Zinc monotherapy is effective in Wilson’s disease patients with mild liver disease diagnosed in childhood: a retrospective study

Wilson’s disease (WD) is an autosomal-recessive disorder caused by mutations in the ATP7B gene[1]. Clinical presentation can vary widely[2, 3], but the key features of WD are liver disease, neuropsychiatric disturbances, Kayser–Fleischer (KF) rings, and acute episodes of hemolysis often in association with acute liver failure. WD presents with liver disease more often in children and young adults than in older adults[4]. An early diagnosis is important because WD can be fatal if left untreated. Once the diagnosis has been made[2, 5], treatment is a lifelong necessity, and compliance must be zealously monitored[6].

The approach to treatment (drug of choice and dosage) depends on clinical presentation at diagnosis, and the severity of neurologic or hepatic disease[6]. Current treatment regimens include chelators (D-penicillamine and trientine) that promote the excretion of copper from the body, and/or zinc salts that reduce copper absorption[2, 4].The best therapeutic approach for each specific presentation of the disease remains controversial and there are no clear indications about how to treat WD patients with a mild liver disease[2, 4]. Transplantation remains the treatment of choice for patients with acute liver failure due to WD as well as for treatment of patients with chronic liver failure unresponsive to medical therapy[2]. In patients with severe neurological presentation the use of zinc seems to be preferred[6].

Studies conducted on distinct groups of WD patients have demonstrated that zinc monotherapy is safe and inexpensive[7]. Zinc was successfully used as maintenance therapy in presymptomatic and pregnant patients; as first-line treatment in patients with neurological onset and in WD children with hepatic presentation[8‐16]. Somewhat in contrast with these findings, Weiss et al. questioned the efficacy of zinc therapy in WD based on the retrospective observation that, in adult patients, zinc monotherapy was less effective than chelating agents in preventing the progression of liver disease and in terms of survival in the absence of liver transplantation[17].

In the attempt to provide indications regarding the treatment of WD patients with mild liver disease, and to shed light on the discordance between evidence supporting the efficacy of zinc treatment and the studies against this therapy[17, 18], we evaluated the long-term response to therapy and particularly the efficacy of zinc monotherapy in a series of WD patients with mild liver disease diagnosed in childhood.

As recommended[2, 4], D-penicillamine was used as initial and maintenance therapy for symptomatic patients, zinc salts were used as first-line treatment and maintenance for presymptomatic patients, and as maintenance therapy after a first phase with penicillamine for symptomatic patients. Starting from 1995, zinc was also used as first-line therapy in WD patients with a mild liver disease.

D-penicillamine was used as initial therapy at the dosage of 20 mg/kg daily divided in two to four doses; the maintenance dose was between 750–1500 mg daily in two or three doses. Zinc was given in sulphate form until 2004, and subsequently, when licensed in Italy, as acetate at the dosage of elemental zinc 25 mg twice daily in children younger than 6 years; 25 mg three times a day for children aged between 6 and 16 years of age (or weight <57 kg); and 50 mg three times daily in patients older than 16 years of age (or weight >57 kg). Patients were instructed to take their medication at least one hour before meals or at least 2 hours after meals. The study complies with the Declaration of Helsinki.

Considering the rarity of WD and the lack of clear indications on how to treat WD patients with mild liver disease[2, 4], the importance of the present study lies in the fact that it evaluated zinc monotherapy in a large and homogeneous group of patients with mild liver disease due to WD, diagnosed in childhood (median age: 6 years) and monitored for a long period (median duration: 12 years). The features of our series are remarkably different from those of other pediatric reports, which in most cases included WD children with either acute or chronic symptomatic liver disease[11, 17‐19]. In fact, the WD patients evaluated in the present study were affected by mild liver disease. This reflects the fact that in Italy aminotransferase serum levels are measured during all routine checkups and before surgical procedures. Regarding the retrospective nature of the study, given the rarity of WD, it is virtually impossible to carry out prospective randomized controlled trials in the short-mid term to determine the optimal therapeutic schedules. In the analyzed setting, zinc monotherapy was effective both as first-line monotherapy and as maintenance treatment after initial decoppering with the chelator D-penicillamine. Changes of therapy were significantly more frequent in patients receiving D-penicillamine or combination therapy than patients receiving zinc monotherapy. Similarly, treatment failure and adverse events occurred more frequently on D-penicillamine. Interestingly, zinc failure was more frequently related to non-adherence to therapy than D-penicillamine failure.

