What are the clinical features, diagnosis, and treatment options for Wilson disease?

Wilson Disease: Clinical Features, Examination, Diagnosis, and Treatment

Clinical Features

Wilson disease presents most commonly with hepatic manifestations in children and younger adults, while neurological and psychiatric symptoms predominate in older patients, though any combination can occur at any age. 1

Hepatic Presentations

• Asymptomatic hepatomegaly or incidental aminotransferase elevation may be the only finding in early disease 2
• Chronic hepatitis with features indistinguishable from autoimmune hepatitis, particularly in younger patients 2
• Cirrhosis develops frequently by the second decade of life, typically macronodular 2
• Acute liver failure with a characteristic constellation:
  • Coombs-negative hemolytic anemia with intravascular hemolysis 2
  • Modest aminotransferase elevations (typically <2000 IU/L) 2
  • Markedly subnormal or normal alkaline phosphatase (typically <40 IU/L) 2
  • Alkaline phosphatase to total bilirubin ratio <2 2
  • Coagulopathy unresponsive to parenteral vitamin K 2
  • Rapid progression to renal failure 2
  • Female predominance (2:1 ratio) 2

Neurological Presentations

• Motor abnormalities with Parkinsonian features: dystonia, hypertonia, rigidity 2
• Movement disorders: tremors (choreic or pseudosclerotic), dysarthria, dysphonia 2
• Disabling symptoms: muscle spasms leading to contractures, dysphagia 2
• Rare presentations include polyneuropathy or dysautonomia 2

Ophthalmologic Findings

• Kayser-Fleischer rings are golden-brownish pigment deposits in Descemet's membrane at the corneal limbus 1, 3
• Present in 50-62% of patients with predominantly hepatic presentations 1
• May be absent in 50% of patients presenting with acute liver failure 2
• Slit-lamp examination by an experienced observer is mandatory, as rings are not always visible by direct inspection 1

Physical Examination

All patients require comprehensive ophthalmologic and neurologic evaluation regardless of presenting symptoms. 2

Key Examination Components

• Slit-lamp examination for Kayser-Fleischer rings (essential, not optional) 1
• Neurologic evaluation should be performed on all patients, with consultation from a neurologist or movement disorder specialist for those with evident symptoms 2
• Assessment for hepatomegaly, stigmata of chronic liver disease, and signs of portal hypertension 2
• Evaluation for psychiatric disturbances and cognitive impairment 2

Neuroimaging

• Brain MRI is preferred over CT and should be obtained prior to treatment in all patients with neurologic symptoms 2
• Typical findings include hyperintensity on T2-weighted images in the basal ganglia 2
• Abnormalities may be present even before symptom onset 2

Diagnosis

Diagnosis requires a combination of clinical findings and biochemical testing, as no single test is definitive in all cases. 2

Diagnostic Algorithm

For patients aged 3-45 years with unexplained liver abnormalities, Wilson disease must be considered, though cases have been diagnosed from age 5 to the eighth decade. 1

Essential Diagnostic Tests

• Serum ceruloplasmin: decreased in most patients (typically <20 mg/dL), though normal levels do not exclude the diagnosis, particularly in acute liver failure 2
• 24-hour urinary copper excretion: elevated (>40 μg/day or 0.6 μmol/day baseline; markedly elevated in acute liver failure, typically >200 μg/dL) 2
• Serum copper: usually elevated, particularly in acute liver failure (typically ≥200 μg/dL or 31.5 μmol/L) 2
• Hepatic copper content on liver biopsy: >250 μg/g dry weight is diagnostic; normal (<40-50 μg/g) almost always excludes Wilson disease 2
• Intermediate values (70-250 μg/g) require further testing, especially with active liver disease 2

Molecular Testing

• ATP7B mutation analysis by whole-gene sequencing should be performed when diagnosis is difficult to establish by clinical and biochemical testing 2
• Haplotype analysis or specific mutation testing is recommended for family screening of first-degree relatives 2
• The His1069Gln point mutation is the most common 4

Critical Diagnostic Pitfalls

All children with apparent autoimmune hepatitis and any adult failing to respond rapidly to corticosteroids must be carefully evaluated for Wilson disease before continuing immunosuppression. 2

• Histologic findings may be indistinguishable from autoimmune hepatitis 2
• Hepatic steatosis may mimic nonalcoholic fatty liver disease 2
• In acute liver failure, ceruloplasmin has poor predictive value 2
• AST may exceed ALT, potentially reflecting mitochondrial damage 2

Treatment

Lifelong treatment is mandatory and must be maintained throughout pregnancy, as interruption has resulted in acute liver failure. 1, 3

Treatment Options

Chelating Agents

D-penicillamine is FDA-approved and was the first effective oral treatment 3

• Dosage for Wilson disease: limited to 750 mg daily during pregnancy; reduced to 250 mg for the last 6 weeks if cesarean section is planned 3
• Major limitation: up to 30% of patients experience adverse events requiring discontinuation 5
• Neurological worsening may occur during initiation; despite this, the drug should not be withdrawn due to increased risk of sensitivity reactions upon resumption 3
• Monitoring requirements: CBC with platelets, liver biochemistries, INR, urinalysis every 2 weeks initially, then monthly 3

Trientine is FDA-approved for patients intolerant to penicillamine 6

• Dosage typically ranges from 1,000-2,000 mg daily 6
• Similar efficacy to penicillamine with potentially fewer adverse effects 6
• Kayser-Fleischer rings improve significantly during treatment 6

Zinc Salts

• Preferred for children under age 3 years 1
• Effective for presymptomatic patients and maintenance therapy 1
• Works by blocking enteral copper absorption 2

Treatment by Clinical Presentation

For presymptomatic patients identified through family screening, treatment should begin immediately with either zinc or chelators for those over age 3 years. 1

For acute liver failure due to Wilson disease, urgent liver transplantation is required for survival, and these patients receive the highest priority category 2

For symptomatic patients with hepatic or neurologic disease, chelating agents are typically initiated, though neurological symptoms may worsen initially 3

Monitoring During Treatment

• Complete blood count with platelets 2
• Liver biochemistries and INR 2
• Serum ceruloplasmin 2
• 24-hour urinary copper excretion 2
• Liver function tests every 6 months (every 3 months during first year for Wilson disease) 3

Critical Treatment Warnings

Interruptions of treatment for even a few days have been followed by sensitivity reactions after reinstitution of therapy. 3

Temporary interruption of penicillamine may result in clinical improvement of neurological symptoms but carries increased risk of developing sensitivity reactions. 3

If neurological symptoms worsen for a month after initiating penicillamine, consider short courses of 2,3-dimercaprol (BAL) while continuing penicillamine. 3

Family Screening

All first-degree relatives of newly diagnosed patients must be screened, as presymptomatic treatment prevents disease progression. 2, 1

Screening Protocol

• History focusing on jaundice, liver disease, and subtle neurological features 2
• Physical examination 2
• Serum copper, ceruloplasmin, and liver function tests 2
• Slit-lamp examination for Kayser-Fleischer rings 2
• 24-hour urinary copper excretion 2
• ATP7B mutation analysis or haplotype studies should be used as primary screening when available 2
• Treatment should be initiated for all individuals greater than 3 years old identified as affected by family screening 2