Wilson disease

Wilson disease is an autosomal recessive metabolic disorder in which impaired copper excretion causes copper to accumulate in the body. Early-stage Wilson disease is characterized by the presence of copper deposits in the liver. As the disease progresses, copper accumulates in other organs as well, most importantly in the brain and cornea. The disease often goes undiagnosed until clinical suspicion is raised by the characteristic combination of hepatitis or cirrhosis, dementia, and parkinsonism. Kayser-Fleischer rings (brownish copper deposits visible around the iris) are a further indication of Wilson disease. Diagnostics involve slit lamp examination and laboratory studies to assess copper metabolism (e.g., ceruloplasmin, urinary copper excretion). Genetic testing or liver biopsies with quantitative copper assays may be necessary if the diagnosis is indeterminate. Management consists of maintaining a low-copper diet and administration of a chelating agent (e.g., penicillamine) or zinc salts. Individuals with Wilson disease have a good prognosis if the condition is diagnosed and treated early.

• Age of onset: : 5–35 years ; (mean age 12–23 years) ^[1][2]
• Prevalence: ∼ 1/30,000 ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13, which encodes for a membrane-bound, copper-transporting ATPase → defective ATP7B protein ^[4]
  • Reduced incorporation of copper into apoceruloplasmin; → ↓ serum ceruloplasmin
  • Reduced biliary copper excretion
• Results in ↑ free serum copper → accumulation in the liver, cornea, CNS (basal ganglia, brain stem, cerebellum), kidneys, and enterocytes ^[5]

• Hepatic: variable degrees of liver disease possible
  • Hepatosplenomegaly
  • Jaundice
  • Ascites
  • Abdominal pain
  • Symptoms of acute or chronic hepatitis (may be indistinguishable from autoimmune hepatitis)
  • Signs of chronic liver disease
    • Hepatic encephalopathy
    • Cirrhosis
    • Portal hypertension
  • Symptoms of acute liver failure
• Ocular
  • Kayser-Fleischer rings
    • Copper accumulation in the Descemet membrane; that results in 1–2 mm wide; golden or green-brown rings in the periphery of the cornea
    • Characteristic for Wilson disease, but absence does not rule out the diagnosis
  • Sunflower cataracts: copper deposits in the lens causing opacification in the shape of a sunflower
• Neurological
  • Cerebellar symptoms, e.g.:
    • Dysarthria (most common)
    • Gait abnormalities
    • Choreoathetosis
  • Extrapyramidal symptoms, e.g.:
    • Dystonia
    • Parkinsonism
    • Tremor (usually asymmetric, affecting the hands), which may be any combination of:
      • Resting tremor
      • Intention tremor
      • Wing-beating tremor: a low frequency, high amplitude tremor that is most prominent when the arms are outstretched anteriorly or laterally
  • Drooling (caused by oropharyngeal dysphagia)
  • Seizures
  • Cognitive impairment
• Psychiatric and behavioral
  • Major depressive disorder
  • Irritability
  • Psychosis
• Other: : e.g., Fanconi syndrome

Wilson disease should be suspected in cases of nonspecific noninfectious liver disease and in nonspecific extrapyramidal movement disorders.

Approach ^[7]

• Consider a diagnosis of Wilson disease in individuals with:
  • Acute liver failure (ALF) with nonimmune hemolytic anemia (i.e., negative Coombs test)
  • Recurrent self-limited hemolysis
  • Unexplained liver disease, especially if accompanied by neuropsychiatric symptoms
  • A first-degree relative with Wilson disease
• Perform a comprehensive clinical assessment.
• Obtain routine laboratory studies to evaluate for liver involvement and hemolysis.
• Obtain copper metabolism studies to assess for Wilson disease.
• Consider advanced studies (e.g., liver biopsy, genetic testing) if the diagnosis remains unclear.

