The Role of Zinc in the Treatment of Wilson's Disease

Abstract

Wilson's disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD.

Keywords: Wilson’s disease; chelating agents; copper intoxication; copper metabolism; zinc therapy.

Figure 1

Schematic copper balance: Panel (a) reflects normal copper metabolism and a normal copper (Cu) balance in which the daily amount of copper ingested from the diet (equal to approximately 30 µmol or 2 mg per 24 h [24 h] [72,73]). Combined excretion of copper via feces and urine is about 25–30 µmol equal to 1.5–2 mg/24 h. Almost 85–95% of total serum copper is tightly bound to ceruloplasmin (shown with a sea green oval) [74], and the rest is in unbound or loosely bound (free) form (shown with a dark red hexagon). Panel (b) reflects impaired copper metabolism in Wilson’s disease (WD), in conditions in which the synthesis of holoceruloplasmin and the excretion of free copper with bile are diminished. Without treatment, the total excretion of copper via the urine and stools remains slightly lower than normal [37,61,75], thereby favoring copper toxicity. The serum free copper can be bound by metallothioneins (shown with yellow squares), deposited in organs (mainly liver), or excreted in the urine. Panel (c) illustrates WD treatments based on chelating agents (i.e., penicillamine (P), trientine (T)), which stimulate the transfer of copper from its organ deposits into the blood, which can induce free copper intoxication. The kidneys counteract high free copper levels by increasing urinary excretion. Panel (d) depicts WD treatment with zinc (Zn), which stimulates the synthesis of intestinal metallothioneins. Since metallothioneins have a greater affinity for copper compared to zinc, the treatment antagonizes exogenous copper absorption (shown with a small green tetragon indicating an impaired entrance of copper from the intestine into serum) and may also neutralize free copper in serum (shown with a lower amount of free copper and light bluish serum color and also by double purple arrows). Intestinal metallothionein-bound copper is excreted in the feces when mucosal cells are sloughed. Overall, the copper balance becomes negative, and the total copper content, including the accumulated organ deposits, is gradually reduced (shown with lower yellow squares in the liver and bluish serum compared to that in Figure 1b). Bound copper is shown in blue and free copper is shown in red. Small green tetragons indicate impaired/blocked pathways. A bluish serum indicates a normal serum free copper and a reddish serum indicates an increased serum free copper level. Similarly, a bluish liver indicates normal serum free copper levels while a reddish liver indicates increased serum free copper levels.