Wilson's Disease Should Be Treated with Zinc rather than Trientine or Penicillamine

Wilson's disease is a unique hereditary disease with known etiology (i.e., copper imbalance) and progressive character and is treatable; however, it may prove fatal without treatment. Unfortunately, its treatment is controversial. Although zinc therapy for Wilson's disease is generally safe, affordable, effective, and fast acting,[1] [2] [3] [4] even as initial treatment,[2] [5] [6] some practice guidelines still recommend initial chelation therapy with penicillamine, trientine, or tetrathiomolybdate.[7] [8] [9] However, chelators mobilize copper and thus increase free (nonceruloplasmin bound) copper levels in serum, which can then pass through the blood–brain barrier and may subsequently cause early neurological worsening. To compensate for the toxicity of copper ions, copper is excreted via the kidneys and an increased urinary copper indicates serum-free copper intoxication. We should rethink whether it is logical to further increase free copper levels with a chelator in a disease that is characterized by high copper levels and assume that kidneys and/or other organs will compensate.

Recently, Schindler et al[10] reported a case of a young patient with Wilson's disease and neuropsychiatric symptoms. The patient was detected with increased levels of free copper in plasma (∼22 µg/dL, normal up to 10 µg/dL) and urine (214 μg/24 hours, normal 15–60 μg/24 hours). Treatment was initiated with zinc gluconate and trientine. Unfortunately, neither the dosages of these treatments were mentioned nor their effect on copper levels, neurological symptoms, and brain magnetic resonance imaging (MRI). The case report could have been of more educational value, if the authors had given the above-mentioned information in addition to the reasons for starting trientine. Although the dysarthria improved (however, method of examination and extent of improvement were not mentioned), the patient was readmitted twice for worsening of psychiatric symptoms (i.e., aggression, impulsive behavior, and suicidal and homicidal ideation) during the year he was on trientine treatment. The case illustrates the risks of treating patients with Wilson's disease using trientine.

Unfortunately, the case report of Schindler and colleagues[10] does not stand on its own. Neurologic deterioration with chelators, such as trientine or penicillamine, has been reported in numerous studies.[11] [12] In 2013, Kim et al[11] described a patient with Wilson's disease who presented with neurological symptoms and in whom treatment was started with trientine. The patient deteriorated severely to a drowsy mental status, bilateral ptosis, and generalized dystonia. Additionally, new lesions were detected on his brain MRI 4 months after initiating trientine, and thus the treatment was changed to zinc. The deterioration during trientine treatment was accompanied by an 8-fold increase in urinary copper compared with baseline, which indicates a free copper intoxication that would justify the neurological worsening. In spite of the rapid clinical improvement with zinc in the following 2 weeks, the authors[11] reintroduced trientine, and unfortunately neurological decline was observed. In our opinion, this was less likely to occur if exclusive zinc therapy was continued.

Moreover, the results of a large retrospective study comprising 467 patients with Wilson's disease demonstrated that neurological deterioration was significantly more prevalent with trientine than with penicillamine.[13] The burden of chelators is not merely limited to the initial worsening of symptoms, but chelators are also associated with an increase of permanent neurological impairments, numerous other side-effects[14] [15] (particularly dermatologic diseases, autoimmune phenomena, bone marrow suppression, and/or nephropathy, some of which are severe and irreversible), and high costs. The analysis of 467 European patients found that chelator monotherapy was associated with a 33 to 45% chance of either deterioration or stabilization of neurological symptoms with penicillamine and trientine, respectively.[13] Despite the apparently more unfavorable outcome with trientine, there was no statistically significant difference between the penicillamine- or trientine-treated groups.[13] The results were even worse if the chelator was used as a second-line treatment (77% deterioration or stabilization of neurological symptoms on penicillamine, 49% on trientine).[13] These counterproductive results highlight the dangers of chelating therapy for Wilson's disease. In short, all these events strongly suggest that the chelating agents—intended to bind to the free copper and thus decrease its levels—counterintuitively increase free copper intoxication, which causes the clinical deterioration.