Routine screening for Wilson disease in patients with acute liver failure is not recommended. ^[8]

Clinical evaluation ^[6]

• Obtain a detailed personal and family history.
• Conduct a comprehensive examination, including:
  • Neurological examination
  • Psychiatric evaluation
  • Slit lamp examination: Kayser-Fleischer rings, sunflower cataract

Laboratory studies

Routine laboratory studies ^[6]

• Liver chemistries
  • ↑ Transaminases; AST > ALT in cirrhosis
  • ↑ Bilirubin, ↓ alkaline phosphatase in patients with ALF and/or hemolysis
• CBC: hemolytic anemia, thrombocytopenia, leukopenia may be present
• BMP: ↑ BUN, ↑ creatinine, ↓ potassium in renal involvement
• Other
  • Coombs test: negative
  • ↑ INR in patients with severe liver damage
  • ↓ Uric acid in patients with associated renal tubular dysfunction
• Urinalysis: may show microscopic hematuria and/or other findings consistent with Fanconi syndrome (e.g., aminoaciduria)

Copper metabolism studies ^[6]

• ↓ Serum ceruloplasmin (< 20 mg/dL)
• ↑ 24-hour urine copper excretion (> ULN)
• Serum copper (optional)
  • ↓ Total serum copper
  • ↑ Free serum copper (i.e., non-ceruloplasmin-bound copper)

Interpretation of initial testing ^[6]

• In patients with one or more clinical features of Wilson disease:
  • ↓ Serum ceruloplasmin and ↑ 24-hour urine copper: Diagnosis is confirmed.
  • Inconclusive serum ceruloplasmin and/or 24-hour urine copper: Obtain advanced studies.
• Scoring systems (e.g., Leipzig score) may help establish the diagnosis.

The absence of typical findings (e.g., Kayser-Fleischer rings) does not exclude the diagnosis.

Advanced studies ^[2][7]

• Liver biopsy: Consider if other tests are inconclusive. ; ^[2]
  • May show positive copper staining (low sensitivity)
  • Hepatic copper concentration > 250 mcg/g (dry weight) indicates Wilson disease. ^[7]
  • Nonspecific findings include mild steatosis, fibrosis, and cirrhosis.
• Genetic testing for ATP7B mutation in patients with either:
  • First-degree relatives with Wilson disease
  • Inconclusive diagnostic tests
• MRI brain
  • Consider in patients with neurological findings.
  • Findings
    • Hyperintensities in the basal ganglia, thalamus, pons, and white matter
    • “Face of the giant panda” sign (rare but pathognomonic): a specific pattern of midbrain copper accumulation

• Hepatic
  • Autoimmune hepatitis
  • Viral hepatitis
  • Hemochromatosis
  • Nonalcoholic fatty liver disease
  • Cirrhosis
• Neuropsychiatric
  • Parkinson disease
  • Huntington disease
  • Multiple sclerosis
  • Schizophrenia
  • Personality disorders

The differential diagnoses listed here are not exhaustive.

General principles ^[6]

• Refer to hepatology for specialist-guided management.
• All patients require lifelong pharmacological therapy.
• Encourage a low-copper diet (e.g., avoidance of organ meats, shellfish, nuts, chocolate, copper-containing dietary supplements).
• Manage hepatic symptoms.
  • Implement treatment of cirrhosis in advanced liver disease.
  • Initiate management of acute liver failure in decompensated cirrhosis.
  • Refer patients with ; refractory decompensated cirrhosis or acute liver failure for liver transplantation.
• Consult neurology and/or psychiatry for symptomatic management.

Pharmacological therapy ^[7]

• Initial therapy
  • First line: chelating agents; , e.g., penicillamine; (preferred) or trientine
  • Alternative: zinc salts (may also be used first-line for asymptomatic individuals)
• Maintenance therapy: : reduced-dose zinc salts or a chelating agent

The goal of initial therapy is to eliminate copper; the goal of maintenance therapy is to prevent reaccumulation of copper.

Chelating agents should be titrated gradually. Rapid mobilization of the copper stored in tissues may exacerbate neurological symptoms.

Monitoring ^[6]

All patients should be regularly monitored for clinical and laboratory-based improvement and treatment side effects.

• Clinical assessment, including neurological examination, at least every 6 months
• Laboratory studies
  • At least every 6 months: serum copper, ceruloplasmin, liver enzymes, INR, CBC, and urinalysis
  • At least once yearly: 24-hour urine copper