**Background:** Wilson disease (WD) is a genetic disorder of copper metabolism caused by autosomal recessive mutations in the ATP7B gene on chromosome 13, leading to impaired biliary copper excretion and toxic accumulation in tissues, especially the liver and central nervous system. The most frequently reported prevalence is ~1 in 30,000 worldwide, with an expected 8,300–11,000 cases in the United States. Studies in the UK suggest a genetic prevalence of ~1:7,026 to ~1:20,000, indicating possible underdiagnosis. Usual age of presentation is 4–40 years, but cases have been reported from age 3 to 70 years. A meta-analysis identified 782 ATP7B variants, with 216 considered likely pathogenic; approximately 1 in 90 people may be carriers. Without treatment, excess copper generates free radicals, causing oxidative damage to mitochondria, nuclei, and peroxisomes, ultimately leading to cirrhosis and death.
**Methods:** This is an expert perspective review that summarizes and streamlines the updated 2022 AASLD Practice Guidance on WD for clinical use. The authors are experts in WD management and members of the Chronic Liver Disease Foundation (CLDF). The review covers epidemiology, pathophysiology, clinical presentation (including sex-specific, age-specific, and ethnicity-specific considerations), diagnostic recommendations, and treatment approaches. It incorporates data from multiple referenced studies, including a retrospective registry study of 627 patients (1958–2010), a survey of 97 patients from the WD Association network, a study of 1,357 WD patients, a retrospective analysis of 229 patients (mean observation 14.8 ± 11.4 years, range 0.5–52.0 years, totaling 3,116 patient years), and the phase 3 CHELATE trial.
**Key Results:** Hepatic symptoms are more predominant in female patients (57%), while neurological symptoms are more common in male patients (60%). Female patients are more likely to develop acute liver failure (ALF), with a female-to-male ratio >2:1 to 4:1. In a post hoc analysis of 51 patients on trientine, sex differences in UWDRS decrease were significant (p = 0.02), with continuous improvement mainly seen in females. A retrospective study of 282 pregnancies in 136 WD patients found an overall spontaneous abortion rate of 73/282 (26%); patients receiving treatment had significantly fewer spontaneous abortions than undiagnosed patients (OR 2.853, 95% CI 1.634–4.982). In a study of 46 patients symptomatic after age 40, 19/27 with available biopsies had cirrhosis. A Canadian study of 52 probands found Caucasians had later disease onset (14 vs 10 years, p = 0.002) and more decompensated cirrhosis (38% vs 7%, p = 0.01). In the Austrian retrospective analysis of 229 patients on chelation therapy, 26% fully recovered, 24% improved, 25% had stable disease, and 15% deteriorated; cirrhosis at diagnosis was the best predictor of death (OR 6.8, 95% CI 1.5–31.03, p = 0.013) and need for liver transplantation (OR 0.07, 95% CI 0.016–0.307, p < 0.001). Only 84% of patients with cirrhosis survived 20 years after diagnosis (vs healthy Austrians, p = 0.008). A retrospective analysis of 288 treated patients found hepatic treatment failure occurred more often with zinc (14/88 treatments) than chelator therapy (4/313 treatments; p < 0.001). Kayser-Fleischer rings are present in 90% of patients with neurological manifestations and absent in ~60% of patients with hepatic manifestations. Approximately 3%–5% of WD patients present with ALF, and without liver transplantation, mortality rates approach 100%.
**Clinical Implications:** WD should be considered in any patient with unexplained liver disease, regardless of age. Diagnosis requires a combination of assessments: serum ceruloplasmin (typically <14 mg/dL in WD), basal 24-hour urinary copper (>100 μg/24 h in symptomatic patients; >40 μg/24 h may indicate WD in asymptomatic individuals), slit-lamp examination for KF rings, and genetic testing for ATP7B mutations when biochemical testing is inconclusive. No single gold standard diagnostic test exists. All patients require lifelong medical therapy: chelating agents (D-penicillamine or trientine) for symptomatic patients, and chelators or zinc for asymptomatic patients. Trientine may be better tolerated than D-penicillamine, which leads to discontinuation in almost one-third of patients due to adverse effects. The first new drug approval for WD in over 50 years was trientine tetrahydrochloride in 2022, based on the phase 3 CHELATE trial demonstrating noninferiority to penicillamine. Regular monitoring includes 24-hour urinary copper excretion, liver biochemistries, INR, complete blood count, and urinalysis. Overtreatment is indicated by cytopenias, increased ferritin, or urinary copper <100 μg/24 h for chelation or <20 μg/24 h for zinc. Dietary counseling for copper intake <0.9 mg/day is recommended. Nonadherence leads to recurrent symptoms, liver failure, and need for transplantation. Novel therapies under investigation include ALXN1840 (bis-choline tetrathiomolybdate) and gene therapies (VTX-801, UX701).