Wilson Disease

GENERAL PRINCIPLES Wilson disease (WD) is an autosomal recessive disorder (ATP7B gene on chromosome 13) that results in progressive copper overload.

• Female-to-male ratio is 2:1.

• Absent or reduced function of ATP7B protein leads to decreased hepatocellular excretion of copper into bile. This results in hepatic copper accumulation and injury. Eventually, copper is released into the bloodstream and deposited in other organs, notably the brain, kidneys, and cornea.

î Extrahepatic manifestations include Kayser-Fleischer rings in the Descemet membrane in the periphery of the cornea due to copper deposition (diagnosed on slit-lamp examination), Coombs­negative hemolytic anemia, renal tubular acidosis, arthritis, osteopenia, and cardiomyopathy.

Diagnosis

Clinical Presentation

• The average age at presentation of liver dysfunction is 6-20 years, but it can manifest later in life. Liver disease can be highly variable, ranging from asymptomatic with only mild biochemical abnormalities to ALF.

• Most patients who present with ALF resulting from WD have a characteristic pattern of clinical findings including Coombs-negative hemolytic anemia with features of acute intravascular hemolysis, rapid progression to renal failure, a rise in serum aminotransferases from the beginning of clinical illness (typically lt;2000 IU/L), and normal or markedly subnormal serum ALP (typically lt;40 IU/L).

• The diagnosis of WD should be considered in patients with unexplained liver disease with or without neuropsychiatric symptoms, first-degree relatives with WD, or individuals with ALF.

• Neuropsychiatric disorders usually occur later, most of the time in association with cirrhosis. The manifestations include asymmetric tremor, dysarthria, ataxia, and psychiatric features.

Diagnostic Testing

• Low serum ceruloplasmin level (lt;20 mg/dL), elevated serum free copper level (gt;25 #956;g#8725;dL), and elevated 24-hour urinary copper level (gt;100 #956;g) are seen in patients with WD.

• Urinary copper excretion gt;1600 #956;g copper per 24 hours following the administration of 500 mg of D- penicillamine at the beginning and again 12 hours later during the 24-hour urine collection is seen in patients with WD.¹⁸

• Liver histology findings (massive necrosis, steatosis, glycogenated nuclei, chronic hepatitis, fibrosis, cirrhosis) are nonspecific and depend on the presentation and stage of the disease. Elevated hepatic copper levels of gt;250 #956;g#8725;g dry weight (normal lt;40 #956;g#8725;g) on biopsy are highly suggestive of WD.

• Mutation analysis by whole-gene sequencing is possible and should be performed on individuals in whom the diagnosis is not established by clinical and biochemical testing. Many patients are compound heterozygotes for mutations in the ATP7B gene, making identification of mutations difficult.

TREATMENT

Medications

Treatment is with copper-chelating agents penicillamine and trientine. Zinc salts that block intestinal absorption of copper are also used.

• Penicillamine 1-1.5 g/d (in divided doses bid or qid) and pyridoxine 25 mg/d (to avoid vitamin B₆ deficiency during treatment) are indicated in patients with hepatic failure. Use may be limited by side effects (e.g., hypersensitivity, bone marrow suppression, proteinuria, systemic lupus erythematosus, Goodpasture syndrome). Penicillamine should never be given as initial treatment to patients with neurologic symptoms, due to the risk of exacerbating neurologic manifestations.

• Trientine 1-1.5 g/d (in divided doses bid or qid) may also be used in hepatic failure. This has similar side effects as penicillamine but at a lower frequency. The risk of neurologic worsening with trientine is less than that with penicillamine.

• Zinc salts 50 mg tid are indicated in patients with chronic hepatitis and cirrhosis in the absence of hepatic failure. Other than gastric irritation, zinc has an excellent safety profile.

Surgical Management

Liver transplantation is the only therapeutic option in FHF or in patients with progressive dysfunction despite chelation therapy.

Monitoring and Follow-Up

• Serum copper and ceruloplasmin, liver biochemistries, INR, complete blood cell count, urinalysis (especially for those on chelation therapy), and physical examination should be performed regularly, at least twice annually.

• Annual measurement of 24-hour urinary excretion of copper may be needed if there is suspicion of noncompliance or if a dose adjustment is required. The estimated serum free copper may be elevated or low in situations of nonadherence and overtreatment, respectively.

• First-degree relatives of any newly diagnosed patient with WD should be screened for WD.

• After liver transplantation, in the absence of neurologic symptoms, patients require no further medical treatment.