Instead, treatment of Wilson's disease should aim to normalize the free copper levels in serum and urine, which can be achieved with exclusive zinc therapy rather than chelating agents that increase free copper levels.[1] Zinc supplementation stimulates the production of the copper binding protein, metallothionein in intestinal mucosal cells and in hepatocytes, which results in the normalization of plasma and urine free copper levels by antagonizing copper and promoting its excretion via the stool.[16]

Accordingly, we strongly discourage continuing trientine or penicillamine and instead recommend starting zinc salts for patients with Wilson's disease with a sufficient dosage (50 mg elemental zinc, 1 to 3 times a day for children and 2 to 4 times a day for adults).[14] Shimizu et al[5] published the results of a prospective study on 37 patients who all improved on zinc monotherapy with a careful assessment of treatment and attentive monitoring of patients and their urinary copper levels. Zinc therapy needs precise monitoring of copper levels, and dosage of the drug should be titrated according to the urinary copper excretion after 1 month from the institution of zinc followed by regular measurements until reaching normal urinary copper level (less than 100 µg/24 hours[17] or 75 µg/g of random urine creatinine[5]). Urinary copper excretion is generally a reliable determinant of serum free copper levels, and the treatment should aim at its normalization.[17]

In conclusion, there is enough evidence against the rationale behind promoting the urinary excretion of copper with chelating agents. We hope that this critical discussion will result in rethinking the current approach to the treatment of Wilson's disease. Based on the best available evidence, zinc is the only treatment that decreases/normalizes copper levels and should be acknowledged as the drug of choice in the treatment of Wilson's disease.

• References

• 1 Hoogenraad TU. Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice. Brain Dev 2006; 28 (03) 141-146
• 2 Avan A, Kianifar HR, Hoogenraad TU. Initial zinc therapy in a Wilson's disease patient with acute liver failure and copper intoxication: a clinical observation. MovDisord 2013; 28 (Suppl. 01) 990
• 3 Avan A, Azarpazhooh MR, Hoogenraad TU. Effective shift from traditional chelation therapy to evidence based zinc monotherapy in four patients with Wilson's disease and parkinsonism. MovDisord 2013; 28 (Suppl. 01) 989
• 4 Hoogenraad TU, Van den Hamer CJ, Van Hattum J. Effective treatment of Wilson's disease with oral zinc sulphate: two case reports. Br Med J (Clin Res Ed) 1984; 289 (6440): 273-276
• 5 Shimizu N, Fujiwara J, Ohnishi S. , et al. Effects of long-term zinc treatment in Japanese patients with Wilson disease: efficacy, stability, and copper metabolism. Transl Res 2010; 156 (06) 350-357
• 6 Hoogenraad TU, Van Hattum J. Zinc therapy as the initial treatment for Wilson's disease. Arch Neurol 1988; 45 (04) 373-374
• 7 Roberts EA, Schilsky ML. ; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology 2008; 47 (06) 2089-2111
• 8 European Association for Study of Liver. EASL clinical practice guidelines: Wilson's disease. J Hepatol 2012; 56 (03) 671-685
• 9 Hermann W. ExtrapyramidalmotorischeSstörungen: Morbus Wilson. In: Diener HC, Weimar C, eds. LeitlinienFürDiagnostik Und Therapie in Der Neurologie, Herausgegeben von Der Kommission “Leitlinien” Der Deutschen Gesellschaft FürNeurologie. Stuttgart: Thieme Verlag; 2012. Available at: http://www.dgn.org/leitlinien-online-2012/inhalte-nach-kapitel/2395-ll-14-2012-morbus-wilson.html . Accessed February 27, 2017
• 10 Schindler EA, Guo XM, Schrag M, Ghoshal S, Schilsky ML, Beslow LA. Neuropsychiatric presentation of Wilson disease in an adolescent male. Neuropediatrics 2016; 47 (05) 346-347
• 11 Kim B, Chung SJ, Shin HW. Trientine-induced neurological deterioration in a patient with Wilson's disease. J ClinNeurosci 2013; 20 (04) 606-608
• 12 Kalita J, Kumar V, Chandra S, Kumar B, Misra UK. Worsening of Wilson disease following penicillamine therapy. EurNeurol 2014; 71 (3–4): 126-131
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• 17 Hoogenraad TU. Wilson's disease. In: Kompoliti K, Verhagen Metman L. , eds. Encyclopedia of Movement Disorders. Vol 3. Oxford: Academic Press: Elsevier; 2010: 335-340