In our study, the rate of normalization of liver enzymes was much higher in patients who started on zinc than in those who started on D-penicillamine. However, we cannot conclude that zinc monotherapy is more effective than D-penicillamine given the heterogeneity of the groups initially treated with D-penicillamine or zinc in terms of age at diagnosis and baseline ALT and GGT levels. Therefore the main message of our study is that both D-penicillamine and zinc are effective in controlling liver involvement in WD patients with mild liver disease diagnosed in childhood. It cannot be excluded that decoppering treatment when used as first drug might favor in some way the beneficial effect of zinc monotherapy in patients switching to this regimen.

In line with previous reports[7, 8, 14, 19], the present study indicates that clinically relevant adverse events, including neurologic worsening, in some cases requiring treatment modifications, are more common on D-penicillamine than on zinc. Contrary to the group on D-penicillamine, none of our patients on zinc needed to change therapy because of side effects.

At variance with our data and those of others[8‐16], the efficacy of zinc treatment for WD was recently questioned[17, 18]. Several factors may be evoked to explain this discordance. Most of the patients evaluated by Weiss et al. started therapy in the adult age, when obviously the liver expression of WD is more severe. In the subset of patients classified as non-responders, they did not include patients who died or who underwent liver transplantation (10 under chelator versus 4 on zinc and 1 on combination therapy). Another important difference is that zinc was given as second-line therapy in their patients with liver disease. Thus, 11/14 patients that had hepatic failure on zinc after a median of 2.7 years (range: 0.67-18.34) of treatment had already received D-penicillamine for a median of 12.31 years (range: 0.27-33.59), and the outcome of these patients on chelator therapy was not reported. Therefore, the clinical status of these patients at the time of starting zinc therapy was not well defined. Moreover, although Weiss et al. reported that liver enzymes normalized in zinc non-responders after reintroduction of a chelating agent (rescue therapy), they did not provide information about rescue therapy. In contrast to these results, liver disease did not worsen in any of our long-term responders to D-penicillamine after switching to zinc monotherapy.

Again, we applied very stringent criteria to identify responders to therapy. In the Weiss’ study, the ranges of ALT and GGT in the responders at the end of the study were very wide (10–226 UI/L and 10–178 UI/L, respectively) and included values more than twice the upper limit of normal. In addition, while we evaluated zinc monotherapy for a median follow-up of 9.3 years, Weiss et al. did not report details about patients treated with zinc alone, apart from stating that the median duration of zinc therapy was 2.7 years in non-responders to zinc.

A major problem with WD treatment is that patients must comply strictly to therapy because low compliance or treatment discontinuation is associated with a high risk of hepatic decompensation that may even require liver transplantation[2]. Treatment compliance was not assessed by Weiss et al. They reported a lack of significant differences in serum and urinary zinc values between their responders and non-responders to zinc therapy; however, they did not report details about urinary copper levels. Consequently, they may have misjudged treatment adherence. It is noteworthy that the patients of Linn et al. that worsened under zinc therapy were later discovered not to have adhered to treatment based on their urinary copper levels[18]. In our study, the evaluation of urinary copper levels revealed an irregular intake of the drug in one of two non-responders to zinc who had appropriate serum and urinary zinc levels. Another important finding of our study is that urinary copper excretion does not represent a reliable efficacy parameter on penicillamine therapy, because some responders persistently maintain urinary copper level higher than 500 mcg/day. On the other hand, urinary copper excretion remains useful for evaluating the adherence to treatment in nonresponders to penicillamine and guiding the shift to zinc monotherapy in patients initially treated with penicillamine[2, 4]. It is important to note that treatment failure was more frequent in our patients on combination therapy than in patients on other regimens, and that it was invariably linked to poor compliance. Given this result and the fact the efficacy of combination therapy is not yet well proven, the latter strategy should probably be avoided.

In conclusion, our study addresses the challenge of how to treat WD patients with mild liver disease, diagnosed in childhood. In fact, we demonstrate that zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in patients with mild liver disease. Its efficacy was evaluated in a large homogeneous cohort of WD patients diagnosed in childhood and followed for a long period. This study raises the possibility of treating, when indicated, WD patients with an effective and safe drug as zinc.

The data sets supporting the results of this article are included within the article and its additional files.