How do you diagnose and manage Wilson disease?

How to Rule Out Wilson Disease and Management

Wilson disease must be excluded in any patient aged 3-55 years with unexplained liver abnormalities, neuropsychiatric symptoms, or both, using a combination of slit-lamp examination for Kayser-Fleischer rings, serum ceruloplasmin, 24-hour urinary copper, and hepatic copper concentration on liver biopsy. 1

Diagnostic Approach

When to Suspect Wilson Disease

Consider Wilson disease in the following clinical scenarios:

• Any individual aged 3-55 years with liver abnormalities of uncertain cause (though cases have been diagnosed from age 5 to the eighth decade) 1, 2
• Unexplained liver disease combined with neurological or neuropsychiatric symptoms 1
• Acute liver failure with Coombs-negative hemolytic anemia and intravascular hemolysis 3, 2
• Pediatric or young adult patients with autoimmune hepatitis-like presentation or poor response to corticosteroid therapy 3, 2
• Acute liver failure with low alkaline phosphatase and alkaline phosphatase to total bilirubin ratio <2 3

Essential Diagnostic Tests

The diagnostic workup requires the following tests:

• Slit-lamp examination by an experienced ophthalmologist for Kayser-Fleischer rings (golden-brownish deposits in Descemet's membrane at the corneal limbus) 1, 2

  • Present in 50-62% of patients with predominantly hepatic presentations 2
  • Absence does NOT exclude Wilson disease, even in neurological presentations 1

• Serum ceruloplasmin (typically <20 mg/dL in Wilson disease) 1, 4

  • Critical caveat: Can be falsely elevated by inflammation, pregnancy, estrogen supplementation, or oral contraceptives 1
  • Can be low in severe end-stage liver disease of any cause or protein-losing conditions 1
  • Immunologic assays may overestimate levels by not distinguishing apoceruloplasmin from holoceruloplasmin 1

• 24-hour urinary copper excretion (typically >100 μg/day; often markedly elevated in acute liver failure, ranging 844-9375 μg/24h) 3, 5

• Hepatic copper concentration on liver biopsy: >250 μg/g dry weight is confirmatory 3, 4

• Serum copper levels (may be elevated in acute liver failure due to Wilson disease) 3

• ATP7B mutation analysis when diagnosis remains uncertain after clinical and biochemical testing 2, 6

Specific Features in Acute Liver Failure

In acute liver failure presentations, look for these distinguishing features:

• Coombs-negative hemolytic anemia with intravascular hemolysis 3, 2
• Modest aminotransferase elevations (disproportionately low for degree of liver failure) 1, 2
• Markedly low or normal alkaline phosphatase 3, 2
• Alkaline phosphatase to total bilirubin ratio <2 3
• Kayser-Fleischer rings may be absent in up to 50% of acute liver failure cases 3

Diagnostic Pitfalls

Be aware of these common diagnostic challenges:

• Age alone should never exclude Wilson disease—cases occur from age 5 to the eighth decade 1, 2
• Approximately 18% of patients with non-fulminant disease have neither Kayser-Fleischer rings nor low ceruloplasmin 5
• Autoimmune hepatitis mimicry is common; all such patients must be evaluated for Wilson disease before starting corticosteroids 3, 2
• Serum aminotransferase elevations may be mild and do not reflect disease severity 1

Family Screening

All first-degree relatives of patients with Wilson disease must be screened because presymptomatic treatment prevents disease progression 3, 2

Screening protocol includes:

• History and physical examination 3, 2
• Serum copper and ceruloplasmin 3, 2
• Liver function tests 3, 2
• Slit-lamp examination for Kayser-Fleischer rings 3, 2
• Consider ATP7B haplotype analysis or mutation testing 2

Management

Treatment Initiation

All diagnosed patients require lifelong treatment, which must be initiated immediately upon diagnosis. 2

For presymptomatic patients identified through family screening:

• Children under age 3 years: Zinc is preferred 3, 2
• Children over age 3 years and adults: Either zinc or chelating agents are effective 3, 2

Treatment Options

Chelating Agents:

• D-penicillamine (FDA-approved for Wilson disease) 4

  • Promotes copper excretion and detoxification 4
  • Critical warning: Neurological symptoms may worsen during initiation; do NOT discontinue therapy despite this 4
  • If neurological worsening continues for one month, consider short courses of 2,3-dimercaprol (BAL) while continuing penicillamine 4
  • Temporary interruption increases risk of sensitivity reactions upon resumption 4

• Trientine (alternative chelating agent) 7, 8

Zinc Salts:

• Zinc acetate (FDA-approved): 50 mg elemental zinc three times daily for adults >50 kg 9
  • Alternative dosing: 25 mg three times daily also appears adequate 9
  • Must be taken at least 30 minutes before meals for optimal absorption 10
  • Taking with food interferes with absorption and reduces effectiveness 10
  • Once-daily dosing is inadequate and should not be used 9
  • Mechanism: Induces enterocyte metallothionein synthesis, which preferentially binds copper and blocks absorption 10

Combination Therapy:

• Critical caveat: When combining chelator plus zinc, careful timing is required to avoid having the chelator bind to zinc 3

Special Populations

Pregnancy:

• Treatment must be maintained throughout pregnancy—interruption has resulted in acute liver failure 3, 2
• Both zinc acetate and penicillamine have been used successfully during pregnancy 9, 4
• From limited experience with zinc acetate (19 women, 26 live births), birth defect rate was 7.7% versus 4% in general population 9

Acute Liver Failure:

• Liver transplantation is the only effective treatment for acute liver failure due to Wilson disease 3, 7
• Also indicated for decompensated cirrhosis unresponsive to medical therapy 2

Monitoring Treatment

Patients should be monitored at least twice yearly with:

• Liver function tests 3
• Indices of copper metabolism 3
• 24-hour urinary copper excretion 3

Target values:

• Patients on chelators: 24-hour urinary copper 200-500 μg/day 3
• Patients on zinc: Urinary copper excretion ≤75 μg/day 3, 10

Overtreatment Warning

Overtreatment can lead to copper deficiency, resulting in:

• Neutropenia 3
• Anemia 3
• Hyperferritinemia 3

Adherence Issues

Poor compliance is a major problem, particularly in:

• Adolescents 8
• Patients with psychiatric disorders 8
• Transition from pediatric to adult care is a vulnerable period requiring coordinated "transition training" starting in early adolescence 8

Prognosis

Long-term survival in Wilson disease patients is similar to the general population if disease is diagnosed early and treated correctly. 8

• Patients with longer delay from diagnosis to therapy have worse outcomes 8
• Those presenting with neurological and psychiatric symptoms have worse quality of life 8
• Symptomatic patients initially treated with chelators showed no deterioration of neuropsychiatric function or liver function tests for up to 14 years 9
• Presymptomatic patients (30 followed for up to 10 years) developed no symptoms of Wilson disease when treated 9