An Update on the Future of Wilson Disease Management

To cite: Brown RS Jr. An update on the future of Wilson disease management. Prim Care Companion CNS Disord. 2022;24(6):AN21065COM1C.
To share: https://doi.org/10.4088/PCC.AN21065COM1C
© Copyright 2022 Physicians Postgraduate Press, Inc.

^aWeill Cornell Medicine, New York, New York

Wilson disease (WD) is a rare autosomal recessive genetic disorder of copper metabolism. Although WD was first described as progressive lenticular degeneration in 1912,¹ and established as a condition related to elevated copper levels in 1948,² it was not until 1956 that the copper chelator penicillamine was introduced³ and 1993 that mutations in the ATP7B gene were implicated as the causative underlying genetic abnormality.⁴ With a broad range of symptoms, including dysarthria, dystonia, tremor, chorea, athetosis, and, in later stages of disease, hepatic failure and neurologic disability, the differential diagnosis of WD may be challenging, leading to delays in initiation of effective therapy.⁵ Although heterozygous mutations of ATP7B may be present in up to 2.5% of the population,⁶ clinical disease manifests in approximately 1 in 30,000 to 100,000 individuals.⁷ WD usually presents in childhood into early adulthood; however, a wider range of ages at onset is recognized.⁸ While it is extremely rare for WD to present after the age of 35, late-onset cases are reported. Given the myriad manifestations of WD, its rarity, and its diversity of presentations, diagnostic acumen and a knowledge of the latest updates in the field, as well as novel therapies in late-stage development, are crucial in ensuring appropriate management.

From a pathophysiologic perspective, WD is caused by dysregulation of the tightly regulated system of transport, retention, and excretion of copper from the diet. Of the roughly 2 to 5 mg of dietary copper ingested daily by an average individual, approximately 2% is retained in the body for use in enzymatic activity, and the remaining portion is excreted in bile.⁹ This process involves multiple transporters. Copper is first absorbed within the small intestines through nonspecific metal uptake transporters, exported from the small intestine to the portal circulation via P-type ATPase copper transporters, and absorbed from portal circulation to the liver via the CTR1 transporter. Within the liver, the ATP7B transporter regulates incorporation of copper into the carrier protein ceruloplasmin, as well as excretion of copper through the biliary system.⁹ In patients with ATP7B mutations, this crucial transport function is impaired, resulting in deficient levels of ceruloplasmin and an accumulation of unbound copper within the liver that ultimately reaches other vital organs, including the brain, eyes, and kidney, resulting in clinical signs and symptoms.¹⁰

The management of WD has evolved over the years. Current guidelines¹⁰ for diagnosis and treatment of WD in adults published by the American Association for the Study of Liver Diseases in 2008 and pediatric guidance¹¹ published in 2018 recommend use of chelation therapies to decrease total body copper stores as well as zinc to reduce intestinal copper absorption. While penicillamine therapy remains a standard treatment for WD,¹¹ trientine is becoming a preferred first-line treatment for WD due to lower rates of side effects and superior tolerability compared with penicillamine.¹² Another chelating agent, tetrathiomolybdate (TTM), was not widely available at the time of publication due to chemical instability of the ammonium salt used initially for WD treatment¹² but is mentioned in guidelines¹⁰ as an experimental decoppering therapy in the United States and Canada. However, a more stable form of this potent and multimodal decoppering agent, bis-choline TTM, has been developed and promising results were reported in a phase 2 clinical trial.¹³ A phase 3 clinical study¹⁴ is underway in patients with WD with a 48-week double-blind phase and an extension period of up to 60 months.

In a systematic review and meta-analysis¹⁵ rating the comparative effectiveness and safety of common WD therapies, although d-penicillamine was associated with lower mortality versus no treatment, the drug was not associated with a lower risk of mortality and improved rates of prevention or amelioration of clinical symptoms compared with zinc alone. In a 10-year follow-up study of 22 children with WD, treatment with zinc sulfate adjusted by age and weight, starting in presymptomatic pediatric patients, resulted in 73% of children (16/22) having normal alanine aminotransferase levels, concurrent with increased urinary copper excretion.¹⁶ A randomized controlled trial comparing trientine hydrochloride plus zinc with TTM plus zinc in primarily newly diagnosed patients with Wilson disease with neurologic symptoms identified a higher risk of neurologic deterioration in patients receiving trientine versus TTM (6 of 23 patients [26%] vs 1 of 25 patients [4%], P < .05).¹⁷ Treatment with another form of trientine—trientine tetrahydrochloride—has also been trialed, with noninferiority to d-penicillamine over 24 weeks of follow-up established in terms of reductions in non-ceruloplasmin copper levels.¹⁸ Clinical efficacy and safety of current therapies and the latest data on bis-choline TTM are reviewed in Table 1.^6,13

In the modern management of WD, consideration of the latest evidence in both diagnosis and long-term treatment are important in optimizing clinical management. In 2022, clinicians should be aware of the role of copper and mutations of the ATP7B gene in disease pathophysiology, as well as the clinical manifestations that may raise clinical suspicion of this rare disease. Through an awareness of key clinical data and novel therapies in late-stage development, clinicians can screen for and maintain awareness of the latest multimodal mechanisms for the management of WD.

 Published online: November 29, 2022.

Unlabeled and investigational usage: The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses. Please refer to the official prescribing information for each product for discussion of approved indicators, contraindications and warnings.

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This commentary was prepared and independently developed by the CME Institute of Physicians Postgraduate Press, Inc., and supported by an educational grant from Alexion Pharmaceuticals, Inc. Dr Brown acknowledges Michael R. Page, PharmD, RPh, for editorial assistance in developing the manuscript.

Robert S. Brown, Jr, MD, MPH, is affiliated with Weill Cornell Medicine, New York, New York.

CME Objective

After completing this educational activity, you should be able to:

• Implement an individualized treatment strategy for the patient with Wilson disease, while watching for new options that could resolve unmet needs

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This Neuroscience Commentary activity was published in November 2022 and is eligible for AMA PRA Category 1 Credit through December 31, 2023. The latest review of this material was June 2022.

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The CME Institute has mitigated all relevant conflicts of interest prior to the commencement of the activity. None of the individuals involved in the content have relevant financial relationships with ineligible companies except the following:

Larry Culpepper, MD, MPH, Editor in Chief, Boston, Massachusetts, has been an advisor for AbbVie, Eisai, and Supernus; has been a stock shareholder of M-3 Information; and has received royalties from UpToDate. Michael R. Page, PharmD, RPh, Independent Medical Director/Medical Writer, Plainsboro, New Jersey, serves as a consultant for BioCentric, Inc., and American Medical Communications, Inc.

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Dr Brown has served as a consultant for Alexion, AbbVie, Gilead, Intercept, Mallinckrodt, Antios, and Ambys and has received grant/research support from AbbVie, Gilead, Intercept, and Mallinckrodt.

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