed WD (compound heterozygous mutation in the gene ATP7B: His1069Gln/Asn1270Ser). Therapy with penicillamine (20 mg kg−1 day−1) was started with a favorable response concerning the improvement in neuropsychiatric symptoms such as disappearance of tremors. Liver function tests persisted normal. Three years later, although the patient showed a good control of WD, cutaneous lesions appeared on the patient's neck (Fig. 1A and B) and right arm (Fig. 1C). A skin biopsy was performed. The 3-mm punch biopsy specimen showed granular cellular debris and fragmented elastic fibers surrounded by the acanthotic epidermidis, configuring perforating channels. As a result, according to the clinical and histological findings, penicillamine-induced EPS was diagnosed and topical steroid treatment was tried with no result. Skin lesions progressed with significant visual impact and severe social consequences for the patient. For this reason, penicillamine therapy was suspended after 3 months from the onset of EPS and replaced with zinc acetate. After the switch, general clinical condition and liver function tests remained normal with a good control of WD and cutaneous lesions persisted unchanged, without any improvement or worsening. Two years after the withdrawal of penicillamine, skin biopsy confirmed the picture with no more progression.
Penicillamine-induced adverse effects, both cutaneous and noncutaneous, may occur variable times after the start of therapy. The potential risk of late severe adverse penicillamine-induced reactions raises the question of maintenance therapy in patients with WD who could be treated with safer drugs such as trientine or zinc. Penicillamine causes a diversity of dermatologic manifestations that include acute hypersensitivity reactions, dermopathies characterized by elastic fiber abnormalities including EPS and pseudo-pseudoxanthoma elasticum, autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and miscellaneous dermatoses that result from undefined mechanisms (3). EPS is an uncommon potential complication of long-term therapy with penicillamine, characterized by transepidermal elimination of abnormal elastic fibers (4). EPS is more frequent in patients ages between 6 and 20 years, and the most common sites affected are face, neck, and upper limbs (4). The pathogenetic mechanism is not yet known, but 2 possible explanations for the role of penicillamine have been evidenced: according to the first explanation, the copper-dependent enzyme lysyl oxidase, which is required for cross-linking of collagen fibers, may be inhibited by the copper-chelating effect of the drug; conversely, according to the second explanation, penicillamine inhibits directly the cross-linking of collagen fibers, resulting in the deposition of abnormal elastic fibers. Such abnormal fibers are reported to cause a foreign body reaction affecting epidermis, which results in the typical aspect of EPS (5). Genetic factors are probably also involved (5). Studies have shown that approximately one quarter of patients with EPS are associated with an underlying systemic disorder, often a connective tissue disease such as Ehlers-Danlos syndrome and osteogenesis imperfecta (4).
Therapeutic management of EPS is challenging, and at the moment there is no resolutive treatment. Some studies show that negative feedback occurs in case of topical and intralesional corticosteroids, cryotherapy, curettage, and oral isotretinoin treatment. Spontaneous resolution of the lesions within 36 months after cessation of penicillamine therapy has been described (5).
Although the effectiveness of penicillamine in WD has long been documented and the overall prevalence of its severe adverse effects is low, the risk of some serious unpredictable adverse events with potential impact on survival (Goodpasture syndrome) or on external appearance with serious social consequences (EPS) emphasizes the question of maintenance therapy in patients with WD. Trientine, which is indicated especially in patients who are intolerant to penicillamine or have clinical features indicating potential intolerance, has a lower toxicity and seems to be a satisfactory alternative therapy.
In contrast with copper chelation therapy, zinc treatment has few adverse effects and rarely leads to worsening of neurological symptoms. Although in adult patients, zinc monotherapy seems less effective than chelating agents in preventing the progression of liver disease and in terms of survival in the absence of liver transplantation, we recently demonstrated that zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in pediatric patients with mild liver disease (6).
The risk of some severe cutaneous and noncutaneous adverse events, related to penicillamine, could suggest a more extensive use of zinc monotherapy, as maintenance therapy, according to American Association for Study of Liver Diseases and European Association for the Study of the Liver practice guidelines (7,8), in patients with WD.
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5. Deguti MM, Mucenic M, Cancado EL, et al. Elastosis perforans serpiginosa secondary to d
-penicillamine treatment in a Wilson's disease patient. Am J Gastroenterol
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8. European Association for the Study of the LiverEASL clinical practice guidelines: Wilson's disease. J Hepatol