Wilson Disease

Definition, Etiology, PathogenesisTop

Wilson disease is characterized by an excessive cytotoxic accumulation of copper in tissues caused by an autosomal recessive defect of a hepatocyte membrane–bound copper transporting protein. This is related to a mutation of the ATP7B gene located on chromosome 13 of which there are >500 known genetic variants. The resulting impaired biliary excretion of copper and its accumulation in the liver, brain, kidney, and cornea lead to damage to these organs. One in every 30,000 Canadians is estimated to be living with Wilson disease.

Clinical Features and Natural HistoryTop

The onset of symptoms usually occurs between 5 and 40 years of age, rarely (~3% of patients) later in life. Clinical manifestations are varied and may involve many systems and organs, as outlined below. When untreated, the disease is progressive and may lead to cirrhosis. Patients may also present with acute liver failure, which is associated with high mortality rates and may require urgent liver transplant. Early diagnosis and treatment is the key to preventing copper accumulation and its complications.

1. Hepatic features are seen in ~40% to 50% of patients. Depending on progression of the disease, patients present with various features secondary to steatosis, hepatitis, cirrhosis, or acute liver failure. These include fatigue, abdominal pain, hepatomegaly, splenomegaly, jaundice, portal hypertension, hepatic encephalopathy, and upper gastrointestinal bleeding.

2. Neuropsychiatric features are present in ~40% to 50% of patients and include dystonia, dysarthria, parkinsonism (tremor, bradykinesia, rigidity, dysarthria), salivation, seizures, personality changes, cognitive impairment, mood disorders, and psychosis. Clinicians should be careful not to mistake hepatic encephalopathy for the above findings.

3. Other organ abnormalities: Kayser-Fleischer rings (copper deposits in the Descemet membrane of the cornea, visible on slit lamp examination as a gold-brown corneal rim), sunflower cataract, Coombs test–negative hemolytic anemia (~15% of patients), Fanconi syndrome, cardiomyopathy, arrhythmia, osteomalacia, osteoporosis, arthritis, pancreatitis, delayed puberty, infertility, amenorrhea, repeated miscarriages, hypothyroidism, or hypoparathyroidism.

DiagnosisTop

Diagnostic Tests

1. Blood tests: Elevated serum aminotransferase levels (essentially all patients), occasionally low alkaline phosphatase levels, low serum ceruloplasmin levels, and decreased total serum copper levels (used more for monitoring than diagnosis).

2. Urine tests: In ~80% of patients 24-hour urine copper excretion is >100 microg (1.6 micromol).

3. Imaging studies: Depending on stage of the disease, ultrasonography may reveal hepatomegaly or features of portal hypertension (splenomegaly). In patients with neurologic symptoms, magnetic resonance imaging (MRI) and computed tomography (CT) can reveal lesions in the basal ganglia.

4. Histologic examination of liver biopsy specimens: Nonspecific abnormalities, elevated copper levels (≥250 microg/g of dry tissue in >90% of patients).

5. Genetic tests: Direct sequencing of the ATP7B gene and haplotype analysis are diagnostic options in challenging cases and in siblings of patients with Wilson disease.

Diagnostic Criteria

The diagnosis of Wilson disease is made most often on the basis of a combination of clinical and laboratory findings. The presence of Kayser-Fleischer rings (although their absence does not exclude Wilson disease) and serum ceruloplasmin levels <200 mg/L or 24-hour urinary cooper excretion >100 microg/24 h in a patient with symptoms of liver disease and associated neurologic or psychiatric manifestations represent a classic presentation of Wilson disease. In reality, many cases are not that straightforward and the Leipzig scoring system (Table 1) is used to aid diagnosis.

Differential Diagnosis

Other causes of liver dysfunction, such as alcoholic liver disease, fatty liver disease, hepatitis B or C, alpha1-antitrypsin deficiency, autoimmune hepatitis, hemochromatosis, and medication hepatotoxicity. Neuropsychiatric conditions to consider include parkinsonism, essential tremor, Huntington disease, idiopathic dystonias, and adverse effects of antipsychotic medications.

TreatmentTop

1. Recommend abstinence from alcohol and avoidance of foods that are high in copper, such as nuts, chocolate, soy, mushrooms, liver, and seafood.

2. Use pharmacotherapy indefinitely in all patients, even in pregnancy:

1) For asymptomatic patients start with a copper chelator (this increases urinary copper excretion). Initially use oral penicillamine 250 to 500 mg/d with the dose titrated up by 250 mg every 4 to 7 days to a total of 1 to 1.5 g/d in 4 divided doses. During therapy the patient should receive pyridoxine supplementation (25-50 mg/d). When treated with penicillamine, 30% of patients develop adverse effects (dysgeusia, nausea, myelosuppression) and may be switched to another chelator: trientine 1 to 1.5 g/d. Reduce the dose of chelators by 25% to 50% during pregnancy.

The cost of trientine in some jurisdictions may exceed $1000 per day and access to the drug is thus limited.

2) For maintenance treatment we recommend oral zinc 75 to 250 mg/d in 2 or 3 divided doses (zinc acts to inhibit gastrointestinal copper absorption). This can be in addition to the copper chelator or as monotherapy in asymptomatic patients and patients in whom chelators are poorly tolerated or contraindicated.

3. Liver transplant is indicated in patients with acute liver failure due to Wilson disease (previously known as “fulminant Wilson disease”) and a prognostic index of ≥11 (Table 2) or in patients with refractory decompensated cirrhosis.

Follow-UpTop

Regular follow-up is necessary after starting copper chelation, initially every week over the first month, 1 to 3 months per the first year of therapy, then 1 to 2 times per year. Follow-up should include history and physical examination, complete blood count (CBC) with differential count (see Diagnostic Tests, above), liver and kidney function parameters, serum copper level, urinalysis, and 24-hour urinary copper excretion (should be 200-500 microg/24 h in a controlled state; at the beginning of therapy initially may be much higher). Nephrotoxicity and myelosuppression are rare but important adverse effects of penicillamine that are often detected on routine blood tests. The thresholds for concern about myelosuppression and decision to stop the drug should follow the manufacturer’s guidelines and may depend on baseline values and time trend of changes, but such thresholds are usually suggested as below 3×109 and 3.5×109 white blood cells/L, ~2×109 neutrophils/L, and 100×109 to 120×109 platelets/L.

PrognosisTop

Acute liver failure is life-threatening (scoring of severity: Table 2). The prognosis for patients receiving treatment with other clinical presentations and complications of Wilson disease is generally good, including those with advanced live disease. The risk of hepatocellular carcinoma is controversial.

TablesTop