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Wilson’s DiseaseWilson’s disease, which may lead to severe copper overload and multiorgan dysfunction, is best managed collaboratively by specialists in hepatology, neurology, psychiatry, and clinical genetics.

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.This Perspective explores the connection between copper and cancer and how challenges in the field could be addressed, and is a synthesis of discussions from the Copper Cancer Consortium, a meeting of experts in the field that took place in March 2020.

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B , which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B . Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD. Wilson disease is an inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. This Primer describes the pathogenesis of this disorder and outlines diagnostic and management strategies.

Background Wilson disease requires lifelong therapy, currently given daily in multiple divided dosages. Aim To prospectively evaluate once-daily trientine as therapy for Wilson disease. Methods Study group: eight patients (seven males) aged 22–71 years with stable Wilson disease treated from 4 to 50 years. Patients were monitored for 3 months then for 12 months on a single daily dose of trientine (15 mg/kg). Results All patients remained clinically well. ALT and AST fluctuated in some, but none required treatment stoppages or side effects. Liver synthetic function was unchanged. Mean 24-h urine copper and zinc excretions at end of treatment were 313.4 ± 191.7 and 2,214 ± 1,346 μg, respectively. Conclusions Once-daily trientine should be explored further for possible maintenance therapy for WD. Single daily dose may improve adherence to therapy. Larger trials and longer-term follow-up will establish the safety and treatment efficacy of this once-daily treatment regimen for WD (registration: NCT01472874).

Progressive hepatolenticular degeneration, or Wilson's disease, is a genetic disorder of copper metabolism. Knowledge of the clinical presentations and treatment of the disease are important both to the generalist and to specialists in gastroenterology and hepatology, neurology, psychiatry, and paediatrics. Wilson's disease invariably results in severe disability and death if untreated. The diagnosis is easily overlooked but if discovered early, effective treatments are available that will prevent or reverse many manifestations of this disorder. Studies have identified the role of copper in disease pathogenesis and clinical, biochemical, and genetic markers that can be useful in diagnosis. There are several chelating agents and zinc salts for medical therapy. Liver transplantation corrects the underlying pathophysiology and can be lifesaving. The discovery of the Wilson's disease gene has opened up a new molecular diagnostic approach, and could form the basis of future gene therapy.

The coronavirus disease 2019 pandemic has had an impact on all facets of our health care system, including life‐saving procedures like organ transplantation. Concerns for potential exposure to the causative severe acute respiratory syndrome coronavirus type 2 have profoundly altered the process of organ donation and recovery that is vital to the execution of organ transplantation. Issues regarding adequate donor evaluation and consent, organ recovery, organ procurement organization, and donor hospital resources as well as the transplant center’s acceptance of organ offers for their candidates have all required new practice paradigms. Consequently, the ability to treat patients with organ failure, in particular patients with end‐stage liver disease in whom no temporizing treatments exist, and to obtain expected excellent outcomes for new liver transplant recipients has been challenged during this time. Conclusion: We summarize some of the negative effects of the current pandemic on organ recovery and liver transplantation as well as offer considerations and strategies for their mitigation that could have a lasting impact on the field even after the coronavirus disease 2019 has waned.

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 retrospective 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 demonstrated 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 alternative treatments are paramount for those without both a normal serum ALT and appropriate urine copper excretion. We describe one of the largest recent studies of Zn therapy in WD and include data on alternative Zn salts which is lacking thus far. In clinical practice, due to issues of intolerance and increased cost of WD medications, many patients have gravitated towards alternative Zn salts, some purchasing non‐prescription Zn over‐the‐counter. An understanding of the potential utility of different Zn preparations and required monitoring will provide benefit in expanding and optimizing treatment options for patients with WD.

The coronavirus disease 2019 (COVID‐19) pandemic created a crisis that disproportionately affected populations already disadvantaged with respect to access to health care systems and adequate medical care and treatments. Understanding how and where health care disparities are most widespread is an important starting point for exploring opportunities to mitigate such disparities, especially within our patient population with liver disease. In a webinar in LiverLearning, we discussed the impact of the pandemic on the United States, United Kingdom and Canada, highlighting the disproportionate effects on infection rates and death for certain ethnic minorities, those socioeconomically disadvantaged and living in higher density areas, and those working in health care and other essential jobs. We set forth a “call to action” for members of the American Association for the Study of Liver Diseases and the larger community of providers of liver disease care to generate viable solutions to improve access to care and vaccination rates of our patients against COVID‐19, and in general help reduce health care disparities and improve the health of disadvantaged populations within their communities. Solutions will likely involve personalized interventions and messaging for communities that honor local leaders and embrace the diverse needs and different cultural sensitivities of our unique patient populations.

[...]many areas of patient care are still reliant on older data with case series, and many articles still lack sufficient statistical power for conclusive recommendations due to their cohort size. There has been a significant shift in focus over the last decade to move away from using just the urinary copper excretion in isolation, and moving to pairing it with methods of measuring circulating bioavailable copper. In the wider setting, the UK/NIHR (National Institute for Health and Care Research) research delivery network (RDN) is a body that helps co-ordinate and support studies and is an important key factor in bringing together patients in less commonly seen conditions (Fig 1). Hopefully, the generation of this multidisciplinary guideline in Portugal will be the first step in its journey along this same route to bring the latest diagnostics and comprehensive evaluation and testing to bear to achieve best patient outcomes for their population of WD, and for the larger community caring for this disorder.