We evaluate Wilson disease (WD) treatment with zinc acetate (U.S. Food and Drug Administration approved) and alternative zinc salts. Studies examining zinc therapy in WD are few, and data on alternative zinc salts are limited. We describe one of the largest recent studies of zinc therapy in WD. First, we conducted a single-center retro-spective review of 59 patients with WD (age 6-88 years, 32 female patients) treated with zinc (50-150 mg) for 0.8 to 52 years (median, 26 years); most were on prior chelation therapy (n = 39). Second, we developed a survey to explore patients’ zinc therapy experience. Primary endpoints were alamine aminotransferase (ALT) and urine copper excretion (µg/24 hours). Urine copper was categorized as low <25 µg (possible overtreatment), target 25-100 µg, or elevated >100 µg (possible noncompliance or treatment failure). The target range was reached in 81% of patients on zinc acetate, 73% on zinc gluconate, and 57% on alternative zinc. Low urine copper was not associated with a high ALT. ALT was normal in 77% of patients with target urine copper but only in 16% with urine copper >100 µg. ALT elevations were not significantly different between zinc salts (Kruskal-Wallis, P = 0.26). Our survey demon-strated the mean age of starting zinc was 26.8 years (3.5-65 years); most were treated with zinc acetate (45%) and zinc gluconate (42%). Before zinc treatment, 45% of patients were symptomatic; the majority of patients (80%) were asymptomatic on zinc. Gastrointestinal side effects were the predominant reason for changing zinc salts (38%), but most reported no side effects on current zinc therapy (67%). Conclusion: Effective treatment with zinc is possible in many patients with WD. The potential for treatment failure suggests close monitoring and consideration of alterna-tive treatments are paramount for those without both a normal serum ALT and appropriate urine copper excretion. (Hepatology Communications 2019;0:1-8).
Wilson disease (WD) is an inherited disor-der of copper metabolism in which copper accumulates and causes toxicity, the liver and brain being the most copper-sensitive organs. Medical therapy for WD is lifelong. The introduction of effective oral treatments began with the chelating agents d-penicillamine and trientine, which mobi-lize copper by increasing urinary copper excretion. Later, zinc salts, which act by blocking dietary copper absorption, were found to be useful for the treatment of WD.Treatment of patients with WD with zinc sul-fate was initially proposed by Shouwink et al.(1) based on its de-coppering potential in sheep. The initial salt used in these studies was zinc chloride, which was abandoned as treatment due to gastric
irritation; however, other zinc salts, such as zinc sul-fate and zinc acetate, were then tested, which led to their clinical use for treating WD.(2-4) It was later discovered that zinc acts by inducing the synthesis of the endogenous metal chelating peptide metal-lothionein in enterocytes.(5-7) Metallothionein is a mainly cytosolic protein with a higher binding affinity for copper than zinc, and when copper is taken up by enterocytes, the copper replaces zinc on the metallothionein peptide.(8) When high levels of metallothionein are induced in intestinal cells by zinc, copper absorption is inhibited.(9) Nonabsorbed intestinal copper from the diet is eliminated along with copper in enterocytes (on the metallothionein peptide) when they are shed into the intestinal lumen and both are excreted into feces. This leads to the negative copper balance necessary for detox-ification of the excess injurious copper within the liver and other tissues. Zinc can also induce metal-lothionein synthesis in the liver, leading to further neutralization of toxic copper.(9,10)
In 1997, the U.S. Food and Drug Administration (FDA) approved the use of zinc acetate for mainte-nance therapy for WD on the basis of studies over a 15-year period, including a long-term follow up study of 141 patients who received only zinc as maintenance therapy for WD. Brewer et al.(2) used copper balance studies that measured the absorption of radiolabeled 64Cu added to a study diet and found that 25 mg of zinc acetate administered 3 times daily or 37.5 mg zinc acetate given twice daily was likely to be the min-imum effective dose of this zinc salt for human use. Once daily administration of 75 mg was found not to be as effective as divided doses. This may indicate that in order to sustain adequate intestinal metallothionein induction, a dosage regimen of twice daily is the min-imum necessary. The standard adult dosage that was pproved by the FDA following these studies was 50 mg 3 times daily, providing a margin of safety so that even if one dose was missed or taken ineffec-tively with food, dietary copper absorption would be effectively blocked. Recommendations were to give zinc acetate at least 30 minutes before or 2 hours after meals. For children <50 kg in weight, the rec-ommended dosage was 25 mg taken in three divided doses.(11) For patients on zinc treatment, Brewer et al. suggested that the efficacy of zinc acetate treatment for WD be assessed by a goal of 24 urine copper val-ues of <125 μg/day, and he recommended measure-ment of urine zinc values to assess for compliance. Others have suggested lower 24-hour urine copper cutoffs than the 125 μg/day proposed by Brewer and colleagues to ensure better copper control.(11)
Zinc treatment is associated with few side effects. The most common side effect of zinc treatment is gastric irritation, which sometimes may be helped by concomitant intake of protein or use of proton pump inhibitors. Occasionally, irritation can be severe, result-ing in erosions and ulcers.(11,12) Other side effects that occur rarely include biochemical pancreatitis, resulting in elevated pancreatic enzymes (lipase/amylase) with-out clinical symptoms.(11) With long-term use, issues of overtreatment and zinc-induced copper deficiency can occur. This typically presents with anemia, neu-tropenia, as well as neurologic symptoms, including sensory or motor sensory neuropathies and myelop-athies, which normally reverse with correction of the deficiency.(13)
Although zinc acetate is the only zinc salt in the United States that is currently FDA approved and in Europe, Wilzin is similarly a European Medicines Agency-approved zinc acetate preparation, there are several zinc salts available to patients as dietary supplements, including zinc sulfate, zinc gluconate,expressed as less than the upper limit of normal (ULN) or a multiple of the ULN for the laboratory perform-ing the testing (1-2, 2-3, or >3 times the upper limit of ALT). Patients were divided into groups based on their response to treatment with respect to ALT and 24- hour urine copper (see Table 1). No patient with low urine copper had a high ALT. ALT was normal in 77% of patients with a target range urine copper of 25-100 µg/24 hours; however, when urine 100 µg/24 hours, ALT was normal in only 1 patient (16%). ALT was elevated in 31% of patients on zinc acetate, 21% on zinc gluconate, and 28% on alter-native zinc. The majority (3 of 4) patients with liver tests >3 times ULN also had an elevated urine copper 100 µg/24 hours. Notes of patients with both an elevated 24-hour urine copper and ALT were reviewed. Only 1 of 5 patients was noted by the treat-ing physician to have compliance issues; the rest were documented to be adherent to treatment. Although NCC was calculated in patients in this study using data from commercial assays (data not shown), 47% of patients had values of 0 or negative results, making these values uninterpretable and sug-gesting that urine copper and serum ALT are better markers for monitoring most patients on zinc therapy.
