Zinc is an essential mineral for human health, being the second most abundant trace element in the human body. Experiments conducted in the 1960s suggested it may compete with copper in the gut, blocking copper absorption and increasing its excretion via feces.

This observation incited further studies aiming to evaluate zinc-based treatments for several disorders, including those caused by alterations in copper metabolism, such as Wilson disease (WD). Zinc treatment for a patient with WD was first reported in 1978.

Subsequent independent studies reported the use of zinc sulfate and zinc acetate in groups of patients with WD. These initial studies supported the efficacy and safety of zinc treatment as first-line therapy for WD, including in severe cases.

How Does It Work?

Most (85%-95%) serum copper is bound to the protein ceruloplasmin. In WD, copper is not incorporated into ceruloplasmin correctly and the biliary excretion of excess copper is compromised. The increase in non-ceruloplasmin-bound copper leads to its accumulation in several organs, including the brain, where it promotes oxidative stress.

Hence, 2 approaches have been explored in the context of WD treatment: chelation and reduction of circulating non-ceruloplasmin-bound copper levels.

Zinc salts (sulfate, gluconate, and acetate) reduce the levels of non-ceruloplasmin-bound copper, thus improving neurologic symptoms. The underlying molecular mechanism involves zinc-mediated induction of metallothioneins in intestinal epithelial cells and hepatocytes, which bind to copper with great affinity. According to a recent study conducted by Munk et al, zinc therapy approximately halved intestinal copper absorption.

“Differing from the action of chelators, zinc—in either sulfate, gluconate, or acetate forms—reduces the intestinal absorption of copper, thereby leading to the normalization of free copper levels, depletion of stored copper, and appreciable clinical improvement,” Avan et al explained in a review article published in the International Journal of Molecular Sciences.

Chelators vs Zinc in WD

The use of chelators to treat WD patients has improved the outcome of the disease. However, there are some limitations. “A high percentage of patients, who cannot be identified pretreatment, suffer from ‘paradoxical’ deterioration as chelators promote a transient increase in free copper intoxication,” Avan et al explained.

In addition, treatment with chelators, such as penicillamine, trientine, or tetrathiomolybdate, has been associated with severe and even fatal adverse effects.

Zinc salt treatment has emerged as a potentially safer alternative, despite no randomized controlled trials having been completed so far to evaluate the efficacy and safety of neither zinc nor chelator monotherapy in WD.

The results of 2 systematic reviews and meta-analyses suggested a comparable efficacy of chelators and zinc salt treatment in hepatic WD patients, but higher efficacy of zinc over D-penicillamine for neurological WD patients. Moreover, the incidence of adverse events and neurological deterioration was higher in patients treated with D-penicillamine, who have also reported more serious and/or permanent side effects. The only side effect reported for zinc treatment was transient gastric discomfort.

Zinc treatment also seems to be equally effective, albeit with lower toxicity, in preventing or reducing hepatic or neurological WD symptoms when compared to penicillamine.

“Zinc was, therefore, recommended for patients with WD, particularly for neurologic and presymptomatic patients, due to lower rates of neurologic worsening, fewer side effects, and better compliance,” Avan et al wrote. Moreover, zinc therapy seems to be safe for long-term initial and maintenance treatment of presymptomatic WD in children, pregnant women, and patients with neurological manifestations, while the benefits for patients with severe hepatic dysfunction are still uncertain.

Importantly, while treatment with chelators needs 1-2 years to decrease the amount of free copper, zinc-mediated induction of metallothionein and reduction of non-ceruloplasmin-bound copper levels are immediate.

Challenges and Recommendations

A major challenge in zinc treatment is compliance. Noncompliance might dictate treatment failure and the deterioration of a patient’s status. Moreover, follow-up of patients is essential as rare adverse events may occur.

“Up to now, 8 patients with anemia after a long period of zinc therapy for WD have been reported, thus regular follow-up during zinc treatment and the involvement of specialists in the long-term management of Wilson disease are recommended,” Coni et al wrote in Molecules.

The lack of large clinical studies may discourage clinicians to choose zinc as first-line treatment. Nonetheless, treatment guidelines have evolved and some associations already support the use of zinc in the treatment of WD. For instance, the European Association for the Study of the Liver recommended zinc as first-line therapy for neurological presentations of the disease and lower doses of chelators or zinc for presymptomatic patients and maintenance therapy.

In India, zinc is recommended as the first choice for presymptomatic patients and as an alternative first-line therapy for all presentations of the disease. In contrast, chelators are recommended as first-line treatment in the UK due to the lack of experience with zinc salts.

In addition, the effect of zinc on hepatic copper content is highly variable and even absent in some cases, as demonstrated by Munk et al. This might explain, at least in part, the variation in zinc treatment efficacy in WD patients. They also found that zinc acetate (50 mg 3 times a day) and zinc gluconate (50 mg 3 times a day) had a similar ability to reduce intestinal copper uptake. Their results did not support once-daily dosing.

Despite the lack of more robust information, for Avan et al, the advantages of using zinc for treating WD are clear. “Zinc is as effective as other anticopper agents and has the advantage of an extremely low level of toxicity and minimal adverse effects as shown by its long, effective, and safe use (at an affordable cost),” they wrote.

References

Avan A, Członkowska A, Gaskin S, Granzotto A, Sensi SL, Hoogenraad TU. The role of zinc in the treatment of Wilson’s disease. Int J Mol Sci. 2022;23(16). doi:10.3390/ijms23169316

Coni P, Pichiri G, Lachowicz JI, et al. Zinc as a drug for Wilson’s disease, non-alcoholic liver disease and COVID-19-related liver injury. Molecules. 2021;26(21). doi:10.3390/molecules26216614

Munk DE, Lund Laursen T, Teicher Kirk F, et al. Effect of oral zinc regimens on human hepatic copper content: a randomized intervention study. Sci Rep. 2022;12(1):14714. doi:10.1038/s41598-022-18872-8