Clinical Pearls & Morning Reports
Published September 6, 2023
Wilson’s disease may present as liver disease, a neurologic disorder, a psychiatric illness, or a combination of these disorders. Read the NEJM Review Article here.
Q: Wilson’s disease is caused by mutations in what gene?
A: ATP7B, on chromosome 13q14, is the only gene with mutations that are associated with Wilson’s disease. The gene product ATP7B is a multifunctional, intracellular P1-type ATPase, found mainly in the liver. In Wilson’s disease, functional ATP7B is decreased or absent, and excessive copper accumulates in hepatocytes. As copper-induced liver injury progresses, extrahepatic sites — notably, the central nervous system — are affected.
Q: Is the diagnosis of Wilson’s disease based on a low serum ceruloplasmin level alone?
A: The clinical diagnosis of Wilson’s disease involves a detailed medical history taking and physical examination focused on liver, neurologic, and psychiatric disease. Laboratory assessment includes liver biochemical and serum ceruloplasmin levels and basal 24-hour urinary copper excretion. The serum ceruloplasmin level alone is not adequate for diagnosis, although a very low level (<5 mg per deciliter) strongly suggests Wilson’s disease. The ceruloplasmin level can be normal in Wilson’s disease, although a normal value is uncommon.
A: Hepatic Wilson’s disease, which tends to develop earlier than neuropsychiatric Wilson’s disease, ranges from mild liver disease to cirrhosis; in children, fatty liver is common. Infrequently, Wilson’s disease manifests as acute liver failure. In patients with Wilson’s disease, neurologic movement disorders involve either increased movement, with tremor or dystonia, or decreased movement, resembling parkinsonian rigidity. Tremors, poor coordination, and loss of fine motor control may occur early. Dysarthria is often the first prominent symptom. Drooling and difficulty swallowing indicate pseudobulbar involvement. In general, cognitive function is intact; however, subtle deficits in executive ability or integrative capabilities may occur. Clumsiness, loss of athletic skills, or deterioration in school performance may be initial features in adolescents. Psychiatric Wilson’s disease is highly variable, although depression is common. Kayser–Fleischer rings are the main ophthalmologic sign. Other manifestations include renal, cardiac, musculoskeletal, and endocrine conditions. Wilson’s disease can manifest at any age, although usually before the age of 50 years; older age does not rule it out.
A: With consistent, effective medical treatment, the longevity of patients with Wilson’s disease is close to that of the general population. The advent of oral chelators revolutionized treatment for Wilson’s disease: both penicillamine (provided as D-penicillamine) and trientine (dihydrochloride) remain the principal treatments. Zinc salts are effective as maintenance therapy. Once the diagnosis of Wilson’s disease is established, lifelong medical therapy should begin, preferably with a chelator in symptomatic patients. Asymptomatic patients with evidence of organ damage on imaging studies, histologic assessment, or biochemical tests should also receive lifelong therapy. Those without evidence of organ damage can be treated with lower-dose chelation therapy or zinc. Most patients with Wilson’s disease can be treated medically; however, liver transplantation can be lifesaving for patients with acute liver failure or decompensated chronic liver disease who do not have a response to medical treatment. Emerging treatments include new chelators and novel interventions aimed at curing Wilson’s disease by rehabilitating the abnormal ATP7B or correcting the genetic abnormality.