Wilson disease (WD) is an autosomal recessive disorder causing copper accumulation, which commonly leads to brain and liver disease in the second to fourth decades of life (1). Agents approved for treatment of WD include penicillamine, trientine, and zinc (1). Both penicillamine and trientine are chelators that bind copper, increasing its urinary excretion. Zinc, first used to treat WD in the Netherlands in the 1960s, acts by inhibiting intestinal copper absorption and increasing metallothionein binding of copper in the liver. Zinc was approved only relatively recently for maintenance treatment by the US Food and Drug Administration, beginning in 1997 (2). In Japan, zinc acetate (Nobelzin) was accepted as therapy by the Ministry of Health, Labor, and Welfare in April 2008. So far, zinc monotherapy has not been advocated for initial treatment of young presymptomatic pediatric patients except in a single report (3). Presymptomatic patients resemble maintenance therapy patients in many ways in their copper toxicity status.
Pediatric patients with presymptomatic WD who continued successful zinc monotherapy for 10 years from time of diagnosis have been reported (3), as have children benefiting from zinc monotherapy with <1 year of follow-up. We lack data concerning 24-hour urinary copper according to body weight (micrograms per kilogram per day) as a measure of successful maintenance zinc monotherapy in young pediatric patients.
In this study, we administered zinc acetate for initial treatment of 4 young presymptomatic patients, beginning at the time of diagnosis, to determine the effectiveness of zinc acetate treatment during a period of approximately 2 years.
PATIENTS AND METHODS
We admitted 4 girls (mean age 5.5 years, range 5–7) to our department at Kurume University Hospital to initiate the study. Informed consent was obtained from their parents or guardians. These 4 patients satisfied diagnostic criteria for WD according to the scoring system of Ferenci et al (4). The patients were also diagnosed as having presymptomatic WD because of increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, without clinical liver abnormalities such as jaundice, hepatomegaly, or other illnesses such as neurologic abnormalities. When 1 patient (patient 3, Table 1) was screened because she was a sibling of a diagnosed patient, markedly elevated hepatic copper content was detected (675 μg/g tissue). The other 3 patients were found to have elevated AST and ALT concentrations when evaluated for enteritis (patient 4) or respiratory infection (patients 1 and 2). No patient received prior drug treatment for WD. Other causes of liver disease such as autoimmune hepatitis, chronic viral hepatitis, and other metabolic conditions were excluded by appropriate laboratory tests. The 4 patients did not undergo molecular analysis.
We started zinc monotherapy immediately after diagnosis. The dosage scheduled at ages of 5 years or younger was 25 mg twice daily; at ages of 6 years or older, the schedule was 25 mg 3 times daily. Accordingly, the zinc dose of patients 1, 2, and 3 was increased from 50 to 75 mg/day beginning at age 6 years. Zinc was taken 1 hour before or after any food or liquid other than water. For example, when the dose was 25 mg twice daily, zinc was taken 1 hour before or after breakfast and supper. Noncompliance was ruled out by serum and urine zinc determinations. Overtreatment remained a concern to some extent, especially in younger children. No patient received a low-copper diet during this study.
We monitored serum AST and ALT, nonceruloplasmin serum copper (serum copper [μg/dL] – 3.15 × ceruloplasmin [mg/dL]), and 24-hour urinary copper for at least 24 months of zinc monotherapy, except in 1 patient, who was studied for 12 months. We also determined white blood cell count, hemoglobin, platelet count, serum total bilirubin, albumin, iron, amylase, lipase, and prothrombin time, as well as 24-hour urinary zinc excretion. Additionally, we performed abdominal ultrasonograpy and evaluated clinical WD manifestations, drug compliance, and adverse effects of zinc.
Since receiving the initial dose of zinc, none of our 4 patients became clinically symptomatic for WD or developed any evidence of zinc toxicity such as elevated serum amylase and lipase, iron-deficiency anemia, or pancytopenia reflecting copper deficiency. Three patients developed nausea, which resolved spontaneously.
AST, ALT, and 24-hour urinary copper decreased sharply after initiation of zinc monotherapy (Table 2). Nonceruloplasmin serum copper was maintained below 25 μg/dL. Urinary copper excretion for 24 hours was kept between 1 and 3 μg · kg−1 · day−1. Results of other liver-related tests such as serum bilirubin and albumin, prothrombin time, and abdominal ultrasonography were normal.
Previous reports demonstrated zinc to be a fully effective, nontoxic therapy for prophylactic treatment of presymptomatic patients with WD (2,5,6). Additionally, these studies found zinc to be efficacious, safe, and cost-effective as an initial treatment of patients with hepatic and neurologic presentations of WD.
For maintenance therapy in presymptomatic patients, zinc is recommended as the first choice (1,6); however, only 3 reported studies have evaluated zinc monotherapy initiated at the time of diagnosis in pediatric patients younger than 10 years with presymptomatic WD (3,7,8). Almost all of the reports described zinc treatment of WD in patients older than 10 years. Our results confirmed the safety and effectiveness of zinc monotherapy from the time of diagnosis in the early pediatric age group.
Previous reports of long-term effectiveness of zinc monotherapy (2,3,7,9,10) provided only limited laboratory data for the first few months of therapy after diagnosis; nonetheless, early changes of AST and ALT and 24-hour urinary copper during the introduction of zinc monotherapy are of considerable clinical interest. One month after we began treatment, AST and ALT decreased to <100 U/L, which we attribute to the removal of toxic copper accumulation from the liver. AST and ALT and 24-hour urinary copper in our 4 patients decreased to a desirable range within 12 months. We evaluated liver function in this disease and concentrations of copper in liver tissue and/or inflammatory liver histopathologic findings. Repeated liver biopsy is difficult to perform in many patients with WD; therefore, serum concentrations of AST and ALT were important in assessing liver function in the present study.
In adulthood and adolescence, laboratory monitoring of therapeutic efficacy during maintenance therapy has relied on 24-hour urinary copper (50–125 μg/day) and nonceruloplasmin serum copper (<25 μg/dL) (1,5,7,9). We lack an equivalent standard for young pediatric patients, such as those younger than 10 years or weight <30 kg. To monitor such young patients based on unproven adult norms for 24-hour urinary copper would appear inadequate. The level of 24-hour urinary copper in our 4 patients decreased to 125 μg/day within 8 months and improved further in 12 months. Moreover, 24-hour urinary copper in our 4 patients was maintained between 1 and 3 μg · kg−1 · day−1 within 12 months of beginning zinc monotherapy. Based upon 24-hour urinary copper excretion per kilogram for follow-up intervals between 1 and 2 years, we suspect that target values would be 1 to 3 μg · kg−1 · day−1 for patients younger than 10 years and/or <30 kg in weight, which represents important information given the lack of established values for this age and weight.
The rapid removal of toxic copper accumulation shown by our data suggests that zinc monotherapy should be the first choice for patients with mild or moderate symptomatic WD and for those with presymptomatic WD. Such monotherapy also may be the best maintenance regimen for patients with WD initially treated by chelation.
In conclusion, zinc monotherapy initiated at the time of diagnosis in 4 young pediatric patients with presymptomatic WD proved highly effective and safe. AST, ALT, and 24-hour urinary copper decreased to the target range within 12 months of initiating zinc monotherapy. A reasonable goal in treating these pediatric patients using zinc appears to be maintaining 24-hour urinary copper excretion between 1 and 3 μg · kg−1 · day−1. Additionally, larger studies are under way to establish appropriate values for patients younger than 10 years and/or <30 kg in weight.
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